Diagnosis Of Dopa-responsive Dystonia Research Articles

Dopa-responsive dystonia masked by biperiden dependence; a case report

Anticholinergic drugs are widely employed for the treatment of various conditions, including extrapyramidal symptoms. However, recent research suggests a potential link between the misuse of anticholinergics and inherited movement disorders, such as dopa-responsive dystonia (DRD). This report presents a case study of a 61-year-old woman who had been experiencing involuntary movements, including dystonia and tremors, for 30 years. Initially, she was prescribed anticholinergic agents like biperiden, which provided partial relief. Nevertheless, her symptoms gradually worsened, and she developed a tolerance to anticholinergics. Subsequently, a diagnosis of DRD was confirmed, and her symptoms exhibited significant improvement following treatment with levodopa. This case underscores the importance of healthcare professionals being aware of the potential association between anticholinergic misuse and inherited movement disorders. Early identification and management of underlying conditions like DRD can aid in preventing unnecessary and potentially harmful utilization of anticholinergics, thereby enhancing patient outcomes and reducing the risks of dependence and abuse.

Commentary on a case report of Dopa-responsive dystonia or Segawa disease in Ghana

The case of Dopa-Responsive Dystonia or Segawa Disease reported in this issue brings to the fore the age-old tenets of medicine which is based on the taking of a detailed history, physical examination, and the request of relevant investigations to achieve a diagnosis. This is followed with an evidence-based treatment planning. This maxim remains important especially in resource poor environments where sometimes one must depend on the history and physical examination findings alone to make a diagnosis and commence treatment. The patient under review had had her condition progressively worsening for two years and had been managed as a case of cerebral palsy.The initial consideration of a possible dyskinetic cerebral palsy from bilirubin encephalopathy which the author indicated was common is understandable as this is one of the commonest causes of such presentation in the setting. However, having a more detailed history and having other differentials in mind such as childhood Dopa-Responsive Dystonia, as was the case presented, helped in identifying subtle differences in presentation that influenced the ultimate diagnosis. In this case, a later onset of symptoms (dystonia), with the symptoms being minimal after sleep and becoming more severe late afternoon having helped to clinch the diagnosis. Considering each patient one sees as eligible for a possible case report allows one to update his or her knowledge on the condition, identify peculiar features and directs the request of relevant investigations. The use of telemedicine is yet to be widespread in the developing world even though telecommunication infrastructure is improving in these regions. This case had the diagnosis essentially made by contacting a paediatric neurologist by telephone. Such specialist consultations need to be encouraged as there are very few specialists across the globe and less still in the developing economies.Governments and Medical Associations may have to lead in creating these platforms to assist in this direction to improve the overall access to specialist care and reviews in less endowed regions. In the case presented, the diagnosis of Dopa-Responsive Dystonia was confirmed after a demonstration of a marked and sustained response to low dose L-dopa without motor fluctuations or dyskinesias. We applaud the author for the diagnosis having been made by essentially a detailed history and physical examination and response to L-dopa. It was however indicated that there are recent developments that involve analysis of cerebrospinal fluid for neurotransmitters that demonstrate low concentrations of biopterin and neopterin with DNA sequencing demonstrating mutation of the GTP cyclohydrolase-1 gene in up to 80% of cases in gene studies. These diagnostic tests hinge on the finding of an autosomal dominant heterozygous mutation in the GTPcyclohydrolase-I gene that results in biopterin deficiency, a cofactor for tyrosine hydroxylase and dopamine deficiency and considered the most classic molecular pathophysiology of this condition [1]. These additional tests were not done bringing to the fore the limited access to investigative tools in some developing economies. While National Reference Laboratories are in existence in some countries, regional efforts could be made to set up reference laboratories that serve entire region to allow for pooling of infrequently performed laboratory tests for analysis. This will make such infrequently encountered medical conditions be accurately diagnosed and treated. Of concern is how to achieve an un-interrupted supply of L-Dopa as the child returns to the village. This should engage the attention of all involved in her treatment as they follow the patient up.To conclude, the suggestion by the author that the diagnosis of Dopa-Responsive Dystopia or Segawa disease must be considered in all cases of dystonia including cases of apparent dystonic cerebral palsy and especially where there is no history of birth asphyxia need being emphasized.

