Nonketotic hyperglycinemia …

Neurogenetic Disorders

Updated 09.03.2024
Released 05.14.2004
Expires For CME 09.03.2027

Nonketotic hyperglycinemia

Authors: Kuntal Sen MD FACMG, Emma Hickman MD

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Editor: Deepa S Rajan MD

Nonketotic hyperglycinemia

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Introduction

Overview

Nonketotic hyperglycinemia is an autosomal recessive inborn error of glycine metabolism that commonly presents in the neonatal period with hypotonia, intractable seizures, apneic attacks, and a burst-suppression pattern on EEG. It is a genetically heterogenous condition caused by pathogenic variants in genes encoding the P and T enzyme subunits of the glycine cleavage system, leading to substantially increased plasma and cerebrospinal fluid glycine concentrations. Defects in lipoic acid or pyridoxal phosphate synthesis may lead to a similar phenotype, known as variant nonketotic hyperglycinemia, as both serve as cofactors for the glycine cleavage system. The rapid onset and often short clinical course may pose a diagnostic challenge in many cases. The authors review this disorder, with emphasis on the early diagnosis, management, and options for genetic testing.

Key points

	• Nonketotic hyperglycinemia is a cause of neonatal encephalopathy and refractory seizures that may mimic hypoxic ischemic encephalopathy or sepsis. A high index of suspicion is required to recognize and diagnose this disorder.
	• There are currently no treatments that alter the course of the disease; however, disease-specific interventions exist in the form of sodium benzoate and dextromethorphan, which serve to lower glycine levels and may improve symptoms.
	• A diagnosis of nonketotic hyperglycinemia can be made by biochemical analysis looking at the CSF to plasma glycine ratio as well as molecular genetic testing of implicated genes. Diagnosis is essential for prognostication and genetic counseling.
	• Late-onset variants present with a very broad range of neurologic signs and symptoms.

Historical note and terminology

“Idiopathic hyperglycinemia” or “hereditary hyperglycinemia” historically referred to a group of metabolic disorders associated with an elevation of glycine concentrations in body fluids. Soon after the first patient was described in 1961 (15), it became apparent that there were two different forms of hyperglycinemia, each representing a distinct condition. “Ketotic hyperglycinemia,” the originally described condition, was characterized by acute ketoacidosis, neutropenia, thrombocytopenia, and vomiting precipitated by infections or the intake of protein leading to coma and early death. These patients have subsequently been recognized as having organic acidemias such as methylmalonic and propionic acidemia. “Nonketotic hyperglycinemia,” or “glycine encephalopathy,” on the other hand, was characterized by lethargy, hypotonia, unresponsiveness, seizures, severe intellectual disability, and developmental delays without ketoacidosis, neutropenia, or thrombocytopenia. The biochemical basis of nonketotic hyperglycinemia was defined in the late 1960s. Gerritsen and colleagues demonstrated hypo-oxaluria and postulated a defect in glycine oxidase (22). A defect in glycine catabolism was subsequently demonstrated (05; 11; 48). By this time, it became apparent that many patients previously reported as having idiopathic/congenital hyperglycinemia with hyperglycinuria actually represented examples of nonketotic hyperglycinemia (32; 41; 10). The structure of the glycine cleavage system was elucidated in the 1970s with the description of the four enzyme subunits (28). The genes encoding for the T and P subunits, AMT and GLDC, respectively, were discovered in the following decades; AMT in 1994 (36) and GLDC in 2000 (49). Pathogenic variants in these genes were subsequently identified in patients with nonketotic hyperglycinemia. The prevalence of nonketotic hyperglycinemia is currently estimated to be 1 in 76,000, with the clinical phenotype now including a number of atypical nonketotic hyperglycinemia variants.

Clinical manifestations

Presentation and course

	• The neonatal-onset form presents with refractory clinical or subclinical seizures, severe lethargy, hypotonia, and apnea in the immediate neonatal period.
	• The infantile-onset form presents at several weeks of life, primarily with hypotonia, developmental delays, and moderate to severe seizure burden.
	• Later-onset forms can show a more variable phenotype of developmental delays with or without seizures.

Nonketotic hyperglycinemia has a broad range of phenotypes with various ages of onset, which are broken down into neonatal-onset, infantile-onset, and late-onset.

