Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Genes (Chromosomal Location)

Comments

Systemic primary carnitine deficiency (212140)

Plasma membrane carnitine transport OCTN2

SLC22A5 (5q31.1)*

Biochemical profile: High urinary carnitine excretion despite very low plasma carnitine, absence of significant dicarboxylic aciduria

Clinical features: Hypoketotic hypoglycemia, fasting intolerance with hypotonia, depressed CNS, apnea, seizures, dilated cardiomyopathy, developmental delay

Treatment: L-Carnitine

Long-chain fatty acid transport deficiency (603376)

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Biochemical profile: Low to normal free carnitine; during acute episodes, elevated plasma C8–C18 acylcarnitine esters

Clinical features: Episodic acute liver failure, hyperammonemia, encephalopathy

Treatment: Liver transplantation

Carnitine palmitoyl transferase I (CPT-I) deficiency (255120)

CPT-I

CPT1A (11q13)*

Biochemical profile: Normal to elevated total and free plasma carnitine, no dicarboxylic aciduria

Clinical features: Fasting intolerance, hypoketotic hypoglycemia, hepatomegaly, seizures, coma, elevated creatine kinase

Treatment: Avoidance of fasting; frequent feeding; during acute episodes, high-dose glucose; replacement of long-chain dietary fat with medium-chain fat

Carnitine/acylcarnitine translocase deficiency (212138)

Carnitine/acylcarnitine translocase

SLC25A20 (3p21.31)*

Biochemical profile: Low total plasma carnitine, with most conjugated to long-chain fatty acids; elevated C16 carnitine ester

Clinical features: In the neonatal form, fasting intolerance with hypoglycemic coma, vomiting, weakness, cardiomyopathy, arrhythmia, mild hyperammonemia

In the mild form, recurrent hypoglycemia with no cardiac involvement

Treatment: Avoidance of fasting; frequent feeding; if plasma level is low, carnitine; during acute episodes, high-dose glucose

Carnitine palmitoyl transferase II (CPT-II) deficiency (255100, 600649, 608836)

CPT-II

CPTII (1p32)*

Biochemical profile: Elevated C16 carnitine ester

In the classical muscle form, carnitine usually normal

In the severe form, low total plasma carnitine, with most conjugated to long-chain fatty acids

Clinical features: In the classical muscle form, presentation in adulthood with episodic myoglobinuria and weakness after prolonged exercise, fasting, intercurrent illness, or stress

In the severe form, presentation in neonatal period or infancy with hypoketotic hypoglycemia, cardiomyopathy, arrhythmia, hepatomegaly, coma, or seizures

Treatment: Avoidance of fasting; frequent feeding; if plasma level is low, carnitine; during acute episodes, high-dose glucose

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (201475)

VLCAD

ACADVL (17p12-p11.1)*

Biochemical profile: Elevated saturated and unsaturated C14–C18 acylcarnitine esters, elevated urinary C6–C14 dicarboxylic acids

Clinical features: In the VLCAD-C type, arrhythmia, hypertrophic cardiomyopathy, sudden death

In the VLCAD-H type, recurrent hypoketotic hypoglycemia, encephalopathy, mild acidosis, mild hepatomegaly, hyperammonemia, elevated liver enzymes

Treatment: Avoidance of fasting; high-carbohydrate diet; carnitine; medium-chain triglycerides; during acute episodes, high-dose glucose

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (600890)

LCHAD

HADHA (2p23)*

Biochemical profile: Elevated saturated and unsaturated C16–C18 acylcarnitine esters, elevated urinary C6–C14 3-hydroxydicarboxylic acids

Clinical features: Fasting-induced hypoketotic hypoglycemia, exercise-induced rhabdomyolysis, cardiomyopathy, cholestatic liver disease, retinopathy, maternal HELLP syndrome

Treatment: Avoidance of fasting; high-carbohydrate diet; carnitine; medium-chain triglycerides; during acute episodes, high-dose glucose

For retinopathy, docosahexanoic acid possibly useful

Mitochondrial trifunctional protein (TFP) deficiency (609015)

Mitochondrial TFP

Biochemical profile: Similar to LCHAD deficiency

Clinical features: Liver failure, cardiomyopathy, fasting hypoglycemia, myopathy, sudden death

Treatment: Similar to that for LCHAD deficiency

α-Subunit

HADHA (2p23)*

β-Subunit

HADHB (2p23)*

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (201450)

MCAD

ACADM (1p31)*

Biochemical profile: Elevated saturated and unsaturated C8–C10 acylcarnitine esters; elevated urinary C6–C10 dicarboxylic acids, suberylglycine, and hexanoylglycine; low free carnitine

