Objective: We describe a patient with a novel ATM gene variant presenting with tremor, neuropathy, and late-onset ataxia.

Background: Ataxia Telangiectasia (AT) is an autosomal recessive condition resulting from ATM gene mutations on chromosome 11q. Classic AT presents in childhood featuring cerebellar ataxia, dysarthria, telangiectasias, oculomotor apraxia, extrapyramidal symptoms, immunodeficiency, and malignancy. Variant AT forms with milder phenotypes and lesser disability have been described. We document a novel case involving a previously unreported frameshift mutation.

Method: N/A

Results: A 52-year-old man initially presented at age 18 with onset of progressive upper limb tremor and neuropathy. Nerve conduction studies documented axonal sensory-motor polyneuropathy. A genetic panel for hereditary neuropathy was unremarkable. At age 40, he developed mild dysarthria. Examination at age 50 revealed limb ataxia. Eye movements were normal; ocular telangiectasias were noted. Brain MRI showed mild cerebellar atrophy. He underwent left thalamic VIM deep brain stimulation (DBS) at age 51 with symptomatic benefit for disabling tremor. Laboratory tests for serum alpha-fetoprotein (AFP) and immunoglobulin levels were normal. Recurrent respiratory infections and malignancies have not occurred. Whole exome sequencing revealed pathogenic compound heterozygous mutations in the ATM gene; a missense c.6200C > A and a frameshift c.1914_1929dup. He is awaiting a second procedure for right VIM DBS placement.

Conclusion: This case highlights a novel variant presentation of AT featuring disabling tremor, neuropathy, and late-onset ataxia. We report the first frameshift mutation c.1914_1929dup in the ATM gene. Previously, a c.6200C > A missense mutation in ATM was associated with a myoclonus-dystonia phenotype. To our knowledge, this is the only other documentation of the c.6200C > A missense mutation in the ATM gene. Our case contributes to the expanding knowledge of ATM gene variants and their relationship with the broadening clinical spectrum of AT phenotypes. This case also demonstrates that limb tremor in AT may respond favorably to DBS treatment. Lastly, it serves as a reminder that current knowledge of hereditary neurologic disease is incomplete and requires further documentation of novel variants.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/variant-ataxia-telangiectasia-a-novel-atm-gene-mutation-with-disabling-tremor-and-response-to-deep-brain-stimulation/