Clear Correlation of Genotype with Disease Phenotype in Very–Long-Chain Acyl-CoA Dehydrogenase Deficiency

Abstract

Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial rate-limiting step in mitochondrial fatty acid beta-oxidation. VLCAD deficiency is clinically heterogenous, with three major phenotypes: a severe childhood form, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypoglycemia as the main presenting feature, low mortality, and rare cardiomyopathy; and an adult form, with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria, usually triggered by exercise or fasting. To examine whether these different phenotypes are due to differences in the VLCAD genotype, we investigated 58 different mutations in 55 unrelated patients representing all known clinical phenotypes and correlated the mutation type with the clinical phenotype. Our results show a clear relationship between the nature of the mutation and the severity of disease. Patients with the severe childhood phenotype have mutations that result in no residual enzyme activity, whereas patients with the milder childhood and adult phenotypes have mutations that may result in residual enzyme activity. This clear genotype-phenotype relationship is in sharp contrast to what has been observed in medium-chain acyl-CoA dehydrogenase deficiency, in which no correlation between genotype and phenotype can be established.

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

“…The first subgroup, with neonatal presentation, is characterized by cardiomyopathy and is frequently fatal in early life. The second subgroup presents in infancy, with hypoketosis and hypoglycaemia, and frequently mimics Reye-Syndrome [111,112].…”

“…The third subgroup has a milder phenotype with adolescent to adult onset, with clinical phenotypes including exercise intolerance and myopathies [111]. Deficiencies in the octameric MTP (OMIM #609015) result in mitochondrial disease which is primarily neuropathological.…”

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

“…We used the objectively verifiable signs and symptoms most frequently reported in the literature 12,22,23 (Supplementary Table S1 online) to develop a CSS. The CSS encompasses the following criteria: (i) hypoglycemia (i.e., documented glucose <2.5 mmol/l); (ii) cardiomyopathy and/or arrhythmia (i.e., documented abnormal results on echocardiography (with left or right ventricular wall thickness of at least one segment >2 SD, corrected for age)) and/or electrocardiogram abnormalities; and (iii) myopathy (i.e., documented creatine kinase concentrations >250 U/L (reference values 70-170 U/L)), as well as at least two of the following clinically relevant symptoms: myoglobulinuria, myalgia, exercise intolerance, muscle weakness (medical research council grade 4 or less), and/or frequent fatigue.…”

“…The available literature is biased by reports of symptomatic patients; consequently, genotype-phenotype correlation studies concern more severe presentations. These studies show that nonsense mutations in the encoding gene (ACADVL) result in a severe and early presentation of cardiomyopathy, [12][13][14] but the more frequent missense mutations are associated with both severe or attenuated presentations. 10 Functional tests, including determination of the residual activity of the VLCAD enzyme, 10,15 have been used to test the effects of various mutations on LC-FAO activity.…”

Activation of PPAR<i>α</i> by Fatty Acid Accumulation Enhances Fatty Acid Degradation and Sulfatide Synthesis

“…VLCAD deficiency is associated with the accumulation of fat in multiple organs and tissues, liver dysfunction, cardiomyopathy, cardiomegaly, muscle weakness, and fasting coma with high frequency (Aoyama et al 1993(Aoyama et al , 1995a. Additionally, mutation analyses have identified a genotype-phenotype relationship for VLCAD deficiency (Aoyama et al 1995a;Souri et al 1996;Andresen et al 1999;Gregersen et al 2001). Mutation analysis of six patients has revealed homozygous loss of 35 amino acids in patients 1 and 6 (Aoyama et al 1995a), homozygous loss of glutamate-130 in patient 2 (Souri et al 1996), point mutation of lysine-382 to glutamine and loss of glutamate-130 in patient 3 (Souri et al 1996), homozygous loss of lysine-299 in patient 4 (Souri et al 1996), and loss of 45 amino acids and point mutation of arginine-613 to tryptophan in patient 5 (Souri et al 1996).…”