Dopa-responsive dystonia (DRD) encompasses a group of clinically and genetically heterogeneous disorders that typically manifest as limb-onset, diurnally fluctuating dystonia and exhibit a robust and sustained response to levodopa treatment. Autosomal dominant GTP cyclohydrolase 1 deficiency, also known as Segawa disease, is the most common and best-characterized condition that manifests as DRD, but a similar presentation can be seen with genetic abnormalities that lead to deficiencies in tyrosine hydroxylase, sepiapterin reductase or other enzymes that are involved in the biosynthesis of dopamine. In rare cases, DRD can result from conditions that do not affect the biosynthesis of dopamine; single case reports have shown that DRD can be a manifestation of hereditary spastic paraplegia type 11, spinocerebellar ataxia type 3 and ataxia telangiectasia. This heterogeneity of conditions that underlie DRD frequently leads to misdiagnosis, which delays the appropriate treatment with levodopa. Correct diagnosis at an early stage requires use of the appropriate diagnostic tests, which include a levodopa trial, genetic testing (including whole-exome sequencing), cerebrospinal fluid neurotransmitter analysis, the phenylalanine loading test, and enzyme activity measurements. The selection of tests for use depends on the clinical presentation and level of complexity. This Review presents the common and rarer causes of DRD and their clinical features, and considers the most appropriate approaches to ensure early diagnosis and treatment.

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Although the clinical features of hemiparkinsonism-hemiatrophy syndrome are variable, suggesting a heterogeneous pathogenesis, perinatal and early childhood cerebral injury appears to play an important role in about half of the cases.

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We reviewed the medical records of 26 patients with the HD-HA syndrome and the data was entered into a database and analyzed. Video recordings as well as imaging studies were also reviewed. Twenty six patients (14 female) with a mean age at onset of HD at 14.9 years (1-46 years) were followed for a mean of 3.4 years. Fourteen (53%) had HD and HA on the left side and 23 (88%) had hemiparesis preceding the onset of HD. The mean latency from the onset of hemiparesis to the onset of HD was 14.7 years (2 weeks-46 years). All patients with hemiparesis had marked improvement in their weakness prior to the onset of HD. Common causes leading to hemiparesis and subsequent HD were birth or perinatal complications (N = 13) and stroke (N = 10). Seven patients (26%) had associated seizures. Twenty two patients (85%) had abnormal brain MRI: eight had lesions directly involving the basal ganglia and nine had cerebral hemiatrophy or non specific diffuse atrophy. Sixteen patients received botulinum toxin injections and responded well to treatment. HD-HA is usually associated with static encephalopathy originating at very young age, but the syndrome may also represent delayed sequelae of a stroke or brain injury.