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Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features

Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features
Author:
V Reid Sutton, MD
Section Editor:
Marc C Patterson, MD, FRACP
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Apr 2022. | This topic last updated: Feb 01, 2022.

INTRODUCTION — Congenital metabolic disorders result from the absence or abnormality of an enzyme or its cofactor, 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). Most of these disorders are transmitted as autosomal-recessive traits.

The possibility of an inborn error of metabolism (IEM) should be considered in infants, children, and adults who present with any of the clinical or laboratory features discussed below or in the topic review on metabolic emergencies, particularly if the findings remain unexplained after standard evaluation [1-6]. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" and 'Age at presentation' below.)

Optimal outcome for children with IEM depends upon early recognition of the signs and symptoms of metabolic disease and prompt evaluation and referral to a center familiar with the management of these disorders [7]. Delay in diagnosis may result in acute metabolic decompensation, progressive neurologic injury, or death.

The epidemiology, pathogenesis, and most common chronic clinical and laboratory manifestations of IEM are discussed below. The presentation, initial diagnosis, and management of IEM presenting as metabolic emergencies are discussed in detail separately. The major classes of IEM and their characteristic clinical and biochemical features are described elsewhere, as is a diagnostic approach to identifying the specific IEM. In addition, many of the individual disorders are covered in separate topic reviews (see specific topic reviews). (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" and "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Identifying the specific disorder".)

EPIDEMIOLOGY — Individual IEM are rare disorders, most having an incidence of less than 1 per 100,000 births. However, when considered collectively, the incidence may approach 1 in 800 to 1 in 2500 births [8,9]. In one review of cases of IEM diagnosed in British Columbia (a predominantly White population) between 1969 and 1996, estimates of incidence of various classes of disorders were as follows:

Amino acid disorders (excluding phenylketonuria) – 7.6 per 100,000

Lysosomal storage diseases – 7.6 per 100,000

Phenylketonuria – 7.5 per 100,000

Organic acidemias – 3.7 per 100,000

Peroxisomal disorders – 3.5 per 100,000

Mitochondrial diseases – 3.2 per 100,000

Glycogen storage diseases – 2.3 per 100,000

Urea cycle diseases – 1.9 per 100,000

In another review of cases of IEM diagnosed in the West Midlands of the United Kingdom (where approximately 11 percent of the population is from Black and underrepresented ethnic groups), the frequency of selected IEM during 1999 to 2003 was as follows [9]:

Mitochondrial diseases – 20.3 per 100,000

Lysosomal storage diseases – 19.3 per 100,000

Amino acid disorders (excluding phenylketonuria) – 18.7 per 100,000

Organic acidemias – 12.6 per 100,000

Phenylketonuria – 8.1 per 100,000

Peroxisomal disorders – 7.4 per 100,000

Glycogen storage diseases – 6.8 per 100,000

Urea cycle diseases – 4.5 per 100,000

The greater incidence of disorders in the West Midlands study may be related to differences in the ethnicity of the populations, diagnostic methods and approaches among laboratories and countries, and improved technology, reporting, and awareness of some disorders (eg, mitochondrial disorders) over time.

PATHOGENESIS — Metabolic disorders can be caused by several mechanisms. Most metabolic disorders are caused by a single enzyme deficiency that disrupts one step of a metabolic pathway. This disruption may lead to the accumulation of metabolites preceding the interrupted step, as in alkaptonuria, or the inability to make certain intermediates or end products of a specific metabolic pathway, such as ketoacids during fasting in patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency [5].

Less frequently, alterations that result in abnormalities of more than one enzyme can affect several metabolic steps. An example is multiple sulfatase deficiency, a lysosomal storage disorder that is caused by impaired posttranslational modification of sulfatases. Disorders of cofactors also can affect multiple enzymes. As an example, defects of cobalamin (vitamin B12) transport and synthesis may lead to accumulation of both methylmalonic acid and homocysteine. (See "Organic acidemias: An overview and specific defects".)

In most cases, a specific metabolic disorder is caused by a defect in one specific gene. However, a single enzyme, such as mitochondrial trifunctional protein, can be composed of multiple subunits encoded by different genes and catalyze more than one metabolic reaction. In addition, defects in different enzymes can result in a similar clinical phenotype (eg, elevated total plasma homocysteine may result from either deficiency of the enzyme cystathionine beta-synthase or from a cobalamin processing defect [complementation group G]).

