INTRODUCTION — Congenital metabolic disorders result from the absence or abnormality of an enzyme or its cofactor or, less frequently, a gene product that modulates the metabolic pathway through different mechanisms, such as substrate transport, leading to either accumulation or deficiency of a specific metabolite (table 1 and table 2 and table 3 and table 4 and table 5 and table 6).
The major classes of inborn errors of metabolism (IEM) and their characteristic clinical and biochemical features are described below. The epidemiology, pathogenesis, clinical presentation, evaluation, and initial management of IEM are discussed separately, as are specific disorders. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Inborn errors of metabolism: Identifying the specific disorder".)
CLASSIFICATION — The traditional classification system for IEM groups the disorders according to the general type of metabolism involved. Some diseases fit into more than one category. These major categories can be further grouped based upon similarities in pathogenesis and/or presenting features (table 1). Other, more detailed nosologies for the classification of IEM that are biochemistry based have been established . (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)
Peroxisomal and lysosomal storage disorders, for example, often have characteristic clinical features and permanent, progressive symptoms that are independent of triggering events (eg, anemia, thrombocytopenia, and hepatomegaly in a child of Ashkenazi Jewish ancestry is suggestive of Gaucher disease) . (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis".)
The other categories of IEM (amino acid disorders, organic acidemias, urea cycle disorders [UCDs], disorders of carbohydrate metabolism, fatty acid oxidation disorders, and mitochondrial disorders) may be considered in two broad categories :
●Disorders of acute or progressive intoxication or encephalopathy – Signs and symptoms in these disorders are caused by accumulation of toxic compounds proximal to the metabolic block. Patients typically present with a symptom-free interval followed by clinical signs of acute or chronic intoxication with progressive or recurrent metabolic disturbances. This category includes amino acid disorders, most organic acidemias, UCDs, and disorders of carbohydrate intolerance (eg, galactosemia, hereditary fructose intolerance).
●Disorders associated with energy deficiency – Signs and symptoms in these disorders are caused at least partly by a deficiency in energy production or utilization in the liver, myocardium, skeletal muscle, or brain. Disorders in this category also may have signs or symptoms related to accumulation of toxic compounds. This category includes disorders of glycogenolysis and gluconeogenesis, fatty acid oxidation defects, disorders of ketogenesis, and mitochondrial disorders.
The major categories of IEM are described below, with examples of representative disorders. Individual clinical and laboratory presenting features of IEM are discussed in detail separately, as is a detailed discussion on initial and specific diagnostic evaluation. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Inborn errors of metabolism: Identifying the specific disorder".)
Amino acid disorders — Amino acids are important for the synthesis of numerous compounds, including structural proteins, peptide hormones, and enzymes needed for gluconeogenesis or in the generation of energy via acetyl coenzyme A (acetyl-CoA) formation. Of the 20 amino acids, 11 can be synthesized in vivo and 9 cannot. The nine that cannot be synthesized in vivo are called "essential amino acids." Their bioavailability relies completely upon dietary intake (table 7).
Amino acid disorders (also called amino acidopathies) are caused by a defect in the metabolic pathways of amino acids. They are called amino acidemias when there is abnormal accumulation of amino acids in the plasma and amino acidurias when there is abnormal excretion of amino acids in the urine. Symptoms typically result from accumulation of the substance that cannot be metabolized. Examples of amino acid disorders include maple syrup urine disease and phenylketonuria. (See "Overview of maple syrup urine disease" and "Overview of phenylketonuria".)
Amino acid disorders often present in newborns who are initially well and become acutely symptomatic (metabolic decompensation with poor feeding and lethargy) after a period of protein feeding. The symptoms may progress to encephalopathy, coma, or death if not recognized and treated promptly . In older children, developmental delay or regression is usually present. Many amino acid disorders can be detected by newborn screening using tandem mass spectrometry. (See "Newborn screening".)
Biochemical findings that may be present in amino acid disorders include metabolic acidosis, hyperammonemia, hypoglycemia with appropriate or increased ketosis, liver dysfunction, and the presence of reducing substances in the urine (table 8) [4,5].
