Cases of dopa-responsive dystonia (Segawa disease) in Estonia

The aim of this report is to present the first four cases from three families of dopa-responsive dystonia diagnosed in Estonia. Diagnosis was performed by clinical evaluation and response to levodopa and was confirmed by gene analyses. The prevalence of dopa-responsive dystonia in Estonia was 1.4 per 100,000 (95%CI = 0.39–3.65) children less than 18 years of age. In all children with dystonia it is important to think about possible dopa-responsive dystonia as this is treatable condition and improving the quality of life of children.     

Anorexia nervosa and mental retardation: a case report.

This is the first published report of a retarded individual developing anorexia nervosa. The authors discuss the interaction between subnormal intelligence and the presentation of anorexic symptomatology. They also discuss the relationship between this disorder and depression. Anorexia nervosa may not be uncommon in retarded adolescents but may go undiagnosed because of the belief that mentally retarded individuals do not develop this disorder.     

Dopa-responsive dystonia: Pathological and biochemical observations in a case

We report the first neuropathological and neurochemical study of a patient with dopa-responsive dystonia. She had onset of foot dystonia at age 5 years and by age 8 years it was generalized with prominent right leg and arm involvement. On levodopa 750 mg daily she had complete symptomatic improvement that was sustained for 11 years until death. Pathological studies revealed normal numbers of hypopigmented substantia nigra neurons, normal tyrosine hydroxylase (TH) immunoreactivity and TH protein in the SN, no inclusion bodies or gliosis, and no evidence of a degenerative process in the striatum. Biochemical studies revealed reduced dopamine in the substantia nigra and striatum (8% in the putamen and 18% of control in the caudate) with a similar but not identical subregional distribution as in idiopathic Parkinson's disease. In the striatum, TH protein and TH activity was reduced, with the loss more pronounced in the putamen than the caudate. The GBR 12935 binding to DA transporter was normal in the caudate and at the lower end of the range of control values in the putamen. We conclude that disturbed dopamine synthetic capacity or a reduced arborization of striatal dopamine terminals may be the major disturbance in dopa-responsive dystonia.     

Dopa-responsive dystonia is induced by a dominant-negative mechanism

Dopa-responsive dystonia (DRD) is induced by a deficiency of GTP cyclohydrolase I (GCH) and has a postulated autosomal dominant inheritance with a low penetrance. G201E is a dominant DRD mutation. Recombinant G201E mutant protein possessed very low enzyme activity. When G201E was expressed in eukaryotic cells, only a small amount of GCH protein could be detected. In baby hamster kidney cells, G201E protein was synthesized normally but was degraded rapidly in pulse-chase experiments. More interestingly, G201E dramatically decreased the level of wild-type protein and GCH activity in cotransfection studies. Therefore, G201E exerts a dominant-negative effect on the wild-type protein, probably going through an interaction between them. We also showed that L79P but not R249S (a recessive DRD mutation) had a dominant-negative effect. Through the dominant-negative mechanism, a single mutation could decrease GCH activity to less than 50% of normal. This study not only explains the inheritance of DRD but also increases the understanding of genetic diseases associated with multiple subunit proteins.     

Adult‐onset dystonia: Atypical manifestation of Segawa disease

A 33‐year‐old woman developed exercise‐induced limb and trunk dystonia with marked diurnal fluctuations. Treatment with levodopa improved her symptoms considerably but incompletely. Molecular genetic analysis revealed a mutation in GTP cyclohydrolase 1 (GCH1). This report illustrates the variability of Segawa disease and underlines the importance of a levodopa test in patients with uncommon dystonic symptoms. © 2007 Movement Disorder Society     

Neuroleptically induced dystonia in Huntington's disease: a case report

A patient with Huntington's disease developed acute dystonia whilst treated with tiapride. Sulpiride and tetrabenazine also induced dystonia. The anticholinergic biperiden depressed the syndrome but worsened psychopathology. Finally a combination of tetrabenazine and clozapine was successful in treatment of both chorea and dystonia. According to this observation, acute dystonia may occur in Huntington's disease as a consequence of neuroleptic treatment.     

