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.

Fig. 1

Muscle MRI imaging in patient 3 (a, b, c) and patient 4 (d, e, f) using T1 sequences (a, d, c, f) and STIR sequences (b, e). Note atrophy of the thigh muscles (a, b) and in the leg muscles (c) in patient 3, while thigh muscles (d, e) and leg muscles (f) in patient 4 are not atrophic. Note hyper-intense signal in STIR sequences at the thigh level (b, e) due to myo-oedema

Fig. 2

Muscle biopsy morphology in patient 3 (a, b, c) and patient 4 (d, e, f) stained for hematoxylin-eosin (a, d), Gomori trichrome (b, e), and Oil-Red-O (c, f). Note that in patient 3 there is lipid storage and fibre size variability, whereas in patient 4 there are many atrophic fibres (d, e) and lipid storage (f). The atrophy is likely due to a prolonged steroid treatment