Yuval Yogev1, Jacob Bistritzer2, Yair Sadaka3,4, Analia Michaelovsky2, Yuval Cavari5, Yael Feinstein5, Munir Abu-Madegem6, Yakov Fellig7, Ohad Wormser1, Max Drabkin1, Daniel Halperin1, Ohad S Birk8,9. 1. The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel. 2. Pediatric Neurology Unit, Faculty of Health Sciences, Soroka Medical Center, Joyce and Irving Goldman Medical School, Ben-Gurion University of the Negev, Beer-Sheva, Israel. 3. The Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. 4. Neuro-Developmental Research Center, Mental Health Institute, Beer Sheva, Israel. 5. The Pediatric Intensive Care Unit, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel. 6. Pediatric Neurology and Child Development Units, Clalit Health Services, Hadarom, Israel. 7. Department of Pathology, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel. 8. The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel. obirk@bgu.ac.il. 9. Genetics Institute, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel. obirk@bgu.ac.il.
Abstract
INTRODUCTION: Congenital myopathies are a broad group of inborn muscle disorders caused by a multitude of genetic factors, often characterized by muscle atrophy and hypotonia. METHODS: Clinical studies, imaging, histology, whole-exome sequencing (WES) and muscle tissue RNA studies. RESULTS: We describe a severe congenital myopathy manifesting at birth with bilateral clubfeet, delayed motor development and hypotonia, becoming evident by 4 months of age. At 3 years of age, the patient had tongue fasciculations, was bedridden, and was chronically ventilated via tracheostomy. Imaging studies demonstrated severe muscle atrophy and, surprisingly, cerebral atrophy; electromyography demonstrated a myasthenic pattern and histological evaluation did not facilitate a definitive diagnosis. Trio WES did not identify a causative variant, except for a non-canonical intronic TPM3 c.118-12G>A variant of uncertain significance. Transcript analysis of muscle tissue from the patient proved the pathogenicity of this homozygous variant, with a 97% reduction in the muscle-specific TPM3.12 transcript. DISCUSSION: This study broadens the phenotypic spectrum of recessive TPM3 disease, highlighting tongue fasciculations and bilateral clubfoot, as well as possibly-related cerebral atrophy. It also shows the importance of a broad approach to genetic analysis and the utility of RNA-based studies, demonstrating efficacy of early genome and transcriptome queries in facilitating rapid and cost-effective diagnosis of congenital myopathies.
INTRODUCTION: Congenital myopathies are a broad group of inborn muscle disorders caused by a multitude of genetic factors, often characterized by muscle atrophy and hypotonia. METHODS: Clinical studies, imaging, histology, whole-exome sequencing (WES) and muscle tissue RNA studies. RESULTS: We describe a severe congenital myopathy manifesting at birth with bilateral clubfeet, delayed motor development and hypotonia, becoming evident by 4 months of age. At 3 years of age, the patient had tongue fasciculations, was bedridden, and was chronically ventilated via tracheostomy. Imaging studies demonstrated severe muscle atrophy and, surprisingly, cerebral atrophy; electromyography demonstrated a myasthenic pattern and histological evaluation did not facilitate a definitive diagnosis. Trio WES did not identify a causative variant, except for a non-canonical intronic TPM3 c.118-12G>A variant of uncertain significance. Transcript analysis of muscle tissue from the patient proved the pathogenicity of this homozygous variant, with a 97% reduction in the muscle-specific TPM3.12 transcript. DISCUSSION: This study broadens the phenotypic spectrum of recessive TPM3 disease, highlighting tongue fasciculations and bilateral clubfoot, as well as possibly-related cerebral atrophy. It also shows the importance of a broad approach to genetic analysis and the utility of RNA-based studies, demonstrating efficacy of early genome and transcriptome queries in facilitating rapid and cost-effective diagnosis of congenital myopathies.
Authors: Steven Marston; Massimiliano Memo; Andrew Messer; Maria Papadaki; Kristen Nowak; Elyshia McNamara; Royston Ong; Mohammed El-Mezgueldi; Xiaochuan Li; William Lehman Journal: Hum Mol Genet Date: 2013-07-25 Impact factor: 6.150
Authors: K Kiiski; V-L Lehtokari; A Y Manzur; C Sewry; I Zaharieva; F Muntoni; K Pelin; C Wallgren-Pettersson Journal: J Neuromuscul Dis Date: 2015-09-21