Screening of newborns for neurogenetic abnormalities

General Child Neurology

Updated 03.27.2024
Released 04.09.2015
Expires For CME 03.27.2027

Screening of newborns for neurogenetic abnormalities

Authors: John Collyer MD, Krrithvi Dharini Ganesh MBBS, Deepa S Rajan MD

See Contributor Disclosures

Editor: Nina F. Schor MD PhD

Screening of newborns for neurogenetic abnormalities

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Introduction

Overview

As we move into the era of personalized therapies for rare diseases, understanding the history and evolution of newborn screening for neurologic disorders is essential. Over 50 years ago, phenylketonuria was diagnosed using a simple screening method that became the prototype for newborn screening. It was found that phenylketonuria, a devastating neurologic disease characterized by intellectual disability and progressive leukodystrophy, could be identified early and treated with diet. The success of early detection and treatment led to universal newborn screening for phenylketonuria. In the United States and internationally, newborn screening has evolved to include screening for an ever-increasing number of neurometabolic and neurogenetic disorders that, if treated early, may lead to improved prognosis and overall functional outcome. Next generation sequencing, which was previously a novel genomic technology, will likely become an increasingly important part of newborn screening. Unfortunately, the discovery of neurogenetic disorders using next generation sequencing has outpaced the development of disease-modifying therapies, which is a hallmark principle of newborn screening. Use of these technologies has enormous promise, but there are ethical implications and difficulties with results interpretation that must be considered.

Key points

	• Newborn screening has been extremely successful in early detection and diagnosis of devastating neurogenetic syndromes, allowing for early treatment.
	• Roughly four million infants born each year in the U.S. undergo newborn screening.
	• The Recommended Uniform Screening Panel (RUSP) for Core Conditions is updated periodically by The Advisory Committee on Heritable Disorders in Newborns and Children and can be accessed at the following website: https://www.hrsa.gov. There are currently 37 core and 26 secondary conditions on the RUSP.
	• Although the RUSP is a recommendation, each state in the U.S. governs its own newborn screening program, testing between 30 to 50 disorders.

Historical note and terminology

Newborn screening originated in 1963, when Robert Guthrie developed a test for phenylketonuria using heel stick blood samples dried on filter paper (58). Screening programs have since been developed on a state-by-state basis, and disorders have been added based on the Wilson and Jungner criteria, published by the World Health Organization in 1968 (57). The Institute of Medicine published the following selection criteria for disorders to be added to newborn screening in 1994: (1) the disorder must be a significant problem with a known natural history; (2) each state’s Public Health Department must offer further diagnostic testing and follow-up for babies with positive screening results; and (3) effective treatment must be available. The selection criteria were further refined by the American Academy of Pediatrics in 1999: (1) the disorder frequency justifies the cost of screening; (2) the test is simple, safe, precise, validated, and acceptable; and (3) there is available safe and effective treatment (11).

The U.S. Secretary’s Advisory Committee on Heritable Disorders reviews new disorders to include in newborn screening and maintains the Recommended Uniform Screening Panel, which was last updated January 2023. As advancements have occurred in diagnosis and treatment, disorders have been added to the current recommended list, including 37 core conditions and 26 secondary conditions.

Clinical aspects

Description

A selected number of neurogenetic and neurometabolic disorders included in newborn screening are discussed in the following sections.

Aminoacidopathies. The amino acid disorders included in the core Recommended Uniform Screening Panel include argininosuccinic aciduria, citrullinemia type I, maple syrup urine disease (MSUD), homocystinuria, classic phenylketonuria (PKU), and tyrosinemia type I.

Classic phenylketonuria is an autosomal recessive disorder caused by a deficiency in phenylalanine hydroxylase (PAH gene), leading to a toxic accumulation of phenylalanine metabolites. Early detection results in dietary management with a special low-phenylalanine diet and ongoing surveillance of phenylalanine levels and neurodevelopmental outcomes. Failure of detection and treatment leads to severe intellectual disability, seizures, and behavioral problems. In the United States, newborn screening for phenylketonuria can diagnose nearly 100% of cases based on hyperphenylalaninemia on a dried blood spot using tandem mass spectroscopy. If hyperphenylalaninemia is identified in the infant, they will need further genetic or biochemical evaluation to determine if the elevated phenylalanine is secondary to a PAH pathogenic variant (for classic phenylketonuria) or from variants in DNAJC12 or other genes involved in tetrahydrobiopterin metabolism (53). Regardless, this screening test has allowed for early referral and intervention, reducing the number of symptomatic cases of phenylketonuria. It is important to note that phenylalanine levels of infants born to mothers with uncontrolled phenylketonuria will still often be normal, as transient levels of elevation resolve by 24 hours of life (43)