Neonatal-onset nonketotic hyperglycinemia. Neonatal-onset nonketotic hyperglycinemia is characterized by significant lethargy within the first few hours to days of life. Pregnancies are often uneventful, though mothers may report fetal hiccups. Lethargy in combination with hypotonia may lead to feeding difficulties and aspiration events early on. Lethargy frequently progresses to apnea and coma, with approximately 80% of patients requiring mechanical ventilation over the first weeks of life. Survivors usually regain spontaneous respiration by 2 to 3 weeks and subsequently manifest profound psychomotor impairment with severe epilepsy. Neonatal reflexes, such as the suck reflex, may be regained transiently, and some early developmental milestones may be achieved with treatment, but these are frequently lost within a few weeks to months. A variety of seizure types may be seen, including myoclonic jerks, tonic spasms, and tonic-clonic convulsions. Intractable seizures eventually occur, though they may be responsive to certain treatments. Hypotonia is prominent in the neonatal period, but thereafter, spasticity supervenes. Death occurs between 3 months to 5 years of age, often as a result of intractable seizures.

Laboratory studies, such as blood counts, liver transaminases, renal function tests, anion gap, organic acids, and lactate and ammonium levels, are usually normal. The diagnosis is suggested by elevated plasma, urine, and CSF glycine concentrations. An EEG at this stage shows a burst suppression pattern, and brain imaging may reveal dysgenesis of the corpus callosum and moderate to severe brain atrophy of gray matter structures, including the globus pallidus, hippocampus, cerebral cortex, and thalamus, and, in severe cases, the cerebellum (45).

Infantile-onset nonketotic hyperglycinemia. Infantile-onset nonketotic hyperglycinemia typically presents with hypotonia and seizures that begin at several weeks of life. These patients are not as significantly affected as those with neonatal-onset nonketotic hyperglycinemia, though they may share features, such as feeding difficulties, developmental delays, and refractory seizures.

Late-onset nonketotic hyperglycinemia. Late-onset nonketotic hyperglycinemia generally occurs after 3 months of life and is clinically heterogenous.

Some patients display progressive neurodegeneration following a period of normal development, whereas others can have slow development leading to mild intellectual disability in adulthood. Yu and colleagues reported a family of three siblings presenting with autism and a varying severity of seizures (55). Late-onset patients with normal intellect, progressive spastic paraparesis, leukodystrophy, and optic atrophy have also been described (44; 16). A 2021 case report of the oldest known patient with nonketotic hyperglycinemia described a 53-year-old male whose nonketotic hyperglycinemia diagnosis was made as a toddler; his ongoing disease manifestations included developmental delays, myoclonic jerks, ataxia, and dystonia (52).

Prognosis and complications

Classification of nonketotic hyperglycinemia is based on long-term outcomes and is divided into severe versus attenuated nonketotic hyperglycinemia (26). Attenuated nonketotic hyperglycinemia is further divided into poor, intermediate, and good outcomes. Those with neonatal-onset nonketotic hyperglycinemia tend to have worse outcomes, with approximately 85% developing severe nonketotic hyperglycinemia and the remaining 15% falling into the attenuated nonketotic hyperglycinemia category. Of those with infantile onset, approximately half develop severe nonketotic hyperglycinemia and half develop attenuated nonketotic hyperglycinemia. Of those with late onset beyond 3 months of age, all develop attenuated nonketotic hyperglycinemia.

Severe nonketotic hyperglycinemia. Patients with severe nonketotic hyperglycinemia have a poor long-term outlook, with almost universal limited survival despite treatment. Severe developmental delays varying from no skills beyond that of a newborn to a developmental age of approximately 3 months are typical in these patients. Additional features include intractable seizures refractory to multiple antiseizure medications, aspiration and feeding difficulties frequently requiring gastrostomy tube placement, early spasticity, microcephaly, and cerebral malformations.

Attenuated nonketotic hyperglycinemia. Those with attenuated nonketotic hyperglycinemia have a wider range of outcomes that are divided into poor, intermediate, and good and correspond with their developmental quotient (53). Patients with attenuated nonketotic hyperglycinemia may be able to sit on their own, walk, attain some degree of language, interact with their environment, and are often able to attend school. These patients generally also experience choreiform movements; seizures responsive to treatment with antiseizure medications or glycine modulators, such as sodium benzoate or dextromethorphan; and varying degrees of hyperactivity.

