Inborn Errors of Carbohydrate, Ammonia, Amino Acid, and Organic Acid Metabolism

Acute, life-threatening disease during the newborn period is a feature of many inborn errors of metabolism, including those of ammonia, carbohydrate, amino acid, fatty acid, ketone, and mitochondrial energy metabolism. Therefore, it is critical that neonatologists are familiar with the clinical symptoms, laboratory findings, methods of diagnosis, and empiric—as well as specific—management of each of these classes of disease ( Table 29.1 ). Importantly, newborn screening (NBS) is only available for some disorders within each class. The use of NBS has resulted in presymptomatic identification, allowing early institution of therapy and improved outcome for many affected individuals. However, clinical presentation before the development of symptoms may still occur because of environmental and biologic factors, as well as local NBS and follow-up protocols. Factors that prevent or delay identification by NBS include when the disease is not detected by NBS or is incompletely ascertained, when the newborn develops symptoms before the NBS result being reported, and when follow-up testing has not been completed. Familiarity with these diseases and their characteristic signs and symptoms is critical for early clinical recognition and the initiation of potentially life-saving empiric management ( Table 29.2 ). First-tier testing, including biochemical and analyte testing, is indicated although broad DNA sequencing, either exome or genome, has demonstrated utility in diagnosis of genetic and metabolic disease in critically ill children in the neonatal intensive care unit, and is increasingly being adopted as first- or second-tier testing. Inborn errors of metabolism should also be considered in infants who develop symptoms outside of the immediate newborn period, as each of these disorders can have a later-onset presentation.

Table 29.1

Presentations of Inborn Errors of Metabolism

	Newborn/Early Onset	Acute Presentation	Chronic Presentation	Currently on Newborn Screening Panels
Carbohydrates
Galactosemia	Yes	Yes	Yes	Yes
Epimerase deficiency	Rare	Yes	Yes	Possibly
Galactokinase deficiency	No	No	Yes	Possibly
GSD Ia and Ib	Rare	Yes	Yes	No
GSD II	Yes	Yes	Yes	Possibly
GSD IV	Yes	Yes	Yes	No
Hereditary fructose intolerance	No	Yes	Yes	No
Fructose-1,6-bisphosphatase deficiency	No	Yes	No	No
Urea Cycle Disorders
All types	Yes	Yes	Yes	Not all
Transient hyperammonemia of the newborn	Yes	Yes	No	No
Aminoacidemias
MSUD	Yes	Yes	Yes	Yes
Tyrosinemia type 1	No	Rare	Yes	Yes
Nonketotic hyperglycinemia	Yes	Yes	Yes	No
Cystathionine β-synthase deficiency	Rare	Yes	Yes	Yes
Remethylation disorders	Yes	Yes	Yes	Possibly
Phenylketonuria	No	No	Yes	Yes
Organic Acidemias
Methylmalonic acidemia(s)	Yes	Yes	Yes	Yes
Propionic acidemia	Yes	Yes	Yes	Yes
Isovaleric acidemia	Yes	Yes	Yes	Yes
Holocarboxylase synthase deficiency	Yes	Yes	Yes	Yes
Biotinidase deficiency	No	Possibly	Yes	Yes
Glutaric acidemia type 1	Rare	Yes	Yes	Yes
Fatty Acid Oxidations Disorders
MCADD	Yes	Yes	Yes	Yes
VLCADD	Yes	Yes	Yes	Yes
SCADD	No	Rare	Rare	Yes
LCHADD and TFP	Yes	Yes	Yes	Yes
CTD	Yes	Yes	Yes	Yes
CPTI	Yes	Yes	Yes	Yes
CACT	Yes	Yes	Yes	Yes
CPTII	Yes	Yes	Yes	Yes
MADD	Yes	Yes	Yes	Yes
Ketone Metabolism Disorders
Mitochondrial acetoacetyl-CoA thiolase deficiency	Yes	Yes	Rare	Yes
HMG-CoA lyase deficiency	Yes	Yes	Yes	Yes
Succinyl-CoA 3-ketoacid-CoA transferase deficiency	Yes	Yes	Rare	No
Mitochondrial Disorders
Primary lactic acidosis	Yes	Yes	Yes	No
Pyruvate dehydrogenase complex deficiency	Yes	Yes	Yes	No
Pyruvate carboxylase deficiency	Yes	Yes	Yes	No
Electron chain deficiencies	Yes	Yes	Yes	No
Leigh disease	Rare	Yes	Yes	No
Pearson syndrome	Yes	Yes	Yes	No
Barth syndrome	Yes	Yes	Yes	No

CACT , Carnitine acylcarnitine translocase deficiency; CoA , coenzyme A; CPTI , carnitine palmitoyltransferase type I deficiency; CPTII , carnitine palmitoyltransferase type II deficiency; CTD , carnitine transporter deficiency; GSD , glycogen storage disorder; HMG , 3-hydroxy-3-methylglutaryl; LCHADD , long-chain acyl-CoA dehydrogenase deficiency; MADD , multiple acyl-CoA dehydrogenase deficiency; MCADD , medium-chain acyl-CoA dehydrogenase; MSUD , maple syrup urine disease; SCADD , short-chain acyl-CoA dehydrogenase deficiency; TFP , trifunctional protein deficiency; VLCADD , very long chain acyl-CoA dehydrogenase deficiency.

Table 29.2

Treatments for Inborn Errors of Metabolism

	Dietary	Medications	Vitamin Supplementation	Other(Dialysis, Transplantation)
Carbohydrates
Galactosemia	Yes	No	Yes	–
Epimerase deficiency	Yes	No	Yes	–
Galactokinase deficiency	Yes	No	Yes	–
GSD Ia and Ib	Yes	Yes	Yes	Liver, kidney Txp
GSD II	Yes	Yes	No	–
GSD IV	Yes	No	No	Liver, cardiac Txp
Hereditary fructose intolerance	Yes	No	No	–
Fructose-1,6-bisphosphatase deficiency	Yes	No	No	–
Urea Cycle Disorders
All types	Yes	Yes	Yes	Liver Txp, HD
Transient hyperammonemia of the newborn	No	Yes	No	HD
Aminoacidemias
MSUD	Yes	No	Yes	Liver Txp, HD
Tyrosinemia type 1	Yes	Yes	No	Liver Txp
Nonketotic hyperglycinemia	No	Yes	No	–
Cystathionine synthase deficiency	Yes	Yes	Yes	–
Remethylation disorders	Yes	Yes	Yes	HD
Phenylketonuria	Yes	Yes	No	–
Organic Acidemias
Methylmalonic acidemia	Yes	Yes	Some forms	Liver Txp, HD
Propionic acidemia	Yes	Yes	No	Liver Txp, HD
Isovaleric acidemia	Yes	Yes	Yes	HD
Holocarboxylase synthase deficiency	Variable	No	Yes	–
Biotinidase deficiency	No	No	Yes	–
Glutaric acidemia type 1	Yes	Yes	Yes	–
Fatty Acid Oxidations Disorders
MCADD VLCADD SCADD LCHADD and TFP CTD CPTI CACT CPTII MADD	Variable Yes No Yes No Yes Yes Yes Yes	Yes Yes Variable Yes Yes Yes Yes Yes Yes	No No No No No No No No Yes	– Cardiac Txp – Cardiac Txp – – – – –
Ketone Metabolism Disorders
BK thiolase deficiency HMG-CoA lyase deficiency SCOT deficiency	Yes Yes Yes	Yes Yes Yes	No No No	– – –
Mitochondrial Disorders
Primary lactic acidosis Pyruvate dehydrogenase complex deficiency Pyruvate carboxylase deficiency ETC defects Leigh disease Pearson syndrome Barth syndrome	No Yes No No No No Yes	No Yes Yes Variable Variable Yes Yes	Some forms Yes No Some forms Some forms Yes Variable	– – – – – – Cardiac Txp