MSUD is an autosomal recessive disease caused by decreased activity of the branched chain alpha ketoacid dehydrogenase complex, resulting in elevated branched chain amino acids (leucine, isoleucine, valine). Newborn screening based on altered ratios of branched chain amino acids to alanine using tandem mass spectroscopy, followed by prompt initiation of treatment, can help neonates remain asymptomatic. Untreated infants with classic MSUD become symptomatic within 48 hours of birth with feeding difficulties, irritability, and ketonuria. Symptoms continue with progressive lethargy and coma, apnea, and opisthotonus. Catabolic stress due to intercurrent illness can lead to repeated episodes of encephalopathy and cerebral edema. Early treatment involves dietary restriction of leucine with judicious supplementation of isoleucine and valine. Identifying infants on newborn screening allows for early dietary restriction, which reduces the number of early hospitalizations for acute encephalopathy (48). Although neonatal encephalopathy does not universally portend intellectual disability, there is an increased risk of it, as well as anxiety and depression later in life, if encephalopathy occurs (18). Still, even with dietary treatment, the intelligence quotient (IQ) score can be one standard deviation lower than expected for age in some patients (35). Liver transplant is an effective therapy for maple syrup urine disease and can prevent metabolic decompensation and neurologic damage but does not reverse the preexisting psychomotor disability. Many outcome measures for transplant patients are similar to those for patients treated with diet (48). It is important to note that newborn screening will not detect all cases of intermediate or intermittent MSUD in which branched chain amino acid levels are only abnormal during periods of illness (39).

Argininosuccinic aciduria has autosomal recessive inheritance and involves deficiency of argininosuccinate lyase, which is essential for converting argininosuccinate into arginine and, in turn, is important in preventing accumulation of nitrogen through the urea cycle. Clinical presentation varies from an early-onset variant (< 28 days old), presenting with hyperammonemic coma, to a late-onset variant with a broader phenotype. Most patients develop neurologic consequences, which include cognitive deficits (ranging from borderline to severe), epilepsy, muscular weakness, ataxia, and behavioral problems. Current standard of care relies on protein restriction, oral nitrogen scavengers, and arginine supplementation. Liver transplant is reserved for patients with poor metabolic control. None of these therapies has shown clear neurologic benefit (55; 06). Beyond the urea cycle, argininosuccinate lyase plays a role in the citrulline-nitric oxide (NO) cycle. Although current therapies for argininosuccinate lyase deficiency address hyperammonemia, they do not address NO imbalance, which produces neuronal oxidative stress. Failure to address this pathway therapeutically may explain why the needle has failed to move in preventing neurologic decline (07). Although the neurologic outcomes of patients identified on newborn screening are statistically better than patients who present symptomatically later, this likely represents an intrinsic bias, as newborn screening identifies many patients who may remain clinically asymptomatic but are considered to have argininosuccinate lyase deficiency on screening (06).

Patients with citrullinemia type 1, an autosomal recessive disorder secondary to defects in argininosuccinate synthase 1 (ASS1 gene), can have wide phenotypic variability in clinical presentation. Clinical features include hypotonia, lethargy, seizures, stroke, poor feeding, and emesis (55). Treatment includes protein restriction and ammonia scavenger therapy like argininosuccinic aciduria, but liver transplantation may be more useful in this population (34). Despite early therapy and diagnosis, neurologic morbidity continues to remain high. Clinical severity seems to correlate with degree of residual enzyme activity. Patients with lower than 8% residual activity have more severe hyperammonemic events and lower cognitive functioning (63).

Tyrosinemia type 1 is caused by a deficiency in fumarylacetoacetate hydrolyase (FAH gene), which is required for the catabolism of tyrosine. Patients with this autosomal recessive metabolic disorder will present with symptoms of liver failure, renal dysfunction, and hypophosphatemic rickets before 2 years of age. Patients can have neurologic crises that resemble those of porphyria, which are characterized by severe neuropathic pain/paresthesias, opisthotonic posturing, and autonomic instability (hypertension and tachycardia). These crises are typically precipitated by an illness. Early treatment in presymptomatic infants with 2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), along with a diet restricted in phenylalanine and tyrosine, has been shown to improve these symptoms. There have been reports that despite dietary and NTBC treatment, patients have deficits in their IQ, executive cognition, and social cognition (52).