In addition to age at onset, a combination of other factors may be used to predict outcome in patients with nonketotic hyperglycinemia (46). These factors include the following:

	1. Glycine levels greater than 230 uM indicated severe outcome, whereas a CSF:plasma glycine ratio of 0.08 or lower predicted attenuated outcome; however, there was significant overlap.
	2. Structural brain malformations were rarely seen in milder forms, whereas severe malformations (corpus callosum agenesis or cerebellar cyst with hydrocephalus) only occurred in patients with severe nonketotic hyperglycinemia or neonatal death.
	3. The glycine index (calculated by subtracting glycine intake in food from the dose of sodium benzoate needed to normalize plasma glycine levels divided by body weight) correlated strongly with outcome, being highest in severely affected patients.
	4. EEG with a burst suppression pattern is indicative of severe nonketotic hyperglycinemia.
	5. Two pathogenic variants in the AMT, GCSH, or GLDC genes with no enzyme activity are associated with severe outcome, whereas at least one mutation with residual enzyme activity generally results in attenuated nonketotic hyperglycinemia. Divergent outcomes for the same genotype indicate a contribution of other factors. Clinical and biochemical severity was no different between P or T protein defects.

Clinical vignette

Case 1: Severe nonketotic hyperglycinemia. A female infant was born spontaneously at 38 weeks following an uneventful pregnancy. The birth weight, length, and head circumference were each on the 50th percentiles. Apgar scores were 9 at one minute and 9 at five minutes. She was transferred to the postnatal ward. She was listless, sleepy, and fed poorly in the first 24 hours. On the second day, she was noted to be floppy and intermittently apneic. She was transferred to the neonatal unit where initial investigations including blood counts, liver transaminases, and renal function tests were normal, and septic screen including CSF microscopy and culture were negative. Blood gases revealed respiratory acidosis, and ammonium and bicarbonate levels were normal. She was intubated and ventilated. Oxygen requirements were minimal with assisted ventilation, and respiratory acidosis was easily corrected. Further investigations included echocardiography (normal), EEG (burst suppression pattern), and lactate and creatine kinase levels (normal). A plasma amino acid profile revealed high levels of glycine; CSF glycine levels were also markedly elevated. MRI scanning showed enlarged subdural spaces, mild ventricular dilatation, dysgenesis of the corpus callosum and normal parenchyma. The diagnosis of nonketotic hyperglycinemia was confirmed by two pathogenic variants in the GDLC gene. She remained apneic until day 10 when some spontaneous respiration resumed. Extubation was possible by day 13, after which her tone improved, and she started showing some responses to the environment. Treatment with sodium benzoate, dextromethorphan, and antiseizure medications commenced after the diagnosis of nonketotic hyperglycinemia was made.

Tube feeding was necessary for the first three weeks after which she was able to feed orally. The infant was able to fix her gaze after four weeks but did not develop a social smile. She was always restless during and between feeds and by eight weeks, she had episodes of incessant crying and intermittent twitching. At this point, the ability to visually fix and follow was lost. On examination, she was centrally and peripherally hypertonic; neonatal reflexes were present. She lost the ability to feed orally at three months and tube feeds had to be reintroduced. No further developmental progress was observed subsequently. The episodes of twitching and restlessness initially responded to stepwise increases in the doses of sodium benzoate, dextromethorphan, and antiseizure medications, but by six months there were frequent minor seizures despite maximal doses of these medications. Intermittent dystonic posturing also became apparent at this point and was treated with baclofen. She died at the age of nine months following a prolonged seizure and respiratory failure.

