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Neurology. 2014 Jun 10;82(23):2092-100. doi: 10.1212/WNL.0000000000000491. Epub 2014 May 9.

Partial deletion of AFG3L2 causing spinocerebellar ataxia type 28.

Author information

1
From the Neurogenetics Group, VIB-Department of Molecular Genetics (K.S., T.D., J.B., I.S., P.D.J.), and Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge (K.S., T.D., J.B., A.S., J.-J.M., P.D.J.), University of Antwerp; Departments of Neurology (K.S., J.B., J.-J.M., I.S., P.D.J.) and Radiology (W.V.H., P.M.P.), Antwerp University Hospital; Department of Neurology (A.S.), Ghent University Hospital, Belgium; Biocenter (S.W., E.R.), University of Cologne; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (S.W., E.R.), Cologne, Germany; Unit of Genetics of Neurodegenerative and Metabolic Diseases (F.T., D.D.B.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Icometrix (W.V.H., P.M.P.), Leuven; Department of Neurology (C.J.), AZ Nicolaas, Sint-Niklaas; Department of Neurology (R.D.P.), AZ Sint-Lucas, Gent; and Department of Neurology (F.C.), AZ Klina, Brasschaat, Belgium.
2
From the Neurogenetics Group, VIB-Department of Molecular Genetics (K.S., T.D., J.B., I.S., P.D.J.), and Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge (K.S., T.D., J.B., A.S., J.-J.M., P.D.J.), University of Antwerp; Departments of Neurology (K.S., J.B., J.-J.M., I.S., P.D.J.) and Radiology (W.V.H., P.M.P.), Antwerp University Hospital; Department of Neurology (A.S.), Ghent University Hospital, Belgium; Biocenter (S.W., E.R.), University of Cologne; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (S.W., E.R.), Cologne, Germany; Unit of Genetics of Neurodegenerative and Metabolic Diseases (F.T., D.D.B.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Icometrix (W.V.H., P.M.P.), Leuven; Department of Neurology (C.J.), AZ Nicolaas, Sint-Niklaas; Department of Neurology (R.D.P.), AZ Sint-Lucas, Gent; and Department of Neurology (F.C.), AZ Klina, Brasschaat, Belgium. peter.dejonghe@molgen.vib-ua.be.

Abstract

OBJECTIVE:

To identify the genetic cause of autosomal dominant spinocerebellar ataxia type 28 (SCA28) with ptosis in 2 Belgian families without AFG3L2 point mutations and further extend the clinical spectrum of SCA28 through the study of a brain autopsy, advanced MRI, and cell-based functional assays exploring the underlying disease mechanism.

METHODS:

Two large families were clinically examined in detail. Linkage analysis and multiplex amplicon quantification were performed. A brain autopsy was obtained. Brain MRI with voxel-based morphometry and diffusion tensor imaging was performed. RNA and Western blot analysis and blue native-polyacrylamide gel electrophoresis experiments were performed.

RESULTS:

MRI analysis demonstrated a significant cerebellar atrophy, as well as white matter degeneration in the cerebellar peduncles, corticospinal tracts, corpus callosum, and cingulum. A brain autopsy showed severe atrophy of the upper part of the cerebellar hemisphere. Ubiquitin and p62 immunoreactive intranuclear inclusions were found in cerebral and cerebellar cortical neurons, in neurons of the hippocampus, and in pontine and medullary nuclei. An identical heterozygous partial deletion of exons 14 to 16 of the AFG3L2 gene was found in both families. Additional functional assays in patient-derived cell lines revealed haploinsufficiency as the underlying disease mechanism.

CONCLUSIONS:

Our study expands the phenotypic characterization of SCA28 by means of brain pathology and diffusion tensor imaging/voxel-based morphometry MRIs. The identification of a partial AFG3L2 deletion and the subsequent functional studies reveal loss of function as the most likely disease mechanism. Specific testing for deletions in AFG3L2 is warranted because these escape standard sequencing.

PMID:
24814845
DOI:
10.1212/WNL.0000000000000491
[Indexed for MEDLINE]

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