BK , Beta-keto or mitochondrial acetoacetyl-CoA; CACT , carnitine acylcarnitine translocase deficiency; CoA , coenzyme A; CPTI , carnitine palmitoyltransferase I; CPTII , carnitine palmitoyltransferase II; CTD , carnitine transporter deficiency; ETC , electron transport chain; HD , hemodialysis; HMG , 3-hydroxy-3-methylglutaryl; LCHADD , long-chain acyl-CoA dehydrogenase deficiency; MADD , multiple acyl-CoA dehydrogenase deficiency; MCADD , medium-chain acyl-CoA dehydrogenase deficiency; SCADD , short-chain acyl-CoA dehydrogenase deficiency; SCOT , succinyl-CoA 3-ketoacid-CoA transferase; TFP , trifunctional protein deficiency; Txp , transplantation; VLCADD , very long chain acyl-CoA dehydrogenase deficiency.

Carbohydrate Metabolism Disorders

Galactosemia

Elevated blood galactose, or galactosemia , is a result of a defect in one of three enzymes of the galactose metabolic pathway that converts galactose to glucose ( Fig. 29.1 ). The disorder most clinically relevant in the newborn period is severe galactose-1-phosphate uridyltransferase (GALT) deficiency . It is a cause of neonatal jaundice and coagulopathy and is life threatening. It is commonly referred to as “classic galactosemia.” This condition is the primary target of NBS for galactosemia. The other two enzyme defects that cause elevated blood galactose are galactokinase and uridine diphosphate galactose-4-epimerase deficiencies. Clinical features associated with each disorder are described. In classic galactosemia, with the ingestion of lactose, a disaccharide of glucose and galactose, the substrate of the enzyme galactose-1-phosphate accumulates, as does galactose and the secondary metabolites galactitol and/or galactonate. Elevations of galactitol may cause characteristic “oil drop” cataracts that may be present at birth. The roles of the other metabolites in pathogenesis of the liver, kidney, brain, and ovarian dysfunction of severe GALT deficiency are not understood. They likely include the deficiency of galactose-1-phosphate conjugated to uridine, as well as toxicity of accumulating metabolites.

Fig. 29.1, Overview of metabolism of carnitine transport, fatty acid oxidation, glucose, TCA cycle, and mitochondrial respiratory chain. CACT , Carnitine acylcarnitine translocase; CT , carnitine transporter; CPTI , carnitine palmitoyltransferase I; CPTII , carnitine palmitoyltransferase II; FADH 2 , flavin adenine dinucleotide; DBE , debranching enzyme; GALT , galactose-1-phosphate uridyltransferase; Acyl-CoA , long-chain fatty acid attached to Coenzyme A; LCHAD , long-chain 3-hydroxy acyl-CoA dehydrogenase; ETF/ETF-DH , electron transfer flavoprotein/electron transfer flavoprotein dehydrogenase; these are deficient in MADD; MADD , multiple acyl-CoA dehydrogenase deficiency; MCAD , medium-chain acyl-CoA dehydrogenase; MCT , medium-chain triglyceride; NAD , nicotinamide adenine dinucleotide; PDH , pyruvate dehydrogenase; SCAD , short-chain acyl-CoA dehydrogenase; TCA , tricarboxylic acid; TFP , trifunctional protein; VLCAD , very long chain acyl-CoA dehydrogenase.

The frequency of classic galactosemia is estimated to be 1 in 60,000 to 1 in 75,000 births in the United States and Europe. There are also milder forms of unclear clinical significance, such as Duarte variant galactosemia, with enzyme activity of roughly 25% of wild type, which are frequently identified by abnormal NBS but are currently believed not to require treatment.

NBS methods for identification of classic galactosemia vary by state and include measurement of “total galactose” (galactose plus galactose-1-phosphate) and GALT enzyme activity. Testing after an abnormal NBS may include DNA analysis to identify common mutations in the GALT gene. In states that measure analytes, children with galactokinase or epimerase deficiencies may be identified. These disorders will not be detected through screening for classic galactosemia through deficient GALT enzyme activity alone. The accuracy of NBS is dependent on information provided by the ordering nursery, as transfused red blood cells may cause a false-negative NBS for galactosemia. Transfusion of red blood cells will also impact detection of hemoglobinopathies. Thus, infants transfused before NBS require follow-up testing for galactosemia and hemoglobinopathies at least 4 weeks after transfusion. Also, infants who have not received a lactose-containing feeding (i.e., breast milk or non-soy-based formulas) before screening may not have elevated galactose levels and may have false-negative NBS if the screening method is analyte rather than enzyme-based. False-positive NBS results can occur in hot weather if the screening method is enzyme activity, as the enzyme is denatured in heat. Mutation analysis and enzyme activity help identify neonates with classic galactosemia (<1% control GALT activity), who have a poorer prognosis than those with variant (nonclassic) galactosemia (1% to 10% control GALT activity).

At presentation, total blood galactose levels may be elevated with elevated red blood cell galactose-1-phosphate (Gal-1-P) and urine galactitol levels. During this phase of severe hypergalactosemia, positive reducing substances will be present in urine, but these resolve within hours with dietary restriction of galactose. There may be factitious elevation of glucose in affected individuals, as measured by bedside glucometers. Following the initiation of treatment with a lactose-free diet, Gal-1-P levels decrease but rarely normalize, remaining elevated for the lifetime of the patient. There is a target range for treatment, and maintenance of Gal-1-P levels in treatment range through dietary restriction of galactose is the current goal of short- and long-term dietary therapy.