Amino acid disorders on the Recommended Uniform Screening Panel Secondary Conditions list include: argininemia, citrullinemia type II, hypermethioninemia, benign hyperphenylalanemia, biopterin defect in cofactor biosynthesis, biopterin defect in cofactor regeneration, tyrosinemia type II, and tyrosinemia type III.

Organic acidemias. The organic acidemias included in the core Recommended Uniform Screening Panel include propionic acidemia, methylmalonic acidemia (methylmalonyl-CoA mutase defects), methylmalonic acidemia (cobalamin A, cobalamin B defects), isovaleric acidemia, 3-methylcrotonyl-CoA carboxylase deficiency, 3-hydroxy-3-methyglutaric aciduria, holocarboxylase synthase deficiency, ß-ketothiolase deficiency, and glutaric aciduria type I.

Organic acidemias refer to a group of disorders that can be diagnosed by the abnormal presence of a non-amino organic acid in the urine. They are inherited in an autosomal recessive fashion, resulting in the lack of a specific enzyme in the amino acid metabolism pathway (especially for branched chain amino acids and lysine). Infants are typically born healthy, but within the first week of life, they develop metabolic encephalopathy with seizures, recurrent emesis, poor feeding, lethargy, and coma. Isolated disorders can have associated metabolic strokes as well. This clinical picture of metabolic decompensation can mimic neonatal sepsis, and newborn screening results may not be back at the time of initial presentation. Though most present in infancy, many of these disorders can have a delayed presentation with insidious onset of neurologic symptoms. Regardless, prevention of metabolic decompensation leads to improved outcomes. Liver transplantation is a treatment modality in selected disorders.

Glutaric aciduria type I is the best example of an organic acidemia that is detected on newborn screening for which the neurologic outcome is significantly altered by treatment. Untreated infants develop macrocephaly, followed by failure to thrive, metabolic acidosis, dystonia, and athetosis as a result of acute bilateral striatal injury. The main principle of treatment is to reduce lysine oxidation and enhance detoxification of glutaryl-CoA. Use of a low lysine diet in combination with carnitine supplementation prior to symptom onset can help improve neurologic outcomes. Dietary modification can be relaxed after 6 years of age, as bilateral striatal injury typically occurs prior to this in the setting of a particular stressor, such as a febrile illness or surgery. However, the impact of dietary relaxation on long-term cognitive outcomes remains less clear (10). Deviation from the diet prior to the age of 6 can allow for the insidious onset of a movement disorder, and initiation following the development of a motor deficit or movement disorder cannot reverse these changes (09). There have been reports of missed cases of glutaric aciduria type 1 on newborn screening that have later had acute decompensation or insidious onset of symptoms. These missed cases are associated with a low-excretor phenotype of glutarylcarnitine at birth (47).

Although newborn screening has improved identification and overall survival of patients with propionic acidemia and methylmalonic acidemia, there has been no difference in cognitive function and the number of acute metabolic decompensations between the pre- and post-newborn screening eras (28). Still, it is important for infants with propionic acidemia to have dietary restriction of propiogenic substrates (isoleucine, valine, threonine, and methionine) and initiation of carnitine supplementation as soon as possible. Interestingly, a recurrent genetic variant in the Amish population responsible for propionic acidemia may produce normal or only borderline positive newborn screening results. Although a limited study, Amish patients identified on newborn screening (and therefore who were started on dietary therapy early) did not have improved neurodevelopmental outcomes compared to those patients who had a false negative newborn screening result and who were started on dietary therapy later (21). Even if dietary therapy is initiated quickly in methylmalonic acidemia, there will still be some degree of neurodevelopmental impact. Studies have demonstrated an increase in developmental quotient following initiation of therapy in methylmalonic acidemia, but this increase did not reach statistical significance (13). Liver transplantation in propionic acidemia and methylmalonic acidemia appears to reduce hospital admission time and duration of tube feeds, but impacts on neurocognitive function remain unclear as the enzymatic defect in the cerebrum has not been corrected (15).

