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Fatty acids are the preferred energy source for the heart and an important energy source for skeletal muscle during prolonged exertion. Also, during fasting, the bulk of the body's energy needs must be supplied by fat metabolism. Using fat as an energy source requires catabolizing adipose tissue into free fatty acid and glycerol. The free fatty acid is metabolized in the liver and peripheral tissue via β-oxidation into acetyl CoA; the glycerol is used by the liver for triglyceride synthesis or for gluconeogenesis. Primary disorders of carnitine are discussed in Undernutrition: Carnitine Deficiency, but secondary carnitine deficiency is a secondary biochemical feature of many organic acidemias and fatty acid oxidation defects. For a more complete listing of fatty acid and glycerol metabolism disorders, see Table Disorders of Fatty Acid, Very Long-Chain Fatty Acid, and Glycerol Metabolism.
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Table 3
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| Disorders of Fatty Acid, Very Long-Chain Fatty Acid, and Glycerol Metabolism |
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Disease (OMIM Number)
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Defective Proteins or Enzymes
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Defective Genes (Chromosomal Location)
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Comments
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Disorders of fatty acid transport and mitochondrial oxidation
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Systemic primary carnitine deficiency (212140)
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Plasma membrane carnitine transport OCTN2
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SLC22A5 (5q31.1)*
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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
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Long-chain fatty acid transport deficiency (603376)
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—
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—
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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
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Carnitine palmitoyl transferase I (CPT-I) deficiency (255120)
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CPT-I
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CPT1A (11q13)*
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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
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Carnitine/acylcarnitine translocase deficiency (212138)
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Carnitine/acylcarnitine translocase
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SLC25A20 (3p21.31)*
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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
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Carnitine palmitoyl transferase II (CPT-II) deficiency (255100, 600649, 608836)
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CPT-II
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CPTII (1p32)*
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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
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Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (201475)
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VLCAD
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ACADVL (17p12-p11.1)*
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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
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Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (600890)
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LCHAD
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HADHA (2p23)*
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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
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Mitochondrial trifunctional protein (TFP) deficiency (609015)
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Mitochondrial TFP
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Biochemical profile: Similar to LCHAD deficiency
Clinical features: Liver failure, cardiomyopathy, fasting hypoglycemia, myopathy, sudden death
Treatment: Similar to that for LCHAD deficiency
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α-Subunit
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HADHA (2p23)*
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β-Subunit
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HADHB (2p23)*
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Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (201450)
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MCAD
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ACADM (1p31)*
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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
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Short-chain acyl-CoA dehydrogenase (SCAD) deficiency (201470)
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SCAD
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ACADS (12q22-qter)*
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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
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Glutaric aciduria type II (231680)
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Electron transfer flavoprotein (ETF)
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—
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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
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α-Subunit
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ETFA (15q23-q25)*
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β-Subunit
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ETFB (19q13.3)*
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ETF:ubiquinone oxidoreductase (ETF:QO)
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ETFDH (4q32-qter)*
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Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency (601609)
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SCHAD
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HADHSC (4q22-q26)
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Biochemical profile: Ketotic C8–C14 3-hydroxydicarboxylic aciduria
Clinical features: Recurrent myoglobinuria, ketonuria, hypoglycemia, encephalopathy, cardiomyopathy
Treatment: Avoidance of fasting
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Short/medium-chain 3-hydroxyacyl-CoA dehydrogenase (S/MCHAD) deficiency
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S/MCHAD
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—
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Biochemical profile: Marked elevation of MCHADs and acylcarnitines
Clinical features: Liver failure, encephalopathy
Treatment: Avoidance of fasting
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Medium-chain 3-ketoacyl-CoA thiolase (MCKAT) deficiency (602199)
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MCKAT
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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
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2,4-Dienoyl-CoA reductase deficiency (222745)
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2,4-Dienoyl-CoA reductase
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DECR1 (8q21.3)*
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Biochemical profile: Hyperlysinemia, low plasma carnitine, 2-trans,4-cis decadienoylcarnitine in plasma and urine
Clinical features: Neonatal hypotonia, respiratory acidosis
Treatment: Not established
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Disorders of peroxisome biogenesis and very long-chain fatty acid metabolism
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Cerebrohepatorenal syndrome (Zellweger syndrome; 214100)
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Peroxin-1
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PEX1 (7q21-q22)*
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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
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Peroxin-2
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PEX2 (8q21.1)*
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Peroxin-3
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PEX3 (6q23-q24)*
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Peroxin-5
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PEX5 (12p13.3)*
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Peroxin-6
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PEX6 (6p21.1)*
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Peroxin-12
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PEX12 (17)*
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Peroxin-14
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PEX14 (1p36.2)*
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Peroxin-26
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PEX26 (22q11.21)*
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Neonatal adrenoleukodystrophy (202370)
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Peroxin-1
