Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause Levodopa-responsive infantile-onset Parkinsonism.

Mitochondrial aminoacyl-tRNA synthetases (mtARSs) are essential, ubiquitously expressed enzymes that covalently attach amino acids to their corresponding tRNA molecules during translation of mitochondrial genes. Deleterious variants in the mtARS genes cause a diverse array of phenotypes, many of which involve the nervous system. Moreover, distinct mutations in mtARSs often cause different clinical manifestations. Recently, the gene encoding mitochondrial tryptophanyl tRNA synthetase (WARS2) was reported to cause 2 different neurological phenotypes, a form of autosomal recessive intellectual disability and a syndrome of severe infantile-onset leukoencephalopathy. Here, we report the case of a 17-year-old boy with compound heterozygous mutations in WARS2 (p.Trp13Gly, p.Ser228Trp) who presented with infantile-onset, Levodopa-responsive Parkinsonism at the age of 2 years. Analysis of patient-derived dermal fibroblasts revealed decreased steady-state WARS2 protein and normal OXPHOS content. Muscle mitochondrial studies suggested mitochondrial proliferation without obvious respiratory chain deficiencies at the age of 9 years. This case expands the phenotypic spectrum of WARS2 deficiency and emphasizes the importance of mitochondrial protein synthesis in the pathogenesis of Parkinsonism.

Subthalamic nucleus stimulation in advanced Parkinson's disease: blinded assessments at one year follow up.

OBJECTIVE: To measure the effect of deep brain stimulation (DBS) of the subthalamic nucleus in patients with advanced Parkinson's disease. DESIGN: Open label follow up using blinded ratings of videotaped neurological examinations. PATIENTS: 30 patients with advanced Parkinson's disease (19 male, 11 female; mean age 58.8 years; mean disease duration 12.8 years), complicated by intractable wearing off motor fluctuations and dopaminergic dyskinesias. MAIN OUTCOME MEASURES: Unified Parkinson's disease rating scale (UPDRS), part III (motor), score at one year, from blinded reviews of videotaped neurological examinations. Secondary outcomes included the other UPDRS subscales, Hoehn and Yahr scale, activities of daily living (ADL) scale, mini-mental state examination (MMSE), estimates of motor fluctuations and dyskinesia severity, drug intake, and patient satisfaction questionnaire. RESULTS: Subthalamic nucleus stimulation was associated with a 29.5% reduction in motor scores at one year (p<0.0001). The only important predictors of improvement in UPDRS part III motor scores were the baseline response to dopaminergic drugs (p = 0.015) and the presence of tremor (p = 0.027). Hoehn and Yahr scores and ADL scores in the "on" and "off" states did not change, nor did the mean MMSE score. Weight gain occurred in the year after surgery, from (mean) 75.8 kg to 78.5 kg (p = 0.028). Duration of daily wearing off episodes was reduced by 69%. Dyskinesia severity was reduced by 60%. Drug requirements (in levodopa equivalents) declined by 30%. CONCLUSIONS: The 30% improvement in UPDRS motor scores was a more modest result than previously reported. DBS did not improve functional capacity independent of drug use. Its chief benefits were reduction in wearing off duration and dyskinesia severity.

The natural history and treatment of acquired hemidystonia: report of 33 cases and review of the literature.

OBJECTIVE: To evaluate the natural history and response to treatment in hemidystonia. METHODS: 190 Cases of hemidystonia were identified; 33 patients in this series and 157 from the world literature. Data was collected on aetiology, age of onset, latency, lesion location, and response to treatment. RESULTS: The most common aetiologies of hemidystonia were stroke, trauma, and perinatal injury. Mean age of onset was 20 years in this series and 25.7 years in the literature. The average latency from insult to dystonia was 4.1 years in this series and 2.8 years in the literature, with the longest latencies occurring after perinatal injury. Basal ganglia lesions were identified in 48% of cases in this series and 60% of the cases in the literature, most commonly involving the putamen. Patients experienced benefit from medical therapy in only 26% of medication trials in this series and in only 35% of trials in the literature. In the patients reported here, the benzodiazepines clonazepam and diazepam were the most effective medications with 50% of trials resulting in at least some benefit. In the literature, anticholinergic drugs were most effective with 41% of trials resulting in benefit. Surgery was successful in five of six cases in this series and in 22 of 23 cases in the literature. However, in 12 cases, results were transient. CONCLUSIONS: The most common cause of hemidystonia is stroke, with the lesion most commonly involving the basal ganglia. Hemidystonia responds poorly to most medical therapies, but some patients may benefit from treatment with benzodiazepines or anticholinergic drugs. Surgical therapy may be successful but benefit is often transient.

Neuroleptic malignant syndrome in advanced Parkinson's disease.

Neuroleptic malignant syndrome is a serious complication of levodopa withdrawal in patients with Parkinson's disease. We report a patient with advanced parkinsonism who developed neuroleptic malignant syndrome in the setting of inadequate levodopa intake. His symptoms improved with levodopa replacement, but dramatically worsened when enteral feeding was begun due to interference with intestinal absorption of levodopa.