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DOI: 10.1055/s-0038-1626709
Novel GCH1 Compound Heterozygosity Mutation in Infancy-Onset Generalized Dystonia
Funding None.Publication History
24 October 2017
26 December 2017
Publication Date:
22 February 2018 (online)
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Heterozygous mutations in guanosine triphosphate cyclohydrolase (GCH1) cause autosomal dominant dopa-responsive dystonia (AD-DRD, Segawa syndrome),[1] whereas biallelic mutations result in autosomal recessive DRD (AR-DRD), a more severe phenotype often including encephalopathy and hyperphenylalaninemia. We report the case of a 5-year old girl initially misdiagnosed as dystonic cerebral palsy and who carried compound heterozygous GCH1 mutations without hyperphenylalaninemia. On examination at the age of 18 months, she was unable to sit, had axial hypotonia, action-induced limb dystonia, hyperreflexia, and bilateral Babinski signs. Brain MRI, blood, and urine metabolic tests were normal. Cerebrospinal fluid analysis was suggestive of GCH1 deficiency (homovanillic acid: 247 nmol/L [344–906 nmol/L], 5-hydroindolacetic acid: 114 nmol/L [170–490 nmol/L], tetrahydrobiopterin: 6 nmol/L [12–36 nmol/L], neopterin: 2 nmol/L [10–24 nmol/L]). Levodopa–carbidopa therapy was initiated leading to improvement of her motor phenotype including the ability to walk at 24 months of age (Video 1[*]). At the age of 5 years, her neurological examination in the on-state (6 mg/kg/d levodopa–carbidopa [4:1]) showed mild hand dystonia and normal speech development. GCH1 mutational analysis revealed a novel mutation c.283C > T/p.Pro95Ser, and a previously described mutation c.671A > G/p.Lys224Arg also present in the asymptomatic father.[2] [3] [4] Subclone analysis demonstrated that the two mutations were on different alleles confirming compound heterozygosity ([Fig. 1]). We report a new case of AR-DRD presenting as generalized dystonia adding previous evidence of a phenotypic continuum between AD and AR-DRD[5] [6] including a novel mutation in GCH1.
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Note
The work was performed in Barcelona and the genetic analyses were done in Luebeck.
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References
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