Mutation Spectrum of Primary Lipid Storage Myopathies

Abstract

Background: Lipid storage myopathies (LSM) constitute an important group of treatable myopathies. Genetic testing is essential for confirming the diagnosis and also helps in explaining phenotypic heterogeneity. The objective of this study was to describe the clinical features and genetic spectrum of LSM seen in a quaternary referral center in India. Methods: Eleven cases of suspected LSM underwent clinical, biochemical, histopathological and genetic evaluation. Tandem Mass Spectrometry and clinical exome sequencing with Sanger validation were performed. Results: All patients had exertion induced myalgia and either progressive or episodic limb girdle muscle weakness (LGMW). The age of onset ranged 10 to 31 years (mean- 21 ± 6.7y), age at presentation- 14 to 49 years (mean- 26.5 ± 9.5y). Mutations identified: ETFDH = 5, CPT2 = 3, FLAD1 = 1, ACADVL = 1, FLAD1 = 1. Dropped head syndrome was seen in two patients with ETFDH mutations. Bulbar symptoms and Beevor's sign were noted in a patient with FLAD1 variant. Novel variants were identified in seven patients. Conclusions: This is the first report on the genetic spectrum of LSM from India. LSM should be considered in patients with exertion induced myalgias, LGMW, cranial nerve involvement or dropped head syndrome. Genetic testing is essential for identification of these treatable disorders.

A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene

“…We reviewed literature and listed a summary of 18 cases with MADD/GAII caused by FLAD1 variants including the present case (Supplemental material 3), in which 10 patients were proved with full or partial ribo avin responsiveness(Full ribo avin responsiveness: After ribo avin treatment, the symptoms including muscle weakness disappear and the patient returns to a normal life. Partial ribo avin responsiveness: After ribo avin treatment, the symptoms are partially improved, the patient' condition is stable but not normal) [9,17,[19][20][21][22][23]. The comparison between 10 FLAD1-RRMADD (9 cases from literature and the present case) and 106 ETFDH-RRMADD (in our neuromuscular center) was shown in Table 1.…”

“…To date, there were totally 17 MADD/GAII cases from 9 countries caused by FLAD1 variants according to the publications until April, 2022 [9,17,[19][20][21][22][23][24][25][26]. Among those cases, 9 patients were proved with full or partial ribo avin responsiveness.…”

Detection of FLAD1 mutations and lipid storage myopathy in a 5-year-old boy: a case report study

“…If the disease is not confirmed, riboflavin should be stopped 12 . Prenatal or postnatal treatment of patients with FADS deficiency with high-dose riboflavin, which may prevent or improve disease symptoms, has been suggested, but further investigation and studies are needed 13 .…”

Inherited metabolic disorders in adults: systematic review on patient characteristics and diagnostic yield of broad sequencing techniques (exome and genome sequencing)

“…Diagnosing IMD in adulthood has its specific challenges. First the attenuated phenotypes of many IMD are far less well described in literature compared to the early onset phenotypes seen in children ( 6 , 8 , 12 – 15 ). Second, the symptoms related to the genetic disorder are often combined with acquired symptoms (resulting from factors such as obesity, smoking etc.)…”