Expanding the Spectrum of Dopa-Responsive Dystonia (DRD) and Proposal for New Definition: DRD, DRD-plus, and DRD Look-alike

Previously, we defined DRD as a syndrome of selective nigrostriatal dopamine deficiency caused by genetic defects in the dopamine synthetic pathway without nigral cell loss. DRD-plus also has the same etiologic background with DRD, but DRD-plus patients have more severe features that are not seen in DRD because of the severity of the genetic defect. However, there have been many reports of dystonia responsive to dopaminergic drugs that do not fit into DRD or DRD-plus (genetic defects in the dopamine synthetic pathway without nigral cell loss). We reframed the concept of DRD/DRD-plus and proposed the concept of DRD look-alike to include the additional cases described above. Examples of dystonia that is responsive to dopaminergic drugs include the following: transportopathies (dopamine transporter deficiency; vesicular monoamine transporter 2 deficiency); SOX6 mutation resulting in a developmentally decreased number of nigral cells; degenerative disorders with progressive loss of nigral cells (juvenile Parkinson's disease; pallidopyramidal syndrome; spinocerebellar ataxia type 3), and disorders that are not known to affect the nigrostriatal dopaminergic system (DYT1; GLUT1 deficiency; myoclonus-dystonia; ataxia telangiectasia). This classification will help with an etiologic diagnosis as well as planning the work up and guiding the therapy.

Clinical and genetic study on 5 children with dopa-responsive dystonia due to tyrosine hydroxylase deficiency / 中华实用儿科临床杂志

Objective To explore the clinical characteristics,gene mutations,diagnosis and treatment of chil-dren with dopa-responsive dystonia due to tyrosine hydroxylase(TH)deficiency.Methods Five patients(3 boys and 2 girls)with dopa-responsive dystonia due to TH deficiency were diagnosed and followed up from January 2002 to October 2017.The clinical manifestations,laboratory findings,treatment and TH gene mutations associated with TH defi-ciency were analyzed.Results Five patients came from different families.They had the onset at the age of 8 months to 20 months with dystonia,paroxysmal muscular hypertonia and normal intelligence or mild mental retardation.All of them had been misdiagnosed as cerebral palsy.Two cases with floppy limbs presented with fatigue and tremor.One case with floppy limbs presented with seizures. Complex heterozygous mutations were found in TH gene of all patients,which helped to confirm the diagnosis.Eight mutations were identified in TH gene.Six of them were reported.Two novel muta-tions,c.1077C>A(p.C359X)and c.1228C>T(p.R410C)were detected.After the treatment by levodopa[2.2-5.4 mg/(kg·d)],significant improvement was observed.Three patients recovered their intellectual and motor activi-ties.Two patients were dramatically improved but with slightly uncoordinated movements.Conclusion The patients of dopa-responsive dystonia due to TH deficiency usually have the onset around one year of age with almost normal inte-lligence,motor retardation and dystonia.The patients are likely misdiagnosed as cerebral palsy.The treatment with levo-dopa can dramatically improve the symptoms.The etiological diagnosis is very important.

Dopa-responsive Dystonia with a Novel Initiation Codon Mutation in the GCH1 Gene Misdiagnosed as Cerebral Palsy

Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic response to relatively low doses of levodopa. However, patients with DRD can be misdiagnosed as cerebral palsy or spastic diplegia due to phenotypic variation. Here we report a young woman with DRD who were severely disabled and misdiagnosed as cerebral palsy for over 10 yr. A small dose of levodopa restored wheelchair-bound state to normality. However, thoracolumbar scoliosis has remained as a sequel due to late detection of DRD. Genetic analysis by using PCR-direct sequencing revealed a novel initiation codon mutation (c.1A>T; p.Met1Leu) in GTP cyclohydrolase 1 (GCH1) gene. Although it is known that DRD can be misdiagnosed as cerebral palsy, this case reinforces the importance of differential diagnosis of DRD from cerebral palsy.

Report of three cases of dopa-responsive dystonia in one family / 第二军医大学学报

Objective: To study the clinical characteristics of dopa responsive dystonia (DRD),providing data for earlier diagnosis and treatment. Methods: Three cases of DRD patients from the same family were studied through their clinical data, laboratory investigations and therapeutic effects. Results: Two males and one female were the same generation. The age of onset remembered was about 10 years. The symptoms were insidiously progressive. Clinical features were extrapyramidal presentations such as fast words speed, limbs stiffness and involuntary movements. All 3 patients had leadtube muscle rigidity, exaggerated tendon reflexes; Two patients had feet deformity. Babinski signs were absent.CT, MRI, serum muscular enzymes and EMG, etc . were normal. Madopa,0.125 0.375 g, daily was effective with the longest treatment period for nearly 30 years and no obvious side effects found. Conclusion: The incidence of DRD is rare with specific presentations, early diagnosis and treatment may achieve better results.