Heterogeneous Phenotypes in Lipid Storage Myopathy Due to ETFDH Gene Mutations

Abstract

We present six novel patients affected by lipid storage myopathy (LSM) presenting mutations in the ETFDH gene. Although the diagnosis of multiple acyl-coenzyme-A dehydrogenase deficiency (MADD) in adult life is difficult, it is rewarding because of the possibility of treating patients with carnitine or riboflavin, leading to a full recovery. In our patients, a combination of precipitating risk factors including previous anorexia, alcoholism, poor nutrition, and pregnancy contributed to a metabolic critical condition that precipitated the catabolic state.In the present series of cases, five novel mutations have been identified in the ETFDH gene. We propose clinical guidelines to screen patients with LSM due to different defects, in order to obtain a fast diagnosis and offer appropriate treatment. In such patients, early diagnosis and treatment as well as avoiding risk factors are part of clinical management.Specific biochemical studies are indicated to identify the type of LSM, such as level of free carnitine and acyl-carnitines and studies or organic acidemia. Indeed, when a patient is biochemically diagnosed with secondary carnitine deficiency, a follow-up with appropriate clinical-molecular protocol and genetic analysis is important to establish the final diagnosis, since riboflavin can be supplemented with benefit if riboflavin-responsive MADD is present. In muscle biopsies, increased lipophagy associated with p62-positive aggregates was observed. The clinical improvement can be attributed to the removal of an autophagic block, which appears to be reversible in this LSM.

Patient with multiple acyl-CoA dehydrogenase deficiency disease and ETFDH mutations benefits from riboflavin therapy: a case report

“…Due to its wide variety of clinical symptoms, LSM is difficult to diagnose. For cases highly suggestive of MADD, genetic analysis of ETFDH gene is highly recommended as vast majority of patients carry mutations in this gene [ 29 ]. For LSM, a large number of genes are implicated and targeted screening using Sanger sequencing will be an expensive and tedious option.…”

Novel ETFDH mutations in four cases of riboflavin responsive multiple acyl-CoA dehydrogenase deficiency

“…Thus, MADD may be misdiagnosed as a different type of lipid storage myopathy, a glycogen storage disease, progressive muscular dystrophy, or other muscle disease [ 15 ]. Muscle biopsy has traditionally been diagnostically important to differentiate MADD from other muscle diseases, as muscle biopsy showing accumulation of lipid droplets in muscle fibers in combination with the biochemical pattern of acylcarnitines and urine organic acids can confirm the MADD diagnosis [ 16 ].…”

A Synonymous Variant c.579A>G in the ETFDH Gene Caused Exon Skipping in a Patient With Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Case Report

“…Multiple acyl-CoA dehydrogenase deficiency (MADD; OMIM #231680), also known as glutaric acidemia II or glutaric aciduria II, is an autosomal recessive inherited disorder of fatty acid, amino acid, and choline metabolism. MADD is divided into three clinical types: the neonatal onset form with (type I) or without (type II) congenital anomalies, and the late-onset form (type III) (1,2). The neonatal-onset forms are usually fatal characterized by severe non-ketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid-and amino acid-derived metabolites, while the late-onset form is milder and more variable characterized by recurrent episodes of hypoglycemia, metabolic acidosis, vomiting, and muscle weakness during catabolic stress (3).…”