Abstract
Dopa-responsive dystonia, a rare disorder typically presenting in early childhood with lower limb dystonia and gait abnormality, responds well to levodopa. However, it is often misdiagnosed with the wide spectrum of phenotypes. By exome sequencing, we make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees. One pedigree, presented with prominent parkinsonism, was misdiagnosed as Parkinson's disease until a known mutation in GCH1 (GTP cyclohydrolase 1) gene (NM_000161.2: c.631_632delAT, p.Met211ValfsX38) was found. The other pedigree was detected with a new compound heterozygous mutation in TH (tyrosine hydroxylase) gene [(NM_000360.3: c.911C>T, p.Ala304Val) and (NM_000360.3: c.1358G>A, p.Arg453His)], whose proband, a pregnant woman, required a rapid and less-biased genetic diagnosis. In conclusion, we demonstrated that exome sequencing could provide a precise and rapid genetic testing in the diagnosis of Mendelian diseases, especially for diseases with wide phenotypes.
Highlights
Dopa-responsive dystonia (DRD) is a childhood-onset or adolescent-onset form of dystonia with excellent response to low dose levodopa [1,2,3]
The two patients were initially diagnosed as PD in the family 1, and the diagnosis of DRD or other diseases causing juvenile parkinsonism and dystonia for the index were considered in the referral differential diagnosis
It was very difficult for the differential diagnosis between DRD, early-onset PD and other diseases with juvenile parkinsonism and dystonia without genetic testing for this index case
Summary
Dopa-responsive dystonia (DRD) is a childhood-onset or adolescent-onset form of dystonia with excellent response to low dose levodopa [1,2,3]. DRD has been reported to associate with mutations in genes encoding guanosine 59-triphosphate (GTP) cyclohydrolase (GCH1), tyrosine hydroxylase (TH), and sepiapterin reductase (SPR) [4,5,6]. GCH1 and SPR are crucial enzymes for the biosynthesis of tetrahydrobiopterin (BH4), which serves as an essential cofactor for tyrosine and tryptophan hydroxylases in the initial biosynthesis of the neurotransmitter dopamine. Despite the availability of genetic testing, there still remains a marked delay in establishing the diagnosis with a delay of 15.2613.7 years [2]. Differential diagnosis for some DRD patients is difficult with early-onset Parkinson’s disease, cerebral palsy, spastic paraplegia, and early-onset primary dystonia, et al [7,8]. Besides the wide spectrum of phenotypes, unknown genetic causes were found in five percent of DRD cases [9]. A combination of exon-capture and generation sequencing technology, regarded as a rapid, cost-effective and comprehensive tool, has recently been successfully applied to genetic diagnosis of diseases [10,11]
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