Дофа-зависимая дистония (синдром Сегавы): описание клинического наблюдения

The authors present a case-report of genetically tested dopa-responsive dystonia, also known as Segawa’s syndrome, in a 32-year-old woman. The genetic forms and their clinical presentation are described. Symptoms began in early childhood with running disability. The patient’s first complaint was twisting of her toes during walking when she was 12 years old. The condition remained stable up to 20 y. o., when some improvement was noticed. Symptoms progressed with involvement of upper limbs at the age of 25. By the age of 32 the patient was directed to Movement Disorders Clinic, where Dopa-responsive dystonia was suspected. The manifestations were dramatically responsive to low doses of levodopa-carbidopa, confirming the diagnosis of dopa-responsive dystonia. The genetic test identified a GCH1 (chr14:55369161G>A) pathogenic mutation.

Dyskinesias as a Limiting Factor in the Treatment of Segawa Disease

Patients with autosomal dominant Segawa disease (dopa-responsive dystonia) demonstrate excellent, sustained response to low-dose levodopa. In contrast, the development of levodopa limiting treatment dyskinesias is thought to support the diagnosis of other early-onset dystonia/parkinsonism syndromes. We describe an atypical phenotype of persistent treatment limiting dyskinesias in a family with prominent brachial dystonia and a novel GCH1 mutation. The pedigree comprised two affected members: the proband (aged 13 years) and her mildly affected mother (aged 48 years). A phenylalanine loading test, cerebrospinal fluid for biogenic amines and pterins, guanosine triphosphate cyclohydrolase I enzyme activity, and direct exonic sequencing of GCH1 revealed a novel mutation (c.235_240delCTGAGC [p.L79_S80del]) in the GCH1 gene. Despite continuous levodopa therapy from age 7 years, the proband developed severe writer's cramp at age 10 years and persistent treatment limiting dyskinesias, with even low doses of levodopa leading to treatment challenges. Dyskinesias as limiting side effects of levodopa should not preclude a diagnosis of dopa-responsive dystonia during diagnostic levodopa trials. A diagnosis of Segawa disease should still be considered if partial improvement occurs with levodopa, but with dose-limiting dyskinesias.

Dopa-Responsive Dystonia in a Ten-Year-Old Girl

Children with recent onset dystonia and gait abnormalities may pose a diagnostic challenge. A ten-year-old, developmentally normal girl, presented with a six-month history of gait abnormality and dystonia. Her complaint worsened as the day progressed. In view of typical diurnal variation of dystonia, a therapeutic challenge with levodopa/carbidopa was given and there was a dramatic response. Hence, a diagnosis of dopa-responsive dystonia (DRD) was made. DRD is an inherited disorder characterized by dystonia with diurnal variation and favorable response to levodopa/carbidopa. The inheritance is usually autosomal dominant, however, in some cases, autosomal-recessive inheritance is also seen.

Dopa-responsive dystonia

Dystonia is considered to be a prolonged involuntary contractions of the muscles leading to twisting, repetitive movements or irregular postures. Etiologically, it could be classified as primary and secondary dystonia. Dopa-responsive dystonia (DRD) belongs to a group of primary dystonia. The aim of this study was to detect the presence of gene GCH-I mutation in our population in patients with dopa-responsive dystonic dyskinesia and to analyse clinical specificity of the affected. Out of the group of patients with dystonia of different distribution four patients were separated whose clinical picture indicated the diagnosis of DRD. Two patients had a positive family anamnesis while the other two were sporadic. Genetic analysis was performed by the use of a standard protocol, which included PCR amplification and DNK sequencing according to the method of Senger and autoradiografy. In the patients from the family DRD-1 new hetaerazygote point mutation 520G-->A in 4-m exson gene GCH-I was revealed. First symptoms of the disease showed in the age of seven by the torsion of the left foot, progressively advanced and got into the evolution of numbness in the legs, aggravated gait, tending to worsen in the evening, and the therapy with levodopa (500 mg) produced a dramatic effect. The second mutation in the female patient from the family DRD-2 was homozygote deletion in 1-m intron gene GCH-I (IVS1-85delA). Unwilling torsion of the foot, feeling of weakness in the lower extremities (that caused falling without loss of the consciousness) were clinical demonstrations of the disease. The application of levodopa (300 mg) caused regression of the symptoms of the disease. Hetaerazygote deletion of adenine in the position 209 in the first exon (209del A) was identificated in the patient DRD-3 with negative family anamnesis, in who in the age of ten the torsion of the foot inside occured for the first time following by trembling of both the left and right legs at rest; after a few years, tremor of hands also appeared, which became worse in stressful situations. The father of the patient was an asymptomatic bearer of mutation. The fourth mutation in gene GCH-I was found in I exon gene GCH-I, 208delA. The disease was started by torsion of the left foot, progressing easily, and worsening in the evenings, but at the age of 30, moving became harder, fatigue and pain in muscles, increased and at the age of 40 the patient recognised the change of speech. The application of levodopa (300 mg/daily) made the patient feel better and walk independently. The study presented four patients with genetic confirmation of the diagnosis of dopa-responsive dystonia. This entity is very significant in differential diagnostics of both early dystonia (< 26 years) and early parkinsonism (< 40 years) since it can be successfully managed by applyng relatively low doses of levodopa over a long period of time.