Clinical features: Episodic hypoketotic hypoglycemia after fasting, vomiting, hepatomegaly, lethargy, coma, acidosis, SIDS, Reye-like syndrome

Treatment: Avoidance of fasting; frequent feeding, including bedtime snacks; high-carbohydrate diet; carnitine; during acute episodes, high-dose glucose

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency (201470)

SCAD

ACADS (12q22-qter)*

Biochemical profile: In the neonatal form, intermittent ethylmalonic aciduria

In the chronic form, low muscle carnitine

Clinical features: In the neonatal form, neonatal acidosis, vomiting, growth and developmental delay

In the chronic form, progressive myopathy

Treatment: Avoidance of fasting

Glutaric aciduria type II (231680)

Electron transfer flavoprotein (ETF)

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Biochemical profile: Elevated urinary ethylmalonic, glutaric, 2-hydroxyglutaric, 3-hydroxyisovaleric, and C6–C10 dicarboxylic acids and isovalerylglycine; elevated glutarylcarnitine, isovalerylcarnitine, and straight-chain acylcarnitine esters of C4, C8, C10, C10:1, and C12 fatty acids; low serum carnitine; increased serum sarcosine

Clinical features: Fasting hypoketotic hypoglycemia, acidosis, sudden death, CNS anomalies, myopathy, possibly liver and cardiac involvement

Treatment: Avoidance of fasting; frequent feeding; carnitine; riboflavin; during acute episodes, high-dose glucose

α-Subunit

ETFA (15q23-q25)*

β-Subunit

ETFB (19q13.3)*

ETF:ubiquinone oxidoreductase (ETF:QO)

ETFDH (4q32-qter)*

Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency (601609)

SCHAD

HADHSC (4q22-q26)

Biochemical profile: Ketotic C8–C14 3-hydroxydicarboxylic aciduria

Clinical features: Recurrent myoglobinuria, ketonuria, hypoglycemia, encephalopathy, cardiomyopathy

Treatment: Avoidance of fasting

Short/medium-chain 3-hydroxyacyl-CoA dehydrogenase (S/MCHAD) deficiency

S/MCHAD

—

Biochemical profile: Marked elevation of MCHADs and acylcarnitines

Clinical features: Liver failure, encephalopathy

Treatment: Avoidance of fasting

Medium-chain 3-ketoacyl-CoA thiolase (MCKAT) deficiency (602199)

MCKAT

Biochemical profile: Lactic aciduria, ketosis, elevated urinary C4–C12 dicarboxylic aciduria (especially C10 and C12)

Clinical features: Fasting intolerance, vomiting, dehydration, metabolic acidosis, liver dysfunction, rhabdomyolysis

Treatment: Avoidance of fasting

2,4-Dienoyl-CoA reductase deficiency (222745)

2,4-Dienoyl-CoA reductase

DECR1 (8q21.3)*

Biochemical profile: Hyperlysinemia, low plasma carnitine, 2-trans,4-cis decadienoylcarnitine in plasma and urine

Clinical features: Neonatal hypotonia, respiratory acidosis

Treatment: Not established

Cerebrohepatorenal syndrome (Zellweger syndrome; 214100)

Peroxin-1

PEX1 (7q21-q22)*

Biochemical profile: Decreased dihydroxyacetone phosphate acyltransferase and plasmalogen; elevated very long-chain fatty acids, phytanic acid, pipecolate, iron, and total iron-binding capacity

Clinical features: Growth failure, large fontanelles, macrocephaly, turribrachycephaly, dysmorphic facies, cataracts, nystagmus, congenital heart disease, hepatomegaly, biliary dysgenesis, hypospadias, renal cysts, hypotonia, brain malformation

Treatment: No effective treatment

Ether lipids, low phytanic acid diet, and docosahexanoic acid possibly helpful

Peroxin-2

PEX2 (8q21.1)*

Peroxin-3

PEX3 (6q23-q24)*

Peroxin-5

PEX5 (12p13.3)*

Peroxin-6

PEX6 (6p21.1)*

Peroxin-12

PEX12 (17)*

Peroxin-14

PEX14 (1p36.2)*

Peroxin-26

PEX26 (22q11.21)*

Neonatal adrenoleukodystrophy (202370)

Peroxin-1

PEX1 (7q21-q22)*

Biochemical profile: Elevated very long-chain fatty acids

Clinical features: Dolichocephaly, dysmorphic facies, cataracts, hyperpigmentation, seizures, developmental delay, adrenal insufficiency