CLINICAL MANIFESTATIONS — The clinical manifestations of IEM may include findings in virtually every system. Neurologic and gastrointestinal manifestations are the most frequent. The presenting features of IEM may be acute or chronic. Acute signs include episodic vomiting accompanied by dehydration or shock, lethargy and coma, rhabdomyolysis, and hypoglycemia associated with minor illnesses, stress, or a prolonged fast. Chronic signs of metabolic disease include growth delay/failure to thrive, hepatomegaly, cardiomyopathy, spastic diplegia, and developmental delay or regression.

Clinical presentations of metabolic emergencies, including recurrent vomiting and dehydration, lethargy and coma, seizures, and sudden infant death syndrome (SIDS) or apparent life-threatening event (ALTE), are discussed separately. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Clinical presentations'.)

Neurologic — Neurologic manifestations of IEM include lethargy, coma, seizures, developmental delay or regression, peripheral neuropathy, abnormalities of tone, motor problems, ataxia, and neuropsychiatric manifestations.

Lethargy, coma, and seizures — These neurologic presentations of IEM are discussed in detail separately. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Lethargy and coma' and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Seizures'.)

Developmental delay — It is estimated that IEM are the underlying cause in only 1 to 5 percent of cases of developmental delay [10,11]. However, developmental delay and/or intellectual disability, particularly with progressive worsening, may occur in many IEM. Thus, it is important to evaluate the possibility of IEM as an underlying cause to provide accurate prognosis, genetic counseling, and specific therapy, if available [10,12,13]. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Developmental delay' and "Developmental-behavioral surveillance and screening in primary care", section on 'Follow-up' and "Intellectual disability in children: Evaluation for a cause", section on 'Metabolic testing'.)

Developmental delay and intellectual disability are most commonly associated with the following metabolic disorders:

Disorders of urea cycle and amino acid metabolism (figure 1)

Organic acidemias (table 7)

Disorders of creatine metabolism (see "Congenital disorders of creatine synthesis and transport")

Peroxisomal disorders (table 4)

Lysosomal storage disorders (table 5)

Mitochondrial disorders and disorders of oxidative phosphorylation

Congenital disorders of protein glycosylation

Associated clinical findings may provide a clue to the underlying IEM. As examples, a family history of hearing loss and diabetes with maternal transmission in a patient with developmental delay is typical of a mitochondrial disorder, while spastic diplegia with developmental delay is suggestive of argininemia. Boolean searches of electronic resources, such as the Online Mendelian Inheritance in Man, using the signs and symptoms of an individual patient can be used to generate a differential diagnosis of IEM that could cause the observed signs and symptoms. Another website for IEM allows Boolean searches [14], while a different diagnostic app groups diseases based upon the general metabolic defect or type of clinical presentation but does not for allow Boolean searches [15].

Neuropathy — Peripheral neuropathy may be a feature of disorders of vitamin B12 (cobalamin) transport and processing, lysosomal disorders (table 5), and certain mitochondrial disorders. (See "Neuropathies associated with hereditary disorders", section on 'Lysosomal storage diseases' and "Neuropathies associated with hereditary disorders", section on 'Mitochondrial disorders' and "Overview of acquired peripheral neuropathies in children", section on 'Vitamin deficiency or excess'.)

Abnormal tone — Hypotonia may be a manifestation of fatty acid oxidation disorders, mitochondrial disorders, urea cycle defects, peroxisomal disorders, lysosomal acid maltase deficiency (Pompe disease, glycogen storage disease II), and Smith-Lemli-Opitz syndrome (a disorder of cholesterol biosynthesis) [4,16]. (See "Approach to the infant with hypotonia and weakness" and "Urea cycle disorders: Clinical features and diagnosis".)

Spastic diplegia may occur in arginase deficiency [17]. (See "Urea cycle disorders: Clinical features and diagnosis".)

Myopathy — Myopathy and rhabdomyolysis can occur in lysosomal and nonlysosomal glycogen storage diseases, disorders of fatty acid oxidation, and mitochondrial disorders. Patients may complain of exercise intolerance, muscle pain, and cramps rather than weakness. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Skeletal myopathy' and "Approach to the metabolic myopathies" and "Overview of inherited disorders of glucose and glycogen metabolism" and "Overview of fatty acid oxidation disorders" and "Specific fatty acid oxidation disorders".)

