Brain-derived neurotrophic factor and risk for primary adult-onset cranial-cervical dystonia

Background and purpose:  Adult-onset dystonia may be related, amongst other factors, to abnormal neuronal plasticity in cortical and subcortical structures. Brain-derived neurotrophic factor is a major modulator of synaptic efficiency and neuronal plasticity. Recent works documented that a single nucleotide polymorphism (SNP) of the BDNF gene, the Val66Met SNP, modulates short-term plastic changes within motor cortical circuits. In this study we aimed at exploring the effect of this SNP upon the risk of developing common forms of primary adult-onset dystonia.
Methods:  We explored the influence of the Val66Met SNP of the BDNF gene on the risk of cranial and cervical dystonia in a cohort of 156 Italian patients and 170 age- and gender-matched healthy control subjects drawn from the same population.
Results:  The presence of the rare Met allele was not significantly associated with the diagnosis of dystonia (age- and gender-adjusted odds ratios of 1.22, P  =   0.38). The study had a >90% power to detect a 50% change in the risk of developing cranial-cervical dystonia associated with the presence of the Met allele. Moreover, there was no relationship between Val66Met SNP and age at dystonia onset or type of dystonia.
Conclusion:  Our data do not support the common variant Val66Met of the BDNF gene as an etiologic factor shared by the various forms of primary adult-onset dystonia.     

Focal and segmental primary dystonia in north-western Germany--a clinico-genetic study

OBJECTIVES: To determine the frequency of familial focal and segmental dystonias in a large patient cohort with primary dystonia from north-western Germany. MATERIALS AND METHODS: In this study, 130 patients with focal or segmental dystonia were examined and a family history was obtained. Whenever possible, affected relatives were examined (a total of 789 first-degree relatives). Data on disease duration, age at disease onset and age of the patients were investigated by Student's t-test and a segregation analysis was performed by Weinberg's proband method. RESULTS: Age at onset of disease was significantly later in the blepharospasm group. Only in the writer's cramp group were women outnumbered by men. A positive family history was found in 15 of the 130 index patients (11.5%). None of 102 index patients tested carried the GAG deletion in the DYT1 gene. CONCLUSIONS: In accordance with previous series our study provides evidence that primary focal dystonia may have a genetic etiology, most probably caused by an autosomal dominant trait with reduced penetrance.     

Novel Italian family supports clinical and genetic heterogeneity of primary adult-onset torsion dystonia.

We report on an Italian kindred with adult-onset primary torsion dystonia (PTD). A detailed clinical examination of the six definitely affected family members revealed a mild, purely focal phenotype. The disease involved only one body part (eyes, neck, or arm). PTD in this family was not linked to the known disease loci (DYT1, DYT6, DYT7, and DYT13), and the 3-bp deletion in the DYT1 gene was also excluded. These findings support genetic heterogeneity of PTD and indicate that a novel unassigned gene is responsible for focal dystonia in this family.     

Early cinematographic studies of generalized dystonia.

Among movement disorders, dystonia is a particularly complex phenomenon and difficult to describe. For this reason, cinematographic documents were particularly important to the establishment of this disorder within the neurological nosology. The seminal 1944 article on dystonia by E. Herz anchored its arguments in moving film documentation, published with frame-by-frame demonstrations of dystonic patients. Although the original films that comprised the basis of this article have not been located, two related contemporaneous films, one by Herz in association with T.J. Putnam, and one by S.P. Goodhart and B.H. Balser, have been located. Incorporating standard and several innovative filming techniques, these films and their accompanying text material capture the particular movements of dystonia, revealing the anatomical patterns of the twisting spasms, and emphasize their action exacerbation. The films demonstrate the variety of dystonic movements appreciated during this period, consider psychogenic, postencephalitic, and hereditary forms, and refer to the treatment of dystonia by surgery and plaster casts.     

Recurrent dystonia in homocystinuria: a metabolic pathogenesis.

Dystonia complicating homocystinuria is extremely rare in the absence of thromboembolic disease. We report a unique case of recurrent dystonia in a patient with homocystinuria secondary to pyridoxine-unresponsive cystathionine beta-synthase deficiency. Brain MRI was normal. Two biochemical markers for homocystinuria, homocystine and methionine, were markedly elevated during periods when our patient manifested dystonia. These findings suggest that accumulation of sulfur-containing amino acids may contribute to the pathophysiology of dystonia in patients with homocystinuria.     

