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Oct. 30, 2024
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Lesch-Nyhan disease …
- Updated 04.30.2024
- Released 12.28.1993
- Expires For CME 04.30.2027
Lesch-Nyhan disease
Introduction
Overview
This article reviews classic Lesch-Nyhan disease and less severe Lesch-Nyhan disease variants. These metabolic disorders result from mutations in the HPRT1 gene, which encodes for the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Lesch-Nyhan disease is an X-linked genetic disorder characterized by hyperuricemia, intellectual disability, dysarthric speech, early-onset hypotonia, later-onset dystonic movement disorder, and compulsive self-mutilation accompanied by an extended cognitive and behavioral phenotype.
Management of Lesch-Nyhan disease incorporates psychosocial support to the patient and caregivers, behavioral and pharmacological treatment, use of protective equipment, and dental, orthopedic, and nephrology management. Goals of treatment in Lesch-Nyhan disease include reduction of self-mutilating and aggressive behavior, prevention of renal failure and urologic complications related to hyperuricemia, control of dystonic movements, and orthopedic correction of hip subluxation and dislocation.
Key points
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• Lesch-Nyhan disease is a metabolic disorder resulting from deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase that is involved in recycling the purines hypoxanthine and guanine. | |
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• This X-linked genetic disorder is associated with hyperuricemia, intellectual disability, dysarthric speech, early hypotonia, dystonic movement disorder, and compulsive self-mutilation. | |
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• Lesch-Nyhan disease is characterized by an extended behavioral, neurologic, and neurocognitive phenotype. | |
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• Human studies and animal models of Lesch-Nyhan disease have documented dopaminergic dysfunction. | |
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• Management of Lesch-Nyhan disease incorporates psychosocial support to the patient and caregivers, behavioral and pharmacological treatment, use of protective equipment, and dental, orthopedic, and nephrology management. | |
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• Goals of treatment in Lesch-Nyhan disease include reduction of self-mutilating and aggressive behavior, prevention of renal failure and urologic complications related to hyperuricemia, control of dystonic movements, and orthopedic correction of hip subluxation and dislocation. |
Historical note and terminology
Lesch-Nyhan disease was initially described in 1964 in two brothers by American cardiologist Michael Lesch (1939-2008) and his mentor, pediatrician and biochemical geneticist William Nyhan (b. 1928), both working at the Laboratory of General and Comparative Biochemistry at the NIH National Institute of Mental Health in Bethesda, Maryland (99; 117). The 4-year-old younger brother had been diagnosed with cerebral palsy and presented with hematuria. Both he and his 8-year-old brother had intellectual disability, a movement disorder with dystonia, renal stones, and self-biting.
In 1967, just 3 years after the clinical recognition of the disorder by Lesch and Nyhan, American rheumatologist and biochemical geneticist J(arvis) ("Jay") Edwin Seegmiller (1920-2006) and colleagues from the National Institutes of Health discovered the biochemical basis of Lesch-Nyhan syndrome, establishing it as a disease with a defined cause (150).
American rheumatologist and biochemical geneticist J Seegmiller (1920-2006) c.1966
J(arvis) ("Jay") Seegmiller is best known for his role in discovering the biochemical basis of Lesch-Nyhan syndrome, establishing it as a disease with a defined cause. (Source: National Institutes of Health. See: Anonymous. Drs...
Hypoxanthine-guanine phosphoribosyltransferase (HPRT) was identified as the missing enzyme involved in this metabolic disorder.
Most patients with classical Lesch-Nyhan disease have low or undetectable levels of the HPRT, rarely more than 1%. The complete amino acid sequence for HPRT was described in 1982, and its three-dimensional structure was described using x-ray crystallography in 1994, along with the effects of single amino acid substitutions on the stability and activity (176; 40). Kinetic mechanisms of HPRT function were described in 1997 (182).
The gene was localized to the long arm of the X chromosome (q26-q27) in 1979, and the organization of the HPRT1 gene (approximately 44 kb; 9 exons) was described in 1986 (13; 94).
Clinical manifestations
Presentation and course
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• Lesch-Nyhan disease includes the following features: hyperuricemia, intellectual disability (intellectual developmental disorder), dysarthric speech, hypotonia, dystonia, and compulsive self-injury (usually beginning with the eruption of teeth). | |
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• Self-injury may begin as early as 1 year of age and occasionally as late as the teens. | |
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• Self-injury is the characteristic feature of classic Lesch-Nyhan disease, but it is not characteristic of Lesch-Nyhan variants (ie, with HPRT enzyme activity of more than 2%). |
Lesch-Nyhan disease. Lesch-Nyhan disease includes the following features: intellectual disability (intellectual developmental disorder), dysarthric speech, hypotonia, dystonia, compulsive self-injury (usually beginning with the eruption of teeth), hyperuricemia, tophi, orange-colored and possibly gritty urine (eg, “orange sand” in the diapers of infants with this disorder from urate crystals), and renal dysfunction (99; 183; 58; 22; 106; 85; 95). At birth, infants with Lesch-Nyhan disease have no apparent neurologic dysfunction. Many affected children seem to develop normally for up to 6 months before developmental delay and neurologic signs become evident, but some children have evident manifestations before 3 months of age (eg, hypotonia, recurrent vomiting, and difficulty managing oral secretions). At approximately 6 to 12 months of age, extrapyramidal signs appear, primarily dystonia.
In a cohort of 101 French and Italian patients with Lesch-Nyhan disease or variant cases, the median age of onset was 1.0 years for involuntary movements and 3 years for self-mutilation behavior (106). Renal manifestations occurred in two thirds of patients; renal manifestations occurred at any age with a median onset age of 1.1 years (106). Gout, which occurred in a quarter of patients, appeared later in the disease course (median onset age 18 years) and was more frequent in attenuated variants than in Lesch-Nyhan disease (106).
Tophi may appear in various places, including the external ear, fingers, toes, and ankles (06). Tophi may also spontaneously rupture and discharge tophaceous fragments.
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Tophus on the antihelix of the earlobe in a 15-year-old boy with Lesch-Nyhan disease
(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. h...
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Tophus of the right hand in a 15-year-old boy with Lesch-Nyhan disease
(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. h...
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Tophus of the right foot in a 15-year-old boy with Lesch-Nyhan disease
(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. h...
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Tophus and discharging wound of the left ankle in a 15-year-old boy with Lesch-Nyhan disease
(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. h...
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Stones discharged after the spontaneous rupture of a left ankle tophus in a patient with Lesch-Nyhan disease
In a 15-year-old boy with Lesch-Nyhan disease, a tophus of the left ankle burst and discharged stones. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal dise...
Early reports of Lesch-Nyhan syndrome emphasized spasticity with pyramidal tract signs, choreoathetosis, compulsive self-injurious behavior, and mental handicap as the most characteristic features. Spasticity is a variable feature of Lesch-Nyhan disease. Some cases with spasticity result from secondary complications, including atlantoaxial instability, which can present with neck pain and be the harbinger of progressive quadriparesis or even quadriplegia (154). Later studies noted additional features, including extrapyramidal features characteristic of dysfunction of the motor circuits of the basal ganglia and particularly a dystonic movement disorder (173; 169; 91). In a study of 44 patients ranging in age from 2 to 38 years, the movement disorder was characterized as a severe action dystonia superimposed on baseline hypotonia (91). Other movement disorders also occur, including hemiballismus, blepharospasm, and ocular tics (90). Associated disturbances of ocular motility, cognition, and behavioral control may reflect disruption of other basal ganglia circuits, especially because neurochemical studies have demonstrated 60% to 90% reductions in the dopamine content of the basal ganglia (169).
Intellectual disability is usually in the mild-to-moderate range, although some individuals test in the low-normal range of intelligence. Although affected individuals generally continue to acquire new information and skills over time, their standardized test scores decline, reflecting increasing separation from their age-matched peers (108; 109). Deficits in working memory are common, particularly on tasks that involve considering multiple features simultaneously (108; 109). Dysarthric speech may result in interpersonal communication problems; yet, higher-functioning children can express themselves fully and may participate in their treatment. The language pattern is also characteristic and consists of repeated ambivalent statements that are most commonly accompanied by anxiety and coprolalia. Because intelligence test scores are influenced by difficulty in testing the subjects due to their movement disorder and dysarthric speech, overall intelligence may be underestimated in patients with Lesch-Nyhan disease (09).
Testing of classic and variant cases of Lesch-Nyhan disease revealed qualitatively similar cognitive-deficit profiles in both patient groups, but the variants produced test scores that were intermediate between those with classic Lesch-Nyhan disease and normal participants (145).
Self-injury may begin as early as 1 year of age and occasionally as late as the teens (173; 106). Self-injury occurs even though all sensory modalities, including pain sensation, are intact. Self-injurious behaviors in Lesch-Nyhan disease are typically sudden and violent in onset instead of gradually emerging over time as in other developmental disabilities (73).
Usually, self-injurious behavior is expressed as self-biting; however, other patterns of self-injurious behavior may emerge with time.
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Laceration to the lower lip due to self-mutilation behavior in a patient with Lesch-Nyhan disease
(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. h...
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Damage to the tongue and lip from self-mutilation behavior in a patient with Lesch-Nyhan disease
Clinical presentation of the patient with Lesch-Nyhan disease at eight months of age. An ulcer involves the tip of the tongue with well-defined regular borders and a yellowish central membrane. The lower lip exhibits deformity....
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Deformed lower lip with ulcer involving both the oral mucosa and vermillion lip border in Lesch-Nyhan disease
A deformed lower lip with an extensive ulcer involving both the oral mucosa and vermillion lip border in a patient with Lesch-Nyhan disease. The ulcer has well-defined regular borders and a central yellowish membrane. A white h...
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Deformed left nasal ala and lower lip in a 2.5-year-old patient with Lesch-Nyhan disease
(Source: Eita AA. Congenital anomalies-associated Riga-Fede disease as an early manifestation of Lesch-Nyhan syndrome: rare entities in the same pediatric patient-a case report. BMC Oral Health 2022;22(1):26. Creative Commons A...
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Evidence of a nasal ulcer with complete loss of the columella in a 2.5-year-old patient with Lesch-Nyhan disease
Lip manipulation (sucking/biting) and saliva over the perioral tissues are evident. (Source: Eita AA. Congenital anomalies-associated Riga-Fede disease as an early manifestation of Lesch-Nyhan syndrome: rare entities in the sam...
When 64 families were surveyed regarding self-injury of their family members, the most common initial mode of self-mutilation and the most frequently cited past or current behavior was biting of lips or fingers (139), whereas in other intellectual disability syndromes of self-injury, self-hitting and head banging are the most common initial presentations.
Characteristically, the fingers, mouth, and buccal mucosa are mutilated (173; 18; 106). Self-biting is intense and causes tissue damage, often leading to amputation of fingers and loss of tissue around the lips. The biting pattern is often asymmetrical in that the patient preferentially mutilates the left or right side of the body. Moreover, the intensity of the self-injurious behavior generally requires that the patient be restrained, and the biting of the lips may lead to the extraction of primary teeth as an act of desperation in the hopes of limiting further self-injury. Despite the movement disorder, when restraints are taken away, the individual with Lesch-Nyhan disease may appear terrified and may quickly and accurately place a finger in the mouth. The patient may ask for restraints to prevent elbow movement and self-injury, and when the restraints are placed or replaced, the patient may appear relaxed and more good-humored (116).
Self-mutilation has been conceptualized as a compulsive behavior that the child tries to control but generally is unable to resist; this does not explain why this specific compulsion routinely develops in this disorder. In older children, self-injury may progress to deliberate self-harm and compulsive aggression toward others. The individual with Lesch-Nyhan disease may inflict injury to others through pinching, grabbing, or hitting or by using verbal forms of aggression. Afterward, he may apologize for this behavior and say that it was out of his control. Older individuals become more adept at finding ways to control self-injury, including enlisting the help of others and notifying them when restraints can be removed. Other associated maladaptive behaviors may develop later, including head or limb banging, eye poking, pulling of fingernails, and psychogenic vomiting.
Among 22 patients with varying degrees of HPRT deficiency, patients with severe enzyme deficiency had grossly abnormal ocular motility, whereas patients with moderate enzyme deficiency had clinically normal ocular motility (90). In patients with classic Lesch-Nyhan disease (ie, HPRT less than 1%), target fixation was interrupted by frequent saccadic intrusions toward minor visual distractions. Voluntary saccades were associated with an initial head movement or eye blink in all of these patients. When head motion was prevented, voluntary saccades were frequently delayed and at times, absent. In contrast, saccade velocity, reflexive saccades, and other reflexive eye movements appeared normal. Such ocular motility disturbances are consistent with dysfunction of the basal ganglia or its connections with ocular motor centers in the prefrontal cortex or midbrain.
Lesch-Nyhan variants. Self-injury is the characteristic feature of classic Lesch-Nyhan disease, but it is not characteristic of Lesch-Nyhan variants (ie, with HPRT enzyme activity of more than 2%). In a study of 22 patients with Lesch-Nyhan disease, 11 with Lesch-Nyhan variants, and 11 healthy controls, those with a diagnosis of Lesch-Nyhan disease had severe difficulties with self-injury, aggression toward others, anxious-depressed symptoms, distractibility, motor stereotypies, and disturbing interpersonal behaviors; those with Lesch-Nyhan variants did not show self-injury and were intermediate between Lesch-Nyhan disease cases and controls on several scales (148).