Organic acidemias — Organic acidemias, also known as organic acidurias, are characterized by accumulation of abnormal (and usually toxic) organic acid metabolites and increased excretion of organic acids in the urine . A variety of disorders may result in abnormal urine organic acid profiles, including organic acidemias, phenylketonuria, maple syrup urine disease, certain fatty acid oxidation disorders, disorders of ketogenesis, and mitochondrial disorders (table 10). Examples of organic acidemias include methylmalonic acidemia and propionic acidemia. (See "Organic acidemias: An overview and specific defects" and "Methylmalonic acidemia".)
Most organic acidemias become clinically apparent during the newborn period or early infancy. After an initial period of well-being, affected children develop a life-threatening episode of metabolic decompensation with poor feeding, vomiting, and lethargy. The symptoms may progress if not recognized and treated promptly. In older children, developmental delay or regression is usually present.
Characteristic biochemical findings of organic acidemias include metabolic acidosis with increased anion gap, mild-to-moderate hyperammonemia, sepsis-like features secondary to bone marrow suppression, and ketosis [4,5,7]. Other biochemical findings that may be present include hypoglycemia, liver dysfunction, and secondary carnitine deficiency (table 8) .
Confirmation of diagnosis involves measurement of quantitative plasma amino acids and qualitative urine organic acids and also may include acylcarnitine profile and enzyme analysis [4,8].
Urea cycle disorders — The urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body (figure 1). Deficiency of any of the enzymes in the pathway causes a UCD. Examples of UCDs include ornithine transcarbamylase deficiency and citrullinemia. (See "Urea cycle disorders: Clinical features and diagnosis" and "Urea cycle disorders: Management".)
UCDs often present in newborns who are initially well and become hyperammonemic after a period of protein feeding. However, patients with partial enzyme activity may present later. The characteristic biochemical findings of urea cycle defects include hyperammonemia, respiratory alkalosis, and ketosis (table 8). Liver dysfunction may be present [4,5]. The diagnosis of UCDs is discussed separately. (See "Urea cycle disorders: Clinical features and diagnosis".)
Carbohydrate disorders — Disorders of carbohydrate metabolism can lead to hypoglycemia, liver dysfunction, myopathy, and/or cardiomyopathy. These disorders include deficiencies of enzymes in the pathways of the metabolism of glycogen (figure 2), galactose (figure 3), and fructose. Examples of carbohydrate disorders include galactosemia and the glycogen storage diseases (table 2). (See "Galactosemia: Clinical features and diagnosis" and "Overview of inherited disorders of glucose and glycogen metabolism".)
Children with disorders of carbohydrate metabolism may present with lethargy, encephalopathy, and hypoglycemia during times of decreased carbohydrate intake or fasting. Hepatomegaly is sometimes present .
The characteristic biochemical findings of carbohydrate disorders include hypoglycemia and ketosis (table 8). Metabolic acidosis, liver dysfunction, and nonglucose-reducing substances in the urine may be present [4,5]. Nonglucose-reducing substances are usually present in disorders of carbohydrate intolerance (eg, galactosemia, hereditary fructose intolerance) and usually absent in disorders of glycogenolysis and gluconeogenesis.
Confirmation of diagnosis of disorders of carbohydrate metabolism typically involves DNA analysis and/or assay of enzyme activity in cultured skin fibroblasts, liver, white blood cells, or red blood cells [4,8].
Fatty acid oxidation disorders — Mitochondrial fatty acid oxidation plays an important role in energy production, particularly during fasting . Examples of fatty acid oxidation disorders include medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, fatty acid transportation defects, and defects of beta-oxidation enzymes (table 6). (See "Overview of fatty acid oxidation disorders" and "Specific fatty acid oxidation disorders" and "Causes of hypoglycemia in infants and children".)
Children with disorders of fatty oxidation metabolism may present with lethargy and encephalopathy during times of decreased carbohydrate intake or fasting. Hepatomegaly is sometimes present . Characteristic biochemical features of fatty acid oxidation disorders include hypoglycemia with inappropriately absent ketosis and liver dysfunction (table 8) [4,5]. Hyperammonemia and metabolic acidosis also may occur.
Diagnosis of fatty acid oxidation disorders involves plasma acylcarnitine analysis followed by confirmation through enzyme or in vitro assay in cultured skin fibroblasts or other specialized diagnostic testing, such as DNA analysis [4,8].
