Rare inborn errors of metabolism with movement disorders: a case study to evaluate the impact upon quality of life and adaptive functioning

Background: Inborn errors of metabolism (IEM) form an important cause of movement disorders in children. The impact of metabolic diseases and concordant movement disorders upon children's health-related quality of life (HRQOL) and its physical and psychosocial domains of functioning has never been investigated. We therefore conducted a case study on the HRQOL and development of adaptive functioning in children with an IEM and a movement disorder. METHODS: Children with co-existent IEM and movement disorders were recruited from paediatric outpatient clinics. We systematically collected clinical data and videotaped examinations. The movement disorders were diagnosed by a panel of specialists. The Pediatric Quality of Life Inventory 4.0 and the Vineland Adaptive Behavior Scale were used to assess the HRQOL and adaptive functioning, respectively. RESULTS: We recruited 24 children (10 boys, mean age 7y 5 m). Six types of movement disorders were recognised by the expert panel, most frequently dystonia (16/24), myoclonus (7/24) and ataxia (6/24). Mean HRQOL (49.63, SD 21.78) was significantly lower than for other chronic disorders in childhood (e.g. malignancy, diabetes mellitus, rheumatic disease, psychiatric disorders; p <0.001) and tended to diminish with the severity of the movement disorder. The majority of participants had delayed adaptive functioning, most evident in their activities of daily living (51.92%, SD 27.34). Delay in adaptive functioning had a significant impact upon HRQOL (p = 0.018). CONCLUSIONS: A broad spectrum of movement disorders was seen in patients with IEM, although only five were receiving treatment. The overall HRQOL in this population is significantly reduced. Delay in adaptive functioning, most frequently seen in relation to activities of daily living, and the severity of the movement disorder contribute to this lower HRQOL. We plead for a greater awareness of movement disorders and that specialists should be asked to diagnose and treat these wherever possible

Dystonia: opportunities to gain insights into underlying pathophysiological mechanisms

Dystonia is one of the most common movement disorders, a core component of the isolated and combined dystonias as well as contributing to the motor phenotype of several neurodegenerative movement disorders, such as Parkinson’s disease and Huntington’s disease. In spite of this, the pathophysiological mechanisms underlying dystonia remain poorly understood with the current thinking centered on a circuit-based disorder, with altered synaptic plasticity impacting higher neuronal circuits and networks. In this review, we discuss three publications with distinct approaches in attempting to elucidate these mechanisms. These articles also highlight how the combination of gene discovery, cellular assays, and systems-based analysis can each contribute to building an understanding of complex disorders

Idiopathic rapid eye movement sleep behaviour disorder: a potential gateway to the development of disease-modifying treatments in neurodegenerative disorders

Idiopathic rapid eye movement (REM) sleep behavioural disorder (RBD) is classified as one of the REM parasomnias with clinical characteristics including unpleasant dreams, acting out of dreams, and loss of the typical muscle atonia during the REM phase of sleep. Other associated clinical features include olfactory loss, dysautonomia, colour vision impairment and subtle Parkinsonian signs. RBD has been shown to predict development of an alpha-synucleinopathy in 20–45 % of patients within 5 years, and up to 92 % within 14 years post-diagnosis. Hence, this disorder provides a potential opportunity for understanding the prodromal stages of the synucleinopathies and exploring efficacy of potential neuroprotective agents

Benign Hereditary Chorea: An Update

Benign hereditary chorea (BHC) is a childhood-onset, hyperkinetic movement disorder normally with little progression of motor symptoms into adult life. The disorder is caused by mutations to the NKX2.1 (TITF1) gene and also forms part of the “brain–lung–thyroid syndrome”, in which additional developmental abnormalities of lung and thyroid tissue are observed. In this review, we summarize the main clinical findings in “classical” BHC syndrome and discuss more recently reported atypical features, including non-choreiform movement phenotypes. We highlight additional non-motor characteristics such as cognitive impairment and psychiatric symptoms, while discussing the evidence for BHC as a developmental disorder involving impaired neural migration and other multisystem developmental abnormalities. Finally, we will discuss the efficacy of available therapies in both affected pediatric and adult cohorts. Delineation of the BHC disease spectrum will no doubt expand our understanding of this disorder, facilitating better targeting of genetic testing and establish a framework for future clinical trials

Clinical and genetic investigation of the epsilon-sarcoglycan complex in neurologic and psychiatric disease

Myoclonus Dystonia Syndrome is a childhood onset hyperkinetic movement disorder characterised by alcohol responsive upper body myoclonus and dystonia. A proportion of cases are due to mutations in the maternally imprinted SGCE gene, which encodes the transmembrane epsilon-sarcoglycan protein. Previous studies suggest an increased rate of psychiatric disorders in those with SGCE mutations. This study aimed to establish a cohort of myoclonus dystonia syndrome patients, identify the rate and type of SGCE mutations, determine differences in motor characteristics between mutation positive and negative cases and whether psychiatric disorders form part of the disease phenotype. Eighty-nine probands with clinically suspected MDS were recruited. Information regarding onset and distribution of motor symptoms was collected via systematic questionnaires and video taped examination. SGCE was analysed using direct sequencing and for copy number variants. Psychiatric symptoms were assessed using systematic and standardised questionnaires and compared to a disability-matched, alcohol responsive tremor control group. Nineteen (21%) probands had an SGCE mutation. All had evidence of upper body predominant myoclonus and dystonia during their disease course. Five had contiguous gene deletions ranging from 0.7 to 2.3Mb in size with distinctive clinical features. Recruitment of family members increased the affected SGCE mutation positive group to 27 of whom 21 (77%) had psychiatric symptoms. Obsessive-Compulsive Disorder was eight times more likely (p<0.001) in mutation positive cases, compulsivity being the predominant feature (p<0.001). Generalized Anxiety Disorder (p=0.003) and alcohol dependence (p=0.02) were five times more likely in cases than tremor controls. Overall, SGCE mutations are associated with a narrow clinical and specific psychiatric phenotype. The presence of myoclonus, dystonia, age at onset ≤10 years and a positive family history of the disorder are the strongest predictors of an SGCE mutation. SGCE mutations are likely to have a pleiotropic effect in causing both motor and specific psychiatric symptoms