Mutation in intron 5 of GTP cyclohydrolase 1 gene causes dopa-responsive dystonia (Segawa syndrome) in a Brazilian family

Dopa-responsive dystonia (DRD), also known as Segawa syndrome or hereditary progressive dystonia with diurnal fluctuation, is clinically characterized by the occurrence of simultaneous or late Parkinsonism and by an excellent response to treatment with low doses of L-dopa. Diagnosis of DRD is essentially clinical. It is based on clinical history and the response to treatment with low doses of L-dopa. However, due to the low penetrance of the disease, asymptomatic carriers may exist. In these cases, mutational analysis of the GCH1 gene is an alternative to diagnose DRD. In the present study, we investigated a large DRD-carrier family in an attempt to identify the disease-causing mutation. The proband, a young woman diagnosed at the age of 13 years, is the daughter of a healthy non-consanguineous couple with history of several cases, on the maternal side of the family, of tip-toeing, disturbance of gait, Parkinsonism, rigidity and cramps in the lower limbs. Using single strand conformational polymorphism and DNA sequencing techniques to analyze DNA extracted from blood samples, we identified a mutation in the GCH1 gene, IVS5+3insT, which would preclude the formation of the active enzyme due to the formation of truncated peptides.

Variability of clinical expression and evolution of spinal deformity in a family with late detection of dopa-responsive dystonia

This case report documents an unusual presentation of dopa-responsive dystonia (DRD) in three siblings (two females, one male) which simulated cerebral palsy (CP) and describes the evolution of their spinal deformity in relation to growth and responsiveness to levodopa therapy. The siblings were normal at birth with a negative history of neurological disease or spinal imbalance. They showed marked phenotypic variation but all developed progressive scoliosis and neurological impairment with mixed spastic dystonic features, leading to the misdiagnosis of spastic dystonic CP. Age at establishment of the diagnosis of DRD and levodopa trial for the three patients was 12 years, 9 years 6 months, and 3 years 6 months respectively. In patients 1 and 3, spinal deformity responded dramatically to levodopa treatment and neurological symptoms were ameliorated. Patient 2 developed a rigid scoliotic curve and, despite neurological improvement with levodopa, the spinal curvature remained unresponsive necessitating surgical correction. Spinal decompensation is a common manifestation of DRD, which with early diagnosis and initiation of levodopa treatment has an excellent prognosis. This report highlights the variability of clinical expression in DRD and the importance of an adequate trial of levodopa when unexplained dystonic features are documented.

Torsion Dystonia in Children.

Medical treatment of childhood-onset dystonia can lead to substantial improvement of the condition, often with much more pronounced benefit than in adults. The authors give every patient a trial of levodopa to assess the possible diagnosis of dopa-responsive dystonia, followed-up with centrally acting anticholinergics such as trihexiphenydil. If needed, baclofen or clonazepam is added or substituted. In focal dystonia or segmental and generalized dystonia with prominent involvement of specific muscle groups, botulinum toxin injections are often used. Pallidal deep brain stimulation is offered to selected patients with medically refractory dystonia. Treatment of secondary dystonias, caused by such conditions as Wilson's disease, requires therapy for the underlying disorder. Physical therapy, splints, and occupational therapy can be useful in some patients. The authors do not use intrathecal baclofen unless there is evidence of accompanying spasticity.

