Further Delineation of the Clinical and Pathologic Features of HIKESHI-Related Hypomyelinating Leukodystrophy
| Autor: | Angela N. Viaene, Aviva Fattal-Valevski, Martin Johansson, Alexandra N. LeFevre, Adeline Vanderver, Judith B. Grinspan, Johanna L. Schmidt, Sunetra Sase, Guy Helman, Brian Harding, Chloe A Stutterd, Ryan J. Taft, Yoel Hirsch, Sarah Woidill, Josef Ekstein, Akshata Almad, Amy Pizzino, Cas Simons, Julia L. Hacker, Ayelet Zerem |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Pathology
medicine.medical_specialty Population Autopsy Hyperreflexia Article Corpus Callosum White matter 03 medical and health sciences 0302 clinical medicine Developmental Neuroscience Neuroimaging 030225 pediatrics medicine Humans education Child Dystonia education.field_of_study medicine.diagnostic_test Whole Genome Sequencing business.industry Leukodystrophy Magnetic resonance imaging medicine.disease Magnetic Resonance Imaging Hereditary Central Nervous System Demyelinating Diseases medicine.anatomical_structure Neurology Jews Pediatrics Perinatology and Child Health Neurology (clinical) medicine.symptom business Carrier Proteins 030217 neurology & neurosurgery |
| Zdroj: | Pediatr Neurol |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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