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PEX1 (7q21-q22)*
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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
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Peroxin-5
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PEX5 (12p13.3)*
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Peroxin-10
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PEX10 (1)*
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Peroxin-13
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PEX13 (2p15)*
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Peroxin-26
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PEX26 (22q11.21)*
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Infantile Refsum's disease (266510)
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Peroxin-1
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PEX1 (7q21-q22)*
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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
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Peroxin-2
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PEX2 (8q21.1)*
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Peroxin-26
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PEX26 (22q11.21)*
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Rhizomelic chondrodysplasia punctata
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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
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Type 1 (215100)
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Peroxin-7
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PEX7 (6q22-q24)*
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Type 2 (222765)
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Dihydroxyacetonephosphate acyltransferase
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GNPAT (1)*
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Type 3 (600121)
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Alkyldihydroxyacetonephosphate synthase
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AGPS (2q31)*
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Hyperpipecolicacidemia (239400)
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Pipecolate oxidase
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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
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X-linked adrenoleukodystrophy (300100)
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ATP-binding cassette transporter 1
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ABCD1 (Xq28)*
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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
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Acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy; 264470)
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Straight-chain peroxisomal acyl-CoA oxidase
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ACOX (17q25)*
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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
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D-Bifunctional protein deficiency (261515)
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D-bifunctional enzyme
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HSD17B4 (5q2)*
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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
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2-Methylacyl-CoA racemase deficiency
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2-Methylacyl-CoA racemase
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AMACR (5p13.2-q11.1)*
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Biochemical profile: Elevated plasma pristanic acid
Clinical features: Adult-onset sensorimotor neuropathy, retinopathy
Treatment: Not established
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Primary oxaluria
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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
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Hyperoxaluria type 1 (259900)
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Peroxisomal alanine-glyoxylate aminotransferase
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AGXT (2q36-q37)*
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Hyperoxaluria type 2 (260000)
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D-Glycerate dehydrogenase glyoxylate reductase
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GRHPR (9cen)*
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Refsum's disease (266500)
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Phytanoyl-CoA hydroxylase
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PAHX (10pter-p11.2)*
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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
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Peorxin-7
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PEX7 (6q22-q24)*
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Glutaric aciduria type 3 (231690)
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Peroxisomal glutaryl CoA oxidase
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Biochemical profile: Glutaric aciduria exacerbated by lysine loading
Clinical features: Failure to thrive, postprandial vomiting
Treatment: Not established
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Mevalonic aciduria
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See Table1sec19ch296
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—
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—
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Acatalasemia (115500)
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Catalase
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CAT (11p13)*
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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
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Disorders of glycerol metabolism
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Glycerol kinase deficiency (307030)
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Glycerol kinase
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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)
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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
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Glycerol intolerance syndrome
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—
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—
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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
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Disorders of ketone metabolism
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3-Hydroxy-3-methylglutaryl-CoA synthase deficiency (605911)
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3-Hydroxy-3-methylglutaryl-CoA synthase
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HMGCS2 (600234)
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Biochemical profile: See below
Clinical features: Episodic nonketotic hypoglycemia
Treatment: Avoidance of fasting
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3-Hydroxy-3-methylglutaryl-CoA lyase deficiency
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See Table2sec19ch296
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—
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—
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Succinyl-CoA 3-oxoacid-CoA transferase deficiency (245050)
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Succinyl-CoA 3-oxoacid-CoA transferase
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OXCT (5p13)*
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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
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Mitochondrial acetoacetyl-CoA thiolase deficiency (607809)
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See Table1sec19ch296
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—
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—
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Cytoplasmic acetoacetyl-CoA thiolase deficiency (100678)
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Cytoplasmic acetoacetyl-CoA thiolase
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ACAT2 (6q25.3-q26)
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Biochemical profile: Nonspecific
Clinical features: Intellectual disability, hypotonia
Treatment: Not established
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Other disorders of fat metabolism
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Sjögren-Larsson syndrome (270200)
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Fatty aldehyde dehydrogenase
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ALDH3A2 (17p11.2)*
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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
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*Gene has been identified, and molecular basis has been elucidated.
HELLP = hemolysis, elevated liver enzymes, and low platelet count; OMIM = online mendelian inheritance in man (see database at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM).