A prospective multicenter international study of Lesch-Nyhan disease variants examined neurologic manifestations in 46 patients 3 to 65 years of age from 34 families (86). Motor abnormalities were found in 42 patients (91%) and ranged from subtle clumsiness to severe and disabling generalized dystonia. Cognitive functioning was affected in 31 patients (67%) but was never severe. None of the patients showed self-injurious behaviors; however, maladaptive behaviors were common. Only three patients showed no evidence of neurologic dysfunction. They were most similar to classic Lesch-Nyhan disease cases in regard to their attention deficits.
Gout is more frequent in attenuated variants than in Lesch-Nyhan disease (106; 114). Gout in attenuated variants may be associated with hyperuricemia, renal microcalculi or calculi, renal failure, and a family history of juvenile gout (114).
Variants may present with renal failure due to uric acid lithiasis and nephropathy and may be responsible for previously unexplained renal disease in multigeneration kindreds (12; 181).
Prognosis and complications
Understanding the molecular disorder has led to effective drug treatment for those aspects of the disease related to uric acid accumulation and subsequent arthritic tophi, renal stones, and neuropathy. However, reduction in uric acid has not influenced the neurologic and behavioral aspects of Lesch-Nyhan disease. Children treated from birth for uric acid elevation have behavioral and neurologic symptoms, despite never having high uric acid levels. The most significant complications are renal failure and self-mutilation.
Clinical vignette
A Caucasian male with classic Lesch-Nyhan disease presented with mood lability, a dystonic movement disorder, self-injurious behavior, and deliberate self-harm. He was first diagnosed at 2.5 years of age.
There was a family history of Lesch-Nyhan disease in six of the patient’s male family members, including his maternal great-uncle, two maternal uncles, two maternal cousins, and his older brother. The patient’s brother died of pneumonia at 18 years of age. The patient’s mother, grandmother, and maternal aunt were HPRT1 mutation carriers, as was the 16-year-old first cousin. There was no family history of depression or suicidal ideation.
There was concern with the pregnancy because the mother had two brothers with a then-unknown neurologic disease, and her first child was affected; at the time of the patient’s birth in 1964, the syndrome had not yet been reported in the medical literature.
The patient was the product of a normal, full-term pregnancy and delivery; birth weight was 8 pounds. He returned home with his mother at age 3 days. His mother became concerned when he was 3 to 4 months old because he was floppy and could not hold things in his hands. Because of his floppiness, a towel was wrapped around his waist to hold him in a highchair. At age 6 to 7 months, he began to hold onto objects. His mother ground his food at home because he could not feed properly. He began having tonic-clonic seizures at age 3 to 4 months and was started on phenobarbital (his older brother also had a seizure disorder). As he grew older, he began to crawl and speak, but he did not speak well enough to be understood until 6 years of age.
Following an ultimatum from the patient’s father that the children leave the home or he would, the patient was placed, undiagnosed, at a state hospital at age 2 years along with his older brother, who was then 3.5 years old.
Around 2.5 years of age, he was seen by American rheumatologist and biochemical geneticist Jay Seegmiller from the National Institutes of Health, who diagnosed Lesch-Nyhan disease. Seegmiller is best known for his role in discovering the biochemical basis of Lesch-Nyhan syndrome in 1967, establishing it as a disease with a defined cause (150). According to Seegmiller (personal communication to James C Harris), the patient and his brother were the fourth and fifth cases to be diagnosed with this disease.
The boy entered a rehabilitation program and eventually was placed in leg braces. He began to injure himself with finger biting at approximately 6 years of age. This problem persisted and required the continuous use of arm restraints. He banged his head, requiring the use of a helmet to prevent injury. However, he had not bitten his fingers for 2 or 3 years and never bit his lips, so his teeth were not removed as is the case with many other affected individuals.
He remained at the center until his adulthood with regular visits from his mother, and at 22 years of age, he graduated from high school. As an adult, he entered an alternative living program that allowed him to remain in the community. He lived in an apartment with community support and attended a day program that included computer training; he made greeting cards and banners.
As an adult, he had multiple psychiatric admissions and had been seen for outpatient counseling for mood and behavior problems linked to his demoralization and depression. His caregiver reported, “He goes through depressed times and wants to harm himself about every 6 months.” He was periodically demoralized and said he was tired of being in “that body.” When frustrated or annoyed, he harmed himself by throwing himself from his wheelchair. He attempted suicide by trying to jump out of a car, and on another occasion, he got a knife and threatened to kill himself. He was aware of the impulse to injure himself and tried to avoid it or to elicit the help of others in doing so, but he warned them not to get too close to him. He could hurt others with head thrusts or head butting, and at times he cursed at others and used inappropriate sexual talk. If he did harm or upset others, he showed remorse and apologized.
Biological basis
Etiology and pathogenesis
Lesch-Nyhan disease is an inborn error of metabolism with multisystemic involvement, including neurologic, skeletal, urinary, and skin components. Mutations in the HPRT1 gene, which encodes the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), cause Lesch-Nyhan disease and more mildly affected Lesch-Nyhan disease variants (150; 140). HPRT enzyme is normally present in each cell in the body, but its highest concentration is in the brain, particularly the basal ganglia. HPRT is important for recycling both guanine and hypoxanthine (50). Absence of HPRT prevents the normal metabolism of hypoxanthine, resulting in excessive uric acid production and manifestations of gout and renal dysfunction unless specific drug treatment is carried out (ie, allopurinol).
Genetics. Because the gene responsible for Lesch-Nyhan disease is on the X-chromosome, the disease almost always occurs in males (121; 11; 29; 137; 72; 101), although there are very rare circumstances in which cases can occur in females (03).
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A large pedigree with Lesch-Nyhan disease, showing x-linked transmission
Note that males in multiple generations are affected, but obligate female carriers are unaffected. (Source: Laróvere LE, Fairbanks LD, Jinnah HA, et al. Lesch-Nyhan disease and its variants: phenotypic and mutation spectrum of ...
Most families have a unique mutation; 302 different mutations were identified among 271 families (87; 88). Two cases with a normal HPRT1 cDNA were attributed to a defect in the regulation of the gene or a defect in HPRT1 gene expression regulation (28; 55). Although rare, in one family, a single mutation led to three different phenotypes in five related family members (80).
A review of more than 600 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype found that the disease phenotype depends heavily on how mutations influence enzyme activity (49). However, additional genetic and nongenetic factors also influence genotype-phenotype correlations (19).
In a study comparing the "transcriptome" (ie, the set of all RNA transcripts, including coding and noncoding transcripts, in an individual or a population of cells) from human Lesch-Nyhan disease fibroblasts and normal human fibroblasts (using a microarray with 60,000 probes corresponding to the entire human genome), clusters of genes were identified that most significantly affected biological processes in Lesch-Nyhan disease cells; these affected genes were components of specific cellular processes involving the cell cycle (eg, cell division) and cellular metabolism (eg, purine catabolism and nucleic acids) (27).
MicroRNAs (miRNAs), critical in the transcriptional regulation of genes, are dysregulated in Lesch-Nyhan disease (70; 69; 71; 68; 67). HPRT1 mRNA transcripts may act as competitive endogenous RNAs (ceRNAs) engaged in multiregulatory crosstalk between key neural transcripts and miRNAs, which may explain how a gene such as HPRT1, responsible for housekeeping metabolic functions, can have pleiotropic effects on disparate genes and signal transduction pathways. (67). HPRT deficiency causes dysregulated expression of key genes essential for striatal patterning, most notably the striatally-enriched transcription factor B-cell leukemia 11b (Bcl11b) (68).
Female cases
Females may be carriers of the disease gene but typically do not exhibit any symptoms (134), except in rare circumstances (03).
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Analysis of X-inactivation of blood DNA in 4-year-old girl with Lesch-Nyhan disease
Analysis of X-inactivation of blood DNA from the affected 4-year-old girl and her parents as signified by the human androgen receptor (AR) locus.
The methylation status of the methylation-sensitive enzyme’s restriction s...
Seventy-five percent of carrier females have skewed X chromosome inactivation (165), but there have been only 14 cases of Lesch-Nyhan disease reported among females (81; 74; 121; 168; 185; 11; 180; 87; 82; 30; 29; 137; 149; 21; 03).
A wide range of genetic mutations has been detected across the female cases.
Therapeutic approaches to self-injurious oral trauma in 19 patients with Lesch-Nyhan disease
Frequency of therapeutic approaches to self-injurious oral trauma in 19 Italian patients with Lesch-Nyhan disease according to a structured telephone interview of their parents.
Key: (1) Tooth extraction. (2) Painkilling...
Among the 10 cases for whom the responsible mutation was identified, two exhibited nonsense mutations (p.Arg170* and p.Tyr153*) (11; 30); two had missense mutations (p.Glu14Lys and p.Tyr72Cys) (82; 149); two had a splice site mutation (c.609+4A> G) (87; 29; 21); one had a stop mutation (180); one carried a severe translocation (46,XX,t[X: 2][q26:p25]) (137); one had a microdeletion of HPRT1 (121); and one had a frameshift mutation (03). One case was reported twice (87; 29).
Biochemistry
Purine metabolism. The first and rate-limiting step of de novo purine synthesis is mediated by the enzyme 5'-phosphoribosyl-1-pyrophosphate (PRPP) amidotransferase. De novo purine synthesis occurs through a multistep process and requires the contribution of four amino acids, one PRPP, two folates, and three adenosine triphosphate (ATP) molecules to synthesize an inosine monophosphate molecule.
The purine salvage pathway is mediated by two enzymes: hypoxanthine phosphorybosyltransferase (HPRT) and adenine phosphorybosyltransferase (APRT). HPRT catalyzes the salvage synthesis of inosine monophosphate and guanosine monophosphate from the purine bases hypoxanthine and guanine, respectively, utilizing PRPP as a co-substrate.
The HPRT defect in Lesch-Nyhan disease results in the accumulation of its substrates, hypoxanthine and guanine, which are converted into uric acid by means of xanthine oxidase. Xanthine dehydrogenase (EC 1.17.1.4) catalyzes the following chemical reaction:
xanthine + NAD+ + H2O <—> urate + NADH + H+
Patients with Lesch-Nyhan disease have low HGPT activity (less than 1% in striatal tissue and 1% to 2% of that of controls in thalamus cortex) but normal adenosine phosphoribosyltransferase (APRT) activity (APRT is the phosphoribosyltransferase for adenine, another amino purine), demonstrating that there is no general deficit in purine metabolism (102).
Neurotransmitter changes. Neurochemical alterations in Lesch-Nyhan disease have been assessed in multiple ways, including the following (75): (1) direct measurement of neurotransmitters in brain tissue (102); (2) measurement of neurotransmitters and their metabolites in cerebrospinal fluid (157); (3) measurement of adenosine, dopamine, and serotonin receptors in peripheral lymphocytes (54); (4) clinical response to neurotransmitter precursor treatment; and (5) measurement of the presynaptic dopamine transporter using PET scanning (179) or 18F fluorodopa (45).
Low dopamine levels and decreased levels of homovanillic acid, its main metabolite, as well as low levels of the synthesizing enzymes, dopamine decarboxylase, esterase, and hydroxylase, are found in terminal-rich dopamine areas, including the caudate nucleus, putamen, and nucleus accumbens in patients with Lesch-Nyhan disease (102; 143; 100; 20). Dopaminergic dysfunction in the basal ganglia may contribute to the expression of dystonia in Lesch-Nyhan disease (102; 45; 179; 77). Despite a functional loss of 65% to 90% of the nigrostriatal and mesolimbic dopamine terminals, the cells of origin in the substantia nigra have normal dopamine levels (102). The loss of HPRT-mediated purine recycling is associated with significant loss of dopamine and its metabolites, indicating an important connection between purine and dopamine pathways (63). An important functional link between purine nucleotides and the dopamine system involves guanine, the precursor of guanine triphosphate (152): (1) The absence of HGPT may affect dopamine systems due to limited recycling of guanine; for example, guanine nucleotide depletion induces differentiation and aberrant neurite outgrowth in human dopaminergic neuroblastoma units (113); and (2) The binding of dopamine to its receptor leads either to activation (D1 receptor) or inhibition (D2 receptor) of adenylcyclase, with both processes mediated by guanine triphosphate-binding proteins. In a genetic mouse model of Lesch-Nyhan disease, HPRT deficiency disrupts dopaminergic circuit development (177).
Other neurotransmitters are also affected in Lesch-Nyhan disease. HPRT deficiency results in elevated extracellular levels of hypoxanthine, which can bind to the benzodiazepine agonist recognition site on the GABA(A) receptor complex (36). In addition, guanine-based purines may be important regulators of the synaptic availability of L-glutamate (36).
Thus, both neurodevelopmental (eg, a failure to "arborize" dopaminergic synaptic terminals) and neurotransmitter (eg, disruption of GABA and glutamate receptor-mediated neurotransmission) consequences of Lesch-Nyhan disease may contribute to the disorder (102; 14; 36).