Case 2: Attenuated nonketotic hyperglycinemia. A male infant was born at term following an uneventful pregnancy. He was admitted to the hospital with a history of poor feeding at six weeks of age. There was no history of hiccupping or apnea. On examination he was sleepy, poorly responsive, and generally hypotonic. Reflexes were preserved and no other abnormalities on examination were noted. Investigations revealed no evidence of infection. Tests for plasma electrolytes, renal function, liver transaminases, ammonium, and lactate were normal. Plasma and urine amino acid profiles revealed elevated glycine levels. CSF glycine levels were moderately elevated as was the CSF/plasma glycine ratio, suggesting a diagnosis of nonketotic hyperglycinemia. The diagnosis was confirmed by molecular testing. Treatment for this condition was started. EEG and MRI of the brain were normal. Over the next few days, the infant’s tone and responsiveness improved though he started to have intermittent twitching episodes, which were well controlled with antiseizure medication. He made slow and steady developmental progress over the next few years on treatment with benzoate, dextromethorphan, and antiseizure medications. He continued having intermittent seizures, mainly absence but with intermittent tonic-clonic seizures. An EEG at three years of age showed excess slow-wave activity with intermittent high-amplitude bursts during sleep. At the age of 5 years, his developmental level was that of a 2 year old. He was able to feed himself, walk, and speak a few meaningful words. He had a behavioral disorder characterized by poor communication skills, poor sleep pattern, and episodes of severe temper tantrums.

Biological basis

	• Nonketotic hyperglycinemia is caused by a defect in the glycine cleavage enzyme system.
	• Nonketotic hyperglycinemia is due to biallelic pathogenic variants in the GLDC, AMT, or GCSH genes.
	• Increased glycine levels disturb motor and sensory functions in the brain.

Etiology and pathogenesis

A defect in the glycine cleavage enzyme system (GCS) leads to markedly increased concentrations of glycine in urine, plasma, and cerebrospinal fluid. Although there is no evidence that the high concentration of glycine affects any nonneural functions, the high levels in the brain lead to serious neurologic problems.

Genetics. The glycine cleavage enzyme system is located on the inner mitochondrial membrane and consists of a complex of four polypeptides (P, H, T, and L proteins) encoded by four different genes. It requires the cofactors pyridoxal phosphate, tetrahydrofolate, lipoic acid, and NAD.

Abnormalities have been found in the P, T, and H subunits in patients with nonketotic hyperglycinemia. The L-protein is shared by a number of other dehydrogenases, and defects in this subunit produce a different clinical and biochemical phenotype.

The genes for the P (glycine decarboxylase, GLDC), T (aminomethyl transferase, AMT), and H (glycine cleavage system H protein, GSCH) proteins have been isolated and their genes have been cloned. Variants have been reported in all three of these genes in individuals with nonketotic hyperglycinemia; however, the vast majority of cases of nonketotic hyperglycinemia are due to pathogenic variants in the GLDC and AMT genes. Two cases of homozygous variants in the GSCH gene have been reported in individuals with nonketotic hyperglycinemia. Coughlin and colleagues compiled a comprehensive review of mutations in 578 nonketotic hyperglycinemia families, with more than 400 different mutations described (18).

Variant nonketotic hyperglycinemia is a phenotypically similar disorder that is also related to a deficiency of the glycine cleavage enzyme system; however, it is caused by pathogenic variants in genes other than those encoding the four functional subunits, notably genes involved in lipoic acid and pyridoxal phosphate production. Lipoic acid and pyridoxal phosphate are cofactors required for GCS activity. In addition, lipoic acid is also required for proper functioning of pyruvate dehydrogenase complex, branched-chain ketoacid dehydrogenase, and alpha-ketoglutarate dehydrogenase.

Pathogenic variants have been reported in the NFU1, BOLA3, LIAS, LIPT2, and GLXR5 genes, which are all involved in Fe-S cluster synthesis and synthesis of lipoic acid (14; 38; 34; 09). These patients present with various manifestations of mitochondrial dysfunction, such as seizures, ataxia, hypotonia, weakness, leukodystrophy, optic atrophy, cardiomyopathy, and deafness. Plasma and CSF glycine levels are typically elevated, though often not to the level seen in classic nonketotic hyperglycinemia. Alanine and lactate may also be raised but not always. A mutation in the IBA57 gene, also involved in the biosynthesis of mitochondrial [Fe-S] proteins, has been reported in siblings with a similar clinical phenotype. Although the activity of the glycine cleavage enzyme was not measured, the patients did have elevated glycine and PDH deficiency (02).

Pathophysiology. Glycine is a major component of dietary proteins and predominantly synthesized in the body from serine, which itself can be synthesized from glucose. It participates in a myriad of biosynthetic and detoxification reactions. Its major route for degradation is the glycine cleavage enzyme system, which ultimately converts it to carbon dioxide and ammonium (28).

