Novel Mutation In The APT13A2 Gene Associated With Ataxia, Cerebellar Tremor, Bipolar Disease and Epilepsy
Muhammad Ismail khalid Yousaf1, Talita D'Aguiar Rosa1, Mohammad Ravi Ghani1, Peter Hedera1
1Neurology, University Of Louisville School of Medicine
Objective:

OBJECTIVE

To Report a Novel Mutation In The ATP13A2 Gene Causing Cerebellar Ataxia With Bipolar Disorder And Epilepsy Without Parkinsonism.

Background:
ATP13A2 gene mutations are rare and initially were identified in patients with autosomal recessive (AR) juvenile onset of parkinsonism with supranuclear gaze palsy, and dementia, also known as Kufer-Rakeb disease. Subsequently, recognized phenotypic variability of biallelic mutations in this gene widened and include AR hereditary spastic paraplegia or spastic ataxia. Pure cerebellar ataxia is rarely caused by mutations in this gene.
Design/Methods:
Case report and genetic analysis of the ATP13A2 gene in affected proband and both parents.
Results:

The proband is a 40-year-old male of Iranian descent who developed difficulties walking with multiple falls as a teenager. He transitioned from a walker to a wheelchair dependency in his 20s. He was diagnosed with spinocerebellar ataxia with Holmes tremor in both arms. His examination showed vertical ophthalmoplegia without any signs of Parkinsonism or spasticity. The patient had signs of a mild developmental delay and in his 20s he was also diagnosed with bipolar disorder. He developed seizures in his 40s and they were well-controlled on levetiracetam. Brain MRI showed cerebellar atrophy with no iron deposits in basal ganglia.

His parents were first cousins. Family history was noticeable for similar problems in two deceased cousins who were also from consanguineous marriages. Genetic testing showed a novel homozygous mutation in exon 26 of ATP13A2, c.2899G>C (p.Asp967His). We did not find this in 100 controls. Both parents were heterozygous at the same codon. We also confirmed the mutation in the CLIA certified laboratory, which is cataloged as rs772870846. In vitro analysis showed this variant being deleterious.

Conclusions:
We report a novel mutation in the ATP13A2 gene with unique constellation of clinical features, further expanding the phenotypic spectrum of movement disorders associated with this genetic condition.
10.1212/WNL.0000000000202835