Objective: To highlight the wide phenotypical variability among GCH1 gene mutation carriers and the importance of molecular work-up and establishing genotype-phenotype correlations in GCH1 related disorders.

Background: Dopa-responsive dystonia (DRD) is an uncommon childhood-onset dystonia with sustained, uncomplicated response to levodopa. Penetrance rate is higher amongst females (80% vs 40% in males), with a variable course of progression, while parkinsonian symptoms may evolve over time. The most common form of DRD is dominantly inherited with incomplete penetrance caused by mutations in the GCH1 gene on chromosome 14 (DYT5), which encodes guanosine triphosphate cyclohydrolase 1, the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin. While next-generation-sequencing (NGS) is becoming more available, the molecular diagnosis is mostly based upon the clinical features. The absence of clear data regarding genotype-phenotype correlation may result in a delay in diagnosis of this treatable disease.

Method: Case description

Results: The proband, of Syrian Jewish origin presented at the age of 9 years with lower limbs muscle cramps, evolving later to dystonia with diurnal fluctuations alleviated with levodopa treatment. His mother is reported to have nocturnal leg cramps, while his maternal grandfather presented at the age of 75 with parkinsonian signs and lower limbs dystonia responding well to levodopa. In addition, proband’s sister suffers at times from a mild gait difficulty. Whole exome sequencing was performed, identifying a heterozygote GCH1 intronic deletion variant, c.510-9_510-6delCTTT  inherited from the mother. The variant has been detected in the symptomatic sister as well. The variant may cause loss of function by deleting a splice acceptor site and effecting an enhancer site. Such a variation has not been described amongst healthy populations. At present the variant is classified as being of unknown significance (VOUS).

Conclusion: Our findings emphasize the wide clinical variability among individuals with GCH1-related disease. Among our pedigree, male carriers were clinically more affected than female carriers, and wide variety in the age of onset was seen. Clinical suspicion is of high importance in such cases. Along with the advance of NGS, timely diagnosis and a rational therapeutic use of levodopa can be attained in such cases.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/phenotypic-variability-and-extreme-age-of-presentation-of-gch1-gene-mutation-in-dopa-responsive-dystonia/