The organic acid disorders on the “Secondary Conditions” Recommended Uniform Screening Panel include methylmalonic acidemia with homocystinuria (cobalamin C, cobalamin D defects), malonic acidemia, isobutyrylglycinuria, 2-methylbutyrylglycinuria, 3-methylglutaconic aciduria, and 2-methyl-3-hydroxybutyric aciduria.

Long-chain fatty acid oxidation disorders. The fatty acid oxidation disorders on the core Recommended Uniform Screening Panel include carnitine uptake defect/carnitine transport defect, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, and mitochondrial trifunctional protein (TFP) deficiency.

MCAD deficiency is the most common in this group of disorders. Infants are normal at birth and will typically have their first clinical decompensation at 3 to 15 months of age after a period of fasting or another stressor, such as a febrile illness. Presentation can be in the first 72 hours of life, however, if the infant is breastfeeding and the maternal milk supply is inadequate. Acute decompensation is characterized by hypoglycemia (with associated seizures), poor feeding, and encephalopathy (23). Early identification of MCAD deficiency via newborn screening has nearly cut medical costs for this condition in half (51). Patients that have recurrent hypoglycemic events also have high mortality from sudden death. Twenty to 25% of patients not identified on newborn screening will experience death or significant disability (26). Studies have demonstrated that no genotype or octanoylcarnitine (C8) level on newborn screening is protective from future catabolic crisis, and adverse outcomes still occur in this disorder despite newborn screening (05). Treatment involves frequent feeding and avoiding fasting. Maximum time for fasting varies by age (8 hours for 6 to 12 months, 10 hours for 1 to 2 years old, and 12 hours for over 2 years old). Toddlers can be given complex carbohydrates, like cornstarch, so they can sleep throughout the night without waking to feed (23).

Many cases of VLCAD deficiency identified via newborn screening are asymptomatic, but this condition can have severe manifestations up to death as well. Like MCAD deficiency, patients can experience catabolic crises with prolonged fasting and intercurrent illness, which is usually characterized by hypoketotic hypoglycemia and muscle pain with or without rhabdomyolysis. Death can be secondary to cardiomyopathy, although this is a rare complication (37). Management includes use of low-fat formula or low long-chain/high medium-chain formula in combination with triheptanoin oil and carnitine supplementation.

Patients with MTP and LCHAD deficiencies can have a more variable presentation, ranging from a severe neonatal phenotype characterized by cardiomyopathy and early death to a milder phenotype with later onset associated with peripheral neuropathy, retinopathy, and intermittent episodes of rhabdomyolysis. Patients with mitochondrial TFP and LCHAD deficiencies can also develop hypoglycemia associated with illness or fasting, like MCAD and VLCAD deficiency patients. Newborn screening is helpful in identifying these disorders early to prevent the hypoglycemic episodes, but there is unfortunately no effective treatment for the remaining complications at this time (45).

Fatty acid oxidation disorders are screened using acylcarnitine testing from heel stick dried blood spots. Newborn screening has been very specific for MCAD deficiency, with few false negatives when the correct cut-offs are used. However, the positive predictive value of elevated acylcarnitines, especially C8, varies significantly (05).

In addition to those discussed in detail above, the fatty acid oxidation disorders on the “Secondary Conditions” Recommended Uniform Screening Panel also include short chain acyl-CoA dehydrogenase (SCAD) deficiency, medium/short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency, glutaric acidemia II, medium-chain ketoacyl-CoA thiolase deficiency, 2,4 dienoyl-CoA reductase deficiency, carnitine palmitoyltransferase type I (CPT IA) deficiency, carnitine palmitoyltransferase type II (CPT II) deficiency, and carnitine acylcarnitine translocase (CACT) deficiency.

Other disorders

Mucopolysaccharidosis I (MPS I). MPS I is a progressive multisystem disorder with features ranging from a severe phenotype (Hurler syndrome) to a milder phenotype (Scheie syndrome). Patients with severe MPS I develop symptoms in the first year of life with progressive skeletal dysplasia, coarsening of facial features, severe intellectual disability, hearing loss, corneal clouding, and death by progressive respiratory failure in the first decade of life. Other neurologic symptoms include carpal tunnel syndrome, obstructive hydrocephalus, cervical myelopathy from cord compression, and neuropsychiatric and behavioral problems.

