Guy Helman1, Ayelet Zerem2, Akshata Almad3, Julia L Hacker3, Sarah Woidill3, Sunetra Sase3, Alexandra N LeFevre4, Josef Ekstein5, Martin M Johansson5, Chloe A Stutterd6, Ryan J Taft7, Cas Simons1, Judith B Grinspan8, Amy Pizzino3, Johanna L Schmidt3, Brian Harding9, Yoel Hirsch5, Angela N Viaene10, Aviva Fattal-Valevski2, Adeline Vanderver11. 1. Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Melbourne, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. 2. Pediatric Neurology Institute, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel. 3. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 4. University of Maryland Brain and Tissue Bank, Baltimore, Maryland. 5. Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Brooklyn, New York. 6. Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia. 7. Illumina Inc., San Diego, California. 8. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 9. Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 10. Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 11. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: vandervera@email.chop.edu.
Abstract
BACKGROUND: A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study. METHODS: Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case. RESULTS: Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia. CONCLUSIONS: We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population.
BACKGROUND: A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study. METHODS: Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case. RESULTS: Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia. CONCLUSIONS: We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population.
Authors: Rachel Rabin; Yoel Hirsch; Martin M Johansson; Joseph Ekstein; David A Zeevi; Beth Keena; Elaine H Zackai; John Pappas Journal: Am J Med Genet A Date: 2019-07-09 Impact factor: 2.802
Authors: Sietske H Kevelam; Marjan E Steenweg; Siddharth Srivastava; Guy Helman; Sakkubai Naidu; Raphael Schiffmann; Susan Blaser; Adeline Vanderver; Nicole I Wolf; Marjo S van der Knaap Journal: Neuropediatrics Date: 2016-08-26 Impact factor: 1.947
Authors: Guy Helman; Bryan R Lajoie; Joanna Crawford; Asako Takanohashi; Marzena Walkiewicz; Egor Dolzhenko; Andrew M Gross; Vladimir G Gainullin; Stephen J Bent; Emma M Jenkinson; Sacha Ferdinandusse; Hans R Waterham; Imen Dorboz; Enrico Bertini; Noriko Miyake; Nicole I Wolf; Truus E M Abbink; Susan M Kirwin; Christina M Tan; Grace M Hobson; Long Guo; Shiro Ikegawa; Amy Pizzino; Johanna L Schmidt; Genevieve Bernard; Raphael Schiffmann; Marjo S van der Knaap; Cas Simons; Ryan J Taft; Adeline Vanderver Journal: Ann Clin Transl Neurol Date: 2020-01-07 Impact factor: 4.511
Authors: Petra J W Pouwels; Adeline Vanderver; Genevieve Bernard; Nicole I Wolf; Steffi F Dreha-Kulczewksi; Sean C L Deoni; Enrico Bertini; Alfried Kohlschütter; William Richardson; Charles Ffrench-Constant; Wolfgang Köhler; David Rowitch; A James Barkovich Journal: Ann Neurol Date: 2014-06-24 Impact factor: 10.422
Authors: Konrad J Karczewski; Laurent C Francioli; Grace Tiao; Beryl B Cummings; Jessica Alföldi; Qingbo Wang; Ryan L Collins; Kristen M Laricchia; Andrea Ganna; Daniel P Birnbaum; Laura D Gauthier; Harrison Brand; Matthew Solomonson; Nicholas A Watts; Daniel Rhodes; Moriel Singer-Berk; Eleina M England; Eleanor G Seaby; Jack A Kosmicki; Raymond K Walters; Katherine Tashman; Yossi Farjoun; Eric Banks; Timothy Poterba; Arcturus Wang; Cotton Seed; Nicola Whiffin; Jessica X Chong; Kaitlin E Samocha; Emma Pierce-Hoffman; Zachary Zappala; Anne H O'Donnell-Luria; Eric Vallabh Minikel; Ben Weisburd; Monkol Lek; James S Ware; Christopher Vittal; Irina M Armean; Louis Bergelson; Kristian Cibulskis; Kristen M Connolly; Miguel Covarrubias; Stacey Donnelly; Steven Ferriera; Stacey Gabriel; Jeff Gentry; Namrata Gupta; Thibault Jeandet; Diane Kaplan; Christopher Llanwarne; Ruchi Munshi; Sam Novod; Nikelle Petrillo; David Roazen; Valentin Ruano-Rubio; Andrea Saltzman; Molly Schleicher; Jose Soto; Kathleen Tibbetts; Charlotte Tolonen; Gordon Wade; Michael E Talkowski; Benjamin M Neale; Mark J Daly; Daniel G MacArthur Journal: Nature Date: 2020-05-27 Impact factor: 69.504