Treatment: Similar to that for Zellweger syndrome

Peroxin-5

PEX5 (12p13.3)*

Peroxin-10

PEX10 (1)*

Peroxin-13

PEX13 (2p15)*

Peroxin-26

PEX26 (22q11.21)*

Infantile Refsum's disease (266510)

Peroxin-1

PEX1 (7q21-q22)*

Biochemical profile: Elevated plasma phytanic acid, cholesterol, very long-chain fatty acids, dihydroxycholestanoic acid, trihydroxycholestanoic acid, and pipecolic acid

Clinical features: Growth and developmental delay, peripheral neuropathy, hypotonia, deafness, facial dysmorphism, retinopathy, osteoporosis, steatorrhea, episodic bleeding, hepatomegaly

Treatment: Similar to that for Zellweger syndrome

Peroxin-2

PEX2 (8q21.1)*

Peroxin-26

PEX26 (22q11.21)*

Rhizomelic chondrodysplasia punctata

Biochemical profile: In type 1, plasmalogen deficiency, elevated plasma phytanic acid and unprocessed 3-oxoacyl CoA thiolase, acyl-CoA dihydroxyacetonephosphate acyltransferase deficiency

In type 2, normal plasmalogen, phytanic acid, alkyl dihydroxyacetonephosphate synthase, and peroxisomal thiolase; dihydroacetonephosphate acyltransferase deficiency

In type 3, abnormal peroxisomes, alkyl dihydroxyacetonephosphate synthase deficiency

Clinical features: Dwarfism with rhizomelic limb shortening, punctuate epiphyseal calcification, and metaphyseal splaying; severe growth and developmental delay; microcephaly; midface hypoplasia; micrognathia; sensorineural deafness; cataracts; cleft palate; ichthyosis; respiratory difficulties; kyphoscoliosis; vertebral clefts; spasticity; cortical atrophy; seizures; death before 2 yr

Treatment: Similar to that for Zellweger syndrome

Type 1 (215100)

Peroxin-7

PEX7 (6q22-q24)*

Type 2 (222765)

Dihydroxyacetonephosphate acyltransferase

GNPAT (1)*

Type 3 (600121)

Alkyldihydroxyacetonephosphate synthase

AGPS (2q31)*

Hyperpipecolicacidemia (239400)

Pipecolate oxidase

Biochemical profile: Elevated plasma pipecolate, mild generalized aminoaciduria

Clinical features: Hepatomegaly, demyelination, CNS degeneration, severe intellectual disability and developmental delay, retinopathy

Treatment: Reduced intake of very long-chain fatty acids

X-linked adrenoleukodystrophy (300100)

ATP-binding cassette transporter 1

ABCD1 (Xq28)*

Biochemical profile: Elevated plasma very long-chain fatty acids, peroxisomal lignoceroyl-CoA ligase deficiency

Clinical features: Hyperpigmentation, blindness, cognitive hearing loss, spastic paraplegia, impotence, sphincter disturbance, ataxia, dysarthria, adrenal insufficiency, hypogonadism, pontine and cerebellar atrophy

Treatment: Adrenal hormone replacement, bone marrow transplantation

4:1 mixture of glyceryl trioleate and glycerol trierucate (Lorenzo's oil) apparently of no clinical benefit

Acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy; 264470)

Straight-chain peroxisomal acyl-CoA oxidase

ACOX (17q25)*

Biochemical profile: Elevated plasma very long-chain fatty acids; normal peroxisomal phytanate, pipecolate, dihydroxycholestanoic acid, and trihydroxycholestanoic acid

Clinical features: Neonatal hypotonia, developmental delay, sensorineural deafness, retinopathy, no dysmorphic features, leukodystrophy at age 2 to 3 yr

Treatment: Not established

D-Bifunctional protein deficiency (261515)

D-bifunctional enzyme

HSD17B4 (5q2)*

Biochemical profile: Elevated serum very long-chain fatty acids and pipecolate, elevated trihydroxycholestanoic acid in duodenal aspirate, peroxisomal 3-oxoacyl-CoA thiolase defect

Clinical features: Hypotonia, exaggerated startle reflex, facial diplegia, seizures, high-pitched and weak cry, developmental delay, myopathic facies, high-arched palate, abducted limbs, ventricular heart disease

