Description
A selected number of neurogenetic and neurometabolic disorders included in newborn screening are discussed in this section.
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.
Phenylketonuria is caused by a deficiency in phenylalanine hydroxylase, leading to a toxic accumulation of phenylalanine. 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. Newborn screening for phenylketonuria can diagnose nearly 100% of cases based on hyperphenylalaninemia on a dried blood spot and has subsequently resulted in fewer symptomatic cases of classic phenylketonuria.
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, 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. 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, and overall outcome is similar to that for those patients treated with diet (10).
Argininosuccinic aciduria is caused by a deficiency in argininosuccinate lyase, which is essential for transforming argininosuccinate into arginine and, in turn, important in preventing accumulation of excess nitrogen through the urea cycle. Clinical presentation varies from an early-onset presentation (< 28 days old), presenting with hyperammonemic coma, to a late-onset presentation with a broader phenotype. Most patients develop neurologic consequences: neurocognitive deficits, which can range from borderline to severe; epilepsy; muscular weakness; ataxia; and behavioral difficulties. Current standard of care relies on protein restriction, oral nitrogen scavengers, and arginine supplementation, with liver transplant reserved for patients with poor metabolic control, all of which has not shown clear neurologic benefit.
Patients with citrullinemia type 1, which is due to a defect in argininosuccinate synthetase 1, present like those with argininosuccinic aciduria with similar phenotypic variability. Treatment is also similar, although some have reported more promising results after liver transplantation. Despite early therapy and diagnosis, morbidity continues to remain high.
Tyrosinemia 1 is caused by a deficiency in fumarylacetoacetate hydrolyase, which is required for the catabolism of tyrosine. Most patients will present with symptoms before 2 years of age, with liver failure and renal dysfunction. Patients can have neurologic symptoms, including episodes of neuropathic pain and hypertonic posturing with associated hyponatremia and hypertension, which is usually preceded by an illness. However, 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 treatment, patients treated with NTBC and dietary restriction have deficits in their intellectual quotient, executive cognition, and social cognition.
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), methylmalonic acidemia (cobalamin A, cobalamin B), isovaleric acidemia, 3-methylcrotonyl-CoA carboxylase deficiency, 3-hydroxy-3-methyglutaric aciduria, holocarboxylase synthase deficiency, ß-ketothiolase deficiency, and glutaric acidemia 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 of branched chain amino acids or lysine. Infants are typically born healthy, but within the first week of life, develop a metabolic encephalopathy and seizures with vomiting, poor feeding, lethargy, and coma. Some can present with metabolic strokes as well. In the neonate, sepsis and metabolic decompensation are clinically identical, and the newborn screening results may not be back when the infant becomes sick. Therefore, a high index of suspicion for inborn error of metabolism is warranted in any sick neonate for rapid diagnosis and treatment. Though most present as a neonate or infant, many of these disorders can have variable presentations with later onset of symptoms. Regardless, prevention of metabolic decompensation leads to improved outcomes. Treatment is also available with liver transplantation in selected disorders.
Glutaric aciduria type I is the best example of an organic acidemia that is detected on newborn screening and 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. Early detection and treatment prevent neurologic disease in patients. The main principle of treatment is to reduce lysine oxidation and enhance detoxification of glutaryl-CoA. Dietary supplements with carnitine along with a low lysine diet aim to minimize CNS exposure to lysine and its toxic metabolic byproducts.
Patients with propionic acidemia and methylmalonic acidemia present like other organic acidemias: metabolic decompensation as a neonate. However, it is important to note that these patients tend to have worse neurologic outcomes despite early therapy, though overall survival has improved since the advent of newborn screening.
The organic acid disorders on the “Secondary Conditions” Recommended Uniform Screening Panel include methylmalonic acidemia with homocystinuria (cobalamin C, cobalamin D), 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 deficiency (MCAD), very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency (LCHAD), and trifunctional protein deficiency (TFP).
MCAD deficiency is the most common. Infants are normal at birth and progress rapidly to developing hypoglycemia, lethargy, and seizures. Symptoms are triggered by fasting or intercurrent illness, and these patients have high mortality from sudden death. Treatment involves avoidance of fasting and may require frequent feeds with cornstarch.
Patients with MTP and LCHAD deficiencies can have a more variable presentation, ranging from a severe neonatal phenotype presenting with cardiomyopathy and death to a later onset with mild peripheral neuropathy and intermittent episodes of rhabdomyolysis. Patients with MTP and LCHAD deficiencies can also develop hypoglycemia associated with illness or fasting.
Fatty acid oxidation disorders are screened using acylcarnitine testing from heel stick dried blood spots. Newborn screening has been very specific for MCAD, with few false negatives when the correct cut-offs are used. However, the positive predictive value of elevated acylcarnitines, especially octanoylcarnitine, varies significantly. When diagnosed early in a presymptomatic infant, treatment can prevent metabolic decompensation and may improve long-term outcomes.
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 deficiency (SCAD), 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 deficiency (CPT IA), carnitine palmitoyltransferase type II deficiency (CPT II), and carnitine acylcarnitine translocase deficiency (CACT).
Mucopolysaccharidosis I (MPS I). MPS I is a progressive multisystem disorder with features ranging from severe (Hurler syndrome and Hurler-Scheie syndrome) to a more mild (Scheie syndrome) phenotype. The course of disease is severe or attenuated, and treatment is based on the severity of symptoms. 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, 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 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 sulphate) and oligosaccharides. Diagnosis is established by confirmatory 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, though 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 (13; 01; 07). The degree to which HSCT relieves neurologic complications is unclear at this time. Enzyme replacement therapy with laronidase is effective for non-CNS manifestations of MPS I (06). 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 combined therapy with enzyme replacement therapy and HSCT, intrathecal ERT, and with gene- and stem cell–based therapies.