MPS I is an autosomal recessive disease due to a deficiency of the lysosomal enzyme α-L-iduronidase. Though not specific, supportive testing includes urine glycosaminoglycans (heparan and dermatan sulfate) and oligosaccharides. Diagnosis is established by genetic testing of the IDUA gene or by deficient activity of the lysosomal enzyme, α-L-iduronidase.

Treatment with hematopoietic stem cell transplantation (HSCT) is considered standard of care in severe MPS I; however, the outcome is significantly affected by disease burden at the time of diagnosis. HSCT should be used only after in-depth pretransplantation clinical assessment and counseling (40; 02; 17). Enzyme replacement therapy with laronidase is effective for non-CNS manifestations of MPS I as it does not cross the blood-brain barrier (16). With the success of enzyme replacement therapy, multiple other therapies are currently being explored, with a goal of addressing symptoms affecting the central nervous system, including enzyme replacement therapy that penetrates the blood-brain barrier, combined therapy with serum enzyme replacement therapy and HSCT, and intrathecal enzyme replacement therapy. There are ongoing trials of ERT combined with the transferrin receptor to enable crossing the blood-brain barrier as well as autologous HSCT following IDUA gene therapy that have had promising motor outcomes with measurable levels of IDUA activity in the CSF (24).

Mucopolysaccharidosis II (MPS II). MPS II, also known as Hunter syndrome, is an X-linked recessive lysosomal storage disorder associated with accumulation of heparan and dermatan sulfate. Clinically, patients have the same multiorgan involvement seen in MPS I but will not have corneal clouding. There is also a distinct behavioral and developmental phenotype characterized by hyperactivity, aggression, poor sleep, and difficulty with bowel/bladder training (19).

Once again, supportive testing includes elevated urine glycosaminoglycans (nonspecifically heparan and dermatan sulfate). Confirmatory diagnosis is achieved by identifying a pathogenic variant in the iduronate-2-sulfatase (IDS) gene or by demonstrating decreased function of this enzyme with leukocyte or fibroblast studies (19). MPS II was added to the RUSP in August 2022 after the development of an efficacious enzyme replacement therapy, idursulfase. Similarly, idursulfase does not cross the blood-brain barrier and, therefore, does not ameliorate the neuropsychiatric manifestations of this disease, but it has been helpful for many of the somatic consequences of the disorder (12; 42). There are ongoing trials exploring enzyme replacement therapy options that penetrate the blood-brain barrier, with promising initial results.

X-linked adrenoleukodystrophy (X-ALD). X-ALD is a rare peroxisomal disorder with a wide range of phenotypes, including isolated adrenal insufficiency (or an Addison disease only phenotype), adrenomyeloneuropathy in older males and females, and a cerebral demyelinating form. Childhood cerebral X-ALD has a typical age of onset between 4 and 10 years of age, with initial symptoms related to learning and behavior issues and eventually progressing to blindness, seizures, spasticity, and adrenal failure. More than 20% of female carriers develop mild to moderate spastic paraplegia in middle age – symptoms consistent with the adrenomyeloneuropathy phenotype.

Newborn screening for X-ALD is performed using tandem mass spectroscopy analysis, specifically for hexacosanoic acid-lysophosphatidylcholine (C26:0-LPC). If C26:0-LPC is elevated, the patient should have serum very long chain fatty acid (VLCFA) analysis and genetic testing to identify a pathogenic variant in the ABCD1 gene as soon as possible. Interestingly, C26:0-LPC can also be elevated in other peroxisomal biogenesis disorders, like Zellweger syndrome and Aicardi-Goutieres syndrome, so this test is not specific for X-ALD. Some newborn screening programs have coupled tandem mass spectroscopy analysis with ABCD1 gene sequencing as a second-tier test to make a diagnosis as fast as possible, but this has led to the unintended consequence of finding variants of uncertain significance (54).

When adrenal insufficiency is diagnosed, corticosteroid therapy can be lifesaving and is essential. Hematopoietic stem cell transplantation (HSCT) is an option for boys and adolescents in early stages of symptom onset who have minimal evidence of brain involvement on MRI, but it is not recommended in individuals with advanced neurologic disease (46; 38). VLCFA levels and the specific ABCD1 pathogenic variant do not correlate consistently with disease severity, so continued monitoring with neuroimaging is needed (54).

Ex vivo gene therapy (elivaldogene autotemcel) was finally approved for this disorder in 2022 for patients with active cerebral disease who do not have an appropriate match for HSCT (32; 27).