Ataxia and dystonia — Ataxia may be a manifestation of peroxisomal disorders, mitochondrial disorders, disorders of metal metabolism, and lysosomal storage disorders. Ataxia associated with a dysplastic cerebellum is seen in congenital disorders of glycosylation. (See "Peroxisomal disorders" and "Neuropathies associated with hereditary disorders", section on 'Mitochondrial disorders' and "Overview of the hereditary ataxias", section on 'Mitochondrial ataxias' and "Overview of the hereditary ataxias", section on 'Sialidosis'.)

Dystonia may be a feature of mitochondrial disorders or organic acidurias after a metabolic crisis associated with damage to the basal ganglia [10]. (See "Etiology, clinical features, and diagnostic evaluation of dystonia" and "Mitochondrial myopathies: Clinical features and diagnosis" and "Organic acidemias: An overview and specific defects".)

Neuropsychiatric — IEM may present with psychiatric or behavioral manifestations, such as [10,18]:

Self-injurious behavior in Lesch-Nyhan syndrome (see "Hyperkinetic movement disorders in children", section on 'Lesch-Nyhan syndrome')

Increased activity and aggression in Sanfilippo syndrome and other mucopolysaccharidoses (see "Mucopolysaccharidoses: Clinical features and diagnosis")

Personality changes, deteriorating school performance, depression, paranoia, or catatonia in Wilson disease (see "Wilson disease: Epidemiology and pathogenesis")

Psychosis in some patients with adult Tay-Sachs disease, homocystinuria, the porphyrias, and purine disorders

Gastrointestinal — Gastrointestinal presentations of IEM include recurrent episodes of vomiting or dehydration, poor feeding, failure to thrive, decreased gastrointestinal motility, hepatomegaly or hepatosplenomegaly, and jaundice [4].

Vomiting and poor feeding — Recurrent vomiting, poor feeding, and associated dehydration are discussed in detail separately. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Gastrointestinal and feeding problems'.)

Organomegaly — Hepatomegaly and/or splenomegaly can be seen in the following conditions:

Glycogen storage diseases

Lysosomal storage diseases (Gaucher, Niemann-Pick)

Galactosemia

Peroxisomal disorders

Tyrosinemia type 1

Bile acid disorders

Congenital disorders of glycosylation (also referred to as carbohydrate-deficient glycoprotein syndromes)

Lysosomal acid lipase deficiency (Wolman disease/cholesteryl ester storage disorder) [19]

Hepatosplenomegaly and isolated splenomegaly occur primarily in lysosomal storage disorders [20], whereas isolated hepatomegaly is more typical of glycogen storage diseases and certain mitochondrial diseases. In addition, signs or symptoms that accompany hepatosplenomegaly may suggest a particular diagnosis:

Hepatomegaly with hypoglycemia and poor growth is suggestive of glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease), glycogen debrancher deficiency (glycogen storage disease III, Cori disease, Forbes disease), disorders of gluconeogenesis, or severe hyperinsulinism. (See "Approach to hypoglycemia in infants and children" and "Causes of hypoglycemia in infants and children" and "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)" and "Glycogen debrancher deficiency (glycogen storage disease III)".)

Hepatomegaly with liver failure suggests hereditary fructose intolerance, galactosemia, tyrosinemia type 1, neonatal hemochromatosis, a mitochondrial disorder, or Wilson disease [3,16]. (See "Causes of hypoglycemia in infants and children" and "Galactosemia: Clinical features and diagnosis" and "Disorders of tyrosine metabolism" and "Causes of cholestasis in neonates and young infants", section on 'Gestational alloimmune liver disease (neonatal hemochromatosis)'.)

Gaucher disease should be suspected in a child of Ashkenazi-Jewish ancestry with anemia and thrombocytopenia in addition to hepatosplenomegaly. (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis".)

Jaundice — Cholestatic jaundice may be a manifestation of galactosemia, citrin deficiency, alpha-1 antitrypsin deficiency, disorders of bile acid metabolism, transaldolase deficiency, peroxisomal disorders, Niemann-Pick disease, neonatal hemochromatosis, and congenital disorders of glycosylation [16]. (See "Causes of cholestasis in neonates and young infants".)

Cardiomyopathy — Hypertrophic or dilated cardiomyopathy may occur in several IEM and is typically related to impaired energy metabolism or storage material. Hypertrophic cardiomyopathy occurs in lysosomal acid maltase deficiency (glycogen storage disease type II, Pompe disease) and in the mucopolysaccharidoses. Dilated cardiomyopathy can occur in fatty acid oxidation disorders, organic acidemias, and mitochondrial disorders (eg, disorders of oxidative phosphorylation). (See "Metabolic myopathies caused by disorders of lipid and purine metabolism" and "Approach to the metabolic myopathies" and "Inborn errors of metabolism: Identifying the specific disorder", section on 'Cardiomyopathy'.)

