Lubov Blumkin1, Teisha Bradshaw2, Marina Michelson3, Tal Kopler4, Dvir Dahari5, Tally Lerman-Sagie1, Dorit Lev3, J Paul Chapple2, Esther Leshinsky-Silver6. 1. Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel; Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 2. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 3. Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 4. Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel. 5. Toldot Genetics Ltd., Tel Aviv, Israel. 6. Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Toldot Genetics Ltd., Tel Aviv, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: leshinsky@wolfson.health.gov.il.
Abstract
BACKGROUND: ARSACS (autosomal-recessive spastic ataxia of Charlevoix-Saguenay) is a neurodegenerative disorder caused by SACS gene mutations and characterized by a triad of symptoms: early-onset cerebellar ataxia, spasticity and peripheral neuropathy. A characteristic retinal nerve fiber hypertrophy has been reported in several individuals with ARSACS. METHODS: We describe a patient with a unique clinical presentation of ataxia, nystagmus, dysarthria, hearing impairment, and retinal degeneration. Whole-exome-sequencing was performed as well as morphological studies in the patient's fibroblasts. RESULTS: A compound heterozygosity for a novel D3269N and N2380K mutations in the SACS gene was found. The parents are carriers. Morphological studies revealed a dramatic decrease in the number of cell mitochondria as well as a difference in mitochondrial network morphology. CONCLUSIONS: Retinal degeneration has never been reported in ARSACS. Since sacsin is involved in the mitochondrial fusion-fission process, we speculate that defected fission process may be responsible for an impaired mitochondrial function and retinal degeneration. Our patient has a unique clinical presentation of SACS mutations inconsistent with the classic ARSACS triad but also different from the "atypical" presentations described in the literature. Further studies are necessary to clarify the factors that modify the SACS related phenotype.
BACKGROUND:ARSACS (autosomal-recessive spastic ataxia of Charlevoix-Saguenay) is a neurodegenerative disorder caused by SACS gene mutations and characterized by a triad of symptoms: early-onset cerebellar ataxia, spasticity and peripheral neuropathy. A characteristic retinal nerve fiber hypertrophy has been reported in several individuals with ARSACS. METHODS: We describe a patient with a unique clinical presentation of ataxia, nystagmus, dysarthria, hearing impairment, and retinal degeneration. Whole-exome-sequencing was performed as well as morphological studies in the patient's fibroblasts. RESULTS: A compound heterozygosity for a novel D3269N and N2380K mutations in the SACS gene was found. The parents are carriers. Morphological studies revealed a dramatic decrease in the number of cell mitochondria as well as a difference in mitochondrial network morphology. CONCLUSIONS:Retinal degeneration has never been reported in ARSACS. Since sacsin is involved in the mitochondrial fusion-fission process, we speculate that defected fission process may be responsible for an impaired mitochondrial function and retinal degeneration. Our patient has a unique clinical presentation of SACS mutations inconsistent with the classic ARSACS triad but also different from the "atypical" presentations described in the literature. Further studies are necessary to clarify the factors that modify the SACS related phenotype.
Authors: Marie Ménade; Guennadi Kozlov; Jean-François Trempe; Harshit Pande; Solomon Shenker; Sihara Wickremasinghe; Xinlu Li; Hamed Hojjat; Marie-Josée Dicaire; Bernard Brais; Peter S McPherson; Michael J H Wong; Jason C Young; Kalle Gehring Journal: J Biol Chem Date: 2018-06-26 Impact factor: 5.157