Heredodegenerative Dystonia Research Articles

Progression to musculoskeletal deformity in childhood dystonia.

Dystonia is a movement disorder characterized by involuntary muscle contractions, resulting in abnormalities of posture and movement. Children with dystonia are at risk of developing fixed musculoskeletal deformities (FMDs). FMDs cause pain, limit function and participation and interfere with care. We aimed to explore factors relating to the development of FMD in a large cohort of children with dystonia. The case notes of all children referred to our Complex Motor Disorder service between July 2005 and December 2011 were reviewed. Data from 279 children (median age 9 years 10 months, Standard Deviation 4 years 2 months) with motor disorders including a prominent dystonic element were analyzed. Parametric accelerated failure time regression was used to identify the factors related to development of contractures. FMDs were present at referral in more than half (n = 163, 58%) of cases. Three quarters (n = 120, 74%) of children with FMD had deformities around the hip, and 42% had spinal deformity (n = 68). Compared to pure primary dystonia, FMD onset was earlier with a diagnosis of secondary or heredodegenerative dystonia, and a mixed spastic-dystonic phenotype (all p < 0.001). FMD onset was also earlier with increasing Gross Motor Function Classification System (GMFCS) level (p < 0.001). The effect of aetiological classification was lost when controlling for GMFCS level and motor phenotype. Children with secondary or heredodegenerative dystonia are at greater risk of progression to FMD compared to primary dystonia, likely due to more severe dystonia within these groups. Children with additional spasticity are at particular risk, requiring close monitoring.

Dystonia: an update on phenomenology, classification, pathogenesis and treatment.

This article will highlight recent advances in dystonia with focus on clinical aspects such as the new classification, syndromic approach, new gene discoveries and genotype-phenotype correlations. Broadening of phenotype of some of the previously described hereditary dystonias and environmental risk factors and trends in treatment will be covered. Based on phenomenology, a new consensus update on the definition, phenomenology and classification of dystonia and a syndromic approach to guide diagnosis have been proposed. Terminology has changed and 'isolated dystonia' is used wherein dystonia is the only motor feature apart from tremor, and the previously called heredodegenerative dystonias and dystonia plus syndromes are now subsumed under 'combined dystonia'. The recently discovered genes ANO3, GNAL and CIZ1 appear not to be a common cause of adult-onset cervical dystonia. Clinical and genetic heterogeneity underlie myoclonus-dystonia, dopa-responsive dystonia and deafness-dystonia syndrome. ALS2 gene mutations are a newly recognized cause for combined dystonia. The phenotypic and genotypic spectra of ATP1A3 mutations have considerably broadened. Two new genome-wide association studies identified new candidate genes. A retrospective analysis suggested complicated vaginal delivery as a modifying risk factor in DYT1. Recent studies confirm lasting therapeutic effects of deep brain stimulation in isolated dystonia, good treatment response in myoclonus-dystonia, and suggest that early treatment correlates with a better outcome. Phenotypic classification continues to be important to recognize particular forms of dystonia and this includes syndromic associations. There are a number of genes underlying isolated or combined dystonia and there will be further new discoveries with the advances in genetic technologies such as exome and whole-genome sequencing. The identification of new genes will facilitate better elucidation of pathogenetic mechanisms and possible corrective therapies.

The impact and prognosis for dystonia in childhood including dystonic cerebral palsy: a clinical and demographic tertiary cohort study

Introduction and methodsThe impact of dystonia in childhood is poorly understood. We report our experience of referrals between 2005 and 2012.ResultsOf 294/315 assessable children, 15/294 had pure spasticity, leaving 279/294...

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

The majority of studies investigating the molecular pathogenesis and cell biology underlying dystonia have been performed in individuals with primary dystonia. This includes monogenic forms such as DYT1and DYT6 dystonia, and primary focal dystonia which is likely to be multifactorial in origin. In recent years there has been renewed interest in non-primary forms of dystonia including the dystonia-plus syndromes and heredodegenerative disorders. These are caused by a variety of genetic mutations and their study has contributed to our understanding of the neuronal dysfunction that leads to dystonia These findings have reinforced themes identified from study of primary dystonia including abnormal dopaminergic signalling, cellular trafficking and mitochondrial function. In this review we highlight recent advances in the understanding of the dystonia-plus syndromes and heredodegenerative dystonias.