Pompe disease. Pompe disease, also known as glycogen storage disease type II or acid maltase deficiency, is caused by enzyme deficiency of acid alpha-glucosidase (GAA) due to biallelic pathogenic variants in the GAA gene. GAA deficiency causes excessive storage of glycogen in lysosomes, leading to skeletal muscle weakness and cardiomyopathy. Two main phenotypes, infantile onset and late onset, are classified based on age of onset, organ involvement, severity, and rate of progression.

Infantile-onset (classic) Pompe disease presents in the first few months of life with hypotonia, muscle weakness, poor feeding with failure to thrive, cardiomyopathy, classic EKG high-voltage QRS complexes, and respiratory distress. Creatine phosphokinase is typically elevated but may be normal and is not a good screening test for Pompe disease. A late-onset form can present during childhood, adolescence, and adulthood with proximal muscle weakness and respiratory distress, but typically without cardiac involvement (33). With newborn screening, there is currently no way to definitively differentiate the infantile-onset versus the late-onset phenotype, and newborn screening has unfortunately identified a nonsignificant number of false positives in infants with pseudo-deficiency alleles (49).

Enzyme testing readily identifies symptomatic infants, and early detection with rapid initiation of enzyme replacement therapy has improved long-term outcomes. The majority of infants who were given enzyme replacement therapy before 6 months of age, who did not need ventilator support, had improved survival, cardiomegaly, and neurodevelopmental milestones during the pivotal clinical trial of enzyme replacement therapy versus placebo (33; 03; 14). Pompe disease was added to the core RUSP in 2016 with the rationale being that early treatment with enzyme replacement therapy improves cardiac and developmental outcomes (61). Without enzyme replacement therapy, infantile-onset Pompe disease is typically fatal in the first year of life due to cardiomyopathy. Current guidelines indicate that enzyme replacement therapy should be initiated no later than 2 months of age (50). At this time, it remains unclear whether enzyme replacement therapy should be initiated asymptomatically or as soon as clinical signs appear in the late-onset group. A 2022 meta-analysis noted that enzyme replacement therapy improved walking distance but did not statistically improve muscle strength or respiratory capacity. Of note, the majority of patients included in this study were given enzyme replacement therapy post symptom-onset (44). A 2023 study demonstrated that enzyme replacement therapy may not be addressing the CNS manifestations of Pompe disease. Nineteen patients had evidence of white matter disease (starting at age 3) that was progressive and correlated with worsening cognitive function as well as increased neurofilament light chain levels (30). Other pipeline therapies, including gene therapy, will attempt to address the neurodegenerative aspects of this disorder as well.

Spinal muscular atrophy. Spinal muscular atrophy is a motor neuron disease inherited in an autosomal recessive fashion. It is caused by loss of survival motor neuron (SMN) protein, leading to degeneration of alpha motor neurons. There are two genes that contribute to SMN protein production: SMN1, which is the primary gene for producing SMN, and SMN2. There are five subtypes of the disorder: Types 0 through 4, which are mediated by SMN2 copy number. Type 0 is characterized by prenatal onset and death within the first few weeks of life due to respiratory failure. Spinal muscular atrophy type 1 accounts for 50% to 60% of cases with areflexia, hypotonia, and weakness presenting at less than 6 months of age. Spinal muscular atrophy type 2 is predominantly a motor rather than respiratory weakness, with onset after 6 months of age. Spinal muscular atrophy type 3 begins after 18 months and presents with progressive proximal muscle weakness. Spinal muscular atrophy type 4 will typically present in later adolescence or adulthood with proximal muscle weakness but with no increase in mortality (04).

In 2016, the Food and Drug Administration approved an antisense oligonucleotide therapy, nusinersen, which is intrathecally administered to enhance the function of the SMN2 gene, allowing for increased SMN protein production. The first clinical trial (performed with type 1 patients) showed decreased mortality and improved motor functional scores. Improvement was most notable with earlier treatment (< 3 months) compared to treatment after 5 months of age, and later trials demonstrated efficacy with type 2 and type 3 patients as well. With the success of nusinersen, spinal muscular atrophy was added to the RUSP in 2018. The second novel therapy, approved in 2019, was gene therapy (onasemnogene abeparvovec) via an AAV9 vector. This therapy is provided as a single intravenous dose for children under 24 months irrespective of SMN2 copy number and has been shown to increase survival, delay time to ventilation, and improve motor function when compared to the natural history of patients with spinal muscular atrophy. Furthermore, data have shown improved efficacy over nusinersen in symptomatic infants. The third novel therapy was the development of risdiplam, an oral splicing modifier of the SMN2 gene, in 2020, which also demonstrated an improvement in motor outcomes and has an easier route of administration compared to nusinersen (04; 22). Efforts are now directed at reducing barriers, such as cost, to access these disease-modifying therapies.