Untreated classic galactosemia may present with severe multiorgan (liver and kidney) disease in the first days to weeks of life. The most common clinical symptoms are vomiting, poor feeding, failure to thrive, and lethargy, with jaundice and hepatomegaly on physical examination. About 10% of affected neonates develop sepsis, often due to Escherichia coli ; other causative organisms include Klebsiella and Enterobacter . Characteristic laboratory findings are indirect hyperbilirubinemia and apparent liver failure with markedly elevated coagulation parameters out of proportion to the transaminase elevations. With continued lactose/galactose ingestion, liver disease can progress to cirrhosis with portal hypertension and splenomegaly. Renal Fanconi syndrome may also develop. Cataracts may develop in the first few weeks of life in untreated individuals, while some neonates are born with cataracts.

Management of the liver disease entails dietary restriction of galactose and supportive care. The coagulopathy resolves over several days. A lactose-free formula should be initiated as soon as classic galactosemia is suspected as this can be life-saving. An early change to soy formula may mask the symptoms of the disease. With early dietary restriction, improvement has been seen in severe clinical presentations and in neonatal mortality. While growth and feeding return to normal, treated individuals may develop long-term complications including speech and language disorders, below average intelligence and cognitive functioning, cataracts, primary ovarian insufficiency (in most females), decreased bone mineral density, tremor, dystonia, coordination problems, or severe ataxia. The cause of these complications is unknown, and they may not be improved by dietary restriction.

Patients with classic galactosemia are advised to continue a lactose-restricted diet for their entire lives, but this diet does have significant risk of calcium and vitamin D deficiencies, and these must be supplemented. Dairy and high galactose nondairy foods including fruits, legumes, and vegetables are restricted. Not all galactose is exogenous; there is some endogenous galactose production. Treatment compliance is monitored through frequent assessment of Gal-1-P levels. The restriction of galactose-containing fruits and vegetables may not be necessary lifelong.

NBS has changed the clinical outcome of classic galactosemia and when results are provided as early as 3 to 4 days of life—before significant clinical symptoms—hospitalization is often avoided. A systematic review of NBS for galactosemia in Europe identified significant variability in galactosemia screening methods, cutoff values, and screening ages. Mortality ranged from 0% to 100% with no agreement regarding treatment of variant forms, or timing of clinical follow-up, and evidence in favor of NBS was considered insufficient. The greatest confounder of the cost-benefit assessment of NBS was the false-positive testing rate and the effects of these test results on families.

Epimerase Deficiency Galactosemia

Uridine diphosphate-galactose 4-epimerase (GALE) deficiency has several forms. Generalized GALE deficiency may present similarly to GALT deficiency when the enzyme is deficient in all tissues. Peripheral or intermediate forms of GALE deficiency are associated with deficient enzyme activity in red blood cells, with normal or only partially decreased enzyme activity in other tissues (i.e., white blood cells or fibroblasts). For the peripheral or intermediate forms, children receiving a normal, lactose-containing diet will not become symptomatic. GALE deficiency may be detected on newborn screen in states that test for classic galactosemia by analyte. These children have elevated Gal-1-P levels with normal GALT enzyme testing. Individuals with generalized disease can develop severe liver and renal disease if untreated, and they can be diagnosed with GALE deficiency through assessment of activity in red blood cells. GALE deficiency is treated identically to GALT deficiency, when symptomatic.

Galactokinase Deficiency

Galactokinase (GALK ) deficiency causes elevated galactose with a normal Gal-1-P level. Affected individuals also have elevated galactitol and may develop dense cataracts if untreated. GALK deficiency is also associated with pseudotumor cerebri, but the disease does not cause systemic effects. As for GALE deficiency, GALK deficiency may be detected on newborn screen in states that test for classic galactosemia by analyte. GALT enzyme testing is normal. Cataracts may develop in the neonatal period, and early treatment may improve or resolve cataracts if infants are treated with galactose restriction before 4 to 8 weeks of life. A recent evaluation of the GalNet registry has identified additional complications in neonates of elevated transaminases, bleeding diathesis, and encephalopathy. Dietary galactose restriction may be necessary but is milder than that required for GALT deficiency.

Glycogen Storage Diseases

Glycogen storage diseases (GSDs) are due to abnormalities in glycogen synthesis or utilization for energy production. They are divided into types primarily affecting the liver (types I, IIIb, IV, VI, and IX), the muscles (types II, V, and VII), or mixed (type IIIa and forms of IX). Hypoglycemia is often a presenting symptom of the liver-based GSDs. Most GSDs are inherited in an autosomal recessive manner, except GSD IXa and IXd (hepatic and muscle phosphorylase kinase deficiencies, respectively), which are X-linked. Severe GSD II is associated with an infantile cardiomyopathy and is the GSD that is most likely to be encountered in the neonatal intensive care unit. Treatments for GSDs are of variable efficacy given the spectrum of these diseases. Currently, there are multiple clinical trials underway including gene therapy technologies for many types of GSDs, including GSD 1a and GSD II.

Hepatic Glycogen Storage Diseases

GSD I is due to glucose-6-phosphatase deficiency (von Gierke disease, Ia) or to deficient glucose-6-phosphate transport (Ib). Glucose-6-phosphatase plays a critical role in both glycogenolysis and gluconeogenesis (see Fig. 29.1 ). The frequency of GSD type I is estimated to be 1 in 100,000 births, with 80% of cases being type Ia. The frequency is 1 in 20,000 in Ashkenazi Jews due to a founder mutation.

GSD I may not manifest in the neonatal period, as frequent newborn feeding may prevent symptomatic hypoglycemia and the development of hepatomegaly. Major clinical findings include failure to thrive, with an enlarged abdominal girth from hepatomegaly and hypoglycemia. Major laboratory findings are a rapid fasting hypoglycemia (typically within a few hours) with ketosis and lactic acidosis. Because of the high lactate level, individuals may appear relatively asymptomatic from the hypoglycemia. Hypercholesterolemia, hypertriglyceridemia, and hyperuricemia may be seen in older individuals. The disease also affects the kidneys and causes focal segmental glomerulosclerosis and progressive renal insufficiency. Patients with GSD Ib develop recurrent infections because of neutropenia and defective neutrophil function along with inflammatory bowel disease that may develop in the first year of life. Diagnosis is now often confirmed through DNA sequencing of the G6PC (GSD Ia) and SLC37A4 (GSD Ib) genes, although liver biopsy for enzyme activity may also be performed.

Therapy focuses on the prevention of hypoglycemia and resultant brain damage and growth failure through frequent feedings and restriction of lactose and sucrose, as galactose and fructose derived from these feed into the blocked pathway. Continuous nasogastric feedings or boluses of uncooked cornstarch are essential at night and often during the day and do improve glucose control and growth but do not completely correct other biochemical abnormalities. A comprehensive plan for treatment of intercurrent illnesses and emergencies is required. Neutropenia in type Ib may be treated with granulocyte colony-stimulating factor. Liver transplantation has been shown to improve metabolic control, fasting hypoglycemia, and growth.