Mitochondrial disorders — The frequency of recognition of disorders of mitochondrial metabolism is increasing [10,11]. Within the mitochondria, organic acids, fatty acids, and amino acids are metabolized to acetyl-CoA, which condenses with oxaloacetate to form citric acid, which is oxidized in the Krebs cycle (figure 4). Mitochondrial disorders can affect muscle alone, muscle and brain, or multiple systems with variable involvement of the heart, kidney, liver, skeletal muscle, or brain. The genetics and clinical manifestations of defects of the respiratory chain are discussed separately. (See "Mitochondrial myopathies: Clinical features and diagnosis".)
Examples of mitochondrial disorders include (table 3):
●Cytochrome c oxidase deficiency (see "Overview of peripheral nerve and muscle disorders causing hypotonia in the newborn", section on 'Cytochrome c oxidase deficiency')
●Kearns-Sayre syndrome (see "Myopathies affecting the extraocular muscles in children", section on 'Kearns-Sayre syndrome')
Children with mitochondrial disorders may present with skeletal or visceral abnormalities, poor feeding, vomiting, cardiomyopathy, myopathy, liver failure, seizures, central nervous system abnormalities, developmental delay, retinopathy, blindness, deafness, focal neurologic findings (such as choreoathetosis), or renal Fanconi syndrome [3,5,10]. Kidney involvement is discussed in detail separately. (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children", section on 'Fanconi syndrome' and "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) renal tubular acidosis' and "Etiology and clinical manifestations of renal tubular acidosis in infants and children", section on 'Clinical manifestations'.)
Confirmation of diagnosis of mitochondrial disorders may involve either assay of enzyme activity in cultured skin fibroblasts, muscle, or liver or DNA testing [4,8]. Muscle biopsy for routine histology and electron microscopy and magnetic resonance imaging (MRI) and/or spectroscopy of the brain may be helpful in diagnosis.
Peroxisomal disorders — Numerous catabolic and anabolic functions in cellular metabolism occur in peroxisomes. Catabolic functions include beta-oxidation of very long chain fatty acids (VLCFAs); oxidation of pipecolic, phytanic, pristanic, and many dicarboxylic acids; and degradation of hydrogen peroxide by catalase. Anabolic functions include synthesis of bile acids and plasmalogen (an important component of cell membranes and myelin).
Peroxisomal disorders are a heterogeneous group of IEM that result in impairment of peroxisome function. Some features of peroxisomal disorders include microcephaly, dysmorphic facial features, hepatomegaly, hypotonia, and neurologic dysfunction to a varying extent. Examples of peroxisomal disorders include Zellweger syndrome and adrenoleukodystrophy (table 4). (See "Peroxisomal disorders".)
The diagnosis of peroxisomal disorders may be suspected in patients with an increased plasma concentration of VLCFA and/or phytanic acid. Confirmation requires specialized testing. (See "Peroxisomal disorders", section on 'Approach to diagnosis'.)
Lysosomal storage disorders — Lysosomes are cytoplasmic, single membrane-bound organelles that contain enzymes responsible for the degradation of a variety of compounds including mucopolysaccharides, sphingolipids, and glycoproteins. Deficient activity of specific enzymes leads to progressive accumulation of partially degraded material, leading to distention of the cell, disruption of cellular function, and, sometimes, failure of active transport of small molecules from the lysosomes .
Lysosomal storage disorders (sometime called "storage diseases") are caused by defective lysosomal metabolism or export of naturally occurring compounds that leads to accumulation of various glycosaminoglycans, glycoproteins, or glycolipids within lysosomes of various tissues (table 5) .
Lysosomal storage diseases can be subdivided according to the involved compound or pathway as follows [4,7]:
●Mucopolysaccharidoses (eg, Hurler syndrome). (See "Mucopolysaccharidoses: Clinical features and diagnosis".)
●Sphingolipidoses (eg, GM1 [monosialotetrahexosylganglioside] gangliosidosis, Tay-Sachs disease, Fabry disease, Gaucher disease, Niemann-Pick disease, Krabbe disease, metachromatic leukodystrophy, multiple sulfatase deficiency) . Several of these disorders are discussed in detail separately. (See appropriate topic reviews.)
●Glycoproteinoses (eg, mannosidosis, sialidosis). (See "Overview of the hereditary ataxias", section on 'Sialidosis'.)
●Disorders of lysosomal enzyme transport (eg, mucolipidoses).