Lower limb involvement in adult‐onset primary dystonia: frequency and clinical features

Background and purpose: Despite the growing number of reports describing adult‐onset primary lower limb dystonia (LLD) this entity has never been systematically evaluated in the general population of patients with primary adult‐onset dystonia. Methods: From outpatients with adult‐onset primary dystonia attending nine Italian University centres for movement disorders we consecutively recruited 579 patients to undergo a standardized clinical evaluation. Results: Of the 579 patients assessed, 11 (1.9%) (8 women, 3 men) had LLD, either alone (n = 4, 0.7%) or as part of a segmental/multifocal dystonia (n = 7, 1.2%). The age at onset of LLD (47.9 ± 17 years) was significantly lower than the age at onset of cranial dystonias (57.9 ± 10.7 years for blepharospasm, and 58.9 ± 11.8 years for oromandibular dystonia) but similar to that of all the other adult‐onset primary dystonias. The lower limb was either the site of dystonia onset (36.4%) or the site of dystonia spread (63.6%). In patients in whom LLD was a site of spread, dystonia seemed to spread following a somatotopic distribution. Only one patient reported a recent trauma involving the lower limb whereas 36.4% of the patients reported pain at the site of LLD. Only 64% of our patients needed treatment for LLD, and similarly to previously reported cases, the most frequently tried treatments was botulinum toxin and trihexyphenidyl. Conclusion: The lower limb is an uncommon but possible topographical site of dystonia in adulthood that should be kept in consideration during clinical evaluation.     

成人型肌张力障碍的手术治疗(附16例分析)

目的探讨立体定向核团毁损手术及脑深部电刺激手术治疗成人型肌张力障碍的疗效。方法将16例成人型肌张力障碍病人按受累部位分成3组：A组：书写痉挛．12例；B组：节段性肌张力障碍，3例，A、B组采用立体定向核团毁损手术治疗；C组：痉挛性斜颈，1例，采用脑深部电刺激手术治疗，并根据颈部痉挛肌群肌电活动强度．进行脑深部电刺激参数的调整。随访1年．观察运动功能改善情况。结果A组均治愈；B组平均改善率59、7％；C组在肌电监测之前．临床改善率为23．1％．根据肌电活动强度调整双侧脑深部电极刺激参数后临床改善率为67．3％。结论立体定向丘脑腹外侧核毁损手术是治疗书写痉挛的有效手段。肌电活动强度是设定和调整脑深部电刺激参数的量化指标，可以缩短反复调整的时间．减少电池耗费。     

Prevalence study of primary dystonia in Iceland.

In Iceland, the crude prevalence for all types of primary dystonia was 37.1/10(5) (confidence interval, 30.4-44.9). Focal dystonia had the highest prevalence (31.2/10(5)), followed by segmental (3.1/10(5)), multifocal (2.4/10(5)) and generalized dystonia (0.3/10(5)). Cervical dystonia was the most common focal dystonia (11.5/10(5)), followed by limb dystonia (8.0/10(5)), laryngeal dystonia (5.9/10(5)), blepharospasm (3.1/10(5)), and oromandibular dystonia (2.8/10(5)). The male:female ratio for all patients was 1:1.9 (P=0.0007), and females outnumbered males in all subtypes except oromandibular dystonia. Mean age of onset for all patients was 42.7 years (range, 3-82 years). This prevalence of primary dystonia is higher than in most reported studies, possibly because of more complete ascertainment but the relative frequencies of dystonia subtypes is similar.     

Exercise-induced dystonia as a preceding symptom of familial Parkinson's disease.

Paroxysmal exercise-induced dystonia can occur with Parkinson's disease (PD), and in rare cases, this can also be the presenting symptom. We report on 2 second cousins (no known consanguinity) who presented with paroxysmal exercise-induced dystonia who later developed clinical features of PD. Although autosomal recessive inheritance was suggested, and the dystonic features further suggest parkin as a possible cause, sequencing for parkin mutations was negative and this family may represent a genetic variant of PD. Further genotype-phenotype studies in this and similar families may give clues to pre-symptomatic symptoms in PD and may reflect a particular phenotype of interest for genetics studies in the future.     

Prevalence of dystonia in Akita Prefecture in Northern Japan.

We investigated the prevalence of dystonia in Akita Prefecture (population was 1,166,967 as of 1 November 2004). The prevalence of primary generalized and focal dystonia is estimated to be 0.68 and 14.4 per 100,000 persons, respectively. Blepharospasm is the most common primary dystonia in this area.     

