Rapid-onset dystonia-parkinsonism with ATP1A3 mutation and left lower limb paroxysmal dystonia.

BACKGROUND: Rapid-onset dystonia-parkinsonism (RDP) is a disease characterized by an abrupt onset of dystonia accompanied by signs of parkinsonism and prominent bulbar symptoms. CASE REPORT: We describe a case of a female patient, born after normal delivery, but diagnosed with mild intellectual disability at age 7. She presented with an abrupt onset of upper limb dystonia and bradykinesia without tremor in parkinsonism, as well as dysarthria and dysphagia caused by prominent bulbar symptoms, at age 9. She had normal findings on brain magnetic resonance imaging, electroencephalography, and blood examination but was diagnosed with a psychogenic disorder. At age 10, she developed left lower limb paroxysmal stiffness with pain, and at 14, she was hospitalized due to lasting paroxysmal symptoms. Whole-exome sequencing was performed for this index case and her parents, and a de novo missense variant c.829G > A, p.Glu277Lys in ATP1A3 was identified. DISCUSSION: This RDP case highlights a rare clinical feature of paroxysmal dystonia that affects the lower left limb and develops after the abrupt onset of permanent dystonia. Currently, there are only three reported RDP cases associated with the same missense mutation, and we summarized the clinical features of all cases including ours, such as onset of age, time for stable, RDP score, relapse and exacerbation. Various symptoms owing to ATP1A3 mutation could develop as ATP1A3-related neurological disorders beyond classical phenotypes such as alternating hemiplegia of childhood (AHC) or RDP. Although RDP is extremely rare during childhood, it is important to understand its clinical characteristics in children.

Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene.

The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.

Discinesia paroxística primaria kinesiogénica y no kinesiogénica: Reporte de 3 casos y revisión de la literatura / Paroxysmal Kinesiogenic Dyskinesia and Paroxysmal Non-Kinesiogenic Dyskinesia: Three Case Reports and a Review

Las discinesias paroxísticas son un grupo de entidades consistentes en paroxismos de diversos movimientos anormales de corta duración asociados o no a factores precipitantes. Suele afectar a sujetos jóvenes y la prevalencia es desconocida. La fisiopatología es incierta; se han identificado ciertas mutaciones que expliquen su origen. Clínicamente se pueden manifestar como ataques paroxísticos de movimientos de tipo coreoatetósico, distónicos o balísticos de corta duración y con preservación de la conciencia. Los estudios electrofisiológicos y de imagen suelen ser normales. Este grupo de trastornos del movimiento hacen parte del diagnóstico diferencial de las crisis epilépticas. El pronóstico suele ser bueno y el tratamiento es sintomático con anticonvulsivantes. Se presentarán tres casos de dos tipos de trastornos paroxísticos del movimiento y revisión de la literatura.

Paroxysmal dyskinesias are a group of entities consisting of paroxysms of diverse abnormal movements of short duration, associated or not with precipitating factors. It usually affects young subjects and its prevalence is unknown. The pathophysiology is uncertain; some mutations have been identified that explain their origin. Clinically, they can manifest as paroxysmal attacks of choreoathetosis, dystonic or ballistic movements of short duration and with preservation of consciousness. Electrophysiological and imaging studies are usually normal. This group of movement disorders are part of the differential diagnosis of epileptic seizures. Prognosis is usually good and the treatment is symptomatic with anticonvulsants. Three cases of two types of paroxysmal movement disorders and a review of the current literature are presented.

Movement disorders in multiple sclerosis and neuromyelitis optica: A clinical marker of neurological disability.

INTRODUCTION: Movement disorders are not rare in demyelinating diseases but there are few studies comparing their frequency between multiple sclerosis and neuromyelitis optica spectrum disorder. Our aim was to determine the frequency and the related features of movement disorders in a cohort of patients with multiple sclerosis and neuromyelitis optica spectrum disorder. METHODS: It is a cross-sectional study of patients with multiple sclerosis and neuromyelitis optica spectrum disorder. Patients were evaluated by a movement disorder specialist. Data from a personal interview and neurological examination were collected. Fahn-Tolosa-Marin tremor rating scale was used for tremor evaluation. Health-related quality of life was assessed using EuroQol instrument. RESULTS: Two hundred fifty-three patients were included (mean [SD] age, 40 [12] years; 74.3% female; median [IQR] EDSS score 2.5 [1.0-6.0]); 26% presented with movement disorders. Paroxysmal dystonia (n = 32) and tremor (n = 27) were the most common movement disorders. Patients with multiple sclerosis and low Expanded Disability Status Scale score (below 4.0) have fewer movement disorders than patients with neuromyelitis optica spectrum disorder. The diagnosis of neuromyelitis optica spectrum disorder was strongly associated with paroxysmal dystonia (OR = 22.07, 95% CI = 2.56-189.78; p = 0.005). Patients with multiple sclerosis and patients without movement disorders have a slightly better quality of life. CONCLUSIONS: Paroxysmal dystonia was the most common movement disorder in demyelinating diseases and strongly associated with neuromyelitis optica spectrum disorder.

