Pontocerebellar hypoplasia type 11: Does the genetic defect determine timing of cerebellar pathology?
| Autor: | Mona Grimmel, Samuel Groeschel, Marc Sturm, Marion Döbler-Neumann, Georg Gohla, Stefanie Beck-Wödl, Tobias B. Haack, Angelika Riess, Rebecca Buchert, Lucia Laugwitz, Ingeborg Krägeloh-Mann |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cerebellum Microcephaly Pathology medicine.medical_specialty Ataxia Adolescent Pontocerebellar hypoplasia 030105 genetics & heredity Nervous System Malformations 03 medical and health sciences Atrophy Cerebellar Diseases Exome Sequencing Genetics medicine Humans Child Genetics (clinical) business.industry GTPase-Activating Proteins Homozygote Brain morphometry Brain Infant Exons General Medicine medicine.disease Magnetic Resonance Imaging Hypoplasia Pedigree 030104 developmental biology medicine.anatomical_structure Child Preschool Mutation Female Cerebellar atrophy medicine.symptom business |
| Zdroj: | European Journal of Medical Genetics. 63:103938 |
| ISSN: | 1769-7212 |
| DOI: | 10.1016/j.ejmg.2020.103938 |
| Popis: | Pontocerebellar hypoplasia (PCH) comprises a clinically and genetically heterogeneous group of disorders characterized by hypoplasia and degeneration of the cerebellum and ventral pons. To date at least 18 different clinical subtypes of PCH associated with pathogenic variants in 19 different genes have been described. Only recently, bi-allelic variants in TBC1D23 have been reported as the underlying molecular defect in seven index cases with a suspected non-degenerative form of PCH, PCH type 11 (PCH11). We used exome sequencing to investigate an individual with global developmental delay, ataxia, seizures, and progressive PCH. Brain volume was evaluated over a disease course of 14 years using volumetric magnetic resonance imaging (MRI). Volume alterations were compared to age-matched controls as well as data from children with PCH2. We identified a homozygous frameshift variant in exon 9 of 18 of TBC1D23 predicting a loss of protein function. Brain morphometry revealed a pattern of pontine, brain stem, and supratentorial volume loss similar to PCH2 patients although less pronounced. Intriguingly, cerebral MRI findings at the age of 1 and 15 years clearly showed progressive atrophy of the cerebellum, especially the hemispheres. In four of the cases reported in the literature cerebellar hemispheres could be evaluated on the MRIs displayed, they also showed atrophic foliae. While pontine hypoplasia and pronounced microcephaly are in line with previous reports on PCH11, our observations of clearly postnatal atrophy of the cerebellum argues for a different pathomechanism than in the other forms of PCH and supports the hypothesis that TBC1D23 deficiency predominantly interferes with postnatal rather than with prenatal cerebellar development. |
| Databáze: | OpenAIRE |
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