Whilst the liver degrades the majority of body glycine, the glycine cleavage enzyme system in the brain has a crucial role. Glycine is a major synaptic neurotransmitter having mixed inhibitory and excitatory functions; it has excitatory effects as a co-agonist of NMDA receptors in the cerebral cortex, whereas it has inhibitory effects in the spinal cord and the brain stem (08). Catabolism of glycine is essential to regulate the extracellular concentration of this neurotransmitter.

The failure to remove glycine effectively from the intercellular fluid is the likely cause of the neurologic symptoms. The presence of brain malformations in affected individuals suggests that this excess in intercellular glycine may result in prenatal developmental abnormalities. Postnatally, its effects are postulated to cause seizures and brain damage through excitatory effects at the cortical level, whereas its inhibitory effects on the brain stem and spinal cord are believed to cause hiccupping, apnea, and hypotonia (57; 47; 23). High glycine concentrations have also been shown to induce bioenergetic dysfunction in the brains of young rats by impairing the functions of citric acid cycle, the respiratory chain, Na+, K+ ATPase, and mitochondrial creatine kinase (13).

Differential diagnosis

Differential based on clinical manifestations

Hypoxic-ischemic encephalopathy, neonatal sepsis, intracranial hemorrhage, drug withdrawal, intrauterine infection, hypoglycemia, and hypocalcemia, among other conditions, can cause acute neonatal encephalopathy with a clinical presentation similar to that seen in nonketotic hyperglycinemia. These disorders may also be associated with transient elevations in the CSF to plasma glycine ratio. Some metabolic disorders, such as sulfite oxidase deficiency, congenital disorders of glycosylation, respiratory chain defects, urea cycle defects, maple syrup urine disease, propionic acidemia, and methylmalonic acidemia, can also present with neonatal encephalopathy in the first few days of life. In particular, pyridoxine-dependent epilepsy, urea cycle disorders, and pyruvate dehydrogenase deficiency can all present with refractory seizures in the neonatal period and should be considered in those circumstances. Patients with a defect in glycine transporter GlyT1 show many clinical and biochemical features of classical neonatal nonketotic hyperglycinemia (04).

Differential based on biochemical findings

Glycine can be artifactually raised in plasma as a result of hemolysis. A common cause of elevated CSF glycine is blood contamination of CSF resulting from a traumatic lumbar puncture. A study of 22 infants with encephalopathy revealed that elevated cerebrospinal fluid glycine was encountered in a variety of clinical conditions, most commonly hypoxic-ischemic encephalopathy (01). Hyperglycinemia is a common secondary response to a number of acquired and inherited conditions. Newborns, particularly premature ones, may also show elevated urinary glycine excretion due to immaturity of the renal glycine transport system. Additional causes of elevated plasma glycine that should be considered in the differential diagnosis are detailed below:

Elevated plasma glycine

Nonketotic
	• Valproate therapy: the most common cause of hyperglycinemia due to a secondary decrease in liver GCS activity
Ketotic
	• Beta-ketothiolase deficiency • Isovaleric acidemia • Methylmalonic acidemia • Propionic acidemia

These organic acidemias lead to an accumulation of branched-chain amino acid metabolites that may suppress the hepatic GCS, resulting in hyperglycinemia. GCS activity in the brain is not affected; thus, CSF glycine levels are normal. Analysis of urine organic acids in these cases will show ketonuria and specific organic aciduria. These disorders do not clinically resemble nonketotic hyperglycinemia.

Elevated CSF and plasma glycine

Disorders of iron-sulfur cluster biogenesis/lipoate deficiency (such as LIAS, LIPT2, BOLA3, GLRX5, IBA57, NFU1) cause a defect in the GCS, which can clinically and biochemically resemble nonketotic hyperglycinemia but have other features due to defects in pyruvate dehydrogenase (PDHC), alpha-ketoglutarate dehydrogenase (α-KGDH), and branched-chain ketoacid dehydrogenase (BCKDH).

Patients with methylmalonic acidemia and homocysteinemia type cbIX (HCFC1) can also have elevated plasma and CSF glycine as well as similar clinical manifestations to nonketotic hyperglycinemia.