Muscular Glycogen Storage Diseases

The most common and significant form of muscular GSD is type II, commonly called Pompe disease ( acid alpha-glucosidase deficiency [abbreviated as GAA], also known as acid maltase deficiency or lysosomal α-1,4-glucosidase deficiency ). This GSD was the first identified lysosomal storage disease (LSD), as glycogen accumulates within the lysosome because of a defect in lysosomal-mediated glycogen degradation. Muscle pathology will demonstrate vacuolar myopathy with glycogen storage within lysosomes and free glycogen in the cytoplasm demonstrated by electron microscopy. The vacuoles are periodic acid-Schiff positive, digestible by diastase, and positive for acid phosphatase. As for some other LSDs, enzyme replacement therapy has been developed for Pompe disease and is the only currently effective therapy.

Pompe disease has an estimated incidence of 1 in 40,000 in the Netherlands, based on the country’s screening for three common mutations in newborn blood spots. The incidence ranges from 1 in 57,000 for late-onset disease to 1 in 138,000 for classic infantile disease. The classic infantile presentation of Pompe disease is hypotonia and hypertrophic cardiomyopathy. Creatine kinase, lactate dehydrogenase, and aspartate aminotransferase are elevated. The electrocardiogram is abnormal with a short PR interval and giant QRS complex in all leads, suggesting biventricular hypertrophy ( Fig. 29.2 ). Late-onset presentations are of myopathy and have been diagnosed as early as the second year of life. Diagnosis is made through the identification of decreased GAA activity in dried blood spots—from newborn screening or diagnostic testing—or in fibroblasts or muscle biopsy. Confirmation via sequencing of the GAA gene is recommended following any GAA enzyme testing due to the presence of pseudodeficiency alleles in which the in vitro enzyme activity is abnormal, but in vivo activity is normal, and to avoid muscle biopsy.

Fig. 29.2, Pompe disease electrocardiogram.

Decisions regarding which disorders are included on a state’s NBS panel are made by each state, and many states now include Pompe disease due to the markedly improved outcome of infantile-onset Pompe disease (IOPD) with early treatment. NBS and early initiation of enzyme replacement therapy has demonstrated improvement in cardiac size, muscle pathology, growth, and gross motor function in affected individuals but not in arrhythmias such as Wolff-Parkinson-White or in dysphagia or osteopenia. Long-term follow-up of early-treated individuals has demonstrated increased life span and increased ambulation with individuals not requiring mechanical ventilation and increased muscle strength and function. Gene therapy is being investigated with promising results in a mouse model and with initial clinical trials being implemented.

Andersen disease , or GSD IV, is due to deficiency of glycogen branching enzyme, expressed in multiple tissues, and may manifest primarily as hepatic or muscular disease, with involvement of the heart and/or the nervous system in up to five different clinical presentations. Two rare neuromuscular subtypes may present in the newborn period. The fatal perinatal neuromuscular subtype presents with fetal akinesia sequence with polyhydramnios, decreased fetal movement, fetal hydrops, and neonatal death or with hypotonia, muscular atrophy, arthrogryposis, and death in the neonatal period from cardiopulmonary failure. The second congenital neuromuscular subtype presents with profound hypotonia, respiratory distress requiring mechanical ventilation, dilated cardiomyopathy, and death in early infancy. The classic GSD IV subtype is the progressive hepatic subtype. Children are often normal at birth but develop failure to thrive, hypotonia, and potentially progressive liver dysfunction leading to cirrhosis and cardiomyopathy requiring liver and heart transplantation, respectively. Death may result from progressive cardiomyopathy despite liver transplantation. There is also a non-progressive hepatic subtype and a childhood neuromuscular subtype. GSD IV is a rare autosomal recessive disorder, and diagnosis is confirmed through DNA sequencing of the GBE1 gene or by detection of abnormal enzyme activity in muscle, liver, or skin fibroblasts.

Fructose Metabolism

The primary disorder of fructose metabolism is hereditary fructose intolerance (HFI). This is a rare autosomal recessive disorder triggered by ingestion of fructose, sucrose, or sorbitol, which may present clinically when infants are weaned from breast milk or formula and juice or fruit are added to the diet or when they receive a formula that contains fructose. Affected infants or neonates who are given sucrose solutions for pain relief during minor procedures may develop hypoglycemia, and a diagnosis of HFI should be considered in these cases. Clinical findings include pallor, lethargy, poor feeding, vomiting, loose stools, poor growth, hepatomegaly, and hypoglycemia, lactic acidemia, hyperuricemia, transaminase elevations, and positive urine reducing substances with ingestion of fructose. There are reports of neonates who developed life-threatening acute liver failure after receiving fructose-containing formulas. Renal tubular dysfunction may be present. Diagnostic testing consists of measuring enzyme activity in liver tissue and/or sequencing of ALDOB . Treatment includes elimination of fructose, sucrose, and sorbitol from the diet and medications. In practice, complete elimination of these can be quite difficult but is necessary for optimal outcome. There is no current newborn screening for HFI.

Fructose-1,6-bisphosphatase deficiency is not a disorder of fructose metabolism. It is a disorder of gluconeogenesis, although as with other disorders of gluconeogenesis, therapy may include some limitation of dietary fructose. Patients may present in the newborn period with lactic acidosis and hypoglycemia when glycogen reserves are limited and then be clinically silent and present later (typically before 2 years of age) during times of fasting or following a fructose load. Acute crisis presents similarly to HFI and GSD Ia, and these are in the differential diagnosis for symptoms of acidosis and hypoglycemia. This is a very rare autosomal recessive disorder resulting from mutations in the FBP1 gene, with an estimated incidence between 1 in 350,000 and 1 in 900,000.