Biochemical-clinical relationships. Classification of cases across the clinical spectrum of HPRT activity has been attempted based on neurologic symptoms, dependency for personal care, HPRT activity in hemolysate and in intact erythrocytes, and predicted protein size (135):
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• Group 1: normal development with no neurologic symptoms, HPRT activity detectable in both hemolysates and intact erythrocytes, and the mutation did not affect the predicted protein size. | |
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• Group 2: mild neurologic symptoms that did not prevent independent living, HPRT activity detectable in intact erythrocytes, and normal protein size. | |
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• Group 3: severe neurologic impairment that precluded independent living, no residual HPRT activity, and normal protein size. | |
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• Group 4: clinical characteristics of Lesch-Nyhan syndrome (although some may not show self-injurious behavior), no residual HPRT activity, and typically (although not universally) an altered predicted protein size. |
There are widespread cerebral changes in Lesch-Nyhan disease. A study utilizing volumetric MRI in seven patients with Lesch-Nyhan disease demonstrated a 34% decrease in caudate volume and a 17% decrease in total cerebral volume compared with normal controls (78). Another study involving 21 classic cases, 17 variant cases, and 33 control subjects documented neuroanatomical abnormalities that extend beyond the basal ganglia (146); compared to healthy controls, in patients with classic Lesch-Nyhan disease and variant cases that involve the basal ganglia, limbic, and frontotemporal regions, there was sparing of the parieto-occipital regions. In addition, there are substantial white matter volume abnormalities in Lesch-Nyhan disease that may be more severe than gray matter deficits in classic Lesch-Nyhan disease and also characterize variant cases (147; 31).
Self-injurious behavior in Lesch-Nyhan disease is not caused by hyperuricemia or excess hypoxanthine; patients with partial variants with hyperuricemia do not self-injure (02), and infants with Lesch-Nyhan disease who were treated for hyperuricemia alone from birth still develop self-injurious behavior. Uric acid is not produced in the brain and does not cross the blood-brain barrier (103). Thus, uric acid is not responsible for brain dysfunction; purine nucleotide depletion or accumulation of other toxic purine intermediates could be more relevant (103). Self-mutilation in Lesch-Nyhan disease is caused by dopaminergic denervation (61).
Attenuated clinical phenotypes are associated with residual HPRT activity, whereas the most severe phenotype is usually associated with null activity (127; 129). In cases of gouty arthritis with urate overproduction, a careful evaluation for motor impairments or neurocognitive abnormalities may help to identify attenuated variants of Lesch-Nyhan disease (49; 114).
Hypoxanthine and guanine recycling and the resultant compensatory changes in the de novo synthesis of purines are important to understanding the full pathogenesis of Lesch-Nyhan disease (51). Loss of guanine recycling may be more tightly linked to Lesch-Nyhan disease or variant phenotype than loss of hypoxanthine recycling (151; 144). Moreover, patients with inherited GTP cyclohydrolase deficiency show clinical features of dystonia in common with Lesch-Nyhan disease (166; 53; 37; 52).
HPRT activity is related to the extent of motor symptoms, presence or absence of self-injury, and possibly to the degree of cognitive function (129). Partial deficiency in HPRT (Kelley-Seegmiller disease) is associated with hyperuricemia and variable neurologic dysfunction (107; 135). Most commonly, partial HPRT deficiency leads to a severe form of gout. However, in one study, five of nine partial variant patients (HPRT levels 1.8 to 20%) had IQ scores below 70 and had deficits in working memory (145). Due to the enzyme deficiency, hypoxanthine accumulates in the cerebrospinal fluid, but uric acid does not.
Pathology
Early histopathologic and electron microscopic studies found nonspecific abnormalities in Lesch-Nyhan disease, including loss of neurons and gliosis of the cerebral cortex and focal demyelination of the cerebral white matter (173). A subsequent study of neuropathological findings in 33 cases (two new cases and 31 previously reported cases) found that a small cerebrum (39%) and chronic cerebellar lesions (27%) were the most frequent abnormalities (32).
Histopathological studies using autopsy tissue from five Lesch-Nyhan disease cases and six controls found no signs suggestive of a degenerative process or other consistent abnormalities in any brain region, although neurons of the substantia nigra in the cases showed reduced melanization and reduced immunoreactivity for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis (64). A comparison HPRT-deficient knockout mouse model showed reduced tyrosine hydroxylase expression in the striatum and flow-activated cell sorting in a cell model of HPRT deficiency, revealed significantly reduced tyrosine hydroxylase immunoreactivity compared to the control parent line. These results are consistent with a neurochemical phenotype involving dopaminergic neurons not linked with a degenerative process.
Selected findings in animal models. HPRT deficiency is strongly associated with a loss of basal ganglia dopamine (92; 89). During the first 8 weeks of postnatal development, dopamine levels in whole-brain extracts from the mutant HPRT-deficient mice failed to increase at rates comparable to normal animals resulting in 40% lower dopamine levels throughout adulthood (92). Regional analysis in adult animals showed dopamine levels to be most severely depressed in the caudoputamen and less severely and less consistently depressed in the mesolimbic area, whereas other neurotransmitter systems appeared relatively unaffected (92; 89). These results suggest an abnormality in the dopamine system despite apparently normal spontaneous behavior.
Both HPRT-deficient mice and "doubly-deficient" HPRT-APRT-deficient mice devoid of any purine salvage pathways exhibit none of the behavioral symptoms associated with the human Lesch-Nyhan syndrome, including self-injurious behavior (44).
A relationship between dopaminergic supersensitivity and self-injury has been demonstrated in an experimental animal model (16). When neonatal (5-day-old) and adult rats that were not HPRT-deficient were administered 6-hydroxydopamine to denervate basal ganglia regions, the age when neural function is disrupted determined the type of motor and behavioral symptoms observed. Neonatally treated rats exhibited self-biting and self-mutilation when challenged as adults with either L-dopa or a D1-receptor agonist, whereas this self-injurious behavior was not seen in adult rats treated with 6-hydroxydopamine. Self-biting in neonatally exposed rats was blocked by a D1 dopamine antagonist. Repeated stimulation of D1 receptors in adulthood ("D1 priming") interacts with a developmental loss of dopamine to profoundly and persistently modify neuronal signaling and dendrite morphology in the mature prefrontal cortex in the absence of associated markers of neurodegenerative change (132).
Epidemiology
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• A population study in the United Kingdom estimated the prevalence of classic Lesch-Nyhan disease as 1 in 2 million. | |
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• Over 20 years of study, the mean incidence rate in the United Kingdom was 0.18 per 100,000 live births. | |
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• Those with the classical form of the disease rarely survive the third decade; however, lifespan may be normal for those with partial variants without severe renal involvement. |
Early estimates of the prevalence of classic Lesch-Nyhan disease were 1 in 100,000 to 1 in 380,000 (25). However, based on the number of known cases in the United States, it may be as rare as 1 in 800,000 to 1 in 1.2 million. A population study in the United Kingdom estimated the prevalence of classic Lesch-Nyhan disease as 1 in 2 million (110).
Over 20 years of study, the mean incidence rate in the United Kingdom was 0.18 per 100,000 live births (110). The incidence of partial variants is not known.
Those with the classical form of the disease rarely survive the third decade; however, lifespan may be normal for those with partial variants without severe renal involvement.
Prevention
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• Precise molecular genetic methodologies are available for carrier and prenatal diagnosis. | |
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• Prenatal diagnosis is available for mothers of affected children by measurement of HPRT and APRT in chorionic villus samples or in cultured amniotic fluid cells. | |
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• Preimplantation diagnosis with in vitro fertilization has been successfully accomplished. |
Precise molecular genetic methodologies are available for carrier and prenatal diagnosis (04). Due to the large number of known mutations, a cloning assay has been developed that allows determination of carrier status when the HPRT1 mutation is not known or is difficult to determine; carrier status can be determined in 10 days (126). As this condition is extremely rare, this approach is used primarily in those families with an affected family member.
Because there may be delays in determining the mutation, there continues to be a place for enzyme analysis (120). Although uncultured chorionic villi may be used for prenatal diagnosis by direct enzyme assay, the use of cultured amniocytes or chorionic villi cells for enzyme assay is preferable (118). For mutation carrier status, a peripheral blood T lymphocyte cloning assay uses resistance to the purine analog 6-thioguanine to measure the frequency of cells in females expressing a mutant HPRT1 allele (126). This assay allows determination of the carrier status of females even when the HPRT1 mutation is not yet known or is difficult to determine. Information on carrier status is available within 10 days.
Prenatal diagnosis is available for mothers of affected children by measurement of HPRT and APRT in chorionic villus samples or in cultured amniotic fluid cells (65). Preimplantation diagnosis has been offered in some medical centers for couples who prefer selection prior to pregnancy rather than during pregnancy (15; 33). Preimplantation diagnosis with in vitro fertilization has been successfully accomplished (136; 24).
Germline mosaicism may rarely complicate molecular diagnosis of Lesch-Nyhan syndrome (174).
Differential diagnosis
Confusing conditions
The diagnosis of Lesch-Nyhan disease is straightforward when fully developed with the classic clinical triad: uric acid overproduction, neurologic dysfunction, and cognitive and behavioral disturbances (85). There are no other genetic causes of the full phenotype. The main diagnostic difficulties arise in two situations: (1) during the early stages when all of the features are not yet apparent; and (2) in individuals who have milder phenotypes (85). The index of suspicion for HPRT deficiency should be raised when developmental delay is associated with evidence of overproduction of uric acid, such as hyperuricemia, uric acid nephrolithiasis, urate crystals in the urine, or gouty arthritis (85).
The differential diagnosis includes other causes of infantile hypotonia and dystonia. Most commonly, children are diagnosed as having athetoid cerebral palsy. When a diagnosis of cerebral palsy is suspected in an infant with a normal prenatal, perinatal, and postnatal course, Lesch-Nyhan disease should be considered.
Lesch-Nyhan disease is often first suspected when self-injurious behavior emerges. However, self-injurious behaviors occur in other conditions, including psychiatric diseases (eg, schizophrenia, obsessive-compulsive disorder) and autism spectrum disorder.
Self-injurious behavior can also be seen in other neurodevelopmental, neurometabolic, and neurodegenerative disorders as well as in disorders with characteristic structural brain changes and heterogeneous etiologies (eg, autoimmune and drug-induced) (48; 85). These include nonspecific intellectual disability, Tourette syndrome, McLeod neuroacanthocytosis syndrome (chorea-acanthocytosis), Rett syndrome, Cornelia de Lange syndrome, glutaric acidemia type 1, familial dysautonomia, and sensory neuropathy (eg, hereditary sensory neuropathy type 1) (85).
Finger and lip biting is so severe and so characteristic of Lesch-Nyhan disease that it is referred to as a behavioral phenotype (85). In other conditions associated with self-injury, the behavior tends to be less severe (85). In addition, in other conditions with self-injury behaviors, the range of behaviors is different, usually with head banging or nonspecific self-biting--but not biting of the fingers and lips to a degree that results in tissue damage as is the case with Lesch-Nyhan disease (85).
Diagnostic workup
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• The preliminary diagnosis is ordinarily based on the physical and behavioral phenotype. | |
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• The presence of dystonia in conjunction with self-injury and hyperuricemia is usually diagnostic. | |
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• Serum levels of uric acid that exceed 4 to 5 mg uric acid/dL and a urate-to-creatinine ratio of 3 or more are highly suggestive of HPRT deficiency, especially when associated with neurologic symptoms. | |
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• Definitive diagnosis requires an analysis of HPRT enzyme activity. | |
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• Molecular genetic techniques are used primarily for the identification of carriers. |
Early diagnostic genetic testing can play an important role in helping families make difficult decisions (187). Given the implications of Lesch-Nyhan disease diagnosis, the management complexity of the disease, and the limitations of available therapies, parental values must guide clinical decision-making (187). Careful and empathic discussion of such rare genetic diagnoses with families is complex but essential for facilitating critical discussions to empower families to make informed decisions (187).
Laboratory studies. The preliminary diagnosis is ordinarily based on the physical and behavioral phenotype. The presence of dystonia in conjunction with self-injury and hyperuricemia is usually diagnostic. With partial deficiency, the diagnosis will be less clear. In virtually all cases, hyperuricemia and increased secretion of uric acid are present. Serum levels of uric acid that exceed 4 to 5 mg uric acid/dL and a urate-to-creatinine ratio of 3 or more highly suggest HPRT deficiency, especially when associated with neurologic symptoms.
Definitive diagnosis requires an analysis of HPRT enzyme activity in an erythrocyte lysate (85). Patients with classic Lesch-Nyhan disease have enzyme activity near 0%, whereas variant cases have values between 0% and 60% (127). The enzyme activity in partial variants shows little correlation with the clinical phenotype (152). The intact cell assay in skin fibroblasts provides a good correlation between enzyme activity and the severity of the disease (128).
Molecular genetic techniques are also used, primarily in the identification of carriers (152; 04; 85). Sequence analysis of HPRT1 is performed to detect small intragenic deletions or insertions and missense, nonsense, and splice-site variants (85). If no variant is detected by the sequencing method, the next step is to perform gene-targeted deletion and duplication analysis to detect exon and whole-gene deletions or duplications. A multigene panel that includes HPRT1 is most likely to identify the genetic cause of the condition while limiting the identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype (85). The proportion of probands with a pathogenic variant detectable by sequence analysis is approximately 80%, whereas the proportion of probands with a pathogenic variant detectable by gene-targeted deletion and duplication analysis is approximately 20% (85).
Female heterozygotes also have purine overproduction and enhanced purine nucleotide degradation (134). An elevated hypoxanthine or xanthine excretion rate differentiates most heterozygotes for HPRT deficiency from noncarrier women (134).
