Myofibrillar Myopathy: Clinico-Genetic Spectrum From a Neuromuscular Center in South India.

Objective: Myofibrillar myopathy (MFM) is a group of hereditary neuromuscular disorders with heterogenous manifestations in skeletal and cardiac muscles. Little is known about phenotype-genotype spectrum of MFM in Indian population. This study aims to characterize the clinico-genetic spectrum of 12 MFM ptients from India.

Methods: A detailed description of the clinical, radiological and mutation spectrum of genetically confirmed MFM patients were done.

Results: The M:F ratio was 3:1. Median age of onset, presentation and illness duration were 20 (range: birth - 57 years), 31.5 (range: 6-59 years) and 9 (range: 1 - 28 years) years, respectively. Consanguinity was noted in n = 3 (25%) and motor developmental delay in n = 2 (16.7%). Clinical features noted include ptosis (n = 5, 41.7%) and ophthalmoparesis (n = 3, 25%), bifacial weakness (n = 3, 25%), flaccid dysarthria (n = 3, 41.7%), neck weakness (n = 5, 41.7%), limb-girdle weakness (n = 5, 41.7%), foot drop (n = 1, 8.3%), distal upper limb weakness (n = 2, 16.7%), proximo-distal weakness (n = 5, 41.7%), exertional dyspnoea (n = 4, 33.3%) and joint contractures (n = 8, 66.7%). Cardiac involvement (n = 4, 33.3%) including restrictive, dilated, hypertrophic cardiomyopathy. Median creatine kinase level was 884U/L (range: 347 - 3070 U/L). Muscle biopsy revealed reduced/absent sarcoplasmic desmin expression. Muscle MRI in three patients with predominant fatty infiltration in gluteus maximus and minimus, sartorius, gracilus and semitendinosus in DES; anterior and posterior compartments of distal legs in CRYAB; glutei, hamstrings, adductors of hip and legs with relative sparing of quadriceps, adductor magnus, medial gastrocnemius and peroneal muscles in TTN. Next generation sequencing (NGS) showed the most common gene involved is DES (n = 7, 58.3%) followed by other genes such as HSPB8 (n = 1), FLNC (n = 1), CRYAB (n = 1), LDB3 (n = 1) and TTN (n = 1).

Conclusions: This is the first study on clinic-genetic features of MFM from India. The various novel phenotypes noted in our cohort include: CRYAB with late symptom onset without cardiac or bulbar involvement, LDB3 with early onset limb girdle syndrome, ptosis and FLNC with distal myopathy and cardiomyopathy and HSPB8 with limb girdle syndrome and ptosis, further expanding the phenotypic spectrum of MFM.