# Variant Ataxia–Telangiectasia Presenting as Tremor–Dystonia Syndrome in a Bulgarian Religious Minority

## TL;DR

A rare genetic disorder caused by ATM gene mutations can present as tremor and dystonia without typical brain symptoms, highlighting the need for broader diagnostic consideration.

## Contribution

Identifies a novel variant form of Ataxia-telangiectasia with dystonia and tremor as primary symptoms, not previously well characterized.

## Key findings

- Patients with ATM gene mutations presented dystonia and tremor without significant cerebellar involvement.
- Most patients were homozygous for the c.8147T>C mutation in ATM, with some compound heterozygous mutations.
- Clinical onset varied widely, from infancy to adulthood, with slowly progressive symptoms and normal brain imaging in most.

## Abstract

Background: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder due to mutations in the ATM gene. Given the residual kinase activity and the type of ATM mutation, its clinical spectrum varies from a severe classic phenotype to a variant atypical form. Material and methods: This study included 28 patients belonging to four big Bulgarian Muslim pedigrees with tremor and dystonia. Whole-exome sequencing was performed in seven affected individuals from two unrelated pedigrees, followed by Sanger sequencing of the coding sequences and exon–intron borders of the ATM gene. Results: Twenty-four of the affected individuals were homozygous for c.8147T>C (p.Val2716Ala) in ATM, while four of the affected individuals were compound heterozygous. The targeted Sanger sequencing along the ATM gene revealed as a second mutation in three of the patients the splice-site variant c.4909+1G>A and in one patient a synonymous pathogenic variant with a splicing effect, c.3576G>A, p.Lys1192. The age at onset in our group varied between 14 days and 40 years. The main symptoms were dystonia and tremor, more prominent in the upper limbs and the neck, and dystonic dysarthria and dysphagia. The clinical course was very slowly progressive. Brain imaging was normal in the majority of the patients. Conclusion: Clinical features due to mutations in the ATM gene can be very broad. The disease may appear as dystonia, especially of early onset, without frank cerebellar involvement and also normal cerebral imaging. A-T should be considered in all patients with unexplained, even mild movement disorders and elevated α fetoprotein.