Carnitine Palmitoyltransferase I Deficiency

A number sign (#) is used with this entry because carnitine palmitoyltransferase deficiency I is caused by homozygous or compound heterozygous mutation in the gene encoding carnitine palmitoyltransferase IA (CPT1A; 600528) on chromosome 11q13.

Description

CPT I deficiency is an autosomal recessive metabolic disorder of long-chain fatty acid oxidation characterized by severe episodes of hypoketotic hypoglycemia usually occurring after fasting or illness. Onset is in infancy or early childhood (Bougneres et al., 1981)

Clinical Features

Bougneres et al. (1981) reported 2 sisters who developed severe hypoketotic hypoglycemia at age 8 months, resulting in death in 1 of them. Other features included hepatomegaly, nonketotic hypoglycemia, and coma. Liver CPT activity was absent in the patient who was tested.

Demaugre et al. (1988) reported 2 patients with carnitine palmitoyltransferase deficiency and hepatic symptoms. Biochemical analysis of fibroblasts showed a decrease in CPT1 activity which resulted in impaired long-chain fatty acid oxidation. Bonnefont et al. (1989) reported a patient who presented at age 14 months with seizures and hypoketotic hypoglycemia. Administration of medium-chain triglycerides relieved the hypoglycemia and generated a brisk ketogenesis. Biochemical analysis showed decreased CPT I activity (approximately 10% of controls) in fibroblasts; oxidation of palmitate was about 5% of controls.

Falik-Borenstein et al. (1989) reported a 26-month-old Mexican female born to parents from a sparsely populated genetic isolate. Beginning at 1 year of age, she had suffered 3 severe Reye syndrome-like episodes precipitated by mild viral illnesses. These episodes were characterized by coma, aketotic hypoglycemia, mild hyperammonemia, elevated serum transaminases, elevated plasma free fatty acids, and hepatomegaly with fatty infiltration. Recovery with glucose treatment and other nonspecific measures was accompanied by severe hypertriglyceridemia. Renal tubular acidosis, both proximal and distal, was noted. Within 20 minutes of administration of medium-chain triglycerides, plasma glucose rose to 75 mg/% without hypertriglyceridemia. After 2 months of treatment with medium-chain triglycerides, renal tubular acidosis completely resolved. Falik-Borenstein et al. (1992) reported a girl with CPT I deficiency in whom clinical manifestations began at 14 months of age and were followed by renal tubular acidosis. Therapy with medium-chain triglycerides resulted in the disappearance of the renal defects, catch-up growth within 2 months, and the ability to tolerate viral infections without developing hypoglycemia or other problems.

In a boy with CPT I deficiency, Stanley et al. (1992) found that plasma carnitine levels were twice the normal levels. Urinary dicarboxylic acids were not elevated.

Haworth et al. (1991, 1992) described this disorder in a brother and sister and a female second cousin in an extended Hutterite family. The patients were first seen between 8 and 18 months of age with recurrent episodes of hypoketotic hypoglycemia accompanied by a decreased level of consciousness and hepatomegaly. One patient had 2 Reye syndrome-like episodes. The patients were successfully treated with medium-chain triglycerides and avoidance of fasting.

IJlst et al. (1998) reported a child, born of consanguineous parents, who presented at age 15 months with diarrhea and feeding difficulties. She was hypotonic and lethargic, and physical examination showed hepatomegaly, hypoketotic hypoglycemia, and elevated liver function tests. Biochemical studies showed decreased beta-oxidation of long-chain fatty acids and decreased CPT Ia activity and protein levels.

Innes et al. (2000) reported a 19-year-old Inuit woman who presented in pregnancy with acute fatty liver of pregnancy and hyperemesis gravidarum. Laboratory analysis showed elevated liver enzymes, direct hyperbilirubinemia, and ultrasound findings consistent with fatty liver. After induced labor and delivery, the mother's illness resolved. A second pregnancy was complicated by hyperemesis without documented liver disease. Biochemical analysis showed decreased fibroblast palmitate oxidation in both offspring (34% and 14% of control, respectively) and in the mother (50% of control). Both offspring had complete absence of CPT I activity. Innes et al. (2000) postulated that the defect in long-chain fatty acid oxidation in the fetus produced abnormal metabolites that entered the maternal circulation, leading to liver toxicity, hepatocellular necrosis, and acute fatty liver. The findings increased the spectrum of disorders of the fetus causing maternal liver disease in pregnancy.

Olpin et al. (2001) reported 4 cases of CPT I deficiency in 3 families showing variable renal tubular acidosis, transient hyperlipidemia, and, paradoxically, myopathy with elevated creatine kinase or cardiac involvement in the neonatal period.

Diagnosis

Sim et al. (2001) described a neonate at risk for hepatic CPT I deficiency who was investigated from birth. The free carnitine and acylcarnitine profile in dried whole blood filter paper samples collected at ages 1 and 4 days showed a markedly elevated concentration of free carnitine (141 and 142 micromoles per liter), normal concentrations of acetyl- and propionylcarnitine, with the near absence of all other species. The newborn population distribution of free carnitine (n = 143,981) showed that only 3 samples had free carnitine of greater than 140 micromoles per liter, 2 from CPT I-deficient neonates and 1 from a baby with sepsis. Sim et al. (2001) concluded that whereas there are other conditions that can cause elevated concentrations of free carnitine, an isolated elevation of free carnitine in an apparently healthy term neonate warrants further investigation to exclude CPT I deficiency.

Roomets et al. (2006) reported brain proton MR spectroscopy (MRS) findings in an infant with CPT I deficiency. At age 11 months, she presented with coma after fasting and showed hepatomegaly and metabolic acidosis. Brain MRI was normal, but MRS showed a high N-acetyl aspartate/choline ratio, excess of glutamine/glutamate, and large lipid peaks in the thalamus, white matter, and cortex. Biochemical and genetic analysis confirmed the diagnosis.

Molecular Genetics

In a patient with CPT I deficiency, IJlst et al. (1998) identified a homozygous mutation in the CPT1A gene (600528.0001).

Gobin et al. (2002) characterized 6 novel mutations in 4 CPT1A-deficient patients (600528.0003-600528.0008).