Macrocytic erythrocytes occur in 81% to 92% of subjects with Lesch-Nyhan disease or its neurologic variants (17). After excluding cases with iron deficiency (that may pseudonormalize erythrocyte volumes), macrocytosis occurred in 97% of subjects (17). Macrocytic erythrocytes were sometimes accompanied by mild anemia but rarely by severe anemia (17). Macrocytosis is so characteristic that its absence should prompt suspicion of a secondary process (eg, iron deficiency) in patients with Lesch-Nyhan disease (17). Because macrocytosis is uncommon in unaffected children, it may also be a clue for early diagnosis of Lesch-Nyhan disease in children with neurodevelopmental delay. Recognition of this characteristic feature of Lesch-Nyhan disease should help prevent unnecessary diagnostic testing and inappropriate treatment with folate or B12 supplements.
Recommended laboratory studies after the initial diagnosis of HPRT-deficiency disorders include: (1) serum uric acid, (2) serum chemistries including BUN and creatinine, (3) complete blood count, (4) renal function studies, and (5) urinalysis (85).
Urinary stones. Urinary stones in patients with Lesch-Nyhan disease are typically composed of hydrogen urate, but urine may contain either urate or struvite (magnesium ammonium phosphate) stones or crystals (124; 101) or xanthine stones or crystals.
Uric acid stones form in acidic urine and typically in the setting of hyperuricemia. Uric acid stones are radiolucent. Uric acid crystals are rounded parallelograms or flat, four-sided plates.
Struvite crystals and stones (also known as triple phosphate stones and "infection stones") are associated with urinary tract infections. The organisms implicated in the urinary tract infections of patients with struvite stones are overwhelmingly urea-splitting, meaning they possess an enzyme, urease, to breakdown urea, which is abundant in urine (eg, Klebsiella, Proteus, Providencia, Pseudomonas, and some species of staphylococci). Struvite stones are also often referred to as staghorn calculi, based on how they typically appear in radiologic studies. Struvite calculi are radiopaque, and the microscopic appearance of struvite crystals is often described as "coffin-lid" shaped.
Patients with Lesch-Nyhan syndrome who are treated with allopurinol may also develop multiple and bilateral renal and bladder stones by precipitation of xanthine (104; 122; 124; 79; 172; 130; 156; 162; 123; 155; 112; 153). Treatment with allopurinol inhibits the formation of uric acid and modifies renal excretion of oxypurines. Under certain circumstances (ie, decreased urinary output and pH, aggressive lowering of uric acid levels), patients can precipitate forming radiolucent xanthine stones, often in conjunction with uric lithiasis (66). Xanthine stones, both in-vitro and in-vivo, appear dense on CT and echogenic on ultrasound and lack signal on MRI (153). Xanthine urolithiasis is usually a relatively benign condition, which is easy to prevent or cure by appropriate alkalinization, forced hydration, and restriction of dietary purines, but asymptomatic or unrecognized stones may cause destruction of renal parenchyma and renal failure (156; 57; 167). Even patients with Lesch-Nyhan syndrome can have renal pelvis calculi dissolve within 10 days with urine alkalinization and hydration (123).
Radiology. Cranial MRI or CT in Lesch-Nyhan disease may show mild cerebral atrophy and small caudates (78; 77; 146; 147). Volumetric studies demonstrate significant decreases in both caudate volume and total cerebral volume (78; 146; 147).
Cervical spine films may demonstrate evidence of atlantoaxial instability in Lesch-Nyhan syndrome (154).
X-rays of the limbs may show evidence of tophi in the form of soft tissue masses adjacent to joints, possibly with intramass calcifications (06).
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X-ray of the left wrist of a 15-year-old boy with Lesch-Nyhan disease
X-ray image of the left wrist showing a soft tissue mass adjacent to the metacarpal and proximal to the second finger due to a collection of sodium urate monohydrate, or uric acid. (Source: Ambarsari CG, Cahyadi D, Sari L, et a...
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Anteroposterior x-ray of the left foot of a 15-year-old boy with Lesch-Nyhan disease
The x-ray shows a large soft tissue mass with intramass calcification due to a collection of sodium urate monohydrate, or uric acid. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complic...
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Lateral x-ray of the left foot of a 15-year-old boy with Lesch-Nyhan disease
The x-ray shows a large soft tissue mass with intramass calcification due to a collection of sodium urate monohydrate, or uric acid. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complic...
Radiographic findings in Lesch-Nyhan syndrome commonly include faintly radiopaque stones on abdominal radiographs, and when renal disease is present, small kidneys with poor function on intravenous urogram. Radiolucent stones in patients with Lesch-Nyhan disease are usually composed of uric acid; however, several cases of xanthine and hypoxanthine-containing calculi, which may also be radiolucent, have been described in patients with Lesch-Nyhan disease receiving allopurinl therapy. Indeed, all oxypurines (ie, the collective name for the compounds of hypoxanthine, xanthine, and uric acid) may be radiolucent.
Renal parenchymal oxypurine deposition may be readily demonstrated by ultrasonography but not detected on standard radiographs or intravenous urograms (159). Therefore, abdominal ultrasound is recommended after the initial diagnosis of an HRPT-deficiency disorder to assess for renal calculi (06; 85; 153).
In some cases, abdominal CT may demonstrate stones (153).
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Multiple stones in the right renal pelvis on abdominal/renal ultrasonography in a patient with Lesch-Nyhan disease
(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. h...
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Abdominal ultrasound showing a xanthine urinary stone in a patient with Lesch-Nyhan disease
The stone is echogenic with posterior acoustic shadowing. (Source: Shamir SB, Peng Q, Schoenfeld AH, Drzewiecki BA, Liszewski MC. CT, US and MRI of xanthine urinary stones: in-vitro and in-vivo analyses. BMC Urol 2020;20(1):157...
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In vivo ultrasound of xanthine urinary stone in a patient with Lesch-Nyhan disease
The stone demonstrates posterior twinkle artifact on color Doppler imaging (right). (Source: Shamir SB, Peng Q, Schoenfeld AH, Drzewiecki BA, Liszewski MC. CT, US and MRI of xanthine urinary stones: in-vitro and in-vivo analyse...
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Abdominal CT of xanthine urinary stones in a patient with Lesch-Nyhan disease
Coronal CT image showing a stone within the left kidney along with measurement of CT number utilizing region of interest sampling. (Source: Shamir SB, Peng Q, Schoenfeld AH, Drzewiecki BA, Liszewski MC. CT, US and MRI of xanthi...
Chest radiography may show thoracic scoliosis (06).
Management
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• Management of Lesch-Nyhan disease incorporates psychosocial support to the patient and caregivers, behavioral and pharmacological treatment, use of protective equipment, and dental, orthopedic, and nephrology management. | |
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• Goals of treatment in Lesch-Nyhan disease include reduction of self-mutilating and aggressive behavior, prevention of renal failure and urologic complications related to hyperuricemia, control of dystonic movements, and orthopedic correction of hip subluxation and dislocation. | |
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• Behavioral approaches can substantially reduce self-injury and phobic anxiety associated with being unrestrained in patients with Lesch-Nyhan disease, especially if combined with stress management to assist patients in developing more effective coping mechanisms. | |
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• The issue of restraints is complicated, even in the setting of self-injury, but parents and providers invoke this as a last resort to limit self-mutilation in Lesch-Nyhan disease. | |
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• A nonsurgical splint or mouth guard should be the first method tried to limit self-biting in Lesch-Nyhan disease, and only if unsuccessful should more complicated devices or surgical procedures (eg, dental extraction) be considered. | |
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• Pharmacological approaches to decrease anxiety, self-injury, and spasticity with medication have met with mixed results; there are no well-designed randomized controlled trials that support any medication for control of these problems in Lesch-Nyhan disease. | |
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• In Lesch-Nyhan disease, the overproduction of uric acid must be controlled to prevent the development of urologic and articular complications. | |
|
• The control of uric acid in Lesch-Nyhan disease requires: (1) inhibiting the metabolism of hypoxanthine and xanthine to uric acid with allopurinol (or possibly febuxostat); and (2) generous hydration, which should be increased during periods of increased fluid loss. | |
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• Enzyme replacement therapy, bone marrow transplant, and gene therapy are not presently viable for Lesch-Nyhan disease. | |
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• Multiple anecdotal reports indicate improvement or resolution of self-mutilating and aggressive behavior following bilateral chronic stimulation of the globus pallidus internus for control of dystonic movements in Lesch-Nyhan disease. |
Management incorporates psychosocial support to the patient and caregivers, behavioral and pharmacological treatment, use of protective equipment, and dental management (76). Treatment goals include reduction of self-mutilating and aggressive behavior, prevention of renal failure and urologic complications related to hyperuricemia, control of dystonic movements, and orthopedic correction of hip subluxation and dislocation.
Behavioral management. Behavioral approaches (eg, time-outs and differential reinforcement of behaviors that are not self-injurious) can substantially reduce self-injury and phobic anxiety associated with being unrestrained, especially if combined with stress management to assist patients in developing more effective coping mechanisms (39; 116; 96; 125).
Most parents identify stress reduction and awareness of the patient's needs as the most effective means of reducing self-injury (08). The most common methods used by families to minimize self-injury are attending to physical comfort, judicious use of restraints, talking to the child, distraction (eg, finding something more interesting), and attending to their specific needs (08). Such positive behavioral techniques of reinforcing appropriate behavior were rated effective by almost half of the families. The least commonly used interventions are negative behavioral approaches, such as stopping talking to the child, turning away from the child, or taking away something the child likes.
Anxiety may manifest through posturing, facial grimacing, and increases in choreoathetoid and spastic movements. The patient should be allowed to respond and give permission before proceeding with the behavioral program. Relaxation procedures may be taught, particularly those that encourage the patient to relax various body parts. Music may be utilized in conjunction with stress-reducing exercises. As with any patient, careful explanations (presented at a cognitive level that the patient can understand) should be given about what is to follow when initiating a medical or behavioral procedure.
Individuals with Lesch-Nyhan disease do not respond favorably to contingent electric shock that suppresses self-injury in other contexts. Indeed, in this disorder, an increase in self-injury is observed when aversive methods (eg, shock) are utilized (39; 07).
Restraints to prevent self-injury. The issue of restraints is complicated, even in the setting of self-injury, but parents and providers invoke this as a last resort to limit self-mutilation.
Wraps to prevent finger biting in a 12-year-old boy with Lesch-Nyhan disease
(Source: Ferrao J, Rodrigues Barros C, Figueiredo L, Fernandes A. Oral self-mutilation in Lesch-Nyhan syndrome: a case report. Cureus 2022;14[8]:e27874. Creative Commons Attribution License [CC BY], https://creativecommons.org/...
Elbow restraints allow hand use without the possibility of finger mutilation (164).
A survey of the families of 40 patients found that 45% of the patients were constantly restrained to limit self-injury, whereas 20% were restrained 75% of the time (08). Nearly three fourths (72%) were always restrained at night. Only 12% were never in restraints. The older the patient was at the onset of self-injury, the less time was used for restraint. Half of the patients asked to be restrained in a particular way, and 42% insisted on techniques that a priori would be considered ineffective (eg, a lightweight glove, small bandage, or something else that could not physically prevent biting). When family members were surveyed about the patient's attitude toward restraints, 88% said the patient was at ease when restrained and liked to be restrained. Only three patients (0.7%) said they did not want to have restraints.
Botulinum toxin is useful and safe for treating self-biting behavior in patients with Lesch-Nyhan disease (59; 56), but this should be considered a pharmacologic form of restraint.
Dental management to reduce self-injury. Compulsive self-mutilation includes, in particular, biting behavior on the oral mucosa, tongue, lips, fingers, and shoulders, typically before 1 year of age. Unfortunately, no standard methods have been established to prevent self-biting in Lesch-Nyhan disease (26). In general, preventive dental treatments must be developed for each patient based on clinical findings.
Conservative approaches to preventing self-harm in patients with Lesch-Nyhan disease should be tried before radical approaches are employed (47). For example, from the age of 8 years, a boy with Lesch-Nyhan disease displayed self-harm behavior, with finger and oral injuries. He presented at age 12 with deep ulcerated lesions and tissue loss of the lips and tongue, associated with a significant decrease in food intake and consequent weight loss (47). To delay radical treatments, conservative options were initially employed (ie, therapy with gabapentin, lorazepam, and botulinum toxin injections), which successfully reduced self-mutilation, facilitated wound healing, and produced a significant improvement in nutritional status at the follow-up visit 2 months later.
In general, a nonsurgical splint or mouth guard should be one of the first approaches tried (164), and only if unsuccessful should more complicated devices (46) or surgical procedures (eg, vital pulpotomy and coronal resection or dental extraction) be considered (97).
Although dental devices are recommended, failure rates are high (08; 62). In one survey, 15 of 40 patients (38%) had previously tried a protective mouth guard designed by a dentist, but this was deemed helpful in only 20% of the selected group, whereas in contrast, 24 patients (60%) had teeth extracted to prevent self-injury, which the families generally endorsed as necessary and helpful (08). In another smaller study, among five patients with Lesch-Nyhan disease who used mouth guards to spare their teeth, dental extraction was ultimately required in four cases (62).
