It should not be confused with glutaric acidemia type I (see Chapter 54). When the enzyme essentially is nonfunctional, congenital anomalies are common, including renal cysts, facial abnormalities, rocker-bottom feet, and hypospadias. Severely affected infants have nonketotic hypoglycemia, metabolic acidosis, and the odor of sweaty feet soon after birth; these infants may die within the neonatal period. Less severely affected infants may have a more episodic, Reye syndrome–like illness. Skeletal and cardiac myopathy can be prominent in this complex, multisystemic disease. Onset in later childhood may be marked by recurrent hypoglycemia and myopathy. Treatment has not been effective in infants with complete deficiency. Milder forms respond to avoidance of fasting and caloric support during metabolic stress. Some patients respond to administration of riboflavin. Glutaric aciduria type II exhibits autosomal recessive inheritance. Confirmatory testing is similar to that for the other fatty acid oxidation disorders.
Carnitine is a crucial cofactor in the transport of long-chain fatty acids across the mitochondrial inner membrane (see Fig. 55-1). It is synthesized from lysine by humans and is present in dietary red meat and dairy products. Carnitine deficiency is either primary (caused by failure of intake, synthesis, or transport of carnitine) or secondary (caused by the excretion of excessive amounts of carnitine as carnityl esters in patients with other inborn errors of metabolism; treatment with drugs that complex carnitine, such as valproic acid; or as a result of renal replacement therapy). Primary systemic carnitine deficiency is rare and results from inadequate renal reabsorption of carnitine secondary to a mutation in the sodium-dependent carnitine transporter. It responds well to carnitine supplementation. There are numerous examples of secondary carnitine deficiency among the organic acidurias, most prominently in disorders of the propionate pathway and in disorders of the β-oxidation of long-chain and medium-chain fatty acids. Clinical manifestations of carnitine deficiency include hypoketotic hypoglycemia, lethargy, lassitude, muscle weakness, sudden death, and cardiomyopathy.
Peroxisomes are subcellular organelles involved in metabolism and biosynthesis of bile acids, membrane phospholipids, and some β-oxidation of long-chain fatty acids. Disorders include conditions caused by abnormal peroxisomal enzyme function and abnormal peroxisomal biogenesis. Clinical symptoms are diverse and frequently include developmental delay and dysmorphic features that can involve the skeleton and the head. Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease are examples of disorders of peroxisome biogenesis. Zellweger syndrome, an autosomal recessive disease (1:100,000 births), is also called cerebrohepatorenal syndrome. Peroxisomes are virtually absent, as are normal peroxisomal functions, which include the oxidation of very long chain fatty acids. Affected infants have high
Table 56-1 Lysosomal Storage Diseases DISEASE (EPONYM) ENZYME DEFICIENCY CLINICAL ONSET DYSOSTOSIS MULTIPLEX CORNEA RETINA LIVER, SPLEEN CNS FINDINGS STORED MATERIAL IN URINE WBC/BONE MARROW COMMENT MULTIPLE FORMS MUCOPOLYSACCHARIDOSES (MPS)
MPS I (Hurler) α-L-Iduronidase ∼1 yr Yes Cloudy — Both enlarged Profound loss of Acid mucopoly-Alder-Reilly Kyphosis Yes— function saccharide bodies (WBC) Scheie and compounds