Urea Cycle Disorders

Removal of excess nitrogen is the function of the urea cycle. Urea cycle disorders (UCD) result from inhibition of the synthesis of urea from ammonia and classically manifest in the newborn period, although these may manifest at any age. Symptoms of hyperammonemia are provoked during episodes of protein catabolism (e.g., because of illness and poor oral intake) or dietary protein excess. Hyperammonemia is treated by controlling protein catabolism through dietary limitation of protein and removing offending toxic products (chiefly ammonia) with ammonia-scavenging medications or dialysis. UCDs are frequently classified as proximal (mitochondrial) and distal (cytoplasmic). The three proximal UCDs are N -acetylglutamate synthase deficiency (NAGS), carbamyl phosphate synthetase I (CPSI) deficiency , and ornithine transcarbamylase deficiency (OTCD). The distal UCDs are argininosuccinate synthetase deficiency (known as ASS deficiency or citrullinemia type I , CIT1 ), argininosuccinate lyase (ASL) deficiency (also known as argininosuccinic aciduria , ASA), and arginase 1 deficiency . Additionally, disorders of the urea cycle include two of mitochondrial membrane transport. Deficiency of the mitochondrial ornithine transporter 1 is a cause of hyperammonemia, hyperornithinemia, and homocitrullinuria syndrome, and deficiency of the mitochondrial aspartate–glutamate transporter is a cause of citrullinemia type II or citrin deficiency. A defect of a plasma membrane transporter affects the renal tubular transport of cationic amino acids, including lysine, arginine, and the amino acids required for urea cycle function, and results in lysinuric protein intolerance , a multisystem disorder that only rarely manifests with neonatal hyperammonemia. Incidence estimates of all UCDs are 1 in 35,000 births, with OTCD, the most common UCD, estimated at 1 in 56,500 births. All UCDs are autosomal recessive except for OTCD, which is X-linked. Roughly 20% of heterozygote females manifest symptoms at some time in their life, and some of these present in the newborn period.

One complete turn of the urea cycle will produce a molecule of urea from two molecules of ammonia and one of bicarbonate. The nitrogen in ammonia is generated from the hepatic nitrogen pool of amino acids including glutamine, glutamate, and glycine. N -acetylglutamate is the product of the first enzyme in the cycle and is an essential activator of carbamyl phosphate synthetase I, which converts ammonia and bicarbonate into carbamyl phosphate. Ornithine and carbamyl phosphate are condensed by ornithine transcarbamylase to generate citrulline. Citrulline is combined with aspartate by argininosuccinate synthetase to create argininosuccinic acid. Fumarate is released from this by argininosuccinate lyase to create arginine. Urea is generated from arginine by arginase 1 and is excreted while ornithine reenters the urea cycle ( Fig. 29.3 ).

Fig. 29.3, Overview of urea cycle metabolism ( blue ) and nitrogen scavenger therapies ( green ). Stars indicate supplementation with citrulline or arginine. Plus sign indicates allosteric activator of carbamyl phosphate synthetase I. Dashed line indicates accumulation of orotic acid in ornithine transcarbamylase deficiency. Purple indicates transport between the mitochondrion and the cytosol. ARG , arginase; ASL , argininosuccinate lyase; ASS , argininosuccinate synthetase; ATP adenosine triphosphate; CPSI , carbamyl phosphate synthetase I; CO 2 , carbon dioxide; NAGS ; N -acetylglutamate synthase; NH 3 , ammonia; OTCD , ornithine transcarbamylase.

Clinical symptoms in the newborn period are similar for all UCDs and are due to hyperammonemia. Severely affected newborns exhibit progressive alteration of level of consciousness with drowsiness and lethargy progressing to unresponsiveness, beginning after 24 hours of life. Typical symptoms include poor feeding, vomiting, hyperventilation (caused by ammonia elevation and resulting in a primary respiratory alkalosis), and temperature instability. There may be peripheral circulatory failure that progresses to multiorgan failure. Marked hyperammonemia causes acute encephalopathy, leading to seizures, coma, and death if untreated. Ammonia levels should be checked in any infant with these symptoms, which may mimic sepsis or intestinal obstruction, and, if elevated, should be treated rapidly. Later-onset presentations include recurrent emesis, ataxia, liver dysfunction or apparent failure with coagulopathy, postpartum psychosis, and other psychiatric symptoms such as aggression, agitation, mania, and personality changes.

Without rapid treatment severe UCDs are almost always fatal or result in severe and irreversible brain damage. The primary goal of treatment is to remove excess ammonia, which is neurotoxic. The effects of ammonia include alterations in amino acid pathways, neurotransmitters, energy production, nitric oxide synthesis, axonal and dendritic growth, and signal transduction in the developing brain. Additionally, excess glutamine may cause cerebral swelling and edema in the mature brain. Acute hyperammonemic episodes may be associated with transaminase elevation and synthetic liver dysfunction or apparent liver failure, and it is important to assess transaminases and coagulation parameters.

Individuals affected by proximal UCDs have been reported to present earlier in life, to have a higher peak ammonia level, and to have a longer average length of stay compared with patients with distal UCDs. Reports identify the age at first admission for hyperammonemia as less than or equal to 2 days in 55% of OTCD and CPSI patients and at less than 7 days in 84% of these patients. For OTCD patients, nearly half of the males but only 4% of females will present between 0 and 30 days of age.

The critical laboratory abnormality in a UCD is elevated plasma ammonia. While artifactual elevations may occur due to problems with sample collection and processing, hyperammonemia in a newborn is a medical emergency, and, if elevated, the test should be repeated, and additional evaluation and management initiated immediately. Normal plasma ammonia levels in newborns are as high as 110 μmol/L (although care should be taken to confirm units as some laboratories report mg/dL). A level of greater than 150 μmol/L (255 mg/dL) should prompt suspicion of, and evaluation for, an inborn error of metabolism in neonates. In older infants, children, and adults the reference range for ammonia is less than 35 μmol/L (60 mg/dL). In primary or secondary disorders of the urea cycle that present in the newborn period, ammonia levels may be in the thousands. The differential diagnosis of hyperammonemia in the newborn period includes urea cycle defects, organic acidemias, fatty acid oxidation disorders (FAODs), CA-VA (carbonic anhydrase VA) deficiency, and transient hyperammonemia of the newborn (THAN). In UCDs the hyperammonemia is often associated with a respiratory alkalosis caused by the effect of ammonia on the respiratory control centers in the brainstem. A primary respiratory alkalosis in a newborn should prompt a physician to order an ammonia level. Early involvement of a geneticist with experience in the evaluation and management of inborn errors of metabolism is critical. Specialized biochemical laboratory testing should include plasma amino acids, total and free plasma carnitine, plasma acylcarnitine profile, total plasma homocysteine, plasma B12 level, urine organic acids, urine amino acids, and a quantitative urine orotic acid to assess for UCDs, as well as fatty acid oxidation disorders and organic acidemias, which can also present with marked hyperammonemia in the newborn period.

In proximal UCDs, there is decreased citrulline on plasma amino acid analysis, while patients with distal UCDs have either elevated citrulline (in CIT1 and ASA deficiency), elevated argininosuccinic acid (in ASA deficiency), or elevated arginine (in arginase deficiency). In OTCD, increased urinary orotic acid is present and may be identified on urine organic acid analysis, but a quantitative value is recommended because of variability in detection. NBS for CIT1, ASA, and arginase deficiency is performed through measurements of citrulline (CIT1, ASA) and arginine (arginase deficiency) in blood spots as these are elevated in these conditions. Proximal UCDs are not well identified on NBS because of the poor sensitivity of low citrulline levels, and only a few states have started screening for proximal UCDs. When a UCD is suspected, further evaluation through blood and urine metabolite testing and confirmation of a diagnosis is necessary through DNA testing. For OTCD this should include analysis for gene copy number and intronic variants through deep sequencing, but still may only detect mutations in about 90% of patients. In some cases, liver biopsy and enzyme analysis of liver tissue are required.