Most of these patients eventually require several procedures, including dental extractions, to prevent significant secondary lesions (83). In a study of 19 Italian patients, using structured telephone interviews, 71% had tooth extractions, 36% used obstructive methods (eg, placing objects between the teeth to prevent biting lesions), and 29% used orthodontic appliances (eg, an acrylic maxillary device, designed and constructed with an occlusal plate raising the bite, or a soft resin mouth guard), whereas just 14% used dental recontouring (ie, filing the teeth to make them less likely to cut the oral and perioral tissues) (83).
Therapeutic approaches to self-injurious oral trauma in 19 patients with Lesch-Nyhan disease
Frequency of therapeutic approaches to self-injurious oral trauma in 19 Italian patients with Lesch-Nyhan disease according to a structured telephone interview of their parents.
Key: (1) Tooth extraction. (2) Painkilling...
Pharmacotherapy. Pharmacological approaches to decrease anxiety, self-injury, and spasticity with medication have met with mixed results; there are no well-designed randomized controlled trials that support any medication for control of these problems in Lesch-Nyhan disease.
Drugs to control hyperuricemia. In Lesch-Nyhan disease, the overproduction of uric acid must be controlled to prevent the development of urologic and articular complications. The goal is to maintain uric acid levels in the normal range without suppressing uric acid below normal levels, which risks the development of oxypurine stones instead. Oxypurine is the collective name for the compounds hypoxanthine, xanthine, and uric acid--all of which may be radiolucent.
The control of uric acid requires: (1) inhibiting the metabolism of hypoxanthine and xanthine to uric acid with a xanthine oxidase inhibitor allopurinol (or possibly febuxostat); and (2) generous hydration, which should be increased during periods of increased fluid loss (eg, febrile illness or recurrent emesis). The dosage of allopurinol, a xanthine dehydrogenase (formerly called xanthine oxidase) inhibitor, must be carefully monitored because excessive dosage can result in xanthinuria and xanthine urolithiasis (163). Excessive doses of allopurinol may result in acute renal failure from xanthine urolithiasis (156).
Drugs to control self-injury and agitation. Very little high-quality information supports pharmacological approaches to self-injurious behavior in patients with Lesch-Nyhan disease (142). In general, drug treatments have not been successful in eliminating self-injury, including the use of diazepam, haloperidol, fluphenazine, clomipramine, L-dopa, and pimozide (173). For a discussion of botulinum therapy see “Restraints to prevent self-injury” section above.
In a parent survey, 35 of 40 patients (88%) had used medication for self-injury or agitation (08). Seven classes of medications had been tried: benzodiazepines, neuroleptics, antidepressants, opiate antagonists, chloral hydrate, beta-blockers, and carbidopa-levodopa. The medications parents reported to be most effective were benzodiazepines (especially diazepam). An open-label trial of levodopa showed no benefit, and all six participants stopped the medication early because of loss of effect or worsening of motor symptoms (170). Anecdotally, several medications were reported to reduce self-injurious behavior, including atypical antipsychotics (eg, risperidone) (05), carbamazepine (138), and gabapentin (111).
Oral supplementation with S-adenosylmethionine has been introduced as a treatment for self-injury and aggression (60; 38; 21; 141). Theoretically, S-adenosylmethionine (SAMe) has therapeutic potential to replenish the brain purine nucleotide pool. Following a favorable case report on the purported benefits of SAMe in lessening self-injury (60), two small, institutional-review-board approved, open-label trials were conducted (38; 21). Both were "add-on" dose-escalation trials in which SAMe was used in conjunction with current medications. In one study, oral supplementation in five patients for at least a year (at maximum doses from 21 to 39 mg/kg per day) produced a substantial reduction in self-injury and aggression and a milder reduction of dystonia (21). In the other study of 14 patients (11 classic cases and three variant cases aged 18 to 49 years), only four tolerated the drug and reported beneficial effects, whereas seven discontinued in the first 2 months because of increased anxiety and excitability, and three experienced worsening of self-injury and increased excitement that prevented dose escalation (38).
A double-blind, 3-period, crossover trial of a single dose of the D1 dopamine-receptor antagonist ecopipam in 10 patients with Lesch-Nyhan disease was terminated early because of side effects when the drug was administered without a titration phase (93).
Enzyme replacement therapy. Two patients received enzyme replacement therapy by partial exchange transfusions every 2 months for 3 to 4 years (41); Erythrocyte HPRT activity was maintained at 10% to 70% of normal during this period, but no reduction of neurologic or behavioral symptoms was apparent.
Bone marrow transplantation. Bone marrow transplant has not been demonstrated to be either safe or effective for Lesch-Nyhan disease; it remains an experimental and potentially dangerous procedure in this condition.
A bone-marrow transplant was carried out in the United States in a 22-year-old patient with Lesch-Nyhan disease, supposedly justified on the possibility that the CNS damage is produced by a circulating neurotoxic substance of low molecular weight (119). Although the transplantation restored HPRT enzyme activity in the patient's peripheral blood cells, no change in neurologic symptoms or behavior resulted. PET scanning before and after the bone marrow transplant using a D2-dopamine-receptor ligand demonstrated no changes in receptor density following the transplantation.
Because it might be too late to reverse the cerebral symptoms in an adult, a second bone-marrow transplantation was attempted in Germany in a 16-month-old boy who had begun to show signs of psychomotor delay (43). Neither this patient nor two other affected preschool children on whom bone marrow transplantation was performed survived the procedure.
Wojcik employed a mouse model of Lesch-Nyhan disease to assess the efficacy of bone marrow transplant in ameliorating the decrease in striatal dopamine levels and behavioral hypersensitivity to amphetamine. Marrow-ablated adult HPRT-deficient mice were transplanted with marrow from congenic HPRT-expressing mice. Bone marrow transplant altered neither the neurochemical nor the behavioral phenotypes in either HPRT-expressing or HPRT-deficient mice (178).
Gene therapy. Due to the lack of success with enzyme replacement therapy and bone-marrow transplantation, the HPRT1 gene should be targeted to cells in the CNS to address the neurologic and behavioral symptoms in Lesch-Nyhan disease (152). This approach was explored by infecting mice in vivo by direct intracranial injection of a recombinant Herpes simplex type 1 virus vector containing the human HPRT1 gene (131); expression of human HPRT1 mRNA transcripts was detected in the brains of these animals. Gene therapy is not presently available, and prospects for gene therapy remain limited (105; 184). However, cell culture studies have suggested the possibility that CRISPR-mediated base editors and prime editors are a potential therapeutic strategy (84).
Surgical management. Issues addressed in a case series of nine patients with Lesch-Nyhan disease treated for orthopedic problems included (1) hip subluxation or dislocation (9 of 18 hips), fractures (n=3), infections (n=3), contractures, autoamputation, and minor scoliosis (158). Surgery results were satisfactory and resembled those of patients with spastic cerebral palsy. All seven patients who had hip surgery maintained good reduction after an average of 6-years of follow-up. With adequate cast technique, fractures, hip subluxation, and dislocation were treated successfully. Complicating factors for orthopedic management of patients with Lesch-Nyhan disease include infection, heterotopic ossification, hardware failure, and femur fracture if appropriate immobilization is not carried out.
Tophi in Lesch-Nyhan disease may require bone biopsies for definitive diagnosis; bone biopsies may show urate crystals and demineralization. Tophi that rupture, interfere with joint use, or are evidently painful may require surgical debridement (06).
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Bone biopsy showing urate crystals in a patient with Lesch-Nyhan disease (1)
Bone biopsy revealed the presence of urate crystals (arrow). Hematoxylin and eosin staining. 100x magnification. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage ...
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Bone biopsy showing urate crystals in a patient with Lesch-Nyhan disease (2)
Bone biopsy revealed the presence of urate crystals (arrow). Hematoxylin and eosin staining. 100x magnification. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage ...
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Bone biopsy showing demineralization in a patient with Lesch-Nyhan disease
Hematoxylin and eosin staining. 100x magnification. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;4...
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Surgical debridement in a patient with Lesch-Nyhan disease following spontaneous rupture of left ankle tophi
(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. h...
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Surgery on a left index-finger tophus following spontaneous rupture of an ankle tophus in a patient with Lesch-Nyhan disease
Palmar view. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attributi...
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Surgery on a left index-finger tophus following spontaneous rupture of an ankle tophus in a patient with Lesch-Nyhan disease
Dorsum view. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attributi...
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Surgery on a left wrist tophus following spontaneous rupture of an ankle tophus in a patient with Lesch-Nyhan disease
(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. h...
Lithotripsy or surgery may be required for renal stones that form despite treatment (85).
Deep brain stimulation. There are now multiple anecdotal reports of improvement or resolution of self-mutilating and aggressive behavior following bilateral chronic stimulation of the globus pallidus internus for control of dystonic movements (160; 133; 23; 35; 01; 161; 171; 34; 186). Children as young as 7 years of age have been successfully treated for dystonia and self-injury with deep brain stimulation (35). Results have generally been more robust effects on self-injurious behavior than dystonia (186). When improvement in injurious or aggressive behaviors occurred, it was typically gradual over several months. In one case the parents refused a recommendation to temporarily turn off the stimulation to see if the effects were reversed (160). In another case, the behaviors returned when the stimulation was turned off but subsequently again resolved with the resumption of stimulation (23). In a 15-year-old boy who underwent bilateral placement of globus pallidus internus and deep-brain stimulation electrodes for the treatment of generalized dystonia, self-mutilating behavior gradually disappeared several weeks after the start of stimulation but returned when the right lead was fractured (01). Although deep brain stimulation appears to be a promising treatment for both the motor and behavioral disorders of patients with Lesch-Nyhan disease, the reported results have varied widely, especially for motor outcomes (34).
Sudden death. Sudden death may occur despite comprehensive case management. Although there are several causes, respiratory events are common. Factors that may cause or contribute to sudden death in these patients include aspiration, laryngospasm, central apnea, and high cervical spine injury (115). Episodes of respiratory compromise and chest imaging results may identify a need for additional tests, including potentially tracheal endoscopy, polysomnography, EEG, and imaging of the chest, brain, or cervical spine.
Special considerations
Anesthesia
Patients with Lesch-Nyhan disease often require general anesthesia for dental procedures, diagnostic tests requiring immobility (eg, imaging studies), and more invasive procedures and surgeries.
Various factors complicate the use of anesthesia in this population, including increased risks of vomiting and aspiration. In addition, patients with Lesch-Nyhan disease are susceptible to severe bradycardia, apnea and other respiratory abnormalities, and sudden, unexplained death (175).
Although various anesthetic agents have been used in these patients, propofol has been advocated because of its rapid emergence and antiemetic effects (175). However, propofol anesthesia using target-controlled infusion does not provide significant clinical advantages in rapid emergence from anesthesia and management of hyperuricemia (98).
Media
References
- 01
- Abel TJ, Dalm BD, Grossbach AJ, Jackson AW, Thomsen T, Greenlee JD. Lateralized effect of pallidal stimulation on self-mutilation in Lesch-Nyhan disease. J Neurosurg Pediatr 2014;14(6):594-7. PMID 25303157
- 02
- Adler CH, Wrabetz L. Lesch-Nyhan variant: dystonia, ataxia, near-normal intelligence, and no self-mutilation. Mov Disord 1996;11:583-4. PMID 8866505
- 03
- AlBakheet A, AlQudairy H, Alkhalifah J, Almoaily S, Kaya N, Rahbeeni Z. Detailed genetic and clinical analysis of a novel de novo variant in HPRT1: case report of a female patient from Saudi Arabia with Lesch-Nyhan syndrome. Front Genet 2023;13:1044936.** PMID 36778911
- 04
- Alford RL, Redman JB, O'Brien WE, Caskey CT. Lesch-Nyhan syndrome: carrier and prenatal diagnosis. Prenat Diagn 1995;15:329-38. PMID 7617574
- 05
- Allen SM, Rice SN. Risperidone antagonism of self-mutilation in a Lesch-Nyhan patient. Prog Neuropsychopharmacol Biol Psychiatry 1996;20:793-800. PMID 8870064
- 06
- Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. PMID 31985336
- 07
- Anderson L, Dancis J, Alpert M, Hermann L. Punishment learning and self-mutilation in Lesch-Nyhan disease. Nature 1977;265:461-3.** PMID 834300
- 08
- Anderson L, Ernst M. Self-injury in Lesch-Nyhan disease. J Autism Dev Disord 1994;24:67-81. PMID 8188575
- 09
- Anderson L, Ernst M, Davis SV. Cognitive abilities of patients with Lesch-Nyhan disease. J Autism Dev Disord 1992;22:189-203. PMID 1624404
- 10
- Anonymous. Drs. Decker, Seegmiller head new sections of NIAMD's A&R Branch. The NIH Record 1966;18(9):8.
