Novel GCH1 Compound Heterozygosity Mutation in Infancy-Onset Generalized Dystonia

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.

Fig. 1 Compound heterozygous mutations in our patient illustrated by respective electropherograms. Upper panel: Two different mutations were detected in a cDNA sample of the patient. Middle panel: The cDNA sequencing results of Clone 3 containing the paternal GCH1 allele as indicated by the paternally inherited c.671A > G mutation (arrow). Lower panel: The cDNA sequencing results of Clone 7 containing the maternal allele as indicated by the absence of the c.671A > G mutation. However, this clone also includes the de-novo c.283C > T mutation (arrow).

Note

The work was performed in Barcelona and the genetic analyses were done in Luebeck.

• References

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