Treatments with medications, dialysis, or liver transplantations will control ammonia levels, though neurologic outcomes are poorer when presenting blood ammonia levels are greater than 360 μmol/L. Hemodialysis is the primary method for rapid removal of ammonia. Recent consensus guidelines have been published for hyperammonemia management through medical management and renal replacement therapy. Renal replacement therapy was recommended in cases of a rapidly increasing ammonia level greater than 150 μmol/L with a rapidly deteriorating neurological status, rapidly increasing levels greater than 300 μmol/L that are uncontrolled, or an ammonia level of greater than 400 μmol/L when medical measures are ineffective. Continuous arteriovenous hemofiltration (CAVH) provides a lower clearance rate but has the added benefit of continuous use and a lesser likelihood of major swings in intravascular volume that can exacerbate an already fragile state and cerebral edema. Ammonia clearance with peritoneal dialysis is approximately one-tenth that of CAVH and is not recommended unless other methods of kidney replacement therapy are not available. Ammonia is not cleared effectively by exchange transfusion.

Medical treatment of hyperammonemia through alternative pathway or nitrogen-scavenging therapies are effective and are critical in acute and chronic management (see Fig. 29.3 ). When hyperammonemia is recognized and a UCD suspected, alternative pathway therapy can be rapidly implemented before hemodialysis, continued throughout, and maintained afterward and transitioned from intravenous (IV) to oral therapy for chronic management. The only approved IV therapy for treatment of hyperammonemia is sodium benzoate plus sodium phenylacetate (Ammonul). Arginine becomes an essential amino acid in severe early urea cycle defects; it stimulates the CPSI enzyme and is required for urea cycle function as it is one of the amino acids that comprises the urea cycle. Thus, arginine should be provided IV for suspected neonatal OTCD or CPSI and is especially effective in patients with CIT1 and ASA. It should not be given in known or suspected arginase 1 deficiency. Ammonul is rarely stocked except in pharmacies of tertiary care metabolic centers, and 10% arginine HCl is commonly available.

Nitrogen-scavenging therapies can effectively help control hyperammonemia and should be considered when the ammonia level is greater than 150 μmol/L. When combined with other therapies, nitrogen-scavenging therapies are critical to the acute management of marked hyperammonemia. In acute management of hyperammonemia, Ammonul is given as a loading dose of 250 mg/kg (of sodium benzoate and of sodium phenylacetate) over 90 minutes followed by a 250 mg/kg dose over 24 hours by continuous IV infusion. Arginine hydrochloride should be provided in known or suspected cases of NAGS, CPSI, or OTCD and is given as a 250 mg/kg loading dose over 90 minutes followed by a 250 mg/kg 24-hour maintenance dose. The dose is 600 mg/kg for known or suspected CIT1 or ASA. Also critical is reversal of catabolism, and at least age appropriate and even higher calories must be provided by IV glucose at high concentration and IV intralipid (once a disorder of fat metabolism has been excluded). Parenteral nutrition, including provision of catabolism-sparing essential amino acids, should be initiated when ammonia has been controlled, ideally within 24 to 36 hours of the initiation of treatment. This treatment should be performed in collaboration with a clinical biochemical geneticist with experience in the treatment of UCDs. An enzyme replacement therapy is now being investigated for arginase deficiency has shown improvements in baseline lower-limb spasticity, developmental delay, and previous hyperammonemic events.

Chronic management of infants with UCDs consists of providing adequate dietary protein, which will require a combination of natural (whole) protein from a regular infant formula as well as a special metabolic formula consisting of only essential amino acids to decrease the nitrogen burden, oral/enteral ammonia-scavenging medications, and arginine or citrulline, depending on the defect and severity. Also critical is the prevention of protein catabolism during times of illness or other physiologic stress, and an emergency sick-day diet and emergency letter should be provided at hospital discharge. Children must be monitored frequently, and medications and diet adjusted to prevent hyperammonemia and to allow adequate growth without over-restriction of protein resulting in poor growth and provoking catabolism. Long-term management requires a multidisciplinary team of a clinical biochemical geneticist, biochemical nutritionist, and genetic counselors and, in some cases nurses, a neurodevelopmental pediatrician, a neurologist, and rehabilitative medicine specialist, depending on the presence and severity of early brain injury.

The height of the initial ammonia concentration is associated with cognitive impairment in the proximal UCDs, hyperornithinemia–hyperammonemia–homocitrullinuria syndrome, and citrin deficiency, as compared with the distal UCDs. A 2005 review estimated a poor outcome with a mortality of 84% in neonatal-onset cases and 28% in late-onset cases, before the use of nitrogen-scavenging therapies in Europe. When reviewing survival according to age, diagnosis, and first or recurrent episodes, the lowest survival is seen in male OTCD neonates at first episode. In an open label trial, newborns less than 30 days old had survival rates of 73% compared with 94% in infants greater than 30 days of age. In a 2009 study, intellectual disability in neonatal-onset cases was reported at almost 50%, compared with historical estimates of 60% to 80%. Currently, early liver transplantation in the first year of life, especially if initial rescue therapy has limited the peak and duration of hyperammonemia, is recommended. Early recognition of hyperammonemia and rapid lowering of ammonia is critical to decreasing the extent and severity of early brain injury.

Rare cases of carbonic anhydrase VA (CA-VA) deficiency are being more frequently confirmed through whole exome sequencing with mutations in the CA5A gene following neonatal presentations of hyperammonemia with elevated orotic acid and glutamine levels (similar on initial interpretation to a proximal UCD) with lactic acidosis and ketosis. Following treatment this disorder may have a good prognosis.

Transient Hyperammonemia of the Newborn

THAN is most common in preterm newborns less than 36 weeks gestational age that have a birth weight of less than 2.5 kg. Typically, it occurs following respiratory distress syndrome in the first 24 hours of life, and coma develops within the first 48 hours of life. Serum ammonia levels can surpass 1500 μmol/L, and infants may require hemodialysis and protein restriction.

The cause of this disease is unknown. When suspected, a Doppler ultrasound of the portal vein should be performed to evaluate for a clot in the portal vein. Plasma amino acid levels may have elevations of citrulline and arginine. The glutamine-to-ammonia ratio may distinguish this from a urea cycle defect (glutamine to ammonia ratio <1.6 in THAN, ensuring units are the same). There may be no respiratory alkalosis. The mortality rate in THAN appears to be linked to the duration of coma; outcome can be good in surviving infants, and long-term treatment and protein restriction may not be necessary.