Contribution of multi-modal imaging to our understanding of dystonia pathogenesis

Dystonia is one of the most common forms of movement disorder, involving repetitive or sustained contractions of antagonistic muscle groups causing pain and abnormal posturing. The motor phenotypes observed in dystonia are varied with single muscle group involvement (focal), multiple adjacent (segmental) and more generalised forms involving multiple body regions. Some dystonia’s are task specific, being induced by undertaking a particular task or movement, whereas with others the involuntary movements and posturing are independent of activity. Dystonia is increasingly considered to be a network-based disorder involving multiple motor pathways in the brain, with the cerebellum, basal ganglia and sensorimotor cortex particularly implicated. Injected botulinum toxin represents the mainstay of treatment for many patients with focal and segmental forms and Deep Brain Stimulation (DBS) is used in the treatment of more severe forms

Internet-based cognitive behavioural therapy programme as an intervention for people diagnosed with adult-onset, focal, isolated, idiopathic cervical dystonia: a feasibility study protocol

Background Dystonia is one of the most common forms of movement disorder, caused by the co-contraction of antagonistic muscles, leading to abnormal postures and considerable disability. Non-motor symptoms, notably psychiatric disorders, are well recognised comorbid features of the disorder. However, there is no standardised model for the management of these symptoms in dystonia, with them frequently going undiagnosed and untreated. An internet-based cognitive behavioural therapy programme may provide a future model of care that also maximises available resources. Methods This study represents a two-armed randomised feasibility trail, aiming to recruit a total of 20 participants with a diagnosis of adult-onset primary focal cervical dystonia. Participants will be recruited from the Global Myoclonus Dystonia Registry and Dystonia Non-Motor Symptom Study (conducted at Cardiff University) based on presence of moderate symptoms of anxiety/depression as indicated by standardised questionnaires. All participants will undergo assessment at baseline, 3 and 6 months, with this including questionnaires for assessment of non-motor symptoms and clinical assessment of motor symptom severity. Participants will be randomised to either the control (n = 10) or treatment (n = 10) groups. The treatment group will be asked to complete one session of the online CBT program a week, for 8 weeks. The primary outcome measure will be the engagement of participants with the programme, with secondary outcomes of non-motor and motor symptom scores. Discussion Promising results have been shown using face-to-face cognitive behavioural therapy to reduce levels of anxiety and depression in individuals with a diagnosis of dystonia. However, no studies to date have sought to determine the feasibility of an internet-delivered cognitive behavioural therapy programme. A number of effective internet-based programmes have been developed that combat anxiety and depression in the general population, suggesting the potential for its effectiveness in cervical dystonia patients. Success with this study would significantly impact the clinical care delivery for patients with cervical dystonia, as well as widening potential access to effective treatment

Internet-based cognitive behavioural therapy as a feasible treatment of adult-onset, focal, isolated, idiopathic cervical dystonia

Introduction Psychiatric symptoms are well recognised co-morbid traits in adult-onset idiopathic, isolated, focal cervical dystonia (AOIFCD), although few studies have sought to address their management. Internet-based cognitive behavioural therapy (iCBT) may provide an accessible solution. Here, we determine the feasibility of using iCBT in the management of non-motor symptoms for individuals with AOIFCD. Methods Participants were randomised to receive an 8-week iCBT programme (n=10) or not (n=10), both alongside routine clinical care. All participants underwent assessments at baseline, 3-, and 6- months for anxiety, depression, quality of life and motor symptoms, and engagement with iCBT was recorded. Group differences over time were determined using two-way mixed ANOVA, and simple statistics evaluated change on an individual participant level. Results Over half of participants receiving iCBT (6/10) showed high engagement, with feedback indicating most participants found iCBT useful (6/8), would continue to use it (7/8), and try it again if offered (7/8). Although no between-group significant differences were observed (e.g. Beck’s Depression Inventory p=0.067) anxiety and depression levels showed trends towards improvement at 3-months in those receiving iCBT. Individual level analysis also indicated higher percentage level improvements in these symptoms, with this sustained in 86% participants. Conclusion iCBT represents a feasible therapeutic option in the management of co-morbid anxiety and depression in AOIFCD. Further work is needed to replicate these findings in a larger cohort, identify those most likely to benefit from this form of therapy and overcome barriers hindering those less likely to engage with this form of treatment

Nitrous oxide misuse and vitamin B12 deficiency

A 36-year-old man presented to hospital with a 5-week history of ascending limb paraesthesiae and balance difficulties. He had no medical or travel history of note, but admitted habitual nitrous oxide (N2O) inhalation. Neurological examination revealed a sensory ataxia with pseudoathetosis in the upper limbs and reduced vibration sensation to the hips bilaterally. Significant investigation results included a low serum vitamin B12 concentration, mild macrocytosis and raised serum homocysteine concentration. T2 MRI of the spinal cord demonstrated increased signal extending from C1 to T11 in keeping with a longitudinal myelitis. The patient was diagnosed with a myeloneuropathy secondary to vitamin B12 deficiency, resulting from heavy N2O inhalation. He was treated with intramuscular vitamin B12 injections and received regular physiotherapy. At discharge, he was able to mobilise short distances with the aid of a zimmer frame, and was independently mobile 8 weeks later