- 11
- Aral B, de Saint Basile G, Al-Garawi S, Kamoun P, Ceballos-Picot I. Novel nonsense mutation in the hypoxanthine guanine phosphoribosyltransferase gene and nonrandom X-inactivation causing Lesch-Nyhan syndrome in a female patient. Hum Mutat 1996;7:52-8. PMID 8664901
- 12
- Augoustides-Savvopoulou P, Papachristou F, Fairbanks LD, Dimitrakopoulos K, Marinaki AM, Simmonds HA. Partial hypoxanthine-Guanine phosphoribosyltransferase deficiency as the unsuspected cause of renal disease spanning three generations: a cautionary tale. Pediatrics 2002;109(1):E17. PMID 11773585
- 13
- Becker MA, Yen RC, Itkin P, et al. Regional localization of the gene for human phosphoribosylpyrophosphate synthetase on the X chromosome. Science 1979;203:1016-9. PMID 218284
- 14
- Boer P, Brosh S, Wasserman L, et al. Decelerated rate of dendrite outgrowth from dopaminergic neurons in primary cultures from brains of hypoxanthine phosphoribosyltransferase-deficient knockout mice. Neurosci Lett 2001;303(1):45-8. PMID 11297820
- 15
- Braude PR, Monk M, Pickering SJ, Cant A, Johnson MH. Measurement of HPRT activity in the human unfertilized oocyte and pre-embryo. Prenat Diagn 1989;9:839-50.** PMID 2626409
- 16
- Breese GR, Criswell HE, Johnson KB, et al. Neonatal destruction of dopaminergic neurons. Neurotoxicology 1994;15:149-59.** PMID 8090354
- 17
- Cakmakli HF, Torres RJ, Menendez A, Yalcin-Cakmakli G, Porter CC, Puig JG, Jinnah HA. Macrocytic anemia in Lesch-Nyhan disease and its variants. Genet Med. 2019;21(2):353-360. PMID 29875418
- 18
- Cauwels RG, Martens LC. Self-mutilation behaviour in Lesch-Nyhan syndrome. J Oral Pathol Med 2005;34(9):573-5. PMID 16138897
- 19
- Ceballos-Picot I, Auge F, Fu R, et al. Phenotypic variation among seven members of one family with deficiency of hypoxanthine-guanine phosphoribosyltransferase. Mol Genet Metab 2013;110(3):268-74. PMID 24075303
- 20
- Ceballos-Picot I, Mockel L, Potier MC, et al. Hypoxanthine-guanine phosphoribosyl transferase regulates early developmental programming of dopamine neurons: implications for Lesch-Nyhan disease pathogenesis. Hum Mol Genet 2009;18(13):2317-27. PMID 19342420
- 21
- Chen BC, Balasubramaniam S, McGown IN, et al. Treatment of Lesch-Nyhan disease with S-adenosylmethionine: experience with five young Malaysians, including a girl. Brain Dev 2014;36(7):593-600. PMID 24055166
- 22
- Cho JH, Choi JH, Heo SH, et al. Phenotypic and molecular spectrum of Korean patients with Lesch-Nyhan syndrome and attenuated clinical variants. Metab Brain Dis 2019;34(5):1335-40. PMID 31129767
- 23
- Cif L, Biolsi B, Gavarini S, et al. Antero-ventral internal pallidum stimulation improves behavioral disorders in Lesch-Nyhan disease. Mov Disord 2007;22(14):2126-9.** PMID 17853483
- 24
- Cram DS, Song B, Trounson AO. Preimplantation diagnosis of Lesch-Nyhan using mini-sequencing primer extension. Reprod Biomed Online 2003;7:342-5. PMID 14653897
- 25
- Crawhall JC, Henderson JF, Kelley WN. Diagnosis and treatment of the Lesch-Nyhan syndrome. Pediatr Res 1972;6:504. PMID 4558815
- 26
- Cusumano FJ, Penna KJ, Panossian G. Prevention of self-mutilation in patients with Lesch-Nyhan syndrome: review of literature. ASDC J Dent Child 2001;68(3):175-8.** PMID 11693008
- 27
- Dauphinot L, Mockel L, Cahu J, et al. Transcriptomic approach to Lesch-Nyhan disease. Nucleosides Nucleotides Nucleic Acids 2014;33(4-6):208-17. PMID 24940671
- 28
- Dawson PA, Gordon RB, Keough DT, Emmerson BT. Normal HPRT coding region in a male with gout due to HPRT deficiency. Mol Genet Metab 2005 85:78-80. PMID 15862284
- 29
- De Gregorio L, Jinnah HA, Harris JC, et al. Lesch-Nyhan disease in a female with a clinically normal monozygotic twin. Mol Genet Metab 2005;85: 70-7. PMID 15862283
- 30
- De Gregorio L, Nyhan WL, Serafin E, Chamoles NA. An unexpected affected female patient in a classical Lesch-Nyhan family. Mol Genet Metab 2000;69(3):263-8. PMID 10767182
- 31
- Del Bene VA, Crawford JL, Gómez-Gastiasoro A, et al. Microstructural white matter abnormalities in Lesch-Nyhan disease. Eur J Neurosci 2022;55(1):264-76. PMID 34738666
- 32
- Del Bigio MR, Halliday WC. Multifocal atrophy of cerebellar internal granular neurons in Lesch-Nyhan disease: case reports and review. J Neuropathol Exp Neurol 2007;66:346-53. PMID 17483691
- 33
- Delhanty JD. Preimplantation diagnosis. Prenat Diagn 1994;14:1217-27. PMID 7617568
- 34
- Deng H, Xiong BT, Wu Y, Wang W. Deep brain stimulation in Lesch-Nyhan syndrome: a systematic review. Neurosurg Rev 2023;46(1):40. PMID 36694014
- 35
- Deon LL, Kalichman MA, Booth CL, Slavin KV, Gaebler-Spira DJ. Pallidal deep-brain stimulation associated with complete remission of self-injurious behaviors in a patient with Lesch-Nyhan syndrome: a case report. J Child Neurol 2012;27(1):117-20.** PMID 21940691
- 36
- Deutsch SI, Long KD, Rosse RB, Mastropaolo J, Eller J. Hypothesized deficiency of guanine-based purines may contribute to abnormalities of neurodevelopment, neuromodulation, and neurotransmission in Lesch-Nyhan syndrome. Clin Neuropharmacol 2005;28:28-37. PMID 15711436
- 37
- Dobricic V, Tomic A, Brankovic V, et al. GCH1 mutations are common in Serbian patients with dystonia-parkinsonism: challenging previously reported prevalence rates of DOPA-responsive dystonia. Parkinsonism Relat Disord 2017;45:81-4. PMID 28958832
- 38
- Dolcetta D, Parmigiani P, Salmaso L, et al. Quantitative evaluation of the clinical effects of S-adenosylmethionine on mood and behavior in Lesch-Nyhan patients. Nucleosides Nucleotides Nucleic Acids 2013;32(4):174-88. PMID 24001191
- 39
- Duker P. Behavioral control of self-biting in a Lesch-Nyhan patient. J Ment Defic Res 1975;19:11-9.** PMID 1177294
- 40
- Eads JC, Scapin G, Xu Y, Grubmeyer C, Sacchettini JC. The crystal structure of human hypoxanthine-guanine phosphoribosyltransferase with bound GMP. Cell 1994;78:325-34. PMID 8044844
- 41
- Edwards NL, Jeryc W, Fox H. Enzyme replacement in the Lesch-Nyhan syndrome with long-term erythrocyte transfusions. Adv Exp Med Biol 1984;165(Pt A):23-6. PMID 6720384
- 42
- Eita AA. Congenital anomalies-associated Riga-Fede disease as an early manifestation of Lesch-Nyhan syndrome: rare entities in the same pediatric patient-a case report. BMC Oral Health 2022;22(1):26. PMID 35109856
- 43
- Endres W, Helmig M, Shin YS, et al. Bone marrow transplantation in Lesch-Nyhan disease. J Inherit Metab Dis 1991;14:270-1. PMID 1886412
- 44
- Engle SJ, Womer DE, Davies PM, et al. HPRT-APRT-deficient mice are not a model for Lesch-Nyhan syndrome. Hum Mol Genet 1996;5:1607-10. PMID 8894695
- 45
- Ernst M, Zametkin AJ, Matochik JA, et al. Presynaptic dopaminergic deficits in Lesch-Nyhan disease. N Engl J Med 1996;334:1568-72.** PMID 8628337
- 46
- Fardi K, Topouzelis N, Kotsanos N. Lesch-Nyhan syndrome: a preventive approach to self-mutilation. Int J Paediatr Dent 2003;13:51-6. PMID 12542625
- 47
- Ferrao J, Rodrigues Barros C, Figueiredo L, Fernandes A. Oral self-mutilation in Lesch-Nyhan syndrome: a case report. Cureus 2022;14(8):e27874. PMID 36110449
- 48
- Fischer JF, Mainka T, Worbe Y, Pringsheim T, Bhatia K, Ganos C. Self-injurious behaviour in movement disorders: systematic review. J Neurol Neurosurg Psychiatry 2020;91(7):712-9. PMID 32430438
- 49
- Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain 2014a;137(Pt 5):1282-303.** PMID 23975452
- 50
- Fu R, Chen CJ, Jinnah HA. Genotypic and phenotypic spectrum in attenuated variants of Lesch-Nyhan disease. Mol Genet Metab 2014b;112(4):280-5. PMID 24930028
- 51
- Fu R, Sutcliffe D, Zhao H, et al. Clinical severity in Lesch-Nyhan disease: the role of residual enzyme and compensatory pathways. Mol Genet Metab 2015;114(1):55-61. PMID 25481104
- 52
- Furukawa Y. GTP cyclohydrolase 1-deficient dopa-responsive dystonia. 2002 Feb 21 [updated 2019 Jan 24]. In: Adam MP, Mirzaa GM, Pagon RA, et al, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle, 2022. PMID 20301681
- 53
- Furukawa Y, Kish SJ. Parkinsonism in GTP cyclohydrolase 1-deficient DOPA-responsive dystonia. Brain 2015;138(Pt 5):e351. PMID 25416181
- 54
- Garcia MG, Puig JG, Torres RJ. Adenosine, dopamine and serotonin receptors imbalance in lymphocytes of Lesch-Nyhan patients. J Inherit Metab Dis 2012;35(6):1129-35. PMID 22403020
- 55
- Garcia MG, Torres RJ, Prior C, Puig JG. Normal HPRT coding region in complete and partial HPRT deficiency. Mol Genet Metab 2008;94:167-72. PMID 18316217
- 56
- Garcia-Romero MD, Torres RJ, Garcia-Puig J, Pascual-Pascual SI. Safety and efficacy of botulinum toxin in the treatment of self-biting behavior in Lesch-Nyhan disease. Pediatr Neurol 2022;127:6-10. PMID 34891105
- 57
- Gargah T, Essid A, Labassi A, Hamzaoui M, Lakhoua MR. Xanthine urolithiasis. Saudi J Kidney Dis Transpl 2010;21(2):328-31. PMID 20228523
- 58
- Gasperini S, Stagi S, Gasperini U, Guerrini R, la Marca G, Donati MA. Orange-colored diapers as first sign of Lesch-Nyhan disease in an asymptomatic infant. Pediatr Nephrol 2010;25(11):2373-4. PMID 20517618
- 59
- Gilbert C, Sauer M, Cheng J. Reduction of self-mutilating behavior and improved oromotor function in a patient with Lesch-Nyhan syndrome following botulinum toxin injection: a case report. J Pediatr Rehabil Med 2021;14(1):133-6. PMID 33720862
- 60
- Glick N. Dramatic reduction in self-injury in Lesch-Nyhan disease following S-adenosylmethionine administration. J Inherit Metab Dis 2006;29(5):687.** PMID 16906475
- 61
- Goldstein M, Anderson LT, Reuben R, Dancis J. Self-mutilation in Lesch-Nyhan disease is caused by dopaminergic denervation. Lancet 1985;1:338-9. PMID 2857386
- 62
- Goodman EM, Torres RJ, Puig JG, Jinnah HA. Consequences of delayed dental extraction in Lesch-Nyhan disease. Mov Disord Clin Pract 2014;1(3):225-9. PMID 25419535
- 63
- Gottle M, Burhenne H, Sutcliffe D, Jinnah HA. Purine metabolism during neuronal differentiation: the relevance of purine synthesis and recycling. J Neurochem 2013;127(6):805-18. PMID 23859490
- 64
- Gottle M, Prudente CN, Fu R, et al. Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease. Ann Neurol 2014;76(1):95-107. PMID 24891139
- 65
- Graham GW, Aitken DA, Connor JM. Prenatal diagnosis by enzyme analysis in 15 pregnancies at risk for the Lesch-Nyhan syndrome. Prenat Diagn 1996;16:647-51. PMID 8843475
- 66
- Greene ML, Fujimoto WY, Seegmiller JE. Urinary xanthine stones--a rare complications of allopurinol therapy. N Engl J Med 1969;280(8):426-7. PMID 5763090
- 67
- Guibinga GH. MicroRNAs: tools of mechanistic insights and biological therapeutics discovery for the rare neurogenetic syndrome Lesch-Nyhan disease (LND). Adv Genet 2015;90:103-31. PMID 26296934
- 68
- Guibinga GH, Barron N, Pandori W. Striatal neurodevelopment is dysregulated in purine metabolism deficiency and impacts DARPP-32, BDNF/TrkB expression and signaling: new insights on the molecular and cellular basis of Lesch-Nyhan Syndrome. PLoS One 2014;9(5):e96575.** PMID 24804781
- 69
- Guibinga GH, Hrustanovic G, Bouic K, Jinnah HA, Friedmann T. MicroRNA-mediated dysregulation of neural developmental genes in HPRT deficiency: clues for Lesch-Nyhan disease. Hum Mol Genet 2012;21(3):609-22. PMID 22042773
- 70
- Guibinga GH, Hsu S, Friedmann T. Deficiency of the housekeeping gene hypoxanthine-guanine phosphoribosyltransferase (HPRT) dysregulates neurogenesis. Mol Ther 2010;18(1):54-62. PMID 19672249
- 71
- Guibinga GH, Murray F, Barron N, Pandori W, Hrustanovic G. Deficiency of the purine metabolic gene HPRT dysregulates microRNA-17 family cluster and guanine-based cellular functions: a role for EPAC in Lesch-Nyhan syndrome. Hum Mol Genet 2013;22(22):4502-15. PMID 23804752
- 72
- Guo M, Chen Y, Lin L, et al. The study on the clinical phenotype and function of HPRT1 gene. Child Neurol Open 2022;9:2329048X221108821. PMID 35875183
- 73
- Hall S, Oliver C, Murphy G. Self-injurious behaviour in young children with Lesch-Nyhan syndrome. Dev Med Child Neurol 2001;43(11):745-9.** PMID 11730148
- 74
- Hara K, Kashiwamata S, Ogasawara N, et al. A female case of the Leach-Nyhan syndrome. Tohoku J Exp Med 1982;137(3):275-82. PMID 7112549
- 75
- Harris JC. Behavioral phenotypes in mental retardation syndromes. In: Barret R, Matson J, editors. Advances in developmental disorders. New York: Jai Publ, 1987:77-106.