ECHS1 deficiency-associated paroxysmal exercise-induced dyskinesias: case presentation and initial benefit of intervention.

Paroxysmal exercise-induced dyskinesias (PED) are paroxysmal dyskinesias which manifest as dystonic movements brought on by sustained exercise. ECHS1 deficiency-induced EID was recently described by Olgiati et al. Our patient is an 8-year-old boy, who presented with intermittent episodes of stiffness and contractions affecting the legs which were always brought on by vigorous exertion. They began with curling of the toes and flexion, followed by stiffening of gait. These episodes were asymmetric, uncomfortable and often began in the left leg, often spreading to the right leg. They generally lasted for about 30-40 min. The phenomenology was noted to be dystonic affecting mostly the left leg, with equinus at the ankle and hyperextension at the knee. MRI of the brain showed regions of increased T2 and FLAIR signal and of T1 low signal in the globus pallidus bilaterally with mild diffusion restriction. Using Ambry's ExomeNextTM, an integrated exome sequencing assay, the patient was found to be heterozygous for alterations in the ECHS1 gene: missense mutations in c.518C>T (p.A173V) and c.817A>G (p.K273E). After 3 months of treatment with a mitochondrial cocktail, the patient reported that his attacks were somewhat less frequent and less severe. We decided to continue the patient on the cocktail and prescribed clonazepam 0.5 mg 1 tab to be given, as needed, for acute dystonic episodes of severe degree. The missense mutation c.817A>G has never been associated with PED before. Further, we present the first case of ECH1-associated PED with initial symptomatic improvement with a mitochondrial cocktail.

Successful Treatment of Paroxysmal Movement Disorders of Infancy With Dimenhydrinate and Diphenhydramine.

BACKGROUND: Paroxysmal movement disorders including paroxysmal tonic upward gaze of infancy and paroxysmal dystonia of infancy are benign but uncommon movement disorders seen in young children. Although symptoms are intermittent and resolve spontaneously, they can cause discomfort and distress for the child. Current treatment options are limited to dopaminergic agents or anticonvulsants with limited efficacy. PATIENT DESCRIPTION: The authors present a child with paroxysmal tonic upward gaze of infancy and another with paroxysmal dystonia of infancy, both of whom responded successfully to treatment with low-dose dimenhydrinate or diphenhydramine, respectively. DISCUSSION: Dimenhydrinate and diphenhydramine both exert anticholinergic activity and have limited toxicity at low doses. This property makes either compound an attractive therapeutic option for paroxysmal movement disorders in infancy. These agents are generally well tolerated.

Effect of Intrathecal Baclofen on Delayed-Onset Paroxysmal Dystonia due to Compression Injury Resulting From Congenital and Progressive Spinal Bone Deformities in Chondrodysplasia Punctata.

BACKGROUND: Dystonia due to spinal lesions in adult patients is characterized by the provocation and/or amelioration of the spasm by somatosensory stimulation with a sensory trick. PATIENT DESCRIPTION: An infant with brachytelephalangic chondrodysplasia punctata developed flaccid tetraplegia due to cervical cord compression resulting from congenital atlantoaxial dislocation. Episodic, tonic extension of the extremities, neck, and trunk had appeared daily since age two years and was often provoked by tactile stimulation. Although decompression surgery was performed at age three years, progressive spinal deformity resulted in the aggravation of episodic dystonia thereafter, lasting for hours. Foot dorsiflexion and wearing a truncal brace for scoliosis inhibited these spasms. Intrathecal baclofen bolus injection transiently ameliorated the paroxysmal dystonia and detrusor-sphincter dyssynergia in the lower urinary tract. CONCLUSION: Paroxysmal dystonia is unusual in children with spinal cord lesions; however, it should be recognized for appropriate individualized clinical management.

Nocturnal paroxysmal dystonia - case report.

Nocturnal paroxysmal dystonia describes a syndrome consisting of recurrent motor episodes of dystonic-dyskinetic features arising from non-rapid eye movement (NREM) sleep. In the article, the authors present female case of nocturnal paroxysmal dystonia. The patient has had attacks since her childhood and was eventually diagnosed at the age of 48. Therapy with carbamazepine considerably reduced the frequency and entent of seizures. The present case evidences that nocturnal paroxysmal dystonia still is a diagnostic challenge for clinicians. Especially, we emphasize the importance of polysomnography in the verification of the diagnosis.

Paroxysmal movement disorders.

