Adult‐onset very‐long‐chain acyl‐CoA dehydrogenase deficiency (VLCADD)

Abstract

Background and purpose: Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a hereditary disorder of mitochondrial long-chain fatty acid oxidation that has variable presentations, including exercise intolerance, cardiomyopathy and liver disease. The aim of this study was to describe the clinical and genetic manifestations of six patients with adult-onset VLCADD. Methods: In this study, the clinical, pathological and genetic findings of six adult patients (four from Iran and two from Serbia) with VLCADD and their response to treatment are described. Results: The median (range) age of patients at first visit was 31 (27-38) years, and the median (range) age of onset was 26.5 (19-33) years. Parental consanguinity was present for four patients. Four patients had a history of rhabdomyolysis, and the recorded CK level ranged between 67 and 90 000 IU/l. Three patients had a history of exertional myalgia, and one patient had a nonfluctuating weakness. Through next-generation sequencing analysis, we identified six cases with variants in the ACADVL gene and a confirmed diagnosis of VLCADD. Of the total six variants identified, five were missense, and one was a novel frameshift mutation identified in two unrelated individuals. Two variants were novel, and three were previously reported. We treated the patients with a combination of L-carnitine, Coenzyme Q10 and riboflavin. Three patients responded favorably to the treatment. Conclusion: Adult-onset VLCADD is a rare entity with various presentations. Patients may respond favorably to a cocktail of L-carnitine, Coenzyme Q10, and riboflavin.

Very Long-Chain Acyl-CoA Dehydrogenase Deficiency: High Incidence of Detected Patients With Expanded Newborn Screening Program

“…Variant c.1358G > A was also detected on three alleles. The same variant was described in a homozygous state in two adult patients from Serbia (Fatehi et al, 2020). Enzyme activity was grossly reduced in all five patients (P1-P5) and reduced to about 50% of the lower limit in three carriers (P10-P12) tested, which is in agreement with claims in literature (Leslie et al, 1993;Tajima et al, 2008).…”

“…In Southeastern Europe there is currently no NBS for VLCADD in a majority of the countries with exception of Slovenia and Croatia (Groselj et al, 2014a(Groselj et al, ,b, Šmon et al, 2015Bilandžija et al, 2018;Smon et al, 2018;Lampret et al, 2020;Loeber et al, 2021), which would detect more patients than are diagnosed clinically. To the best of our knowledge, only two adult patients with VLCADD were described so far in Southeastern Europe (Fatehi et al, 2020). Our study presents one of the first descriptions of ACADVL variants in Central-Southeastern Europe, detected after implementation of an expanded NBS, showing potentially higher incidence throughout the region as compared to the expected incidence from the literature.…”

A Young Female With Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD): A Case Report

“…Rhabdomyolysis has been reported as a presenting feature both at diagnosis and during a metabolic crisis in patients with fatty acid oxidation disorders, namely, MCADD and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) [4,5]. Rhabdomyolysis is characterized by acute and often severe skeletal muscle damage resulting in the release of intracellular muscle components into the bloodstream frequently resulting in myoglobinuria and, in severe cases, acute renal failure [6,7].…”

Juvenile-Onset Recurrent Rhabdomyolysis Due to Compound Heterozygote Variants in the ACADVL Gene

“…Clinical manifestations of VLCADD range from severe systemic involvement to mild episodic symptoms, thus leading to frequent misdiagnosis or “non-diagnosis” [ 19 ]. Especially, the adult-onset phenotype may be clinically non-specific, and this results in a frequent diagnostic delay [ 19 ].…”

“…Clinical manifestations of VLCADD range from severe systemic involvement to mild episodic symptoms, thus leading to frequent misdiagnosis or “non-diagnosis” [ 19 ]. Especially, the adult-onset phenotype may be clinically non-specific, and this results in a frequent diagnostic delay [ 19 ]. The patient is usually asymptomatic, and serum CK may be normal between acute attacks, thus inducing non-expert practitioners to rule out a muscular disease [ 15 ].…”