- 76
- Harris JC. Lesch-Nyhan syndrome and its variants: examining the behavioral and neurocognitive phenotype. Curr Opin Psychiatry 2018;31(2):96-102. PMID 29227296
- 77
- Harris JC. Neuroimaging in Lesch-Nyhan disease and its variants. In: Schroeder SR, Oster-Granite ML, Thompson T, editors. Self-injurious behavior: gene-brain-behavior relationships. 1st ed. American Psychological Association (APA), March 2002.
- 78
- Harris JC, Lee RR, Jinnah HA, et al. Craniocerebral magnetic resonance imaging measurement and findings in Lesch-Nyhan syndrome. Arch Neurol 1998;55:547-53.** PMID 9561984
- 79
- Hiraishi K, Nakamura S, Yamamoto S, Kurokawa K. Prevention of xanthine stone formation by augmented dose of allopurinol in the Lesch-Nyhan syndrome. Br J Urol 1987;59(4):362-3. PMID 3580782
- 80
- Hladnik U, Nyhan WL, Bertelli M. Variable expression of HPRT deficiency in 5 members of a family with the same mutation. Arch Neurol 2008;65:1240-3. PMID 18779430
- 81
- Hooft C, Van Nevel C, De Schaepdryver AF. Hyperuricosuric encephalopathy without hyperuricaemia. Arch Dis Child 1968;43(232):734-7. PMID: 5702236
- 82
- Inokuchi T, Moriwaki Y, Takahashi S, et al. Identification of a new point mutation in hypoxanthine phosphoribosyl transferase responsible for hyperuricemia in a female patient. Metabolism 2004;53(11):1500-2. PMID 15536609
- 83
- Isola G, Piccardo I, De Mari A, Alberti G, Migliorati M. Oral self-mutilation in Lesch-Nyhan patients: a cross-sectional study. J Clin Med 2022;11(20):5981. PMID 36294303
- 84
- Jang G, Shin HR, Do HS, et al. Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editing. Mol Ther Nucleic Acids 2023;31:586-95. PMID 36910714
- 85
- Jinnah HJ. HPRT1 Disorders In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle, 2020.**
- 86
- Jinnah HA, Ceballos-Picot I, Torres RJ, et al. Attenuated variants of Lesch-Nyhan disease. Brain 2010;133(Pt 3):671-89. PMID 20176575
- 87
- Jinnah HA, De Gregorio L, Harris JC, Nyhan WL, O'Neill JP. The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res 2000;463(3):309-26.** PMID 11018746
- 88
- Jinnah HA, Harris JC, Nyhan WL, O'Neill JP. "The spectrum of mutations causing HPRT deficiency: an update." Nucleosides Nucleotides Nucleic Acids 2004;23(8-9):1153-60.** PMID 15571220
- 89
- Jinnah HA, Jones MD, Wojcik BE, et al. Influence of age and strain on striatal dopamine loss in a genetic mouse model of Lesch-Nyhan disease. J Neurochem 1999;72:225-9. PMID 9886073
- 90
- Jinnah HA, Lewis RF, Visser JE, et al. Ocular motor dysfunction in Lesch-Nyhan disease. Pediatr Neurol 2001b;24(3):200-4. PMID 11301220
- 91
- Jinnah HA, Visser JE, Harris JC, et al. Delineation of the motor disorder of Lesch-Nyhan disease. Brain 2006;129(Pt 5):1201-17.** PMID 16549399
- 92
- Jinnah HA, Wojcik BE, Hunt M, et al. Dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease. J Neurosci 1994;14(3 Pt 1):1164-75. PMID 7509865
- 93
- Khasnavis T, Torres RJ, Sommerfeld B, Puig JG, Chipkin R, Jinnah HA. A double-blind, placebo-controlled, crossover trial of the selective dopamine D1 receptor antagonist ecopipam in patients with Lesch-Nyhan disease. Mol Genet Metab 2016;118(3):160-6. PMID 27179999
- 94
- Kim SH, Moores JC, David D, et al. The organization of the human HPRT gene. Nucleic Acids Res 1986;14(7):3103-18. PMID 3008106
- 95
- Kollios K, Savvidou P, Karipiadou A, et al. Lesch-Nyhan syndrome due to a splice-site mutation in a 14-month-old boy presenting as acute renal failure. Clin Nephrol 2021;96(2):120-3. PMID 33993907
- 96
- Lavecchio F. Behavioral management and Lesch-Nyhan syndrome. Boston: Tufts Univ, 1990.
- 97
- Lee JH, Berkowitz RJ, Choi BJ. Oral self-mutilation in the Lesch-Nyhan syndrome. ASDC J Dent Child 2002;69:66-9, 12. PMID 12119817
- 98
- Lee J, Jung SM, Jeon S. Delayed emergence from propofol anesthesia in a patient with Lesch-Nyhan syndrome: a case report. Medicine (Baltimore) 2020;99(34):e21847. PMID 32846834
- 99
- Lesch M, Nyhan WL. A familial disorder of uric and acid metabolism and central nervous system function. Am J Med 1964;36:561-70.** PMID 14142409
- 100
- Lewers JC, Ceballos-Picot I, Shirley TL, Mockel L, Egami K, Jinnah HA. Consequences of impaired purine recycling in dopaminergic neurons. Neuroscience. 2008;152:761-72. PMID 18313225
- 101
- Li L, Qiao X, Liu F, et al. Description of the molecular and phenotypic spectrum of Lesch-Nyhan disease in eight Chinese patients. Front Genet 2022;13:868942. PMID 35559039
- 102
- Lloyd KG, Hornykiewicz O, Davidson L, et al. Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch-Nyhan syndrome. N Engl J Med 1981;305:1106-11.** PMID 6117011
- 103
- Lopez JM, Outtrim EL, Fu R, Sutcliffe DJ, Torres RJ, Jinnah HA. Physiological levels of folic acid reveal purine alterations in Lesch-Nyhan disease. Proc Natl Acad Sci U S A 2020;117(22):12071-9. PMID 32430324
- 104
- Loris Pablo C, Oliván del Cacho MJ, Heras Gironella M, et al. Litiasis xantínica en un caso de síndrome de Lesch-Nyham tratado con allopurinol [Xanthine lithiasis in a case of Lesch-Nyhan syndrome treated with allopurinol]. An Esp Pediatr 1983;19(5):401-4. PMID 6660658
- 105
- Lowenstein PR, Southgate TD, Smith-Africa JR, Smith J, Castro MG. Gene therapy for inherited neurological disorders: towards therapeutic intervention in the Lesch-Nyhan syndrome. Prog Brain Res 1998;117:485-501. PMID 9932427
- 106
- Madeo A, Di Rocco M, Brassier A, Bahi-Buisson N, De Lonlay P, Ceballos-Picot I. Clinical, biochemical and genetic characteristics of a cohort of 101 French and Italian patients with HPRT deficiency. Mol Genet Metab 2019;127(2):147-57. PMID 31182398
- 107
- Mateos EA, Puig JG. Purine metabolism in Lesch-Nyhan syndrome versus Kelley-Seegmiller syndrome. J Inherit Metab Dis 1994;17(1):138-42. PMID 8051925
- 108
- Matthews WS, Solan A, Barabas G. Cognitive functioning in Lesch-Nyhan syndrome. Dev Med Child Neurol 1995;37:715-22. PMID 7672468
- 109
- Matthews WS, Solan A, Barabas G, Robey K. Cognitive functioning in Lesch-Nyhan syndrome: a 4-year follow-up study. Dev Med Child Neurol 1999;41:260-2.** PMID 10355810
- 110
- McCarthy GT, Green EM, Ogunbona O, et al. A population study of Lesch-Nyhan disease in the UK. Dev Med Child Neurol 2011;53(1):34-9.** PMID 21126241
- 111
- McManaman J, Tam DA. Gabapentin for self-injurious behavior in Lesch-Nyhan syndrome. Pediatr Neurol 1999;20:381-2. PMID 10371385
- 112
- Meagher MF, Bechis SK. Recurrent xanthine stones in a young patient with Lesch-Nyhan syndrome. J Endourol Case Rep 2020;6(4):268-70. PMID 33457651
- 113
- Messina E, Micheli V, Giacomello A. Guanine nucleotide depletion induces differentiation and aberrant neurite outgrowth in human dopaminergic neuroblastoma lines: a model for basal ganglia dysfunction in Lesch-Nyhan disease. Neurosci Lett 2005;375:97-100. PMID 15670649
- 114
- Mishima E, Mori T, Nakajima Y, et al. HPRT-related hyperuricemia with a novel p.V35M mutation in HPRT1 presenting familial juvenile gout. CEN Case Rep 2020;9(3):210-14. PMID 32128695
- 115
- Neychev VK, Jinnah HA. Sudden death in Lesch-Nyhan disease. Dev Med Child Neurol 2006;48(11):923-6. PMID 17044962
- 116
- Nyhan W. Behavior in Lesch-Nyhan syndrome. J Autism Child Schizophr 1976;6:235-52.** PMID 1086851
- 117
- Nyhan WL. The recognition of Lesch-Nyhan syndrome as an inborn error of purine metabolism. J Inherit Metab Dis 1997;20(2):171-8.** PMID 9211189
- 118
- Nyhan W. Reply: prenatal diagnosis of Lesch-Nyhan disease. Prenat Diagn 2004;24:659.