Treatment: Not established

2-Methylacyl-CoA racemase deficiency

2-Methylacyl-CoA racemase

AMACR (5p13.2-q11.1)*

Biochemical profile: Elevated plasma pristanic acid

Clinical features: Adult-onset sensorimotor neuropathy, retinopathy

Treatment: Not established

Primary oxaluria

Biochemical profile: Elevated urinary oxalate excretion, glycolic aciduria

Clinical features: Ca oxalate urolithiasis, nephrocalcinosis, renal failure, heart block, peripheral vascular insufficiency, arterial occlusion, intermittent claudication, optic neuropathy, fractures, death during childhood or early adulthood

Type 2 milder than type 1

Treatment: Hepatorenal transplantation

Hyperoxaluria type 1 (259900)

Peroxisomal alanine-glyoxylate aminotransferase

AGXT (2q36-q37)*

Hyperoxaluria type 2 (260000)

D-Glycerate dehydrogenase glyoxylate reductase

GRHPR (9cen)*

Refsum's disease (266500)

Phytanoyl-CoA hydroxylase

PAHX (10pter-p11.2)*

Biochemical profile: Elevated plasma and tissue phytanic acid

Clinical features: Retinitis pigmentosa, ataxia, ptosis, miosis, peripheral neuropathy, anosmia, heart failure, deafness, ichthyosis, short 4th metacarpal

Treatment: Low phytanic acid diet, plasmapheresis

Peorxin-7

PEX7 (6q22-q24)*

Glutaric aciduria type 3 (231690)

Peroxisomal glutaryl CoA oxidase

Biochemical profile: Glutaric aciduria exacerbated by lysine loading

Clinical features: Failure to thrive, postprandial vomiting

Treatment: Not established

Mevalonic aciduria

See Table1sec19ch296

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Acatalasemia (115500)

Catalase

CAT (11p13)*

Biochemical profile: Failure of tissue to cause hydrogen peroxide frothing

Clinical features: Ulcerating oral lesions in Japanese patients but not in Swiss patients

Treatment: Symptomatic

Glycerol kinase deficiency (307030)

Glycerol kinase

GK (xp21.3-p21.2)*

(Complex form: Deletion of the GK gene and contiguous genes including congenital adrenal hypoplasia, Duchenne muscular dystrophy, or both

Juvenile and adult forms: Isolated GK gene mutation)

Biochemical profile: Hyperglycerolemia

Clinical features: In the complex form, symptoms of the juvenile form, in addition to those due to the specific gene or genes deleted

In the juvenile form, episodic vomiting, acidosis, hypotonia, CNS depression, Reye-like syndrome

In the adult form, pseudohypertriglyceridemia

Treatment: Low-fat diet, avoidance of prolonged fasting

Glycerol intolerance syndrome

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Biochemical profile: Hypoglycemia, ketonuria, reports of decreased activity of fructose-1,6-biphosphatase and increased sensitivity of this enzyme to the inhibition of glycerol-3-phosphate

Clinical features: History of prematurity; after exposure to glycerol, hypoglycemia, lethargy, sweating, seizure, coma

Treatment: Low-fat diet

3-Hydroxy-3-methylglutaryl-CoA synthase deficiency (605911)

3-Hydroxy-3-methylglutaryl-CoA synthase

HMGCS2 (600234)

Biochemical profile: See below

Clinical features: Episodic nonketotic hypoglycemia

Treatment: Avoidance of fasting

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency

See Table2sec19ch296

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Succinyl-CoA 3-oxoacid-CoA transferase deficiency (245050)

Succinyl-CoA 3-oxoacid-CoA transferase

OXCT (5p13)*

Biochemical profile: Ketonuria

Clinical features: Severe episodic ketoacidosis, vomiting, hyperventilation

Treatment: Glucose during acute episode plus judicious use of bicarbonate, high-carbohydrate diet with some restriction of protein and fat

Mitochondrial acetoacetyl-CoA thiolase deficiency (607809)

See Table1sec19ch296

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Cytoplasmic acetoacetyl-CoA thiolase deficiency (100678)

Cytoplasmic acetoacetyl-CoA thiolase

ACAT2 (6q25.3-q26)

Biochemical profile: Nonspecific

Clinical features: Intellectual disability, hypotonia

Treatment: Not established

Sjögren-Larsson syndrome (270200)

Fatty aldehyde dehydrogenase

ALDH3A2 (17p11.2)*

Biochemical profile: No readily detectable plasma or urinary abnormality

Clinical features: Ichthyosis, intellectual disability, spastic diplegia or tetraplegia, retinopathy, seizures

Treatment: Symptomatic; topical keratolytics or systemic retinoids, reduced long-chain fat and increased medium-chain triglycerides in diet