Dysmorphic features — Dysmorphic features may be present at birth or may develop with age in a number of IEM, including [20-22]:

Peroxisomal disorders (eg, high forehead, large anterior fontanelle, hypoplastic supraorbital ridges, epicanthal folds, low and broad nasal bridge, high-arched palate, and deformed ear lobes in Zellweger syndrome) (picture 1) (see "Peroxisomal disorders", section on 'Zellweger syndrome')

Lysosomal storage diseases (eg, coarse facial features may be present at birth in mucolipidosis II and monosialotetrahexosylganglioside (GM1)-gangliosidosis; in other mucopolysaccharidoses, coarsening of the facial features develops with age) (see "Mucopolysaccharidoses: Clinical features and diagnosis")

Homocystinuria due to cystathionine-beta-synthetase deficiency (long face and lanky body habitus [Marfanoid phenotype])

Smith-Lemli-Opitz syndrome (cleft palate, congenital heart disease, hypospadias, polydactyly, and syndactyly)

Congenital disorders of protein glycosylation (see "Overview of congenital disorders of glycosylation")

Ophthalmologic — Ophthalmologic presentations of IEM include cataracts, corneal opacities or clouding (picture 2), cherry-red spots (picture 3), retinitis pigmentosa (picture 4), and dislocated lenses (table 8) [23]. (See "Cataract in children" and "Ectopia lentis (dislocated lens) in children" and "Retinitis pigmentosa: Clinical presentation and diagnosis".)

Dermatologic — Dermatologic manifestations of IEM may include [3]:

Rashes – Acrodermatitis enteropathica (picture 5), biotinidase deficiency, methylmalonic acidemia, propionic acidemia (see "Organic acidemias: An overview and specific defects")

Photosensitivity – Porphyrias, Hartnup disease (see "Porphyrias: An overview")

Hyperkeratosis and ichthyosis (picture 6) – Tyrosinemia type II, Sjögren-Larsson syndrome, steroid-sulfatase deficiency, multiple sulfatase deficiency, congenital disorders of glycosylation, Refsum disease (adult form) (see "Disorders of tyrosine metabolism", section on 'Hereditary tyrosinemia type 2' and "Sjögren-Larsson syndrome" and "Peroxisomal disorders", section on 'Refsum disease')

Skin ulceration – Prolidase deficiency

Skin nodules – Farber disease, congenital disorders of protein glycosylation (see "Overview of congenital disorders of glycosylation")

Angiokeratoma – Fabry disease and other lysosomal storage diseases (picture 7A-B) (see "Fabry disease: Clinical features and diagnosis")

Pearly papules – Mucopolysaccharidosis II (MPS II, Hunter syndrome) (picture 8) [24,25]

Hypopigmentation – Untreated phenylketonuria (see "Overview of phenylketonuria")

Melanocytic nevi (formerly known as "Mongolian spots") – Lysosomal storage diseases such as Hurler syndrome (mucopolysaccharidosis type I Hurler [MPS I H]) and GM1 gangliosidosis type 1 (picture 9) [26]

Hydrops fetalis — Nonimmune hydrops fetalis (abnormal fetal fluid collections) may occur in the following IEM (table 9) [27-29] (see "Nonimmune hydrops fetalis"):

Lysosomal storage diseases, including, but not limited to Gaucher disease, MPS types IV and VII, GM1 gangliosidosis, Niemann-Pick disease type C, Farber disease, infantile-free sialic acid storage disease, sialidosis, galactosialidosis, mucolipidosis type II (I cell disease) (see appropriate topic reviews)

Neonatal hemochromatosis [30] (see "Causes of cholestasis in neonates and young infants", section on 'Gestational alloimmune liver disease (neonatal hemochromatosis)')

Mitochondrial respiratory chain disorders [31] (see "Mitochondrial myopathies: Clinical features and diagnosis")

Congenital disorders of glycosylation [32] (see "Overview of congenital disorders of glycosylation")

Glycogen branching enzyme deficiency (glycogen storage disease IV, Andersen disease) [33] (see "Glycogen branching enzyme deficiency (glycogen storage disease IV, Andersen disease)")

Red blood cell (RBC) enzyme abnormalities (glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, and glucose phosphate isomerase deficiency) (see "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Pyruvate kinase deficiency" and "Disorders of the hexose monophosphate shunt and glutathione metabolism other than glucose-6-phosphate dehydrogenase deficiency")

Abnormal odors — Abnormal odor of the patient's breath, urine (table 10), perspiration, saliva, or cerumen should prompt consideration of organic acidemias, amino acid disorders, urea cycle defects, and fatty acid oxidation disorders [6,20,34]. However, the majority of patients who have an unusual odor do not have an IEM or other underlying medical cause for the odor.

