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Neurologic and Psychiatric Manifestations in a Family With a Mutation in Exon 2 of the Guanosine Triphosphate–Cyclohydrolase Gene
Heidi Hahn, MD;
Melissa R. Trant, MS;
Michael J. Brownstein, MD, PhD;
R. Andrew Harper, MD;
Sheldon Milstien, PhD;
Ian J. Butler, MD
Arch Neurol. 2001;58:749-755.
Objective To investigate the range of clinical features to correlate genotypic
and phenotypic manifestations in hereditary progressive and/or levodopa-responsive
dystonia due to a defect in the guanosine triphosphate–cyclohydrolase
(GCH1) gene.
Design and Setting A large family from Texas was studied in an ambulatory setting by clinicians
in genetics, neurology, and psychiatry using structured interviews and examinations.
Patients The family was selected after neurometabolic investigations of a young
boy (proband) with foot dystonia and fatigue and his father, who had a long
history of anxiety and depression. Results of metabolic studies showed decreased
levels of metabolites of biopterin and biogenic amines in cerebrospinal fluid.
Subsequently, a novel mutation (37–base pair deletion) in exon 2 of
the GCH1 gene was demonstrated in 11 family members.
There was no observed female sex bias, but there was a wide variability of
motor dysfunctions in family members. Approximately 50% had clinical deafness
and a similar number had significant psychiatric dysfunction, including depression
and anxiety.
Conclusion Study of additional families with hereditary progressive and/or levodopa-responsive
dystonia using modern molecular methods will be necessary to confirm the neuropsychiatric
spectrum of this disorder, in which important clinical features may be unrecognized
and thus inappropriately managed.
From the Institute of Pathology, GSF Research Center of Environment
and Health, Neuherberg, Germany (Dr Hahn); the Division of Medical Genetics,
Department of Pediatrics (Ms Trant), the Division of Child Psychiatry, Department
of Psychiatry (Dr Harper), and the Division of Child Neurology, Department
of Neurology (Dr Butler), University of Texas–Houston Health Science
Center; and the Laboratory of Genetics, National Institute of Mental Health
(NIMH)–National Human Genome Research Institute, (Dr Brownstein), and
the Laboratory of Cellular and Molecular Regulation, NIMH (Dr Milstien), Bethesda,
Md.
Corresponding author and reprints: Ian J. Butler, MD, Department
of Neurology, PO Box 20708, Houston, TX 77225-0708.
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