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Neuropathology of childhood-onset basal ganglia degeneration caused by mutation of VAC14.

ABSTRACT: To characterize the clinical features and neuropathology associated with recessive VAC14 mutations.Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressive neurological disease presenting in early childhood in two deceased siblings with distinct neuropathological features on post mortem examination.We identified compound heterozygous variants in VAC14 in two deceased siblings with early childhood onset of severe, progressive dystonia, and neurodegeneration. Their clinical phenotype is consistent with the VAC14-related childhood-onset, striatonigral degeneration recently described in two unrelated children. Post mortem examination demonstrated prominent vacuolation associated with degenerating neurons in the caudate nucleus, putamen, and globus pallidus, similar to previously reported ex vivo vacuoles seen in the late-endosome/lysosome of VAC14-deficient neurons. We identified upregulation of ubiquitinated granules within the cell cytoplasm and lysosomal-associated membrane protein (LAMP2) around the vacuole edge to suggest a process of vacuolation of lysosomal structures associated with active autophagocytic-associated neuronal degeneration.Our findings reveal a distinct clinicopathological phenotype associated with recessive VAC14 mutations.

SUBMITTER: Stutterd C

PROVIDER: S-EPMC5740235 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Neuropathology of childhood-onset basal ganglia degeneration caused by mutation of <i>VAC14</i>.

Stutterd Chloe C Diakumis Peter P Bahlo Melanie M Fanjul Fernandez Miriam M Leventer Richard J RJ Delatycki Martin M Amor David D Chow Chung W CW Stephenson Sarah S Meisler Miriam H MH Mclean Catriona C Lockhart Paul J PJ

Annals of clinical and translational neurology 20171107 12

<h4>Objective</h4>To characterize the clinical features and neuropathology associated with recessive <i>VAC14</i> mutations.<h4>Methods</h4>Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressive neurological disease presenting in early childhood in two deceased siblings with distinct neuropathological features on post mortem examination.<h4>Results</h4>We identified compound heterozygous variants in <i>VAC14</i> in two deceased siblings with early childhood ons ...[more]

PMID: 29296614

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Project description:Bilateral basal ganglia abnormalities on MRI are observed in a wide variety of childhood disorders. MRI pattern recognition can enable rationalization of investigations and also complement clinical and molecular findings, particularly confirming genomic findings and also enabling new gene discovery. A pattern recognition approach in children with bilateral basal ganglia abnormalities on brain MRI was undertaken in this international multicentre cohort study. Three hundred and five MRI scans belonging to 201 children with 34 different disorders were rated using a standard radiological scoring proforma. In addition, literature review on MRI patterns was undertaken in these 34 disorders and 59 additional disorders reported with bilateral basal ganglia MRI abnormalities. Cluster analysis on first MRI findings from the study cohort grouped them into four clusters: Cluster 1-T2-weighted hyperintensities in the putamen; Cluster 2-T2-weighted hyperintensities or increased MRI susceptibility in the globus pallidus; Cluster 3-T2-weighted hyperintensities in the globus pallidus, brainstem and cerebellum with diffusion restriction; Cluster 4-T1-weighted hyperintensities in the basal ganglia. The 34 diagnostic categories included in this study showed dominant clustering in one of the above four clusters. Inflammatory disorders grouped together in Cluster 1. Mitochondrial and other neurometabolic disorders were distributed across clusters 1, 2 and 3, according to lesions dominantly affecting the striatum (Cluster 1: glutaric aciduria type 1, propionic acidaemia, 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome and thiamine responsive basal ganglia disease associated with SLC19A3), pallidum (Cluster 2: methylmalonic acidaemia, Kearns Sayre syndrome, pyruvate dehydrogenase complex deficiency and succinic semialdehyde dehydrogenase deficiency) or pallidum, brainstem and cerebellum (Cluster 3: vigabatrin toxicity, Krabbe disease). The Cluster 4 pattern was exemplified by distinct T1-weighted hyperintensities in the basal ganglia and other brain regions in genetically determined hypermanganesemia due to SLC39A14 and SLC30A10. Within the clusters, distinctive basal ganglia MRI patterns were noted in acquired disorders such as cerebral palsy due to hypoxic ischaemic encephalopathy in full-term babies, kernicterus and vigabatrin toxicity and in rare genetic disorders such as 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome, thiamine responsive basal ganglia disease, pantothenate kinase-associated neurodegeneration, TUBB4A and hypermanganesemia. Integrated findings from the study cohort and literature review were used to propose a diagnostic algorithm to approach bilateral basal ganglia abnormalities on MRI. After integrating clinical summaries and MRI findings from the literature review, we developed a prototypic decision-making electronic tool to be tested using further cohorts and clinical practice.

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Dataset Information

Neuropathology of childhood-onset basal ganglia degeneration caused by mutation of VAC14.

Publications

Neuropathology of childhood-onset basal ganglia degeneration caused by mutation of <i>VAC14</i>.

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