Elevated CSF glycine

Both pyridoxamine-5'-phosphate oxidase (PNPO) deficiency and pyridoxal phosphate binding-protein (PLPBP) present with severe neonatal seizures and coma. Apnea may be present. Seizures respond to pyridoxal-5'-phosphate. In addition to elevated CSF glycine, patients also show low CSF pyridoxal phosphate.

Glycine transporter 1 (SLC6A9) defects can cause neonatal encephalopathy; impaired consciousness; poor respiratory drive; and death, usually before 1 year of age. Patients show raised CSF glycine but normal or only moderately increased serum glycine.

Elevated urine glycine

Hyperglycinuria can occur in a number of conditions, including benign hyperglycinuria (transient immaturity of renal glycine reabsorption), familial iminoglycinuria, type I hyperprolinemia, and type II hyperprolinemia.

Urine glycine is markedly elevated in patients with familial iminoglycinuria and types I and II hyperprolinemia, along with urine proline and hydroxyproline. Patients with types I and II hyperprolinemia also have an elevated plasma proline concentration. Familial iminoglycinuria and type I hyperprolinemia are asymptomatic; type II hyperprolinemia may be asymptomatic or may be associated with seizures and mild intellectual disability.

Diagnostic workup

	• Biochemical testing demonstrates elevated plasma and CSF glycine levels.
	• Genetic testing confirms the diagnosis.
	• MRI brain classically shows diffusion restriction within the first 3 months of life and may demonstrate specific structural changes, such as dysgenesis of corpus callosum.
	• Burst suppression pattern on EEG is seen in patients with severe nonketotic hyperglycinemia.

Biochemical testing. Biochemical testing has become more readily available and is often the first-line test for patients suspected to have inborn errors of metabolism. Urinary and plasma glycine concentrations in patients with nonketotic hyperglycinemia are usually increased several fold above the upper limit of normal. However, other conditions, in particular organic acid disorders, can result in increased glycine concentrations; therefore, it is important that these be excluded. In addition, plasma glycine may be increased in a poor-quality blood specimen (eg, when hemolyzed) or in a urine specimen that has deteriorated. Therefore, the best biochemical screening test for nonketotic hyperglycinemia is simultaneous quantitation of plasma and CSF glycine. The CSF glycine is usually increased several fold above the upper limit of normal and the CSF/plasma glycine ratio is greater than 0.08 in patients with severe nonketotic hyperglycinemia (06). Patients with attenuated nonketotic hyperglycinemia may have ratios as low as 0.04. However, care has to be taken to avoid blood contamination in the CSF sample as erythrocytes have high glycine content and can give spuriously increased results. Diagnosis should not be based solely on an increased CSF to plasma glycine ratio; the plasma and urine glycine concentrations should be taken into account. A low level of blood contamination of CSF, together with an only marginally elevated plasma glycine, may give a spuriously elevated ratio. Patients may often also show lactic acidemia due to the apneic episodes potentially leading to an investigation of a respiratory chain disorder.

Genetic testing. The multiplicity of causes of hyperglycinemia and problems in interpreting CSF glycine concentrations make it important, when possible, to confirm the diagnosis by additional testing. Molecular genetic testing is the main method of diagnostic confirmation.

Mutations in the P protein gene (GLDC) account for the majority of nonketotic hyperglycemia cases (approximately 80%) (17; 30; 18). Mutations reported to date in the GLDC gene include the S564I mutation, which is prevalent in Finnish patients and the R515S mutation found in up to 40% of Caucasians, particularly those from the UK (51; 18). Deletions and duplications spanning one or more exons of the GLDC gene have been found on approximately 20% of alleles in patients with nonketotic hyperglycemia of different ethnic origins (18). Screening for these deletions by MLPA analysis provides a rapid way of picking up a significant number of mutations (29).

Defects in the T protein gene (AMT) account for the remaining cases; only two patients have been described with mutations in the H protein gene (GCSH); however, they have not been confirmed to be pathogenic. Like the GLDC gene, most mutations in the AMT gene are private; however, the R320H mutation accounts for up to 16% of alleles in AMT (18).

In order to best identify the pathogenic variants in patients with nonketotic hyperglycemia, a multigene panel targeting GLDC, AMT, and GCSH genes with deletion and duplication analysis is advised.

