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Cerebellum. 2019 Nov 9. doi: 10.1007/s12311-019-01080-y. [Epub ahead of print]

Alanyl-tRNA Synthetase 2 (AARS2)-Related Ataxia Without Leukoencephalopathy.

Author information

1
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA.
2
Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
3
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA. antonell@umich.edu.
4
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA. antonell@umich.edu.
5
Department of Neurology, University of Michigan, Ann Arbor, MI, USA. antonell@umich.edu.
6
Medical Science II, 3710A, 1241 E. Catherine St. SPC 5618, Ann Arbor, MI, 48109, USA. antonell@umich.edu.
7
Department of Neurology, University of Michigan, Ann Arbor, MI, USA. vikramsh@med.umich.edu.
8
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. vikramsh@med.umich.edu.
9
BSRB, 4009, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA. vikramsh@med.umich.edu.

Abstract

Mutations in the mitochondrial alanyl-tRNA synthetase gene, AARS2, have been reported to cause leukoencephalopathy associated with early ovarian failure, a clinical presentation described as "ovarioleukodystrophy." We present a sibling pair: one with cerebellar ataxia and one with vision loss and cognitive impairment in addition to ataxia. Neither shows evidence of leukoencephalopathy on MRI imaging. Exome sequencing revealed that both siblings are compound heterozygous for AARS2 variants (p.Phe131del and p.Ile328Met). Yeast complementation assays indicate that p.Phe131del AARS2 dramatically impairs gene function and that p.Ile328Met AARS2 is a hypomorphic allele. This work expands the phenotypic spectrum of AARS2-associated disease to include ataxia without leukoencephalopathy.

KEYWORDS:

AARS2; Cerebellar ataxia; Leukoencephalopathy; Ovarioleukodystrophy; Recessive ataxia

PMID:
31705293
DOI:
10.1007/s12311-019-01080-y

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