Biotinidase deficiency. Biotinidase deficiency is caused by a lack or absence of the enzyme biotinidase, which leads to abnormalities in the recycling of biotin. This leads to secondary changes in the metabolism of amino acids, carbohydrates, and fatty acids. It is inherited in an autosomal recessive fashion and has extensive phenotypic variability. Most individuals with profound biotinidase deficiency present with symptoms between 1 week and 10 years of age. Clinical features include seizures, hypotonia, optic atrophy, hearing loss, ataxia, alopecia, candidiasis, other rashes, and developmental delay. Serum metabolic derangements can include lactic acidosis or hyperammonemia. The optic atrophy/visual loss and hearing loss do not seem to be particularly amenable to biotin replacement, especially if there is a delay in initiation of treatment, and damage is typically irreversible. The other clinical manifestations, including seizures and metabolic derangements, will usually respond to biotin supplementation when started in a symptomatic infant. More importantly, treatment in presymptomatic infants can prevent the development of most clinical features, highlighting the importance of early diagnosis and treatment. A study indicated no difference in developmental and behavioral outcomes for preschool-aged children with biotinidase deficiency identified on newborn screening with appropriate supplementation of biotin compared to their unaffected, normal peers (62). Another study with 44 patients demonstrated that all had completed high school, and many were enrolled in college while on appropriate biotin supplementation (60).

Galactosemia. Galactosemia results from deficiency of any of the three enzymes responsible for the metabolism of galactose, with the most severe being secondary to galactose-1-phosphate uridylyltransferase (GALT) deficiency (also referred to as classic galactosemia). This disorder is included on the newborn screening for all 50 states, and one of two screening tests is performed: a fluorometric assay of GALT enzyme activity in red blood cells (RBCs) or a bacterial inhibition assay. If one of these tests is abnormal, the infant should be transitioned to soy formula, and the screening test should be repeated. If it remains abnormal, a confirmatory test (quantitative RBC GALT activity) should be performed (31).

Most patients with classic galactosemia present in the neonatal period with poor feeding, jaundice, hypotonia, lethargy, hepatomegaly, and E coli sepsis. It is important to ensure a high index of suspicion when neonates exhibit these symptoms and initiate treatment early (31). With early treatment, these symptoms can be reversed; however, despite early detection and treatment, patients with classic galactosemia still exhibit speech and cognitive delays, memory impairment, anxiety, mood disorders, and learning disabilities (56; 29). A small cohort of patients had associated tremor, ataxia, dysarthria, EEG abnormalities, and reduction in brain matter on MRI in areas associated with learning, memory, and motor planning (01). The mainstay of treatment is a lifelong diet restricted in galactose and neuropsychological monitoring.

Guanidinoacetate methyltransferase (GAMT) deficiency. GAMT deficiency, an autosomal recessive disease of creatine biosynthesis, is the most recent neurogenetic disorder to be added to the RUSP. Pathogenic variants in the GAMT gene lead to cerebral creatine deficiency and elevation of guanidinoacetate to toxic levels in the CNS. Clinical features of this disorder include hypotonia, delayed achievement or regression of motor milestones, minimal speech development, severe intellectual disability, deficits in social and emotional development up to autism spectrum disorder, epilepsy, and a variety of movement disorders, including tremor and facial tics. MRI of the brain shows a characteristic pattern of symmetric hyperintensity of the bilateral globus pallidi, and magnetic resonance spectroscopy (MRS) shows an absent creatine peak (25).

Although this disorder is exceedingly rare (incidence of 0.5 to 2 per million), it was easily added to the RUSP in January 2023 because the toxic metabolite guanidinoacetate can be detected via tandem mass spectroscopy analysis, which is already used for other diseases included on newborn screening. Treatment of presymptomatic infants with nitrogen scavengers, supplementation with creatine and ornithine, and use of a low-protein diet can help with both seizures and developmental outcomes. Initiation of dietary therapy after developmental delays have accrued is of limited utility (25; 41).