EEG. EEG patterns vary based on age at onset and severity of disease. Commonly, in patients with neonatal onset who then develop severe nonketotic hyperglycemia, an EEG characteristically reveals a burst suppression pattern in the first few weeks of life. By 1 to 3 months, the EEG pattern changes to hypsarrhythmia with evidence of clinical spasms. After 1 year of age, hypsarrhythmia is routinely seen in sleep, but the awake tracing changes to a slow background with multifocal epileptiform discharges (33). Burst suppression, hypsarrhythmia, and multifocal discharges may also be seen in patients with attenuated nonketotic hyperglycemia, though they tend to convey a poor prognosis. Other neurophysiological findings include prolonged latencies on brainstem evoked auditory responses and abnormal visual evoked responses.

Imaging findings. CT and MRI findings may include thinning/shortening of the corpus callosum, delayed myelination, and progressive vacuolating myelinopathy (45). Within the first 3 months of life, diffusion restriction is present on MRI in the posterior limb of the internal capsule, anterior brainstem, posterior tegmental tracts, and cerebellum. From 3 to 12 months, the diffusion restriction spreads to the supratentorial white matter and later fades. Cerebral atrophy may be seen as patients grow older. Corpus callosum abnormalities, hydrocephalus, and atrophy all indicate poor prognosis and are typically seen in patients with severe nonketotic hyperglycinemia. MRI spectroscopy studies have demonstrated elevated intracerebral glycine, lactate, and creatine as well as decreased glutamine and citrate levels in neonatal-onset patients (21; 54). Some patients with attenuated nonketotic hyperglycinemia can have normal MRI scans.

Pathology. At autopsy, spongiform degeneration of myelinated areas of the brain with vacuolation and thinning of myelin has been described on brain histopathology. Electron microscopy has revealed splitting of the myelin lamellae (43; 42).

Enzyme assay. The glycine cleavage enzyme can be assayed in a needle liver biopsy specimen (25). The sample should be frozen immediately and stored frozen until analysis. However, some patients with T protein defects can show normal activity in the assay of whole glycine cleavage enzyme complex activity (the authors’ unpublished work). Liver biopsy for measurement of enzyme activity is of historical importance and is not routinely performed due to wider availability of biochemical and molecular tests and the invasive nature of the testing.

Management

	• Symptomatic treatment can be beneficial but often does not affect the course of the disease.
	• Sodium benzoate and dextromethorphan can help reduce glycine levels.

Symptomatic treatment. Symptomatic treatment includes enteral tube feeding, antiseizure medications, and developmental interventions, such as occupational therapy, physiotherapy, and speech therapy. Long-term survivors are prone to developing severe skeletal problems, including kyphoscoliosis, contractures, joint dislocations, and fractures that may need symptomatic management (40). Choice of antiseizure medication is very important in patients with nonketotic hyperglycinemia due to the particular efficacy of some medications but also due to potential worsening of the disorder with other medications. Antiseizure medications that may be effective and safe in patients with nonketotic hyperglycinemia include phenobarbital and benzodiazepines (such as clonazepam and clobazam). Several newer anticonvulsants, such as felbamate and topiramate, act on glutaminergic pathways and may also be useful, but studies of these agents on seizure control and long-term outcome of nonketotic hyperglycinemia have not been reported. Seizure medications to avoid include vigabatrin as it can result in rapid deterioration and acute encephalopathy as well as valproic acid, which can acutely raise plasma and CSF glycine levels (35; 50).

Reduction of plasma and CSF glycine levels. Glycine-free, glycine- and serine-free, and protein-restricted diets have been reported to reduce plasma glycine levels but have had no effect on seizure frequency or developmental progress (31). Sodium benzoate, which conjugates glycine to form hippurate, has been used in doses of 150 to 750 mg/kg/day to reduce plasma and CSF glycine levels (23). Treatment with sodium benzoate appeared to provide the best improvement (mainly a decrease in seizures) but was dependent on dose and disease severity (26).

There is growing evidence that a ketogenic diet can lower glycine levels and benefit seizure control in some patients with nonketotic hyperglycinemia. The ketogenic diet was found to have the most efficacy when used in conjunction with glycine-lowering agents and appropriately chosen antiseizure medications (19; 27).

