Familial combined hyperlipidemia in children: clinical expression, metabolic defects, and management.

Familial combined hyperlipidemia (FCHL) is a dominantly inherited hyperlipidemia that occurs in at least 1% of the adult population and is responsible for 10% of premature coronary artery disease. In families referred for evaluation because of primary hyperlipidemia in a child, FCHL is expressed three times more commonly than familial hypercholesterolemia and half of the siblings are affected. Several metabolic defects apparently are associated with the FCHL phenotype. Most commonly, excess production of very low density lipoprotein apolipoprotein B can be demonstrated. In other families, reduced lipoprotein lipase activity is associated. One allele at a locus influencing apolipoprotein B levels predicts FCHL in a large proportion of families ascertained through affected children. Whether this allele is responsible for the excess of very low density lipoprotein apolipoprotein B detected in metabolic studies has not been elucidated. Management of FCHL in children begins with dietary modification. A bile acid sequestrant may be considered as well if diet cannot reduce the plasma low-density lipoprotein cholesterol level to less than 4.13 mmol/L (160 mg/dl) after the age of 10 years. Although the hydroxymethylglutaryl-coenzyme A reductase inhibitors are not currently recommended for children younger than 19 years of age, we speculate that they will be increasingly utilized for the management of FCHL in teenage boys who continue to have low density lipoprotein cholesterol levels greater than 4.13 mmol/L (160 mg/dl) after dietary modification.

Use of cholestyramine in the treatment of children with familial combined hyperlipidemia.

We studied the effectiveness of and compliance with the use of cholestyramine in children with heterozygous familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCHL). During a 10-year period, 673 children (aged 10.5 +/- 4.0 years) were referred for evaluation of hyperlipidemia, of whom 87 (36 with FH; 51 with FCHL) were treated with cholestyramine (8 to 24 gm/day). In both groups, total cholesterol, low-density lipoprotein (LDL)-cholesterol, and apolipoprotein B levels were significantly reduced after cholestyramine use. In those with FH, plasma LDL-cholesterol levels decreased from 258 +/- 35 mg/dl (6.67 +/- 0.90 mmol/L) to 190 +/- 31 mg/dl (4.91 +/- 0.80 mmol/L); in those with FCHL, LDL-cholesterol levels dropped from 207 +/- 40 mg/dl (5.35 +/- 1.03 mmol/L) to 141 +/- 35 mg/dl (3.64 +/- 0.90 mmol/L). High-density lipoprotein-cholesterol levels were not significantly changed after cholestyramine use in either group. In the FCHL group, plasma triglyceride levels increased significantly from 81 +/- 35 mg/dl (0.92 +/- 0.40 mmol/L) to 134 +/- 42 mg/dl (1.52 +/- 0.48 mmol/L). Seven patients were lost to follow-up; 18 discontinued the medication within 1 month. Of the remaining 62 children, 59 had a good response to the drug. Of the 62 patients, 52 discontinued the medication after 21.9 +/- 10 months. Adverse effects included foul taste (73%), nausea with bloating (18%), and constipation. Cholestyramine is effective in reducing LDL-cholesterol levels in children with inherited hyperlipidemia, but the majority of children will not comply with its long-term use.

Atypical features of the hepatic form of carnitine palmitoyltransferase deficiency in a Hutterite family.

We describe hepatic carnitine palmitoyltransferase (CPT I) deficiency in three children (a brother and sister and their second cousin) from an extended inbred Hutterite kindred. 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 two Reye syndrome-like episodes. Abnormal organic acids were rarely detected in urine. Serum total and free carnitine levels were elevated in all three patients. Fibroblast acyl-coenzyme A dehydrogenase activities were normal in all, but palmitic acid oxidation, performed in fibroblasts from one patient, was less than 10% of control values. Activity of CPT I in cultured skin fibroblasts from the three patients was 10% to 15% of control levels; CPT II activity was normal. Activity of CPT I and CPT II in muscle from one patient was normal. Atypical features in two of these patients were greatly elevated levels of liver enzymes and creatine kinase during acute episodes. The patients have recently been successfully treated with medium-chain triglycerides and avoidance of fasting. Early identification and treatment of this disorder may avert potentially fatal episodes of hypoglycemia.

Prevalence and expression of familial combined hyperlipidemia in childhood.

The objectives of this study were (1) to determine the incidence of dominantly inherited hyperlipoproteinemia in children referred to our medical center because of hyperlipidemia associated with a family history of premature coronary artery disease and (2) to assess the degree of expression in childhood of the most common inherited hyperlipoproteinemia, familial combined hyperlipidemia. Among 129 families referred to us by area pediatricians, we identified a dominantly inherited hyperlipoproteinemia in 97 of them. Twenty had familial hypercholesterolemia, 65 familial combined hyperlipidemia, 11 hyperapobetalipoproteinemia, and one familial hypertriglyceridemia. As expected, almost half (9/20) of the siblings of probands with familial hypercholesterolemia were affected. Although we expected incomplete gene penetrance in the siblings of the probands with familial combined hyperlipidemia, we found 43 affected and 40 unaffected among the 83 siblings of the 65 probands. Our findings suggest that hyperlipidemia in children, caused by familial combined hyperlipidemia, occurs more than three times as frequently as familial hypercholesterolemia and that in families identified by a child proband, the penetrance is complete. Pediatricians should identify this primary hyperlipidemia in childhood and attempt to prevent the associated risk of premature coronary artery disease by prescribing appropriate diet and life-style modifications.

Genetic polymorphism of esterase B3 in human leukocytes.

Human tissues contain an esterase activity called ESB3, detectable by starch gel electrophoresis followed by staining with alpha-naphthyl butyrate. Using mononuclear leukocytes, we demonstrated an electrophoretic variant of ESB3. Family studies suggest that the variant is inherited as a simple Mendelian trait; individuals with the ESB3 2-1 phenotype are heterozygotes, designated ESB3(1)ESB3(2), to distinguish them from the more common homozygotes, ESB3(1)ESB3(1). The frequency of the ESB3(2) allele is estimated to be 0.035 in U.S. Whites. No homozygotes for this allele have yet been found. Our studies suggest that the enzyme from ESB3 1 individuals exists primarily as a trimer of three identical subunits with a molecular weight of approximately 58,000 daltons. The genetic variant (ESB3(2) allele) appears to be the result of a mutation that does not affect the charge of the subunit, but rather reduces its ability to form and maintain the trimeric structure.

Neonatal presentation of I-cell disease.

Two patients are described in whom the diagnosis of I-cell disease was established in early infancy. These patients lacked many of the clinical and radiographic features described in other children with this disorder. Differences between the neonatal and early childhood presentation of ICD are discussed.