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”), adrenomyeloneuropathy in older males, and a cerebral demyelinating form. Childhood cerebral 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 the female carriers develop mild to moderate spastic paraplegia in their middle age – symptoms consistent with the adrenomyeloneuropathy phenotype. The diagnosis is established by supportive neuroimaging in symptomatic males along with elevated very long-chain fatty acids and abnormal molecular testing of the ABCD1 gene.
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 evidence of brain involvement on MRI, though it is not recommended in individuals with advanced neurologic disease (14; 12).
Dietary supplementation with Lorenzo’s oil (glyceryl trioleate-glyceryl trierucate) has lowered the elevated very long-chain fatty acid hexacosanoic acid (C26:0), but has not provided benefit in symptomatic individuals. Lorenzo’s oil may provide benefit when given to presymptomatic individuals, though its use is still considered investigational (11).
Ongoing therapeutic strategies under investigation include ex vivo gene therapy (08).
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 an excess of glycogen stored 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, a classic EKG high-voltage QRS complex, and respiratory distress. Creatine phosphokinase is typically elevated, but may be normal and is not a good screening test for Pompe disease. Enzyme testing readily identifies symptomatic infants, and early detection with rapid initiation of enzyme replacement therapy (ERT) has improved long-term outcomes. The majority of infants who were given ERT before 6 months of age, who did not need ventilator support, had improved survival, cardiomegaly, and neurodevelopmental milestones during the pivotal clinical trial of ERT versus placebo (09; 02; 05). Pompe disease was added to the Core Panel in 2016 with the rationale being that early treatment with ERT has been shown to improve cardiac and developmental outcomes (18). Without ERT, this form of Pompe disease is typically fatal in the first year of life due to the cardiomyopathy.
A late-onset form can present during childhood, adolescence, and adulthood, with proximal muscle weakness and respiratory distress and typically without cardiac involvement. ERT in this group may prevent further progression of muscle weakness and respiratory involvement, clinically measured by pulmonary function testing and the 6-minute walk test.
Spinal muscular atrophy. Spinal muscular atrophy is a motor neuron disease inherited in an autosomal recessive fashion. It is caused by a loss or dysfunction of the SMN gene, which encodes for the SMN protein, leading to degeneration of alpha motor neurons. There are 2 forms of SMN – SMN1, which is the primary gene for producing the SMN protein, and SMN2. Spinal muscular atrophy 1 is the most severe form, presenting in early infancy with loss of reflexes, hypotonia, and weakness. In 2016, the Food and Drug Administration approved an antisense oligonucleotide therapy, nusinersen, which is delivered directly into the central nervous system to enhance the function of SMN2 allowing for increased SMN protein. However, gene therapy via an AAV9 vector has been approved as a single-dose intravenous delivery. This 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, with data showing improved efficacy over nusinersen in symptomatic infants. With the advent of novel therapies, spinal muscular atrophy was added to the Recommended Uniform Screening Panel for newborn screening in 2018. This highlights the importance of constant revision as new therapies are on the horizon for numerous progressive diseases for which earlier treatment may alter the natural history of the disease.
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 phenotypic variability. Most individuals with profound biotinidase deficiency present with symptoms around 2 to 5 months of age, with abnormalities of the central nervous system. Many can have seizures, ataxia, hypotonia, optic atrophy, skin lesions, developmental delay, and hearing loss. They can also have metabolic derangements such as lactic acidosis or hyperammonemia. Though visual disturbances and hearing loss do not seem to be irreversible, seizures, skin lesions, and metabolic derangements improve when symptomatic infants are treated with biotin supplementation. More importantly, treatment in presymptomatic infants prevent the development of metabolic or neurologic compromise, highlighting the importance of early diagnosis and treatment.
Galactosemia. Galactosemia is due to abnormalities in any of the 3 enzymes responsible for the metabolism of galactose, with the most severe being due to a deficiency in galactose-1-phosphate uridylyltransferase (GALT), also referred to as classic galactosemia. Most patients with classic galactosemia present in the neonatal period with poor feeding, jaundice, hypotonia, lethargy, hepatomegaly, and E coli sepsis. With early treatment, these symptoms in the neonatal period can be reversed; however, despite early detection and treatment, patients with classic galactosemia start developing speech delay and suffer from cognitive and memory impairment, psychiatric issues, and learning disabilities. The mainstay of treatment is a life-long diet restricted in galactose. It is important to ensure a high index of suspicion when neonates exhibit these symptoms and initiate treatment early. Importantly, these patients warrant close monitoring as they can develop long-term consequences from the disease.
Indications
Currently, all states in the United States require newborn screening for every infant.
Special considerations
The success of newborn screening is based on 6 pillars: education, testing, follow-up, diagnosis, intervention and/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 included in 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 test whereas others do not and some 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 spectrometry along with the evolution of other diagnostic tools such as genetic testing, the ability to screen for numerous other diseases has increased. However, multiple challenges exist, including the ability to create sensitive enough biomarkers 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. This addition was driven by parent and advocacy groups despite recommendations from expert committees. Since 2016, of the 2 million infants who were screened for Krabbe disease by the New York State newborn screening, 5 were diagnosed with early infantile Krabbe disease. Of the 5, 3 died (2 of them from HSCT-related complications and 1 from untreated disease), and 2 are currently alive after HSCT but with developmental delays. There are 46 asymptomatic children who are thought to be at risk for later-onset Krabbe disease. 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, but further follow-up and discussion are needed to decide on the true benefit and practicality of newborn screening in this disease. Similar challenges will continue to emerge for multiple diseases as novel therapies, like gene therapy, for rare diseases emerge.