Odors characteristic of selected disorders are listed below [3,6,20,34]:

Burnt sugar, curry, or maple syrup – Maple syrup urine disease (fenugreek, a spice commonly used in Asian cooking; artificial maple syrup; and herbal teas contain sotolon, which can result in a maple syrup smell when consumed)

Sweaty socks or cheese-like – Isovaleric acidemia

Fruity, ammoniacal – Methylmalonic acidemia or propionic acidemia

Mouse urine, musty – Phenylketonuria

Cabbage-like, rotten eggs – Tyrosinemia

Malt or hops – Methionine malabsorption

Cat urine – 3-methylcrotonic acidemia, 3-hydroxy-3-methylglutaric aciduria

Fish-like – Trimethylaminuria and carnitine excess

Urine changes — Abnormal urine color or odor may be suggestive of IEM (table 10). Color changes may only be apparent after the urine stands for some time (permitting oxidation). This is particularly true for alkaptonuria and, in the era of flush toilets and disposable diapers, explains why the diagnosis is rarely made until later in life. (See "Disorders of tyrosine metabolism", section on 'Alkaptonuria'.)

AGE AT PRESENTATION — Initial symptoms of metabolic diseases may occur in any age group, from fetuses and newborns to people in their seventh decade of life [35]. The onset and severity may be influenced by changes in dietary intake, fasting, dehydration, intercurrent illness, medications, strenuous activity, childbirth, trauma, or surgery [1]. The presenting signs and symptoms of some disorders may vary with age. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'History'.)

As an example, the typical presentation of urea cycle disorders or organic acidemias in newborns is an acute, severe illness characterized by lethargy, poor feeding, vomiting, and shock. However, less severe forms of these disorders may present in older children or adults with episodes of vomiting and lethargy, failure to thrive, protein intolerance, seizures, or psychomotor abnormalities. (See "Urea cycle disorders: Clinical features and diagnosis" and "Organic acidemias: An overview and specific defects" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)

In neonates, the age at the time of presentation may be helpful in narrowing down the specific category of IEM, although there are exceptions [4].

Nonketotic hyperglycinemia, urea cycle disorders, and branched-chain organic acidemias often present with life-threatening illness between 12 and 72 hours of age, whereas maple syrup urine disease usually presents later in the first week. However, mild forms of all IEM exist, and many patients may have the first metabolic decompensation anywhere from 1 to 60 years of age. Parturition is an especially dangerous time for women with undiagnosed IEM. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)

In neonates with acute liver failure, neonatal hemochromatosis usually presents during the first week, galactosemia in the first or second week, tyrosinemia type 1 any time after the first week, and alpha-1 antitrypsin deficiency, Niemann-Pick disease, and bile acid synthesis defects after the third week. Mitochondrial disorders may present at any time. (See "Acute liver failure in children: Etiology and evaluation", section on 'Inherited metabolic disease'.)

LABORATORY FINDINGS — The possibility of an IEM should be considered in infants, children, and adults who present with otherwise unexplained acid-base disorders, hyperammonemia, hypoglycemia, hematologic abnormalities, liver dysfunction, and kidney disease. In some disorders, the laboratory abnormalities may be present only during an acute presentation. Thus, for example, a normal plasma ammonia level in an individual who is not acutely ill does not rule out a metabolic disorder.

Acid-base disorders, hyperammonemia, and hypoglycemia — Acid-base disorders (including lactic acidosis), hyperammonemia, and hypoglycemia associated with IEM are discussed in greater detail separately. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Laboratory findings'.)

