General Child Neurology
Acute cerebellar ataxia in children
Jun. 10, 2026
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Screening of newborns for neurogenetic abnormalities
- Updated 05.23.2025
- Released 04.09.2015
- Expires For CME 05.23.2028
Screening of newborns for neurogenetic abnormalities
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. Now, next generation sequencing has unlocked numerous neurogenetic discoveries, and universal newborn screening programs have expanded to include many neurometabolic and neurogenetic conditions that are potentially treatable. However, implementing these new screening tools raises several challenges and ethical considerations that need to be addressed moving forward (30; 28).
Key points
• Newborn screening has been extremely successful in early detection and diagnosis of devastating neurogenetic syndromes, allowing for earlier 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. There are currently 37 core and 26 secondary conditions on the RUSP (January 2023). However, Krabbe disease was formally added to the RUSP in January 2024, bringing the core condition total to 38 (17). | |
• 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 (60). 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 (59). The Institute of Medicine published selection criteria in 1994, further refined by the American Academy of Pediatrics in 1999, mandating that the disorder’s frequency justifies cost, the test is safe and validated, and there is an effective treatment (08).
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 in January 2023 (and updated again in January 2024 to include Krabbe disease). Advancements in diagnosis and treatment have led to the expansion of this panel, reflecting the rapid growth of therapies for rare neurogenetic conditions.
Clinical aspects
Description
• Early detection through newborn screening can markedly reduce morbidity for many conditions, including aminoacidopathies, organic acidemias, and fatty acid oxidation defects. | |
• Some conditions, such as argininosuccinic aciduria or methylmalonic acidemia, still exhibit ongoing neurologic challenges even when identified and treated early, highlighting the need for improved therapies. |
A selected number of neurogenetic and neurometabolic disorders included in newborn screening are discussed in the following sections.
Aminoacidopathies. The amino acid disorders in the core Recommended Uniform Screening Panel recommendations include argininosuccinic aciduria, citrullinemia type I, maple syrup urine disease (MSUD), homocystinuria, classic phenylketonuria (PKU), and tyrosinemia type I phenylketonuria.
Classic phenylketonuria is an autosomal recessive disorder caused by phenylalanine hydroxylase (PAH) deficiency. Early detection allows dietary management with a special low-phenylalanine diet and ongoing surveillance, reducing neurologic sequelae such as seizures and severe intellectual disability.
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. In cases of hyperphenylalaninemia, newborns are further evaluated genetically or biochemically to confirm classic phenylketonuria or alternative causes (eg, DNAJC12 variants) or other genes involved in tetrahydrobiopterin metabolism (55).
Regardless, this screening test has allowed for early referral and intervention, reducing the number of symptomatic cases of phenylketonuria. Of note, maternal phenylalanine can confound infant screening; infants of mothers with uncontrolled phenylketonuria can have transient elevations of phenylalanine that normalize within 24 hours (43).
Maple syrup urine disease (MSUD). MSUD is an autosomal recessive disease caused by decreased activity of the branched chain alpha ketoacid dehydrogenase complex activity, resulting in elevated branched chain amino acids (leucine, isoleucine, valine).
Newborn screening based on altered ratios of branched chain amino acids (ratios of [leucine + isoleucine] to alanine and phenylalanine that are above the cutoff values) using tandem mass spectroscopy (TMS), 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 dietary restriction of leucine and appropriate supplementation of valine and isoleucine can reduce acute encephalopathic episodes. (49). 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 (15). Still, even with dietary treatment, the intelligence quotient (IQ) score can be one standard deviation lower than expected for age in some patients (34). Liver transplantation is an effective therapy for preventing metabolic decompensation but does not always reverse the preexisting psychomotor impairments. Many outcome measures for transplant patients are similar to those for patients treated with diet (49). Of note, 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. This autosomal recessive disorder involves argininosuccinate lyase (ASL) deficiency, 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. Neurologic manifestations include cognitive deficits (ranging from borderline to severe), seizures, muscular weakness, ataxia, and behavioral problems. Treatment focuses on preventing hyperammonemia (with protein restriction, oral nitrogen scavengers, arginine supplementation) and, in severe cases, liver transplant.
Despite early detection, long-term neurologic outcomes can be poor (57; 03). 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 nitric oxide 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 (04). Although the neurologic outcomes of patients identified on newborn screening are statistically better than patients who present symptomatically later, this could 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 (03).
Citrullinemia type I . 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 (57). Treatment includes protein restriction and ammonia scavenger therapy like argininosuccinic aciduria, but liver transplantation may be more useful in this population (33). 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 (66).
Tyrosinemia type 1. Deficiency in fumarylacetoacetate hydrolyase (FAH gene) 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. Early treatment with NTBC and dietary phenylalanine and tyrosine restriction improves prognosis, though some patients continue to show cognitive or executive deficits (54).
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/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 (07). 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 (06). 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 (48).
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 (25). 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 (18). 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 (11). 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 (12).
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 (20). Early identification of MCAD deficiency via newborn screening has nearly cut medical costs for this condition in half (53). 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 (23). 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 (02). 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 (20).
VLCAD deficiency identified via newborn screening can be asymptomatic, but this condition can also have severe manifestations including early death. 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.
LCHAD/TFP deficiencies. 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 (02).
In addition to those discussed in detail above, the fatty acid oxidation disorders on the “Secondary Conditions” of the 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 an autosomal recessive lysosomal storage disorder due to α-L-iduronidase deficiency. This 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.
Supportive testing though not specific 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.