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Disorders of the β-Oxidation Cycle
In these processes, there are numerous inherited defects, which typically manifest during fasting with hypoglycemia and acidosis; some cause cardiomyopathy and muscle weakness.
Acetyl CoA is generated from fatty acids through repeated β-oxidation cycles. Sets of 4 enzymes (an acyl dehydrogenase, a hydratase, a hydroxyacyl dehydrogenase, and a lyase) specific for different chain lengths (very long chain, long chain, medium chain, and short chain) are required to catabolize a long-chain fatty acid completely. Inheritance for all fatty acid oxidation defects is autosomal recessive.
Medium-chain acyl dehydrogenase deficiency (MCADD):
This deficiency is the most common defect in the β-oxidation cycle and has been incorporated into expanded neonatal screening in many states.
Clinical manifestations typically begin after 2 to 3 mo of age and usually follow fasting (as little as 12 h). Patients have vomiting and lethargy that may progress rapidly to seizures, coma, and sometimes death (which can also appear as SIDS). During attacks, patients have hypoglycemia, hyperammonemia, and unexpectedly low urinary and serum ketones. Metabolic acidosis is often present but may be a late manifestation.
Diagnosis is by detecting medium-chain fatty acid conjugates of carnitine in plasma or glycine in urine or by detecting enzyme deficiency in cultured fibroblasts; however, DNA testing can confirm most cases.
Treatment of acute attacks is with 10% dextrose IV at 1.5 times the fluid maintenance rate (see Dehydration and Fluid Therapy in Children: Maintenance requirements); some clinicians also advocate carnitine supplementation during acute episodes. Prevention is a low-fat, high-carbohydrate diet and avoidance of prolonged fasting. Cornstarch therapy is often used to provide a margin of safety during overnight fasting.
Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD):
This deficiency is the 2nd most common fatty acid oxidation defect. It shares many features of MCADD, but patients may also have cardiomyopathy; rhabdomyolysis, massive creatine kinase elevations, and myoglobinuria with muscle exertion; peripheral neuropathy; and abnormal liver function. Mothers with an LCHADD fetus often have HELLP syndrome (hemolysis, elevated liver enzymes, low platelets—see Abnormalities of Pregnancy: Diagnosis) during pregnancy.
Diagnosis is based on the presence of excess long-chain hydroxy acids on organic acid analysis and on the presence of their carnitine conjugates in an acylcarnitine profile or glycine conjugates in an acylglycine profile. LCHADD can be confirmed by enzyme study in skin fibroblasts.
Treatment during acute exacerbations includes hydration, high-dose glucose, bed rest, urine alkalinization, and carnitine supplementation. Long-term treatment includes a high-carbohydrate diet, medium-chain triglyceride supplementation, and avoidance of fasting and strenuous exercise.
Very long-chain acyl-coA dehydrogenase deficiency (VLCADD):
This deficiency is similar to LCHADD but is commonly associated with significant cardiomyopathy.
Glutaric acidemia type II:
A defect in the transfer of electrons from the coenzyme of fatty acyl dehydrogenases to the electronic transport chain affects reactions involving fatty acids of all chain lengths (multiple acyl-coA dehydrogenase deficiency); oxidation of several amino acids is also affected.
Clinical manifestations thus include fasting hypoglycemia, severe metabolic acidosis, and hyperammonemia.
Diagnosis is by increased ethylmalonic, glutaric, 2- and 3-hydroxyglutaric, and other dicarboxylic acids in organic acid analysis, and glutaryl and isovaleryl and other acylcarnitines in tandem mass spectrometry studies. Enzyme deficiencies in skin fibroblasts can be confirmatory.
Treatment is similar to that for MCADD, except that riboflavin may be effective in some patients.
Disorders of Glycerol Metabolism
Glycerol is converted to glycerol-3-phosphate by the hepatic enzyme glycerol kinase; deficiency results in episodic vomiting, lethargy, and hypotonia.
Glycerol kinase deficiency is X-linked; many patients with this deficiency also have a chromosomal deletion that extends beyond the glycerol kinase gene into the contiguous gene region, which contains the genes for congenital adrenal hypoplasia and Duchenne muscular dystrophy. Thus, patients with glycerol kinase deficiency may have one or more of these disease entities.
Symptoms begin at any age and are usually accompanied by acidosis, hypoglycemia, and elevated blood and urine levels of glycerol.
Diagnosis is by detecting an elevated level of glycerol in serum and urine and is confirmed by DNA analysis.
Treatment is with a low-fat diet, but glucocorticoid replacement is critical for those with adrenal hypoplasia.
Last full review/revision February 2010 by Chin-To Fong, MD
Content last modified February 2012
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