Objective: To report a novel mutation in the THAP1 gene presenting with childhood-onset generalized dystonia in a family.

Background: DYT6 or DYT-THAP1 is a genetic dystonia caused by pathogenic mutations in the THAP1 gene. It predominantly presents with early-onset segmental or generalized dystonia with preferential craniocervical and upper limb involvement.

Method: A 37-year-old female (proband) presented with dystonia starting at 12 years of age. She initially developed right-sided neck tilting, progressing to left-side predominant abnormal posturing of the arm and leg within a few years. With time she developed truncal posturing with worsening speech and swallowing functions. All her symptoms developed during her teenage years with slow progression since then. Pertinent exam findings included a high arched palate, mild dysarthria, facial and oromandibular dystonia, right laterocollis with left torticollis, and mild left more than right hand dystonia with minimal leg involvement. Mild truncal leaning to the right was noted. Her Burke-Fahn-Marsden Dystonia Rating scale was 44.

Her parents and siblings are asymptomatic. Her 15-year-old daughter is symptomatic with the onset of dystonia at age of seven years, starting with cervical involvement. She has a similar phenotype.

Results: GeneDx dystonia panel reported a heterozygous THAP1 mutation, c.61T>G for the proband classified as a variant of unknown significance. The daughter also carries the same variant.

Conclusion: The c.61T>G mutation changes the amino acid at position 21 from serine to alanine in exon one. This variant is not observed frequently in large population cohorts. Other variants at nucleotide positions 61 and 62, changing serine to threonine, cysteine, and phenylalanine, have been associated with dystonia. To our knowledge, this is the first description of this variant in a family with early-onset generalized dystonia with craniocervical predominance. Interestingly, the daughter was symptomatic earlier than the proband. Further studies are needed to elucidate the clinical heterogeneity in DYT-THAP1.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-thap1-variant-presenting-with-early-onset-generalized-dystonia-in-a-family/