Indications

Currently, all states in the United States include a no consent, optional opt out mandatory newborn screening for every infant.

Contraindications

There are no contraindications to newborn screening.

Special considerations

The success of newborn screening is based on six pillars: education, testing, follow-up, diagnosis, intervention or management, and evaluation. For newborn screening to be effective, timely education and follow-up is imperative to ensure appropriate diagnosis and treatment, if necessary.

Despite newborn screening being the standard of care for more than 40 years, as technology and our understanding of diseases improve, we are continually faced with novel issues, including the selection of disorders for newborn screening, establishing appropriate protocols for follow-up, and instituting updated education for the providers and parents. Presently, there is wide variability from state to state: some states mandate a 2-tiered testing approach (which is usually a biochemical test followed by another biochemical test or sequencing for the causative gene), whereas others do not. Some states rely on Medicaid or private insurers for reliant care after screening, whereas others have implemented contracts with specialists. This, no doubt, has created ethical concerns with attempts at standardizing care at the federal level. For example, in 2007, Congress passed an act creating the Advisory Committee on Heritable Disorders in Newborns and Children, which is responsible for creating a list of recommended diseases to be screened based on scientific evidence, including diseases with known natural history and approved therapies – also known as the Recommended Uniform Screening Panel (RUSP). However, as the RUSP is not a federal mandate, there is still inconsistency in how newborn screening and follow-up care is delivered state by state.

Additionally, with improvement of tandem mass spectroscopy and the development of new tools, like next generation sequencing, the ability to screen for numerous other diseases is now possible. However, multiple challenges exist, including identifying biomarkers that are sensitive enough to capture as many cases as possible while minimizing false positives, adding diseases for which natural history is not yet clearly defined, and adding diseases for which therapies are not curative but stabilizing at best.

This is best exemplified with the addition of Krabbe disease, a rare lysosomal storage disorder caused by deficiency in the galactocerebrosidase enzyme, to the New York State newborn screening in 2016. This addition was driven by parent and advocacy groups despite recommendations from expert committees. Since that time, Krabbe disease has been added to the newborn screening for 10 additional states. Newborn screening has helped identify children with typical infantile disease as well as asymptomatic children. The goal is for infants to proceed to HSCT prior to the onset of neurologic disease, but there is an inadequate pipeline for identification of patients via newborn screening and then timely referral for HSCT. Patients that have received HSCT seem to have improved developmental outcomes, but they still have some degree of neurodevelopmental morbidity (36). Though there are protocols in place for presumed follow-up of these asymptomatic children, there are still numerous uncertainties, including timing of intervention, anticipatory guidance, and parental education. Fortunately, 2-tiered testing for elevated psychosine has significantly increased specificity (08). On January 30, 2024, Krabbe disease was formally added to the RUSP. It remains to be seen if state infrastructure and therapy pipelines will be able to efficiently identify presymptomatic children and get them to HSCT in a timely manner (20).

References

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Screening of newborns for neurogenetic abnormalities

Also Relevant

Adrenoleukodystrophy
Argininosuccinic acidemia
Biotinidase deficiency
Citrullinemias types 1 and 2
Duchenne muscular dystrophy
- Galactosemia
- Glutaric aciduria
- Globoid cell leukodystrophy
- Hepatorenal tyrosinemia
- Homocystinuria due to cystathionine beta-synthase deficiency
- Isovaleric acidemia
- Long-chain fatty acid oxidation defects
- Maple syrup urine disease
- Medium-chain acyl-CoA dehydrogenase deficiency
- Methylmalonic acidemia
- Mucopolysaccharidoses
- Phenylketonuria
- Propionyl-CoA carboxylase deficiency
- Spinal muscular atrophy

Clinical Categories

General Child Neurology

Screening of newborns for neurogenetic abnormalities

Screening of newborns for neurogenetic abnormalities

Introduction

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Clinical aspects

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Acute cerebellar ataxia in children

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Screening of newborns for neurogenetic abnormalities

Introduction

Overview

Key points

Historical note and terminology

Clinical aspects

Description

Other disorders

Indications

Contraindications

Special considerations

Scientific basis

References

Contributors

Authors

Editor

Former Authors

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Also in This Category

Acute cerebellar ataxia in children

Zika virus: neurologic complications

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CNS germinoma

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Migraine in childhood

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