Amino Acid Metabolism Disorders

Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) is a rare autosomal recessive inborn error of amino acid metabolism caused by branched-chain α-ketoacid dehydrogenase (BCKAD) complex deficiency. This enzyme is involved in the metabolism of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine, at the step of conversion of each of their respective α-ketoacid derivatives into their decarboxylated coenzyme A (CoA) metabolites in the mitochondria ( Fig. 29.4 ). The enzyme complex is composed of three components, E1, E2, and E3. E1 has two subunits, E1α and E1β, encoded by the BCKDHA and BCKDHB genes, respectively. E2 is dihydrolipoamide branched-chain transacylase ( DBT gene). Mutations in the gene encoding the E3 subunit ( DLD ) cause a related but more severe disorder with lactic acidosis and elevations of pyruvate, alanine, and the α-ketoacids, as the E3 subunit is also a component of the pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes. MSUD occurs in 1 in 185,000 newborns, but in the old-order Mennonite communities of the United States in areas of eastern Pennsylvania, Kentucky, New York, Indiana, Wisconsin, Michigan, Iowa, and Missouri, the frequency is 1 in 358 due to a founder effect for a missense mutation (c.1312 T>A in BCKDA , E ₁ α). The classic—and most frequent—presentation of MSUD is seen as early as 48 hours of life with poor feeding, irritability, lethargy, and a shrill and high-pitched cry. Symptoms rapidly progress to intermittent apnea, opisthotonus, and stereotyped movements described as “bicycling” or “fencing” alternating with hypotonia, as cerebral edema progresses. A bulging fontanelle may be present. As the illness progresses, coma, apnea, bradycardia, and respiratory failure will develop and usually result in death in the absence of specific medical intervention. The odor of maple syrup in the cerumen may be detected after the first days of life and then in the saliva, breath, urine, and feces.

Fig. 29.4, Overview of branched-chain amino acid metabolism. Plus sign indicates allosteric cobalamin activator. BCKAD , Branched-chain α-ketoacid dehydrogenase; MMACHC , cobalamin C defect; MS , methionine synthase; GI ; gastrointestinal; IVD , isovaleryl-CoA dehydrogenase; MUT ; methylmalonyl-CoA mutase; PCC ; propionyl-CoA carboxylase.

Neurologic progression is accompanied by, and due to, increasing elevations of the BCAA leucine, which is most readily assessed in plasma. Leucine and the related metabolite α-ketoisocaproic acid (α-KIC) may cause depletion of glutamine, glutamate, aspartate, and pyruvate. The mitochondrial respiratory chain may be inhibited by α-KIC and cause accumulation of lactic acid in the central nervous system (CNS).

Neonates with MSUD present with lethargy and metabolic acidosis may develop or may be present initially. Untreated infants may develop ketonuria, which is separate from the ketoacidosis, and an elevated anion gap. Urine ketones may be negative in the presence of high levels of ketoacids. Quantitative plasma amino acid analysis and urine organic acid analysis should be diagnostic in the severe form of the disorder. The former demonstrates marked elevations of BCAAs and the presence of high levels of allo-isoleucine, a compound considered pathognomonic for MSUD. Analysis of urine organic acids will identify high levels of the relevant α-ketoacids in an ill child with the severe form of the disorder. Leucine may be in the thousands and elevated and rising levels require immediate treatment. This is a medical emergency due to the high risk of death and permanent neurologic damage. NBS results report “leucine,” but this is the sum of leucine + isoleucine + hydroxyproline as these cannot be separated by tandem mass spectrometry without column chromatography. Ratios of leucine:alanine, leucine:phenylalanine, and valine:phenylalanine have improved the sensitivity and specificity of NBS as has implementation of a second-tier test of quantitation of allo-isoleucine after a high leucine value has been identified.

An aggressive nutritional approach appears to work to lower leucine effectively in MSUD. BCAA-free modified parenteral nutrition solution can be used in infants and older children with acute leucinosis but is rarely immediately available locally. This should be given in combination with IV glucose at high concentrations with IV intralipids. An insulin drip may also be necessary to curtail the effects of the catabolic stimulus and prevent hyperglycemia but must be carefully performed to avoid hypoglycemia. CAVH or hemodialysis may achieve more rapid normalization of the plasma BCAAs and their corresponding branched-chain ketoacids.

Neurologic outcomes in classic MSUD have improved with NBS, although the risk for subsequent brain injury or death remains, and long-term follow-up and continued vigilance are necessary to prevent injury. Long-term neuropsychiatric assessments are showing that those who remain asymptomatic in the neonatal time period and in whom strict metabolic control is maintained can optimize their long-term mental health. Liver transplantation appears to result in similar outcomes when compared with those who have not had transplantation, but liver transplant may prevent further neurocognitive impairment from prevention of injury during recurrent acute events.

Long-term MSUD treatment focuses on a BCAA-free formula balanced with the provision of sufficient BCAAs to maintain normal growth and development. The goal is that plasma leucine, isoleucine, and valine levels are in the near-normal range, though this may be difficult to achieve outside of infancy. Affected individuals must be closely monitored, and careful management by a biochemical genetic nutritionist is critical. Care must be given to ensure adequate supplementation with isoleucine and valine as BCAA-free formulas may lead to over-restriction of these. Over-restriction of isoleucine can result in anemia and a severe exfoliative rash similar to acrodermatitis enteropathica. A rare thiamine-responsive variant of MSUD may show improved BCAA levels and a decreased need for protein restriction with thiamine supplementation.

Tyrosinemia Type 1

Tyrosinemia type 1 (TYR1), or hepatorenal tyrosinemia , is an autosomal recessive disorder caused by a deficiency of the enzyme fumarylacetoacetate hydrolase as a result of mutations in the FAH gene. This enzymatic reaction is the last in the catabolism of phenylalanine and tyrosine to fumaric acid and acetoacetate, and the accumulation of tyrosine is due to other accumulating metabolites. The primary metabolites that accumulate are maleylacetoacetic acid and fumarylacetoacetic acid, and these both result in the elevation of succinylacetone. This compound is pathognomonic for this disease and is the primary confirmatory metabolite identified on urine organic acid analysis. It is a more sensitive and specific marker than tyrosine in NBS but is not available in all NBS programs. The estimated incidence is 1 in 100,000 to 1 in 120,000 in the general population. The incidence is higher in specific populations with estimates of 1 in 60,000 to 1 in 74,000 in Norway and Finland, 1 in 16,000 in Quebec, and 1 in 1846 in the Saguenay-Lac Saint-Jean region of Quebec because of common founder mutations in these areas.