- 119
- Nyhan W, Page T, Gruber HE, Parkman R. Bone marrow transplantation in Lesch-Nyhan disease. Birth Defects 1986;22(1):113-7. PMID 3516239
- 120
- Nyhan WL, Vuong LU, Broock R. Prenatal diagnosis of Lesch-Nyhan disease. Prenat Diagn 2003;23(10):807-9. PMID 14558024
- 121
- Ogasawara N, Stout JT, Goto H, et al. Molecular analysis of a female Lesch-Nyhan patient. J Clin Invest 1989;84(3):1024-7. PMID 2760209
- 122
- Ogawa A, Watanabe K, Minejima N. Renal xanthine stone in Lesch-Nyhan syndrome treated with allopurinol. Urology 1985;26(1):56-8. PMID 4012980
- 123
- Oh MM, Ham BK, Kang SH, et al. Urine alkalinization may be enough for the treatment of bilateral renal pelvis stones associated with Lesch-Nyhan syndrome. Urol Res 2011;39(5):417-9. PMID 21331772
- 124
- Oka T, Utsunomiya M, Ichikawa Y, Koide T, Takaha M, Mimaki T, Sonoda T. Xanthine calculi in the patient with the Lesch-Nyhan syndrome associated with urinary tract infection. Urol Int 1985;40(3):138-40. PMID 3925607
- 125
- Olson L, Houlihan D. A review of behavioral treatments used for Lesch-Nyhan syndrome. Behav Modif 2000;24(2):202-22.** PMID 10804680
- 126
- O'Neill JP. Mutation carrier testing in Lesch-Nyhan syndrome families: HPRT mutant frequency and mutation analysis with peripheral blood T lymphocytes. Genet Test 2004;8:51-64. PMID 15140374
- 127
- Page T, Bakay B, Nissinen E, Nyhan WL. Hypoxanthine guanine phosphoribosyl transferase variants: correlation of clinical phenotype with enzyme activity. J Inherit Metab Dis 1981;4:203. PMID 6796771
- 128
- Page T, Broock RL, Nyhan WL, Nieto LH. Use of selective media for distinguishing variant forms of hypoxanthine phosphoribosyl transferase. Clin Chim Acta 1986;154:195. PMID 3955845
- 129
- Page T, Nyhan WL. The spectrum of HPRT deficiency: an update. Adv Exp Med Biol 1989;253A:129-32.** PMID 2624181
- 130
- Pais VM, Lowe G, Lallas CD, Preminger GM, Assimos DG. Xanthine urolithiasis. Urology 2006;67(5):1084.e9-11. PMID 16698380
- 131
- Palella TD, Hidaka Y, Silverman LJ, et al. Expression of human mRNA in brains of mice infected with a recombinant herpes simplex virus-1 vector. Gene 1989;80:137. PMID 2551779
- 132
- Papadeas ST, Halloran C, McCown TJ, Breese GR, Blake BL. Changes in apical dendritic structure correlate with sustained ERK1/2 phosphorylation in medial prefrontal cortex of a rat model of dopamine D1 receptor agonist sensitization. J Comp Neurol 2008;511:271-85. PMID 18785628
- 133
- Pralong E, Pollo C, Coubes P, et al. Electrophysiological characteristics of limbic and motor globus pallidus internus (GPI) neurons in two cases of Lesch-Nyhan syndrome. Neurophysiol Clin 2005:35:168-73. PMID 16530134
- 134
- Puig JG, Mateos FA, Torres RJ, Buno A. Purine metabolism in female heterozygotes for hypoxanthine-guanine phosphoribosyltransferase deficiency. Eur J Clin Invest 1998;28(11):950-7. PMID 9824441
- 135
- Puig JG, Torres RJ, Mateos FA, et al. The spectrum of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. Clinical experience based on 22 patients from 18 Spanish families. Medicine (Baltimore) 2001;80(2):102-12. PMID 11307586
- 136
- Ray PF, Harper JC, Ao A, et al. Successful preimplantation genetic diagnosis for sex Link Lesch--Nyhan syndrome using specific diagnosis. Prenat Diagn 1999;19(13):1237-41. PMID 10694659
- 137
- Rinat C, Zoref-Shani E, Ben-Neriah Z, et al. Molecular, biochemical, and genetic characterization of a female patient with Lesch-Nyhan disease. Mol Genet Metab 2006:87:249-52. PMID 16343967
- 138
- Roach ES, Delgado M, Anderson L, Iannaccone ST, Burns DK. Carbamazepine trial for Lesch-Nyhan self-mutilation. J Child Neurol 1996;11:476-8. PMID 9120227
- 139
- Robey KL, Reck JF, Giacomini KD, Barabas G, Eddey GE. Modes and patterns of self-mutilation in persons with Lesch-Nyhan disease. Dev Med Child Neurol 2003;45:167-71. PMID 12613772
- 140
- Rossiter BJ, Caskey CT. Presymptomatic testing for genetic diseases of later life. Pharmacoepidemiological considerations. Drugs Aging 1995;7(2):117-30. PMID 7579783
- 141
- Ruillier V, Tournois J, Boissart C, et al. Rescuing compounds for Lesch-Nyhan disease identified using stem cell-based phenotypic screening. JCI Insight 2020;5(4):e132094. PMID: 31990683
- 142
- Sabus A, Feinstein J, Romani P, Goldson E, Blackmer A. Management of self-injurious behaviors in children with neurodevelopmental disorders: a pharmacotherapy overview. Pharmacotherapy 2019;39(6):645-64. PMID 30793794
- 143
- Saito Y, Ito M, Hanaoka S, et al. Dopamine receptor upregulation in Lesch-Nyhan syndrome: a postmortem study. Neuropediatrics 1999;30(2):66-71. PMID 10401687
- 144
- Schretlen DJ, Callon W, Ward RE, et al. Do clinical features of Lesch-Nyhan disease correlate more closely with hypoxanthine or guanine recycling? J Inherit Metab Dis 2016;39(1):85-91. PMID 26067813
- 145
- Schretlen DJ, Harris JC, Park KS, Jinnah, HA, del Pozo NO. Neurocognitive functioning in Lesch-Nyhan disease and partial hypoxanthine-guanine phosphoribosyltransferase deficiency. J Int Neuropsychol Soc 2001;7(7):805-12.** PMID 11771623
- 146
- Schretlen DJ, Varvaris M, Ho TE, et al. Regional brain volume abnormalities in Lesch-Nyhan disease and its variants: a cross-sectional study. Lancet Neurol 2013;12(12):1151-8.** PMID 24383089
- 147
- Schretlen DJ, Varvaris M, Vannorsdall TD, Gordon B, Harris JC, Jinnah HA. Brain white matter volume abnormalities in Lesch-Nyhan disease and its variants. Neurology 2015;84(2):190-6.** PMID 25503620
- 148
- Schretlen DJ, Ward J, Meyer SM, et al. Behavioral aspects of Lesch-Nyhan disease and its variants. Dev Med Child Neurol 2005:47(10):673-7.** PMID 16174310
- 149
- Sebesta I, Stiburková B, Dvorakova L, et al. Unusual presentation of Kelley-Seegmiller syndrome. Nucleosides Nucleotides Nucleic Acids 2008;27(6):648-55. PMID 18600521
- 150
- Seegmiller JE, Rosenbloom FM, Kelley WN. Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science 1967;155(3770):1682-4.** PMID 6020292
- 151
- Segawa M. Dopa-responsive dystonia. Handb Clin Neurol 2011;100:539-57. PMID 21496606
- 152
- Sege-Peterson K, Nyhan WL, Page T. Lesch-Nyhan disease and HPRT deficiency. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL, Kunkel LM, editors. The molecular and genetic basis of neurological disease. Boston: Butterworth-Heinemann, 1993:241-58.
- 153
- Shamir SB, Peng Q, Schoenfeld AH, Drzewiecki BA, Liszewski MC. CT, US and MRI of xanthine urinary stones: in-vitro and in-vivo analyses. BMC Urol 2020;20(1):157. PMID 33046039
- 154
- Shewell PC, Thompson AG. Atlantoaxial instability in Lesch-Nyhan syndrome. Spine 1996;21:757-62. PMID 8882700
- 155
- Shields LB, Peppas DS, Rosenberg E. Xanthine calculi in a patient with Lesch-Nyhan syndrome and factor V Leiden treated with allopurinol: case report. BMC Pediatr 2018;18(1):231. PMID 30001695
- 156
- Sikora P, Pijanowska M, Majewski M, Bienias B, Borzecka H, Zajczkowska M. Acute renal failure due to bilateral xanthine urolithiasis in a boy with Lesch-Nyhan syndrome. Pediatr Nephrol 2006;21:1045-7. PMID 16773422
- 157
- Silverstein FS, Johnston MV, Hutchinson RJ, Edwards NL. Lesch-Nyhan syndrome: CSF neurotransmitter abnormalities. Neurology 1985;35:907-11. PMID 2582310
- 158
- Sponseller PD, Ahn NU, Choi JC, Ahn UM. Orthopedic problems in Lesch-Nyhan syndrome. J Pediatr Orthop 1999;19:596-602. PMID 10488858
- 159
- Stevens SK, Parker BR. Renal oxypurine deposition in Lesch-Nyhan syndrome: sonographic evaluation. Pediatr Radiol 1989;19(6-7):479-80. PMID 2671903
- 160
- Taira T, Kobayashi T, Hori T. Disappearance of self-mutilating behavior in a patient with Lesch-Nyhan syndrome after bilateral chronic stimulation of the globus pallidus internus. Case report. J Neurosurg 2003;98:414-6.** PMID 12593632
- 161
- Tambirajoo K, Furlanetti L, Hasegawa H, et al. Deep brain stimulation of the internal pallidum in Lesch-Nyhan syndrome: clinical outcomes and connectivity analysis. Neuromodulation 2021;24(2):380-91. PMID 32573906
- 162
- Torres RJ, Prior C, Puig JG. Efficacy and safety of allopurinol in patients with the Lesch-Nyhan syndrome and partial hypoxanthine-phosphoribosyltransferase deficiency: a follow-up study of 18 Spanish patients. Nucleosides Nucleotides Nucleic Acids 2006;25(9-11):1077-82. PMID 17065067
- 163
- Torres RJ, Prior C, Puig JG. Efficacy and safety of allopurinol in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency. Metabolism 2007;56:1179-86. PMID 17697859
- 164
- Torres RJ, Puig JG. Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome. Orphanet J Rare Dis 2007;2:48. PMID 18067674
- 165
- Torres RJ, Puig JG. Skewed X inactivation in Lesch-Nyhan disease carrier females. J Hum Genet 2017;62(12):1079-83. PMID 28904386
- 166
- Tsao CY. Guanine triphosphate-cyclohydrolase 1-deficient dopa-responsive dystonia presenting as frequent falling in 2 children. J Child Neurol 2012;27(3):389-91. PMID 22068827
- 167
- Umair M, Hussain SZ, Khan A, Murtaza B, Rehman OF, Nawaz M. Pure xanthine pediatric urolithiasis: a cause of acute renal failure. Urol Case Rep 2020;34:101438. PMID 33083235
- 168
- van Bogaert P, Ceballos I, Desguerre I, Telvi L, Kamoun P, Ponsot G. Lesch-Nyhan syndrome in a girl. J Inherit Metab Dis 1992;15(5):790-1. PMID 1434518
- 169
- Visser JE, Bar PR, Jinnah HA. Lesch-Nyhan disease and the basal ganglia. Brain Res Brain Res Rev 2000;32(2-3):449-75.** PMID 10760551
- 170
- Visser JE, Schretlen DJ, Bloem BR, Jinnah HA. Levodopa is not a useful treatment for Lesch-Nyhan disease. Mov Disord 2011;26(4):746-9. PMID 21506156
- 171
- Visser JE, Cotton AC, Schretlen DJ, et al. Deep brain stimulation in Lesch-Nyhan disease: outcomes from the patient's perspective. Dev Med Child Neurol 2021;63(8):963-8. PMID 33689173
- 172
- Volpe P, Peyrottes A, Lammle M, Saquet D, Choquenet C. Calcul urinaire de xanthine chez un patient porteur d'un syndrome de Lesh Nyhan. A propos d'un cas [Xanthine urinary calculus in a patient with Lesch-Nyhan syndrome. Apropos of a case]. Prog Urol 1997;7(1):74-7. PMID 9116742
- 173
- Watts RW, Spellacy E, Gibbs DA, et al. Clinical, post-mortem, biochemical and therapeutic observations on the Lesch-Nyhan syndrome with particular reference to the neurological manifestations. Q J Med 1982;201:43-78. PMID 7111674
- 174
- Willers I. Germline mosaicism complicates molecular diagnosis of Lesch-Nyhan syndrome. Prenat Diagn 2004;24(9):737-40. PMID 15386453
- 175
- Williams KS, Hankerson JG, Ernst M, Zametkin A. Use of propofol anesthesia during outpatient radiographic imaging studies in patients with Lesch-Nyhan syndrome. J Clin Anesth 1997;9:61-5. PMID 9051548
- 176
- Wilson JM, Tarr GE, Mahoney WC, Kelley WN. Human hypoxanthine-guanine phosphoribosyltransferase. Complete amino acid sequence of the erythrocyte enzyme. J Biol Chem 1982;257:10978-85. PMID 7107641
- 177
- Witteveen JS, Loopstok SR, Ballesteros LL, et al. HGprt deficiency disrupts dopaminergic circuit development in a genetic mouse model of Lesch-Nyhan disease. Cell Mol Life Sci 2022;79(6):341. PMID 35660973
- 178
- Wojcik BE, Jinnah HA, Muller-Sieburg CE, Friedmann T. Bone marrow transplantation does not ameliorate the neurologic symptoms in mice deficient in hypoxanthine guanine phosphoribosyl transferase (HPRT). Metab Brain Dis 1999;14(1):57-65. PMID 10348314
- 179
- Wong DF, Harris JC, Naidu S, et al. Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo. Proc Natl Acad Sci U S A 1996;93:5539-43. PMID 8643611
- 180
- Yamada Y, Suzumori K, Tanemura M, Goto H, Ogasawara N. Molecular analysis of a Japanese family with Lesch-Nyhan syndrome: identification of mutation and prenatal diagnosis. Clin Genet 1996;50(3):164-7. PMID 8946118
- 181
- Yang L, Guo H. Case report: early-onset renal failure as presenting sign of Lesch-Nyhan disease in infancy. Front Pediatr 2022;10:1080486. PMID 36601030
- 182
- Xu Y, Eads J, Sacchettini JC, Grubmeyer C. Kinetic mechanism of human hypoxanthine-guanine phosphoribosyltransferase: rapid phosphoribosyl transfer chemistry. Biochemistry 1997;36:3700-12. PMID 9132023
- 183
- Yang MT, Mak SC, Chi CS, et al. Lesch-Nyhan Syndrome: report on two brothers. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1994;35(6):552-8. PMID 7831990
- 184
- Young SN, Palmour RM. Research on genes: promises and limitations. J Psychiatry Neurosci 1999;24(4):300-3. PMID 10516796
- 185
- Yukawa T, Akazawa H, Miyake Y, Takahashi Y, Nagao H, Takeda E. A female patient with Lesch-Nyhan syndrome. Dev Med Child Neurol 1992;34(6):543-6. PMID 1612215
- 186
- Zea Vera A, Gropman AL. Surgical treatment of movement disorders in neurometabolic conditions. Front Neurol 2023;14:1205339. PMID 37333007
- 187
- Zhang T, Briere JM, Leeman KT, Wojcik MH, Agrawal PB. Ethical implications of early genetic diagnosis in an infant with Lesch-Nyhan syndrome. J Genet Couns 2022;31(6):1434-7. PMID 35916015
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Douglas J Lanska MD MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
See Profile
Former Authors
- James C Harris MD†
- Raphael Schiffmann MD
Patient Profile
- Age range of presentation
-
- 1 month to 18 years
- Sex preponderance
-
- Male > female, X-linked disorder
- Heredity
-
- heredity typical
- X-linked recessive
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Lesch-Nyhan syndrome: E79.1
- ICD-11
-
- Lesch-Nyhan syndrome: 5C55.01
- OMIM
-
- Lesch-Nyhan syndrome; LNS: #300322
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