G Heimer1, E Eyal2, X Zhu3, E K Ruzzo4, D Marek-Yagel5, Doron Sagiv6, Y Anikster7, H Reznik-Wolf8, E Pras9, D Oz Levi10, D Lancet10, B Ben-Zeev11, A Nissenkorn12. 1. Pediatric Neurology Unit, Edmond and Lilly Safra Children Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel; Pinchas Borenstein Talpiot Medical Leadership Program, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: md@gmail.com. 2. Cancer Research Center, Pediatric Hemato/oncology Unit, Edmond and Lily Children's Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel. 3. Institute for Genomic Medicine, Columbia University Medical School, Columbia University Medical Center, New York, NY 10032, USA. 4. Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, USA. 5. The Metabolic Disorder Unit, Edmond and Lilly Safra Children Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel. 6. The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Otolaryngology Head and Neck Surgery, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel. 7. The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; The Metabolic Disorder Unit, Edmond and Lilly Safra Children Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel. 8. Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel. 9. The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel. 10. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel. 11. Pediatric Neurology Unit, Edmond and Lilly Safra Children Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 12. Pediatric Neurology Unit, Edmond and Lilly Safra Children Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; The Service for Rare Disorders, Edmond and Lilly Safra Children Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel. Electronic address: Andreea.nissenkorn@sheba.health.gov.il.
Abstract
BACKGROUND: AIFM1 encodes a mitochondrial flavoprotein with a dual role (NADH oxidoreductase and regulator of apoptosis), which uses riboflavin as a cofactor. Mutations in the X-linked AIFM1 were reported in relation to two main phenotypes: a severe infantile mitochondrial encephalomyopathy and an early-onset axonal sensorimotor neuropathy with hearing loss. In this paper we report two unrelated males harboring AIFM1 mutations (one of which is novel) who display distinct phenotypes including progressive ataxia which partially improved with riboflavin treatment. METHODS: For both patients trio whole exome sequencing was performed. Validation and segregation were performed with Sanger sequencing. Following the diagnosis, patients were treated with up to 200 mg riboflavin/day for 12 months. Ataxia was assessed by the ICARS scale at baseline, and 6 and 12 months following treatment. RESULTS: Patient 1 presented at the age of 5 years with auditory neuropathy, followed by progressive ataxia, vermian atrophy and axonal neuropathy. Patient 2 presented at the age of 4.5 years with severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, hyporeflexia and cardiomyopathy. Two deleterious missense mutations were found in the AIFM1 gene: p. Met340Thr mutation located in the FAD dependent oxidoreductase domain and the novel p. Thr141Ile mutation located in a highly conserved DNA binding motif. Ataxia score, decreased by 39% in patient 1 and 20% in patient 2 following 12 months of treatment. CONCLUSION: AIFM1 mutations cause childhood cerebellar ataxia, which may be partially treatable in some patients with high dose riboflavin.
BACKGROUND:AIFM1 encodes a mitochondrial flavoprotein with a dual role (NADH oxidoreductase and regulator of apoptosis), which uses riboflavin as a cofactor. Mutations in the X-linked AIFM1 were reported in relation to two main phenotypes: a severe infantile mitochondrial encephalomyopathy and an early-onset axonal sensorimotor neuropathy with hearing loss. In this paper we report two unrelated males harboring AIFM1 mutations (one of which is novel) who display distinct phenotypes including progressive ataxia which partially improved with riboflavin treatment. METHODS: For both patients trio whole exome sequencing was performed. Validation and segregation were performed with Sanger sequencing. Following the diagnosis, patients were treated with up to 200 mg riboflavin/day for 12 months. Ataxia was assessed by the ICARS scale at baseline, and 6 and 12 months following treatment. RESULTS:Patient 1 presented at the age of 5 years with auditory neuropathy, followed by progressive ataxia, vermian atrophy and axonal neuropathy. Patient 2 presented at the age of 4.5 years with severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, hyporeflexia and cardiomyopathy. Two deleterious missense mutations were found in the AIFM1 gene: p. Met340Thr mutation located in the FAD dependent oxidoreductase domain and the novel p. Thr141Ile mutation located in a highly conserved DNA binding motif. Ataxia score, decreased by 39% in patient 1 and 20% in patient 2 following 12 months of treatment. CONCLUSION:AIFM1 mutations cause childhood cerebellar ataxia, which may be partially treatable in some patients with high dose riboflavin.
Authors: Tonya Moss; Melanie May; Heather Flanagan-Steet; Raymond Caylor; Yong-Hui Jiang; Marie McDonald; Michael Friez; Allyn McConkie-Rosell; Richard Steet Journal: Cold Spring Harb Mol Case Stud Date: 2021-06-11
Authors: Tian Zhao; Caitlin Goedhart; Gerald Pfeffer; Steven C Greenway; Matthew Lines; Aneal Khan; A Micheil Innes; Timothy E Shutt Journal: Int J Mol Sci Date: 2020-11-06 Impact factor: 5.923