●Lysosomal membrane transport disorders (eg, sialic acid storage disease, cystinosis). (See "Cystinosis".)
●Other (eg, lysosomal acid lipase deficiency). (See "Causes of primary adrenal insufficiency in children", section on 'Defects in cholesterol biochemistry'.)
The clinical manifestations vary depending upon the location and extent of storage that occurs but may include progressive hepatomegaly, splenomegaly, neurologic regression, short stature, coarsening of facial features, limitation/restriction of small and large joints, peripheral neuropathy, and/or ataxia [3,14]. Diagnosis of these disorders usually requires specific enzyme assay on samples of white blood cells, serum, or skin fibroblasts [4,8].
Purine and pyrimidine disorders — Purine and pyrimidine nucleotides are important constituents of RNA, DNA, nucleotide sugars and other high-energy compounds, and cofactors, such as adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD) . The clinical presentation of disorders of purine and pyrimidine metabolism varies widely and may include renal calculi, neurologic dysfunction, delayed physical and mental development, self-mutilation, hemolytic anemia, and immune deficiency. Examples include Lesch-Nyhan disease, gout, and adenosine deaminase deficiency. (See "Clinical manifestations and diagnosis of gout" and "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis".)
Porphyrias — The porphyrias are genetic or acquired deficiencies in the activity of enzymes in the heme biosynthetic pathway. They are discussed separately. (See "Porphyrias: An overview".)
Metal metabolism disorders — Disorders of metal metabolism include hemochromatosis, Wilson disease, Menkes disease, and acrodermatitis enteropathica (zinc deficiency). These disorders are discussed separately. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis" and "Wilson disease: Epidemiology and pathogenesis".)
Congenital disorders of glycosylation — Many enzymes, hormones, and other proteins require posttranslational glycosylation to function normally. This complex process of attaching sugars (oligosaccharides) to proteins occurs in the cytosol, endoplasmic reticulum, and Golgi apparatus and requires scores of different enzymes. Congenital disorders of glycosylation (CDGs) are caused by pathogenic variants in genes that encode the enzymes required for synthesis of these oligosaccharides [16-20]. There is a wide range in age of onset of CDGs, although onset occurs most often in infancy. CDGs are typically multisystem disorders with varying clinical manifestations, depending upon the type of CDG. Manifestations include, but are not limited to, developmental delay, hypotonia, failure to thrive, hypoglycemia, and protein-losing enteropathy. CDGs are classified based upon the defect in the pattern of glycosylation and the affected gene. CDG Ia (phosphomannomutase 2 [PMM2]-CDG) is the most common type. CDG Ib (mannosephosphate isomerase [MPI]-CDG) is amenable to therapy with mannose. (See "Overview of congenital disorders of glycosylation".)
Congenital disorders of creatine metabolism — There are three identified congenital metabolic disorders that lead to creatine deficiency. Two are autosomal-recessive disorders that affect the biosynthesis of creatine. They are arginine:glycine amidinotransferase (AGAT) deficiency and guanidinoacetate methyltransferase (GAMT) deficiency. The third disorder, X-linked creatine transporter (CT) deficiency, is caused by a defect in the transport of creatine into the brain and muscle. These disorders are discussed in detail separately. (See "Congenital disorders of creatine synthesis and transport".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of metabolism".)
●Metabolic disorders typically result from the absence or abnormality of an enzyme or its cofactor or impaired transport of a biochemical, leading to either accumulation or deficiency of a specific metabolite. (See 'Introduction' above.)
●The traditional classification system for inborn errors of metabolism (IEM) groups the disorders according to the general type of metabolism involved (table 1 and table 2 and table 3 and table 4 and table 5 and table 6). The major categories of IEM include:
•Amino acid disorders (see 'Amino acid disorders' above)
•Organic acidemias (see 'Organic acidemias' above)
•Urea cycle defects (see 'Urea cycle disorders' above)
•Disorders of carbohydrate metabolism (see 'Carbohydrate disorders' above)
•Fatty acid oxidation defects (see 'Fatty acid oxidation disorders' above)
•Mitochondrial disorders (see 'Mitochondrial disorders' above)
•Peroxisomal disorders (see 'Peroxisomal disorders' above)
•Lysosomal storage diseases (see 'Lysosomal storage disorders' above)