| Autor: |
Akram R; Neurochemicalbiology and Genetics Laboratory (NGL), Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan.; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Anwar H; Neurochemicalbiology and Genetics Laboratory (NGL), Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan., Muzaffar H; Neurochemicalbiology and Genetics Laboratory (NGL), Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan., Turchetti V; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Lau T; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Vona B; Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.; Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37075 Göttingen, Germany., Makhdoom EUH; Neurochemicalbiology and Genetics Laboratory (NGL), Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan.; Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, Faisalabad 38000, Pakistan., Iqbal J; Department of Neurology, Allied Hospital, Faisalabad Medical University, Faisalabad 38000, Pakistan., Mahmood Baig S; Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, Faisalabad 38000, Pakistan.; Department of Biological and Biomedical Sciences, Aga Khan University, Stadium Road, Karachi 74000, Pakistan., Hussain G; Neurochemicalbiology and Genetics Laboratory (NGL), Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan., Efthymiou S; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Houlden H; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK. |
| Abstrakt: |
Background and objectives: Hereditary spastic paraplegia (HSP) is characterized by unsteady gait, motor incoordination, speech impairment, abnormal eye movement, progressive spasticity and lower limb weakness. Spastic paraplegia 75 (SPG75) results from a mutation in the gene that encodes myelin associated glycoprotein (MAG). Only a limited number of MAG variants associated with SPG75 in families of European, Middle Eastern, North African, Turkish and Palestinian ancestry have been documented so far. This study aims to provide further insight into the clinical and molecular manifestations of HSP. Methods: Using whole-exome sequencing, we investigated a consanguineous Pakistani family where three individuals presented with clinical signs of HSP. Sanger sequencing was used to carry out segregation analysis on available family members, and a minigene splicing assay was utilized to evaluate the effect of the splicing variant. Results: We identified a novel homozygous pathogenic splice donor variant in MAG (c.46 + 1G > T) associated with SPG75. RNA analysis revealed exon skipping that resulted in the loss of a start codon for ENST00000361922.8 isoform. Affected individuals exhibited variable combinations of nystagmus, developmental delay, cognitive impairments, spasticity, dysarthria, delayed gait and ataxia. The proband displayed a quadrupedal stride, and his siblings experienced frequent falls and ataxic gait as one of the prominent features that have not been previously reported in SPG75. Conclusions: Thus, the present study presents an uncommon manifestation of SPG75, the first from the Pakistani population, and broadens the spectrum of MAG variants. |