Hematologic abnormalities — Hematologic manifestations of IEM may involve any or all of the cell lines, as described below [3]:

Macrocytic anemia – Homocystinuria, methylmalonic acidemia, hereditary orotic aciduria, lysinuric protein intolerance (a disorder of amino acid transport), Lesch-Nyhan syndrome (see "Organic acidemias: An overview and specific defects" and "Hyperkinetic movement disorders in children", section on 'Lesch-Nyhan syndrome')

Normocytic anemia – Neonatal hemochromatosis, disorders associated with severe liver failure, Wilson disease, porphyria, Wolman disease, methylmalonic acidemia, propionic acidemia, isovaleric acidemia, orotic aciduria, erythropoietic glycolytic enzyme deficiency (eg, pyruvate kinase, phosphofructokinase, glucose-6-phosphate dehydrogenase) (see appropriate topic reviews)

Predominant or isolated neutropenia – Glycogen storage disease type Ib, lysinuric protein intolerance, hereditary orotic aciduria, methylmalonic acidemia, propionic acidemia, isovaleric acidemia, mevalonic aciduria (see "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)" and "Organic acidemias: An overview and specific defects")

Predominant thrombocytopenia – Cobalamin metabolism defect (Cbl C), methylmalonic acidemia, propionic acidemia, isovaleric acidemia (see "Organic acidemias: An overview and specific defects")

Pancytopenia – Gaucher disease, methylmalonic acidemia, propionic acidemia, isovaleric acidemia, mevalonic aciduria, lysinuric protein intolerance (see "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis" and "Organic acidemias: An overview and specific defects")

Liver abnormalities — IEM may be associated with hyperammonemia and jaundice. In addition, IEM that are associated with liver failure also may result in bleeding diathesis (eg, tyrosinemia type 1, glutaric aciduria type I). (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Hyperammonemia' and 'Jaundice' above and "Disorders of tyrosine metabolism" and "Organic acidemias: An overview and specific defects", section on 'Glutaric acidemia type 1'.)

Kidney disease — Kidney disease accompanies several IEM. The spectrum of kidney disease may include [3,18]:

Renal Fanconi syndrome – Tyrosinemia type I, cystinosis, mitochondrial respiratory chain disorders

Renal tubular acidosis – Pyruvate carboxylase deficiency, methylmalonic aciduria, carnitine palmitoyl transferase I deficiency (see "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance")

Nephrolithiasis – Cystinuria, gout and other purine disorders, hyperoxaluria, hereditary renal hypouricemia, Lesch-Nyhan syndrome

Renal cysts – Multiple acyl-CoA dehydrogenase deficiency (glutaric acidemia type II), neonatal carnitine palmitoyltransferase type II (CPT II) deficiency, peroxisomal disorders

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".)

SUMMARY

Congenital metabolic diseases (table 1) can present in newborns, infants, children, or adults. The onset and severity may be influenced by changes in dietary intake, fasting, dehydration, intercurrent illness, medications, strenuous activity, childbirth, trauma, or surgery. The signs and symptoms vary depending upon the age and disorder. (See 'Introduction' above.)

Individual inborn errors of metabolism (IEM) are rare disorders, most having an incidence of less than 1 per 100,000 births. However, the collective incidence may approach 1 in 800 to 1 in 2500 births. (See 'Epidemiology' above.)

Most metabolic disorders are caused by a single enzyme deficiency that disrupts one step of a metabolic pathway. Less frequently, alterations that result in abnormalities of more than one enzyme can affect several metabolic steps. Disorders of cofactors also can affect multiple enzymes. (See 'Pathogenesis' above.)

An individual metabolic disorder is usually caused by a defect in a single gene. However, a single enzyme can be composed of multiple subunits encoded by different genes and catalyze more than one metabolic reaction. In addition, defects in different enzymes can result in a similar clinical phenotype. (See 'Pathogenesis' above.)

Neurologic and gastrointestinal symptoms and signs are the most common presenting features of IEM. Neurologic features of IEM include lethargy, coma, seizures, developmental delay or regression, peripheral neuropathy, abnormalities of tone, weakness, ataxia, and neuropsychiatric manifestations. Exercise intolerance, muscle pain, or muscle cramps rather than weakness may be the presenting complaint in patients with metabolic myopathies. Gastrointestinal presentations of IEM include recurrent episodes of vomiting, diarrhea, organomegaly, and jaundice. (See 'Neurologic' above and 'Gastrointestinal' above and "Approach to the metabolic myopathies" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Clinical presentations'.)

Laboratory presentations of IEM include acid-base disorders (including lactic acidosis), hyperammonemia, hypoglycemia, anemia, neutropenia, thrombocytopenia, and abnormalities of liver function (eg, hyperbilirubinemia, elevated transaminases, coagulopathy). In some disorders, the laboratory abnormalities may be present only during an acute presentation. Thus, for example, a normal plasma ammonia level in an individual who is not acutely ill does not rule out a metabolic disorder. (See 'Laboratory findings' above and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Laboratory findings'.)

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Topic 2936 Version 28.0

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