Myasthenia gravis outcome measure: development and validation of a disease-specific self-administered questionnaire

We describe the development and validation of an outcome measure for patients with myasthenia gravis (MG) and show the correlation of the items with conventional MG measurements. In stage I, item generation, a group of methodologists, clinical experts generated a list of 56 items. The list was based on (1) a previous study on an MG sample, (2) clinical experience and (3) items proposed by MG patients. In stage 2, reduction of items, the list was reduced on the basis of results from field testing (41 patients completed the 56-item questionnaire). In stage 3, reliability and validity were assessed. A 25-item MG questionnaire (MGQ) was generated. Results were related to conventional measures of MG severity. Furthermore, the MGQ appeared reliable, sensitive and reproducible. The questionnaire was validated as an outcome measure. Received: 21 October 2001 / Accepted in revised form: 13 March 2002     

Validity of a modified Parkinson's disease screening questionnaire in India: effects of literacy of participants and medical training of screeners and implications for screening efforts in developing countries.

The prevalence of Parkinson's disease (PD) is low among Indians, except in the Parsis. Data for Indians come from studies using different screening tools and criteria to detect PD. An epidemiological study in India, which has nearly a billion people, more than 18 spoken languages, and varying levels of literacy, requires development and validation of a screening tool for PD. The objectives of this study are to (1) validate a modified version of a widely used screening questionnaire for PD to suit the needs of the Indian population; (2) compare the use of a nonmedical assistant (NMA) with the use of a medical person during screening; and (3) compare the effect of literacy of participants on the validity of the screening tool. The validity of the questionnaire was tested on 125 participants from a home for the elderly. NMAs of similar background and medical personnel administered the modified screening questionnaire. A movement disorder neurologist blind to the responses on the questionnaire, examined participants independently and diagnosed if participants had PD. The questionnaire was validated in the movement disorders clinic, on known PD patients and their family members without PD. In the movement disorders clinic, sensitivity and specificity of the questionnaire were 100% and 89%, respectively. Fifty-seven participants were included for analysis. The questionnaire had a higher sensitivity when NMAs (75%) rather than the medical personnel (61%) administered it, and its specificity was higher with the medical personnel (61%) than with NMAs (55% and 25%). The questionnaire had a higher specificity in literates than illiterates, whereas sensitivity varied considerably. The modified questionnaire translated in a local Indian language had reasonable sensitivity and can be used to screen individuals for PD in epidemiological studies in India. This questionnaire can be administered by NMAs to screen PD and this strategy would reduce manpower costs. Literacy may influence epidemiological estimates when screening PD.     

Clinical and genetic characterization of a large Dutch family with primary focal dystonia

We describe a large family with a primary focal dystonia from a small Dutch village on a former island. Twenty‐four individuals spanning three generations were examined by two movement‐disorder neurologists. Two other movement‐disorder neurologists evaluated the videos independently. Subjects were classified as “affected,” “possibly affected,” or “not affected.” A diagnosis was defined if all the neurologists agreed on the definition. Eight definitely affected and four possibly affected subjects were detected. Clinical presentation consisted of mild cranio‐cervical‐brachial dystonia. Mean age at onset was 45.5 years (range, 39–56). Mean BFMDRS motor score was 4.4 (range, 1–8). Mean TWSTRS score (part I) was 11.3 (range, 8–23). Mutations in DYT1 gene and in the ε‐sarcoglycan (SGCE) genes were not detected. We could not find linkage to the dominant DYT6, DYT7, DYT13, or the recessive DYT16 loci. The identification and accurate clinical evaluation of large dystonia families not linked to known genes is crucial for further advancement in molecular genetic characterization of focal dystonia. © 2008 Movement Disorder Society     

Onset and progression of primary torsion dystonia in sporadic and familial cases

Four hundred and sixty records of patients with primary torsion dystonia (296 women and 164 men) were evaluated. The mean age at disease onset was 48.3 ± 17.7 years; 13 patients carried the DYT1 CAG deletion. The distribution of age at onset was represented by a bi-modal curve, with a nadir at 21 year separating early onset from late onset cases. In 15.9% of cases there was a positive family history of dystonia. Cranial, cervical or lower limb onset was more common amongst women (M:F ratios were 1:2.7, 1:1.9, and 1:3); by contrast, onset in the upper limb was more common in men (M:F ratio 2.2:1). As expected, disease progression was more pronounced in cases with early onset; it was reckoned that onset at or above 32 years was associated with a negligible likelihood to progress to a generalized form. The mean age at onset of familial cases was 44.8 ± 11.2 years, significantly lower than the mean age at onset of sporadic cases (53.5 ± 13.4 years). Familial cases were characterized by more sites involved throughout disease course. Familial cases had a higher tendency to progress to a segmental or generalized form than sporadic cases.     