Motor control in childhood onset dopa-responsive dystonia (Segawa syndrome)

To elucidate the pathophysiological features of childhood onset dopa-responsive dystonia (DRD) we used a variety of quantitative analysis techniques to evaluate aspects of reflex- and voluntary motor control in two brothers with this disorder. The observed patterns were compared with those obtained in patients with adult onset Parkinson's disease (PD) and Huntington's disease (HD). In both brothers onset of the disease was in the first decade. Both responded either to treatment with L-Dopa or a combination of L-Dopa with trihexiphenidyl. Neurophysiological studies revealed slowing of different upper extremity voluntary motor activities and a low frequency postural tremor similar to results in other basal ganglia disorders including PD. In contrast to adult onset PD, fastest isometric voluntary index finger contractions did not show the typical kinetic tremor oscillations superimposed on the force trajectories. Also, different to adult PD, no impairment of stance regulating reflexes or saccadic and smooth pursuit eye movements was found in DRD. Magnetoelectrical stimulation of motor cortex showed normal efferent cortical spinal activity. Data indicate that like in other basal ganglia diseases slowing of voluntary motor activity is also a constant feature in DRD. DRD patients show, however, a clear difference to the pattern of motor abnormalities obtainable in PD. Both the pattern of motor control abnormalities is different, and the longlasting effect. In contrast to PD the pathophysiological mechanism in DRD possibly involves a lack of maturation of dopaminergic substantia nigra neurons rather than a degenerative process.     

Cutis verticis gyrata, mental retardation and Lennox-Gastaut syndrome: a case report

Cutis verticis gyrata (CVG) is an abnormality of the scalp characterized by the formation of furrows and folds which cannot be flattened by traction or pressure. Primary and secondary forms of CVG have been described. We report on a patient affected by cutis verticis gyrata, mental regression and Lennox-Gastaut syndrome (LGS). Serum hormonal levels, karyotype and X fragile studies were normal. Magnetic resonance imaging of the brain showed only atrophic changes. The etiology of primary CVG remains unknown as does its relation with LGS. Received: 29 March 2001 / Accepted in revised form: 2 June 2001     

Folie à deux and mental retardation: review and case report

Despite the known association of folie à deux with low intelligence, very few reports of its occurrence in people with documented mental retardation have been published. A case of folie à deux in a 32 year old man with moderate mental retardation is described and the clinical implications discussed. The need for an increased awareness of the existence of mental illness in the mentally handicapped is also emphasized.     

ECT and mental retardation: a review and case reports.

Electroconvulsive therapy (ECT) in patients with mental retardation has received limited study and is a subject of controversy. Specific difficulties in using ECT for this patient population include diagnostic dilemmas, difficulties with measuring outcome and monitoring side effects, and problems with professional attitudes. We report our experience with two cases in which ECT was applied to treat severe psychotic and catatonic symptoms. In case 1, a 22-year-old male patient with a history of moderate mental retardation, bipolar disorder, and neuroleptic malignant syndrome was admitted to manage his disruptive behavior and psychotic symptoms. The patient responded well to six bilateral ECTs with diminution of his psychotic symptoms and behavioral disturbances. In Case 2, a 39-year-old female patient with a history of mental retardation, schizoaffective disorder, and catatonic symptoms successfully responded to 11 bilateral ECTs. We conclude that ECT can be used safely and effectively in patients with mental retardation and severe or refractory psychotic symptoms.     

A case of late-onset Segawa syndrome (autosomal dominant dopa-responsive dystonia) with a novel mutation of the GTP-cyclohydrase I (GCH1) gene

We report a case of a 46-year-old Japanese woman with hereditary progressive dystonia with marked diurnal fluctuations and dopa-responsive dystonia (HPD/DRD). She developed difficulty in walking at the age of 44 years due to bradykinesia as well as hand tremors, muscle rigidity, increased tendon reflexes and mild dystonia in the lower extremities, all of which responded remarkably to low doses of levodopa (150 mg/day). Biopterin and neopterin concentrations in the cerebrospinal fluid (CSF) were decreased. Analysis of the guanosine 5′-triphosphate cyclohydrolase I (GCH1) gene revealed a novel mutation (W53X) in one allele. The GCH1 activity that was expressed in mononuclear blood cells was almost half the normal value (usually 2–20% of the normal value (39.0 ± 9.2 pmol/ml) in patients with HPD/DRD). The relatively conserved GCH1 activity that is expressed in stimulated peripheral blood mononuclear cells may be related to the late clinical symptoms in this patient.     

一氧化碳中毒迟发性脑病肌张力障碍一例报道

目的通过观察1例一氧化碳(CO)中毒迟发性脑病肌张力障碍患者,探讨该疾病的病程和症状特点。方法收集该病人的病史及我院住院康复治疗期间的体格检查、影像学检查和平衡功能检查,总结肌张力障碍的潜伏期和特点。结果该病例于CO中毒两年后逐渐出现肌张力障碍,造成骨骼的畸形发育,形成永久性障碍。结论在临床中要加强对CO中毒患者,特别是儿童和青少年的长期随访观察,及时发现迟发性脑病,并且及时治疗相关症状。     

Dopa-responsive childhood dystonia: a forme fruste with writer's cramp; triggered by exercise

An 11-year-old girl was evaluated for walking difficulties and fatigue at the end of the day in the last 2 years. Handwriting was also difficult with 'cramps' after a short time of writing. Neurological examination was normal most of the time but in the evening and after exercise, an abnormal walking posture and rare dystonic movements of the foot could sometimes be seen. The mother was found to have mild parkinsonism and is asymptomatic on L-dopa. In the daughter, all symptoms and signs disappeared on L-dopa, but returned when the drug was withdrawn. The changes on- and off-treatment were documented with videofilms and computerized analysis of writing samples. The situation has been stable during a 5-year follow-up. We draw attention to this 'forme fruste' of dopa-sensitive childhood dystonia which becomes manifest with exercise and which can easily go unrecognized. We also discuss and illustrate the methods used for the analysis of writing.     

