Knowledge on rare diseases and orphan drugs

The worldwide birth prevalence is estimated at 1/250,000. However around the Baltic Sea the frequency is higher; birth prevalence is predicted to be 1/120,000 in Poland and 1/20,000 in the Pomeranian district.

Most patients display a severe phenotype that presents in infancy, usually from the neonatal period up until 12 months of age. The disease manifests as hypoketotic hypoglycemia, metabolic acidosis, hypotonia, liver involvement with hepatic encephalopathy, cardiomyopathy and arrhythmias. Clinical presentation is frequently preceded by fasting and/or intercurrent illness and often presents with hypoketotic hypoglycemia. Chronic peripheral neuropathy and pigmentary retinopathy develop over time in many surviving patients. Rarer presentations of LCHADD are sudden cardiac arrest or sudden infant death. HELLP syndrome often occurs in pregnant women carrying a fetus affected with LCHADD.

LCHADD is caused by the isolated deficiency of long chain 3-hydroxyacyl-CoA dehydrogenase, an enzyme of the mitochondrial trifunctional protein complex (TFP). TFP is a heterooctamer of 4 alpha and 4 beta subunits. LCHADD is due to mutations in the HADHA gene (2p23) which encodes for the alpha subunit of TFP. The majority of patients with LCHADD of European origin are homozygous for the common LCHADD alpha-subunit mutation 1528G>C, that is located at the catalytic site of the LCHAD domain.

Urine organic acids show a C6-C14 (hydroxy) dicarboxylic aciduria. Blood acylcarnitine analysis shows increased long chain hydroxyacylcarnitine species (C14-OH, C16-OH, C18-OH, and C18:1-OH). Confirmation is by molecular analysis of the HADHA gene that frequently demonstrates homozygocity for the 1528G>C mutation. Enzyme analysis of cultured fibroblasts or lymphocytes shows isolated deficiency of long chain 3-hydroxyacyl-CoA dehydrogenase activity. Newborn screening for LCHADD is available in Austria, Czech Republic, Denmark, Germany, Hungary, Iceland, Netherlands and Portugal.

Mitochondrial trifunctional protein deficiency (TFPD) is clinically indistinguishable from LCHADD. Some patients present as sudden infant death so this also needs to be excluded.

Prenatal diagnosis is by molecular analysis for established mutation(s) within the family and/or by measuring enzyme activity in chorionic villi samples.

LCHADD is inherited autosomal recessively and genetic counseling is available.

Treatment involves strict adherence to a low fat diet with restriction of long chain fatty acid intake and substitution with medium chain fatty acids and avoidance of fasting as well as limitation of exercise or exposure to environmental extremes. An emergency regimen should be available for all patients and medical attention should be sought at the first sign of any decompensation. Treatment is lifelong.

The prognosis for clinically detected LCHADD patients was generally poor but due to early detection and current treatments, it is improving, with a significant number of patients surviving into adulthood.

Last update: February 2014 - Expert reviewer(s): Dr Simon OLPIN