Diagnostic Approach for Dopa-Responsive Dystonia (Segawa Syndrome)

Introduction

GTP cyclohydrolase 1 (GTPCH) is encoded by the GCH1 gene, located on chromosome 14q22.1-q22.2 1. Patients heterozygous for GCH1 mutations/deletions may develop the autosomal dominant Segawa syndrome, also called autosomal dominant GTPCH (adGTPCH) deficiency, dopa-responsive dystonia (DRD), and DYT5 dystonia (OMIM 128230) 2. GTPCH catalyzes the first and rate-limiting step in the synthesis of tetrahydrobiopterin (BH) 3. DRD may be caused by other forms of BH deficiency such as autosomal recessive GTPCH deficiency, 6-pyruvoyl-tetrahydropterin synthase, dihydropteridine reductase, and sepiapterin reductase, but with the exception of the latter, these deficiencies are characterized by neonatal hyperphenylalaninemia 4. Further, tyrosine hydroxylase (TH) deficiency, secondary dystonia, and early-onset parkinsonism due to mutations and deletions in the parkin gene may present during childhood with a DRD 4, 5. Segawa syndrome due to adGTPCH deficiency causes a BH deficiency, which leads to decreased dopamine and serotonin biosynthesis, without hyperphenylalaninemia. The disease has an estimated prevalence of 0.5 per million 6, although this may be underestimated owing to underdiagnosis and reduced penetrance. The adGTPCH deficiency typically presents insidiously between the ages of 1 and 9 years, average 6 years of age, with a diurnally fluctuating dystonia of one limb spreading to the other extremities after several years, together with subsequent parkinsonian signs developing in some cases 7. Clinical features and response to levodopa remained the diagnostic gold standard for this disorder until recently 8, 9. The increasing number of adGTPCH deficiency patients reported as a consequence of the discovering of new mutations and deletions of the GCH1 gene have broadened the phenotype of the disease including exceptions to each of the cardinal points of the diagnosis and many atypical presentations. The highly variable expressivity of DRD, and the fact that the response of adGTPCH deficiency patients to levodopa is less predictable than previously assumed complicate the classic diagnostic approach based on the clinical features and the response to levodopa. Further, DRD is a syndrome with different causes. For these reasons, there is a need to confirm the clinical diagnosis of this treatable disorder through biochemical and/or molecular investigations. Notwithstanding, up to 40% of patients do not have identifiable mutations by sequencing 10, and the recently incorporated techniques to detect partial and complete deletions of GCH1, the quantitative duplex PCR (qPCR) assay and multiplex ligationdependent probe amplification (MLPA), may only increase the yield of the molecular studies in around 10% 11, 12. Therefore, biochemical studies are many times necessaries.

Abstract

Autosomal dominant guanosine triphosphate cyclohydrolase I (adGTPCH) deficiency, also called dopa-responsive dystonia (DRD) or Segawa disease, is an inborn error of neurotransmitter metabolism, with a prevalence of 0.5 per million, caused by mutations or deletions in the GCH1 gene. Most mutations and deletions in GCH1 are unique and up to 40% of patients do not have identifiable mutations in the coding region or the splice sites. Clinical features and response to levodopa have remained the diagnostic gold standard until recently. However, the adGTPCH deficiency causes a wide phenotypic spectrum of clinical variability including dystonia, parkinsonism, and spasticity, and further, this phenotype is in continuous expansion. Therefore, there is a need to confirm the clinical diagnosis of this treatable disorder through biochemical and/or molecular investigations. In recent years, important progress has been made in biochemical and molecular testing in this disease. The phenylalanine loading test is a useful tool for the diagnosis of adGTPCH deficiency; however, false-positive and false-negative results are possible. The analysis of pterins and biogenic amines in CSF is highly specific for DRD but has the inconvenience of being invasive. The measurement of the activity of GTPCH in cytokine-stimulated fibroblasts provides absolute confirmation in the diagnosis. Recently, the yield of molecular studies has improved with the implementation of two techniques to detect heterozygous GCH1 exon deletions, undetectable by sequencing, the quantitative PCR analyses and multiplex ligation-dependent probe amplification. This article provides a diagnostic approach for adGTPCH deficiency in patients with unexplained dystonia, parkinsonism, and/or spasticity.

Keywords

Segawa Syndrome, Dopa-Responsive Dystonia, Guanosine Triphosphate Cyclohydrolase I Deficiency,

GCH1 Gene