Phenotypic characterization of DYT13 primary torsion dystonia.

We describe the phenotype of DYT13 primary torsion dystonia (PTD) in a family first examined in 1994. A complete neurological evaluation was performed on all available family members: 8 individuals were definitely affected by dystonia. The family was re-evaluated in March 2000: at that time, 3 more individuals had developed symptoms of dystonia. Inheritance of PTD was autosomal dominant, with affected individuals spanning three consecutive generations and male-to-male transmission. Age at onset ranged from 5 to 43 years. Onset occurred either in the craniocervical region or in upper limbs. Progression was mild, and the disease course was benign in most affected individuals; generalization occurred only in 2 cases. We did not find anticipation of age at onset or of disease severity through generations. Most subjects presented with jerky, myoclonic-like dystonic movements of the neck or shoulders. DYT13-PTD is an autosomal dominant disease, with incomplete penetrance (58%). Clinical presentation and age at onset were more variable than in DYT1-PTD, and the neck was involved in most of those affected. Moreover, the individuals with generalised dystonia were not severely disabled and were able to lead independent lives. To date, this is the only family with DYT13-PTD.     

Sporadic and familial myoclonic dystonia: Report of three cases and review of literature

Myoclonic dystonia refers to a clinical syndrome characterized by rapid jerky movements along with dystonic posturing of the limbs. Clinically, it is characterized by sudden, brief, electric shock-like movements, mostly involving the upper extremities, shoulders, neck and trunk. Characteristically, the movements wane with consumption of small dose of alcohol in about 50% of cases. Additionally, dystonic contractions are observed in most of the patients in the affected body parts and some patients may exhibit cervical dystonia or graphospasm as well. It may manifest as an autosomal dominant condition or sometimes, as a sporadic entity, though there are doubts whether these represent cases with reduced penetrance. The condition is usually treated with a combination of an anticholinergic agent like, benztropine, pimozide and tetrabenazine. We report one sporadic case and one familial case where the father and the son are affected. The cases were collected from the Movement Disorders Clinic of Bangur Institute of Neurosciences, Kolkata, West Bengal in a period of ten months. Myoclonic dystonia is a rare condition and to the best of our knowledge, this series is the first one reported from our country. Videos of the patients are also provided with the article.     

Rating scales for dystonia: a multicenter assessment.

The evaluation of dystonia requires a reliable rating scale. The widely used Fahn-Marsden Scale (F-M) has not been sufficiently tested across multiple centers and investigators. The Dystonia Study Group developed the Unified Dystonia Rating Scale (UDRS) and a Global Dystonia Rating Scale (GDS) to serve as instruments to assess dystonia severity. In this study, 25 dystonia experts evaluated the UDRS, F-M, and GDS for internal consistency and reliability. One hundred dystonia patients were videotaped using a standardized videotape protocol. Each examiner rated 20 patients using the UDRS, F-M, and GDS in random order. The examiner then assessed each scale for ease of use. Statistical analysis used Cronbach's alpha, intraclass correlation coefficients (ICC), generalized weighted kappa statistic, and Kendall's coefficient of concordance. The UDRS, F-M, and GDS showed excellent internal consistency (Cronbach's alpha 0.89-0.93) and good to excellent correlation among the raters (ICC range from 0.71-0.78). Inter-rater agreement was fair to excellent (Kendall's 0.54-0.87; kappa 0.37-0.91) being lowest for eyes, jaw, face, and larynx. The modifying ratings (Duration in the UDRS and Provoking Factor in the F-M) showed less agreement than the motor severity ratings. Among scales, the total scores correlated (Pearson's r, 0.977-0.983). Overall, 74% of raters found the GDS the easiest to apply. The GDS with its simplicity and ease of application may be the most useful dystonia rating scale.     

Focal dystonia after removal of a parietal meningioma.

A patient presented at the age of 50 years with a right-sided, writing-specific dystonia which settled without treatment. Ten years later she developed focal seizures affecting the right leg and occasionally spreading to the right arm. A left parietal meningioma was removed and 2 years later she developed dystonic movements of her right hand. Gliotic changes were seen on magnetic resonance imaging in the superficial left parietal lobe. Mechanisms involved in the generation of dystonia associated with cortical injury are discussed.