Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy.

Abstract

OBJECTIVE:

Sepiapterin reductase deficiency (SRD) is an under-recognized levodopa-responsive disorder. We describe clinical, biochemical, and molecular findings in a cohort of patients with this treatable condition. We aim to improve awareness of the phenotype and available diagnostic and therapeutic strategies to reduce delayed diagnosis or misdiagnosis, optimize management, and improve understanding of pathophysiologic mechanisms.

METHODS:

Forty-three individuals with SRD were identified from 23 international medical centers. The phenotype and treatment response were assessed by chart review using a detailed standardized instrument and by literature review for cases for which records were unavailable.

RESULTS:

In most cases, motor and language delays, axial hypotonia, dystonia, weakness, oculogyric crises, and diurnal fluctuation of symptoms with sleep benefit become evident in infancy or childhood. Average age of onset is 7 months, with delay to diagnosis of 9.1 years. Misdiagnoses of cerebral palsy (CP) are common. Most patients benefit dramatically from levodopa/carbidopa, often with further improvement with the addition of 5-hydroxytryptophan. Cerebrospinal fluid findings are distinctive. Diagnosis is confirmed by mutation analysis and/or enzyme activity measurement in cultured fibroblasts.

INTERPRETATION:

Common, clinical findings of SRD, aside from oculogyric crises and diurnal fluctuation, are nonspecific and mimic CP with hypotonia or dystonia. Patients usually improve dramatically with treatment. Consequently, we recommend consideration of SRD not only in patients with levodopa-responsive motor disorders, but also in patients with developmental delays with axial hypotonia, and patients with unexplained or atypical presumed CP. Biochemical investigation of cerebrospinal fluid is the preferred method of initial investigation. Early diagnosis and treatment are recommended to prevent ongoing brain dysfunction.

• Authors: Jennifer Friedman, Emmanuel Roze, Jose E Abdenur, Richard Chang, Serena Gasperini, Veronica Saletti, Gurusidheshwar M Wali, Hernan Eiroa, Brian Neville, Alex Felice, Ray Parascandalo, Dimitrios I Zafeiriou, Luisa Arrabal-Fernandez, Patricia Dill, Florian S Eichler, Bernard Echenne, Luis G Gutierrez-Solana, Georg F Hoffmann, Keith Hyland, Katarzyna Kusmierska, Marina A J Tijssen, Thomas Lutz, Michel Mazzuca, Johann Penzien, Bwee Tien Poll-The, Jolanta Sykut-Cegielska, Krystyna Szymanska, Beat Thöny, Nenad Blau
• Journal: Annals of neurology (Ann Neurol) Vol. 71 Issue 4 Pg. 520-30 (Apr 2012) ISSN: 1531-8249 [Electronic] United States
• PMID: 22522443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Neurological Association.

Chemical References

• Dopamine Agents
• Neurotransmitter Agents
• Alcohol Oxidoreductases
• sepiapterin reductase

Topics

• Age of Onset
• Alcohol Oxidoreductases (deficiency, genetics)
• Base Sequence
• Cerebral Palsy (diagnosis)
• Child
• Child, Preschool
• DNA Mutational Analysis
• Developmental Disabilities (diagnosis, drug therapy, genetics)
• Diagnosis, Differential
• Dopamine Agents (therapeutic use)
• Female
• Humans
• Infant
• Male
• Molecular Sequence Data
• Movement Disorders (diagnosis, drug therapy, genetics)
• Mutation
• Neurotransmitter Agents (analysis, therapeutic use)