NMDA receptor blocking agents. Attempts at treatment have involved the usage of NMDA receptor blocking agents given glycine’s function as an activator at the NMDA receptor. Oral ketamine administration in doses of 5 to 8 mg/kg/day has been successful in improving neurologic symptoms in some cases (39; 12). The antitussive medication dextromethorphan is metabolized to dextrorphan, an antagonist of the NMDA receptor, and has been reported to improve neurologic symptoms as well as lower glycine levels in a number of cases. Hamosh and colleagues have reported results of a long-term study of the treatment of four infants with nonketotic hyperglycinemia using a combination of high-dose sodium benzoate (500 to 750 mg/kg/day) and dextromethorphan (3.5 to 22 mg/kg/day) with follow up over three months to six years (24). With benzoate treatment, plasma glycine levels normalized, and CSF glycine levels fell significantly. Dextromethorphan appeared to improve seizure control in three of the four patients and these patients were reported as being alive and moderately to severely intellectually disabled at ages of 6 to 8 years. One patient died at three months despite being treated early. Other investigators have also reported some benefit from this treatment combination (56; 03).

Currently, a combination of high-dose benzoate, dextromethorphan, and antiseizure medications appears to offer the best (if unsatisfactory) approach to treatment.

Palliative care. Given the wide range of outcomes in patients with nonketotic hyperglycinemia and poor prognosis amongst those who are severely affected, palliative care involvement should be considered early in this condition.

Outcomes

Treatment has not been shown to affect long-term outcomes in patients with nonketotic hyperglycinemia. Interventions and medications can result in improved quality of life and seizure control; however, the course of the disease, which is largely predicted by the most appropriate characterization--severe versus attenuated--remains unchanged.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Kuntal Sen MD FACMG

Dr. Sen of Children’s National Hospital and GWU School of Medicine and Health Sciences has no relevant financial relationships to disclose.
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Emma Hickman MD

Dr. Hickman of Children's National has no relevant financial relationships to disclose.
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Editor

Deepa S Rajan MD

Dr. Rajan of UPMC Children's Hospital of Pittsburgh has no relevant financial relationships to disclose.
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Former Authors

Tim Hutchin PhD
Jennifer Friedman MD
George Gray MD and Anupam Chakrapani MD MRCP

Patient Profile

Age range of presentation: 0 month to 12 years
Sex preponderance: male=female
Heredity: Heredity may be a factor

Heredity typical

autosomal recessive
Population groups selectively affected: Individuals of Finnish and Tunisian descent
Occupation groups selectively affected: None

ICD & OMIM codes

ICD-9: Hyperglycinemia: 270.7
ICD-10: Non-ketotic hyperglycinaemia: E72.5
OMIM: Glycine encephalopathy: #605899

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Nonketotic hyperglycinemia

Differential Diagnosis

hypoxic-ischemic encephalopathy
neonatal sepsis
intracranial hemorrhage
drug withdrawal
intrauterine infection
- hypoglycemia
- hypocalcemia
- sulfite oxidase deficiency
- congenital disorders of glycosylation
- respiratory chain defects
- urea cycle defects
- maple syrup urine disease
- propionic acidemia
- methylmalonic acidemia
- pyridoxine-dependent epilepsy
- urea cycle disorders
- pyruvate dehydrogenase deficiency
- valproate therapy
- beta-ketothiolase deficiency
- isovaleric acidemia
- propionic acidemia
- disorders of iron-sulfur cluster biogenesis/lipoate deficiency
- homocysteinemia type cbIX (HCFC1)
- pyridoxamine-5'-phosphate oxidase (PNPO) deficiency
- pyridoxal phosphate binding-protein (PLPBP)
- glycine transporter 1 (SLC6A9) defects
- benign hyperglycinuria (transient immaturity of renal glycine reabsorption)
- familial iminoglycinuria
- type I hyperprolinemia
- type II hyperprolinemia
- familial iminoglycinuria and types I and II
- urine proline
- hydroxyproline

Nonketotic hyperglycinemia

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Differential based on clinical manifestations

Differential based on biochemical findings

Elevated plasma glycine

Elevated CSF and plasma glycine

Elevated CSF glycine

Elevated urine glycine

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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