Dopa-responsive dystonia: [18F]dopa positron emission tomography.

The syndrome of dopa-responsive dystonia comprises a minority of patients with dystonia, yet it is of considerable diagnostic importance because patients respond dramatically to L-dopa therapy. Benefits from this treatment are lasting, and the problems associated with long-term L-dopa therapy in patients with Parkinson's disease are generally absent. It has been suggested that this condition is due to a defect in the dopamine synthetic pathway, which is bypassed when patients are treated with L-dopa. We have studied [18F]dopa uptake in 6 patients with classic dopa-responsive dystonia (5 familial patients and 1 sporadic patient), aged 18 to 66 years. Data have been analyzed according to a graphic approach, calculating an influx constant for each region studied. We have also studied a seventh, clinically atypical, patient with juvenile dystonia-parkinsonism. Similar data have been calculated for a group of 10 healthy control subjects and 10 patients with Parkinson's disease. The 6 patients with typical dopa-responsive dystonia had a modest but significant reduction in the uptake of tracer into both caudate and putamen, which indicates a defect in the decarboxylation, vesicular uptake, and storage of [18F]dopa. This argues against the proposition that dopa-responsive dystonia is due to an inherited defect of tyrosine hydroxylase alone. In the atypical patient, however, we found a greater reduction of [18F]dopa uptake into both caudate and putamen, comparable with that in patients with Parkinson's disease.     

Ziprasidone-induced tardive laryngeal dystonia: a case report

Tardive laryngeal dystonia, a rare form of dystonic syndrome, was only reported to be induced by typical antipsychotics. Here, we report one case of ziprasidone-induced tardive laryngeal dystonia in a schizophrenic female patient, who showed dysphonia, hoarseness and dyspnea after taking ziprasidone 120 mg/day for 8 months. These symptoms were significantly improved after discontinuing ziprasidone and increasing the dose of trihexyphenidyl for 1 week. Although atypical antipsychotics are associated with a lower risk of extrapyramidal symptoms, caution should be taken for any tardive dystonic movement when using these medications.     

Dopa-responsive dystonia: recent advances and remaining issues to be addressed.

It is evident from this review that there is much that we know and much that we still do not know about DRD. In terms of diagnosis and clinical management, there is general agreement that patients with childhood-onset dystonic symptoms of unknown etiology should be treated initially with levodopa with the later addition, if necessary, of other medications (for example, BH4, 5-hydroxytryptophan). Although the results of molecular genetic and CSF studies are, at this time, unlikely to significantly alter clinical management of the patient, these analyses could be useful in providing information on prognosis (that is, DRD versus progressive neurodegenerative disorders or more severe metabolic disorders). It is also clear that notwithstanding the discovery of GCH1 and hTH mutations responsible for DRD, there remain many important unresolved issues regarding this disorder, including questions of female predominance, phenotypic heterogeneity, and presence of childhood-onset dystonia versus the expected parkinsonism resulting from a striatal DA deficit. We are confident that answers to these interesting questions on DRD will, in addition to providing clarification of the mechanisms of this disorder, provide exciting information relating to the pathogenesis of other types of dystonia as well as PD and to long-standing issues regarding a role of DA and serotonin in normal human brain development.     

Acute focal dystonia induced by a tricyclic antidepressant in a patient with Wilson disease: a case report

The authors present the case of a 19-year-old patient with Wilson disease (WD) who developed symptoms of acute focal dystonia of the left hand (a ‘starfish’ hand presentation) shortly after treatment with the tricyclic antidepressant clomipramine. The diagnosis of WD was made 8 months earlier based on abnormal copper metabolism parameters and was confirmed by genetic testing. Initially, the patient presented with akathisia, sialorrhea, oromandibular dystonia (occasionally grimacing) and slight dysarthria. The patient's symptoms diminished after treatment with d-penicillamine was initiated. No further deterioration was observed after copper-chelating therapy was started.The authors diagnosed acute focal dystonia induced by clomipramine.Botulinum toxin and intensive rehabilitation was initiated; complete regression of hand dystonia was observed. Based on the case, the authors suggest that care should be exercised with regard to starting medications that could potentially impact the extrapyramidal system in WD patients.