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

The majority of studies investigating the molecular pathogenesis and cell biology underlying dystonia have been performed in individuals with primary dystonia. This includes monogenic forms such as DYT1and DYT6 dystonia, and primary focal dystonia which is likely to be multifactorial in origin. In recent years there has been renewed interest in non-primary forms of dystonia including the dystonia-plus syndromes and heredodegenerative disorders. These are caused by a variety of genetic mutations and their study has contributed to our understanding of the neuronal dysfunction that leads to dystonia These findings have reinforced themes identified from study of primary dystonia including abnormal dopaminergic signalling, cellular trafficking and mitochondrial function. In this review we highlight recent advances in the understanding of the dystonia-plus syndromes and heredodegenerative dystonias. Keywords: Dystonia- plus syndrome, Secondary dystonia, Molecular pathogenesis, Neurodegeneration, Mitochondria

Botulism-like syndrome or widespread diffusion syndrome after injection of botulinum toxin A for neurogenic detrusor overactivity

.– A 27-year-old patient, with PKAN heredodegenerative dystonia,has truncal dystonia symptomatology. Suddenly, she complained of low-backpainevaluatedat10/10onaverbalscale.Low-backpainisinducedbyrepetitivedystonic movements with upper limbs anterior elevation, spinal and hipextension (opisthotonos). Radiographs showed a L3 bilateral spondylolysis notshown in the previous radiographs. A classical corset immobilization isn’tpossible because of movement disorders. A first botulinum toxin injection isperformed (150 UI Botox

Pneumothorax after botulinum toxin type A

literature. Case report.– A 27-year-old patient, with PKAN heredodegenerative dystonia, has truncal dystonia symptomatology. Suddenly, she complained of low-back pain evaluated at 10/10 on a verbal scale. Low-back pain is induced by repetitive dystonic movements with upper limbs anterior elevation, spinal and hip extension (opisthotonos). Radiographs showed a L3 bilateral spondylolysis not shown in the previous radiographs. A classical corset immobilization isn’t possible because of movement disorders. A first botulinum toxin injection is performed (150 UI Botox) in lumbar paraspinal muscles for pain relief. Anterior head of deltoideus and gluteus maximus are also injected (for a total dose of 400 UI Botox each session) to break the extension scheme. Four weeks after injections, the pain is evaluated at 5/10 and movement disorders were less frequent. Thanks to the adapted wheelchair and the posterior articulars infiltration bilaterally (125 mg of hydrocortancyl), the patient is totally relieved. Because of pain recurrence, toxin injections are effectively renewed each 3 months. Discussion.– The increase of spondylolysis frequency is shown in CP patients [1], one of the most frequent pathology with dystonia. The effectiveness of botulinum toxin injections in spinal muscles to decrease contractions is hard to prove but some articles agree with a decrease of disorderedmovements and pain [2].

Intraventricular baclofen for dystonia: techniques and outcomes

The aim of this study was to evaluate the use of intraventricular baclofen (IVB) for the treatment of severe generalized secondary and heredodegenerative dystonia. Nine children and 1 adult with severe dystonia unresponsive to multiple oral medications were treated with IVB. Intraventricular catheters were positioned endoscopically in the third ventricle. Eight of the 10 patients responded to IVB; their mean dystonia scores on the Barry-Albright dystonia scale decreased from 23 to 8. The 2 patients who did not respond had not responded to previous high doses of intrathecal baclofen. No adverse side effects related to IVB occurred. One child developed a pump infection that required pump removal, 1 developed a CSF infection that cleared after antibiotic administration, and 1 developed ventriculomegaly that required a shunt placement. Intraventricular baclofen is an effective method of infusing baclofen to treat severe, generalized secondary dystonia, and, at times, heredodegenerative dystonia. The site of baclofen's activity when treating dystonia may be at the cortical level, and intraventricular infusion may result in higher baclofen concentrations over the cortex than intrathecal infusion. Additional studies are necessary to determine whether IVB is effective at lower doses than those used with intrathecal baclofen administration.

Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family with ADAR1 mutation

A family with dystonia associated with dyschromatosis symmetrica hereditaria (DSH), mental deterioration, and tissue calcification is described. The proband possessed an adenosine deaminase acting on the RNA 1 gene (ADAR1) mutation Gly1007Arg. This ADAR1 mutation could disturb RNA editing at Q/R sites of glutamate receptor in the brain and increase Ca(2+) influx into neurons, which is thought to induce dystonia and mental deterioration. The observations in our family raise the possibility that the ADAR1 mutation might be a direct cause or a predisposing factor for heredodegenerative dystonia. Further investigation of ADAR1 mutations will shed light on the genotype-phenotype correlation in DSH.