The phenotype of TYR1 is variable. One presentation is of an acute, early-onset, severe liver disease at less than 2 months of age; there is also an infantile-onset presentation and a chronic presentation after 1 year of age. The acute, early-infantile presentation may be fatal with hepatomegaly, jaundice, elevated transaminases, and profound prolongations of prothrombin time and partial thromboplastin time. Affected individuals develop a renal Fanconi syndrome with generalized aminoaciduria, glycosuria, hypophosphatemia, hypouricemia, proteinuria, and an unusual urine odor of “boiled cabbage.” Children with the chronic phenotype exhibit liver disease, hypophosphatemic rickets as a result of the renal Fanconi syndrome, cardiomyopathy (in 20% to 30%), and porphyria-like neurologic crises with abdominal pain, peripheral neuropathy, and respiratory failure.

Plasma amino acid analysis will demonstrate elevated tyrosine levels, but this is not diagnostic as elevations of tyrosine and methionine are nonspecific and may be found in any disease causing liver dysfunction. Serum alpha fetoprotein levels are abnormally high. The identification of succinylacetone on urine organic acid analysis is diagnostic, and this may be detected within the first 12 hours of life. As for most metabolic disorders, the characteristic metabolite abnormalities may not be present or detectable at all times.

NBS has allowed early treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), and this has improved clinical outcome. Treatment for TYR1 includes NTBC, which inhibits p -hydroxyphenylpyruvate dioxygenase, a proximal enzyme in the pathway, reducing the accumulation of succinylacetone but resulting in increased tyrosine levels. NTBC improves liver and renal disease but requires the implementation of a low-tyrosine, low-phenylalanine diet for improved neurologic outcome. Early treatment, ideally within the first month of life, results in a significant reduction in the development of acute liver disease, hepatomegaly, cirrhosis, hepatocellular carcinoma, renal dysfunction, rickets, and the need for liver transplantation. Before the use of NTBC, most infants with the early-onset form of TYR1 died in early to late infancy. Unfortunately, patients treated with NTBC have shown impaired cognitive outcomes including a lower intelligence quotient, suboptimal executive functioning (working memory and cognitive flexibility), and social cognition (face recognition and the identification of facial emotion) when treated with a natural protein-restricted diet. Dietary over-restriction leading to hypophenylalaninemia may be the cause of these neurocognitive deficits, poor growth, cortical myoclonus, and eczema, although these have been seen to improve or resolve following phenylalanine supplementation.

One complication of TYR1 is the development of hepatocellular carcinoma, typically occurring in later presentations in older children. Monitoring through serial liver ultrasounds and alpha fetoprotein levels is necessary. Treatment with NTBC will improve the biochemical markers and liver dysfunction, but liver transplantation may still be necessary in those who are NTBC-resistant or who have chronic liver disease or poor quality of life.

Other forms of tyrosinemia may be detected with elevated tyrosine levels on NBS or plasma amino acid analysis. Tyrosinemia type 2, or oculocutaneous tyrosinemia, presents with corneal tyrosine crystals, causing photophobia and hyperkeratotic plaques on the hands and soles of the feet. Tyrosinemia type 3 is extremely rare and has a variable phenotype including ataxia and mild mental retardation. These are due to enzyme defects in tyrosine aminotransferase and p -hydroxyphenylpyruvate dioxygenase, respectively.

Transient tyrosinemia of the newborn is common in premature infants and is probably the most common disturbance of amino acid metabolism identified on NBS. It is due to delayed maturation of p -hydroxyphenylpyruvate dioxygenase or liver immaturity.

Nonketotic Hyperglycinemia

Glycine encephalopathy , also termed nonketotic hyperglycinemia (NKH), is an autosomal recessive disorder of the catabolism of glycine to carbon dioxide and ammonia. The incidence is about 1 in 60,000. The glycine cleavage system is composed of four proteins, glycine decarboxylase (GLDC), amino-methyltransferase (AMT), the glycine cleavage H protein, and lipoamide dehydrogenase. These are also called the P (pyridoxal-phosphate) , T (tetrahydrofolate) , H (hydrogen) , and L (lipoamide) proteins , respectively, for the cofactor each utilizes. GLDC removes carbon dioxide, the AMT protein removes ammonia, the H protein removes the hydrogen, and the L protein regenerates the reduced form of the protein. The majority of affected individuals have mutations in the GLDC or AMT genes. The pathophysiology is likely related to glycine’s role in the CNS as both an inhibitory and an excitatory neurotransmitter. The most common form of the disorder manifests in the first week of life as apnea and treatment refractory seizures associated with a burst-suppression pattern on electroencephalogram (EEG). This neonatal-onset form is associated with a very poor prognosis, even with early diagnosis and treatment. There are milder forms of the disorder that manifest in the first months of life or later.

The diagnosis of NKH is based on both the absolute value of glycine in cerebrospinal fluid (CSF) and on the ratio of CSF glycine to plasma glycine. CSF and plasma amino acids must be obtained concurrently. However, the presence of blood in the CSF invalidates the results as CSF amino acid values will not be accurate. CSF glycine is generally greater than 40 μmol/L in affected individuals, and a CSF-to-plasma glycine ratio of 0.08 or greater is considered diagnostic of NKH. This disorder is not identified through NBS because of high false-positive rates of blood spot glycine levels.

One goal of treatment is to lower CSF glycine through high-dose sodium benzoate therapy. Benzoate is conjugated with glycine to form hippuric acid, which is excreted. In addition, dextromethorphan, an N -methyl-D-aspartate (NMDA) receptor antagonist, is prescribed to counteract the activation of the NMDA receptor by glycine. Restriction of dietary protein to restrict the amino acid glycine is not an effective therapy. Other care is supportive as the majority of affected individuals have profound intellectual disability and develop spastic quadriplegic cerebral palsy. Mildly affected individuals with a later-onset presentation with autism have been described. Withdrawal of support in the newborn period has been performed because of the poor prognosis, but the existence of a “mimic” of the disorder associated with identical, but transient, biochemical and clinical features—and with a good outcome—may complicate this decision.

Two classes of disorders that have a secondary effect on the glycine cleavage system have been described. One class was identified through candidate gene sequencing of individuals with defects in the glycine cleavage system that lacked mutations in the known causative genes. The two classes are defects in lipoate synthesis, as lipoate is a cofactor of the L protein, and defects in iron–sulfur cluster biogenesis, as lipoate synthase is an iron–sulfur-containing protein. The disorders have unique clinical and biochemical features, and all have deficient glycine cleavage. It is important to consider these variant disorders in a neonate with apparent NKH. DNA testing should be performed to confirm the correct diagnosis, as the results are necessary for accurate treatment, prognosis, and genetic counseling.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here