Hematopoietic stem cell transplant (HSCT) can slow disease progression but must be performed before significant neurologic compromise (40; 14). Enzyme replacement therapy (ERT) helps somatic but not CNS manifestations (13). Ongoing trials are investigating therapies that penetrate the blood-brain barrier or utilize gene therapy (21).
Mucopolysaccharidosis II (MPS II), also known as Hunter syndrome. MPS II is an X-linked recessive lysosomal storage disease involving iduronate-2-sulfatase deficiency associated with accumulation of heparan and dermatan sulfate. Patients have multiorgan involvement similar to MPS I but no corneal clouding, and many develop neuropsychiatric symptoms. There is also a distinct behavioral and developmental phenotype characterized by hyperactivity, aggression, poor sleep, and difficulty with bowel/bladder training (16).
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 (16). MPS II was added to the RUSP in August 2022 after the development of an efficacious enzyme replacement therapy (idursulfase) improved somatic outcomes (16; 09), but not CNS disease, prompting investigations into blood-brain barrier-penetrating enzymes, which are currently under clinical trial (42).
A rare peroxisomal disorder with a wide range of phenotypes, from including isolated adrenal insufficiency (or an Addison disease only phenotype), adrenomyeloneuropathy in older males and females, to childhood 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 (56). VLCFA levels and the specific ABCD1 pathogenic variant do not correlate consistently with disease severity; thus, continued monitoring with neuroimaging is needed (56).
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.
Early HSCT can be lifesaving if performed at the earliest signs of cerebral involvement, but it is not recommended in individuals with advanced neurologic disease (46; 38). Ex vivo gene therapy (elivaldogene autotemcel) received FDA approval in 2022 (24).
Pompe disease, also known as glycogen storage disease type II or acid maltase deficiency, is caused by enzyme deficiency of acid alpha-glucosidase (GAA). 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, cardiomyopathy, and respiratory distress. Late-onset form can present during childhood, adolescence, and adulthood with proximal muscle weakness and respiratory distress, but typically without cardiac involvement (31). 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 (51).
Enzyme replacement therapy (ERT) in presymptomatic or minimally symptomatic infants improves cardiac and developmental outcomes (31; 63). 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 (52). 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). However, findings suggest that ERT may not fully prevent central nervous system progression, emphasizing the need for next-generation therapies (27). 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 an autosomal recessive motor neuron disorder 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 (01; Yildirim and Tan 2024).
In 2016, the Food and Drug Administration approved nusinersen antisense oligonucleotide therapy, which is administered intrathecally 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 (earlier than 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 onasemnogene abeparvovec (gene therapy) 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 data; this has shown improved efficacy over nusinersen in symptomatic infants. The third novel therapy risdiplam (oral splicing modifier) of the SMN2 gene, which was developed in 2020, can dramatically improve outcomes (01; 19).
Biotinidase deficiency. An autosomal recessive disorder leads to abnormalities in the recycling and depletion of biotin. Most present with symptoms between 1 week and 10 years of age. Clinical manifestations can include seizures, hypotonia, vision and hearing loss, and metabolic derangements, but early biotin supplementation can prevent most symptoms. Preschool-age children identified at birth show normal developments (65). Another study with 44 patients demonstrated that all had completed high school, and many were enrolled in college while on appropriate biotin supplementation (62).
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 (29).
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 (29). Early soy-based diet can reverse the neonatal presentation (jaundice, sepsis, vomiting), but patients often develop speech and cognitive delays later in life (58; 26). The mainstay of treatment is a lifelong diet restricted in galactose and neuropsychological monitoring.
Guanidinoacetate methyltransferase (GAMT) deficiency. The newest addition to the RUSP (January 2023) is GAMT deficiency, an autosomal recessive creatine biosynthesis disorder, leading to cerebral creatine deficiency and elevation of guanidinoacetate to toxic levels in the CNS.
Clinical manifestations include seizures, severe developmental impairment, autism spectrum disorder features, and movement abnormalities. 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 (22).
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 is of limited utility (22; 41).
Indications
All newborns in the United States undergo mandatory newborn screening with an “opt-out” provision in most states. Certain high-risk families may also receive expanded or targeted genetic testing.
Contraindications
There are no contraindications to standard newborn screening.
Results
Newborn screening programs employ TMS (tandem mass spectrometry) and, increasingly, second-tier biochemical as well as DNA sequencing for conditions like X-ALD, SMA, and Krabbe disease. Despite improvements, false positives can occur, creating parental anxiety. False negatives, although rare, still happen, especially for variant or mild phenotypes.
Special considerations
The success of newborn screening is based on six core elements: 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 (10; 50).
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 (35). 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 (05). 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 (17).
Scientific basis
• Tandem mass spectrometry (TMS) offers rapid detection of numerous metabolites, enabling earlier diagnosis of asymptomatic newborns. | |
• Advances in genomic sequencing raise ethical considerations: how to manage uncertain findings, maintain parental autonomy, and handle cost and counseling challenges (61; 32; 36). |
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Leen Alkalbani MD
Dr. Alkalbani of UPMC Children's Hospital of Pittsburgh has no relevant financial relationships to disclose.
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Krrithvi Dharini Ganesh MBBS
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Deepa S Rajan MD
Dr. Rajan of UPMC Children's Hospital of Pittsburgh has no relevant financial relationships to disclose.
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Nina F Schor MD PhD
Dr. Schor of the University of Rochester School of Medicine and Dentistry has no relevant financial relationships to disclose.
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