Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant

Dipti Baskar; Kiran Polavarapu; Veeramani Preethish-Kumar; Seena Vengalil; Saraswati Nashi; Ana Töpf; Aneesha Thomas; Sai Bhargava Sanka; Deepak Menon; Kosha Srivastava; Gautham Arunachal; Bevinahalli N Nandeesh; Hanns Lochmüller; Atchayaram Nalini

doi:10.1212/NXG.0000000000200122

Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant

Neurol Genet. 2024 Jan 3;10(1):e200122. doi: 10.1212/NXG.0000000000200122. eCollection 2024 Feb.

Affiliation

¹ From the Department of Neurology (D.B., S.V., S.N., A. Thomas, S.B.S., D.M., K.S., A.N.), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India; Children's Hospital of Eastern Ontario Research Institute (K.P., H.L.), Ottawa, Canada; Department of Neurology (V.P.-K.), Swansea University, Wales, United Kingdom; Brain and Mind Research Institute (H.L.), University of Ottawa; Division of Neurology (H.L.), Department of Medicine, The Ottawa Hospital, Canada; Centro Nacional de Análisis Genómico (CNAG-CRG) (H.L.), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Catalonia, Spain; Department of Neuropediatrics and Muscle Disorders (H.L.), Medical Center-University of Freiburg, Faculty of Medicine, Germany; John Walton Muscular Dystrophy Research Centre (A. Töpf), Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, United Kingdom; Department of Human Genetics (G.A.); and Department of Neuropathology (B.N.N.), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.

Abstract

Background and objectives: Distal myopathies are a heterogeneous group of primary muscle disorders with recessive or dominant inheritance. ADSSL1 is a muscle-specific adenylosuccinate synthase isoform involved in adenine nucleotide synthesis. Recessive pathogenic variants in the ADSSL1 gene located in chromosome 14q32.33 cause a distal myopathy phenotype. In this study, we present the clinical and genetic attributes of 6 Indian patients with this myopathy.

Methods: This was a retrospective study describing on Indian patients with genetically confirmed ADSSL1 myopathy. Details were obtained from the medical records.

Results: All patients presented in their first or early second decade. All had onset in the first decade with a mean age at presentation being 17.7 ± 8.4 years (range: 3-27 years) and M:F ratio being 1:2. The mean disease duration was 9.3 ± 5.2 years ranging from 2 to 15 years. All patients were ambulant with wheelchair bound state in 1 patient due to respiratory involvement. The median serum creatine kinase (CK) level was 185.5 IU/L (range: 123-1564 IU/L). In addition to salient features of ptosis, cardiac involvement, bulbar weakness, and proximo-distal limb weakness with fatigue, there were significant seasonal fluctuations and decremental response to repetitive nerve stimulation, which have not been previously reported. Muscle histopathology was heterogenous with the presence of rimmed vacuoles, nemaline rods, intracellular lipid droplets along with chronic myopathic changes. Subtle response to pyridostigmine treatment was reported. While 5 of 6 patients had homozygous c.781G>A (p.Asp261Asn) variation, 1 had homozygous c.794G>A (p.Gly265Glu) in ADSSL1 gene.

Discussion: This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients.