Novel mutation variant in GCH1 gene - a new cause for infantile-onset severe dystonic encephalopathy?

Objectives Dystonia is a common symptom in pediatric neurology patients and one of the most common movement disorders. We aimed to identify the underlying etiology of severe infantile- onset generalized dystonia in a 12 year old patient, with non-specific cerebral MRI findings, previously diagnosed as a mixed type cerebral palsy.

Methods We performed whole exome sequencing(WES) testing. Genomic DNA including mitochondrial genome was analized through WES, revealing a heterozygous GCH1 variant c.-252_-235del of unknown significance.

Results Available data suggests that pathogenic GCH1 mutations causing severe dystonia without hyperphenylalaninemia is a dopa-responsive group of disorders. The patient was started on levodopa-carbidopa treatment and showed significant improvement on 600mg/day with a DSAP score going from 3 to 1+/2.

Conclusion Even though the identified mutation has yet an unknown significance, the infantile-onset severe dystonic encephalopathy, otherwise unexplained by structural causes, the marked response to levodopa-carbidopa treatment and the available data suggest that the identified GCH1 deletion is a probable cause in our patient. Further studies of a second variant in the GCH1 gene, for example a variant in a regulatory region or deep intronic region are needed to solidify/ confirm the hypothesis.