Diagnosis of Dopa-responsive Dystonia and Other Tetrahydrobiopterin Disorders by the Study of Biopterin Metabolism in Fibroblasts

Dopa-responsive dystonia (DRD) and tetrahydrobiopterin (BH4) defects are inherited disorders characterized by monoamine neurotransmitter deficiency with decreased activity of one of the BH4-metabolizing enzymes. The aim of the study was to determine the utility of cultured skin fibroblasts for the diagnosis of these diseases. Neopterin and biopterin production and GTP cyclohydrolase I (GTPCH) activity were measured in cytokine-stimulated fibroblasts; 6-pyruvoyltetrahydropterin synthase (PTPS), sepiapterin reductase (SR), and dihydropteridine reductase (DHPR) activities were measured in unstimulated fibroblasts. We examined 8 patients with DRD, 3 with autosomal recessive GTPCH deficiency, 7 with PTPS deficiency, 3 with DHPR deficiency, and 49 controls (35 fibroblast and 14 amniocyte samples). Fibroblasts from patients with DRD and autosomal recessive GTPCH deficiency showed reduced GTPCH activity (15.4% and 30.7% of normal activity, respectively) compared with controls (P < 0.001). Neopterin production was very low and biopterin production was reduced in both disorders. PTPS- and DHPR-deficient cells showed no enzyme activities; in PTPS deficiency the pattern of pterin production was typical (neopterin, 334-734 pmol/mg; controls, 18-98 pmol/mg; biopterin, 0 pmol/mg; controls, 154-303 pmol/mg). Reference values of all enzyme activities and pterin production were measured in fibroblasts and also in amniocytes for prenatal diagnosis. Cultured skin fibroblasts are a useful tool in the diagnosis of BH4 deficiencies. Intracellular neopterin and biopterin concentrations and GTPCH activity in cytokine-stimulated fibroblasts are particularly helpful in diagnosing patients with DRD.

Dopa-Responsive Dystonia, Tyrosine Hydroxylase Deficiency and Aromatic L-Amino Acid Decarboxylase Deficiency: Multifaceted Diseases That Can Masquerade as Cerebral Palsy • 1874

Diagnosis of dopa-responsive dystonia (DRD) due to GTP cyclohydrolase I(GTPCH) deficiency (autosomal dominant), tyrosine hydroxylase (TH) deficiency(autosomal recessive) or aromatic L-amino acid decarboxylase (AADC) deficiency(autosomal recessive) is difficult as symptoms are often non-specific. We have established a series of tests which, either in isolation, or in combination allow identification of these disorders. Measurement of biogenic amine neurotransmitter metabolites in cerebrospinal fluid (CSF) shows low levels of homovanillic acid (HVA - dopamine metabolite) in all three conditions. GTPCH deficiency is distinguished by decreased levels of tetrahydrobiopterin and its precursor, neopterin, and AADC deficiency by high levels of 3-O-methyldopa(3OMD). Low levels of HVA, with normal pterins and 3OMD in the absence of brain lesions is highly suggestive of TH deficiency. Diagnosis is also possible in the absence of CSF. 3OMD concentrations are highly elevated in plasma and urine in AADC deficiency. Confirmation of the diagnosis is accomplished by assay of AADC activity in plasma. Evidence for TH deficiency can be obtained by a finding of reduced concentrations of plasma catecholamines, but final confirmation requires DNA mutation analysis as tissues are not readily available for TH enzyme assay. Due to a secondary inhibition of phenylalanine metabolism, DRD can be diagnosed by measurement of phenylalanine and tyrosine in plasma after an oral phenylalanine load. This battery of tests has to date identified 6 cases of AADC deficiency, 4 cases of TH deficiency, and 4 cases of DRD. Of these, 8 had been described as having cerebral palsy (CP) prior to our diagnosis. As CP is normally considered an untreatable disorder, it is important that patients with CP of unknown etiology be tested, as symptoms in DRD and the TH and AADC deficiencies often respond dramatically to treatment with either levodopa, or a mixture of dopamine agonists and monoamine oxidase inhibitors.