Paroxysmal dyskinesias represent a group of episodic abnormal involuntary movements manifested by recurrent attacks of dystonia, chorea, athetosis, or a combination of these disorders. Paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, paroxysmal exertion-induced dyskinesia, and paroxysmal hypnogenic dyskinesia are distinguished clinically by precipitating factors, duration and frequency of attacks, and response to medication. Primary paroxysmal dyskinesias are usually autosomal dominant genetic conditions. Secondary paroxysmal dyskinesias can be the symptoms of different neurologic and medical disorders. This review summarizes the updates on etiology, pathophysiology, genetics, clinical presentation, differential diagnosis, and treatment of paroxysmal dyskinesias and other episodic movement disorders.

Paroxysmal dyskinesias revisited: a review of 500 genetically proven cases and a new classification.

Paroxysmal movement disorders are a heterogeneous group of conditions manifesting as episodic dyskinesia with sudden onset and lasting a variable duration. Based on the difference of precipitating factors, three forms are clearly recognized, namely, paroxysmal kinesigenic (PKD), non-kinesigenic (PNKD), and exercise induced (PED). The elucidation of the genetic cause of various forms of paroxysmal dyskinesia has led to better clinical definitions based on genotype-phenotype correlations in the familial forms. However, it has been increasingly recognized that (1) there is a marked pleiotropy of mutations in such genes with still expanding clinical spectra; and (2) not all patients clinically presenting with either PKD, PNKD, or PED have mutations in these genes. We aimed to review the clinical features of 500 genetically proven cases published to date. Based on our results, it is clear that there is not a complete phenotypic-genotypic correlation, and therefore we suggest an algorithm to lead the genetic analyses. Given the fact that the reliability of current clinical categorization is not entirely valid, we further propose a novel classification for paroxysmal dyskinesias, which takes into account the recent genetic discoveries in this field.

Sporadic nocturnal frontal lobe epilepsy: A consecutive series of 8 cases.

OBJECTIVE: To present findings on a series of cases of sporadic nocturnal frontal lobe epilepsy (NFLE), a form of NFLE that is infrequently reported, in contrast to familial (autosomal dominant) NFLE. Both forms of NFLE need to be distinguished from parasomnias, nocturnal temporal lobe epilepsy, and other nocturnal disorders. METHODS: Eight consecutive cases of sporadic NFLE were evaluated at a sleep clinic in Taiwan. All patients had clinical evaluations, daytime waking and sleeping EEGs, brain MRIs, and overnight video-polysomnography (vPSG) with seizure montage. RESULTS: Gender was equal (four males, four females); mean age was 18.4 yrs (range, 7-41 yrs). Age of NFLE onset was by puberty. Premorbid history was negative for any neurologic, medical or psychiatric disorder. NFLE subtypes: nocturnal paroxysmal dystonia, n=6; paroxysmal arousals, n=2. MRI brain scan abnormalities with clinical correlates were found in one patient. Daytime awake EEGs were negative for ictal/interictal activity in all patients, but two patients had daytime sleep EEGs with interictal epileptiform EEG activity. During vPSG studies, three of eight patients with NFLE seizure events had concurrent epileptiform EEG activity, and two patients had interictal epileptiform EEG activity during their vPSG studies. No case had a spontaneous remission. Anticonvulsant therapy was highly effective in all eight cases (>75% reduction in seizure frequency). DISCUSSION: These cases confirm that sporadic NFLE closely resembles familial NFLE, and comprises a set of distinct clinical manifestations, with variable intensity, and variable scalp EEG epileptiform abnormalities across sleep and wakefulness, which have previously been identified in Caucasian patients from Europe and North America.

Tonic spasms are a common clinical manifestation in patients with neuromyelitis optica / Espasmos tônicos são manifestações clínicas frequentes em pacientes com neuromielite óptica

Tonic spasms have been most commonly associated with multiple sclerosis. To date, few reports of series of patients with neuromyelitis optica and tonic spasms have been published. Methods: We analyzed the characteristics and frequency of tonic spasms in 19 subjects with neuromyelitis optica. Data was collected using a semi-structured questionnaire for tonic spasms, by both retrospectively reviewing medical records and performing clinical assessment. Results: All patients except one developed this symptom. The main triggering factors were sudden movements and emotional factors. Spasms were commonly associated to sensory disturbances and worsened during the acute phases of the disease. Carbamazepine was most commonly used to treat the symptom and patients showed good response to the drug. Conclusions: Tonic spasms are a common clinical manifestation in patients with neuromyelitis optica. .

Espasmos tônicos têm sido mais frequentemente associados com esclerose múltipla. Foram publicados até agora poucos relatos de série de pacientes com neuromielite óptica e espasmos tônicos. Métodos: Foram analisadas as características e a frequência de espasmos tônicos em 19 indivíduos com neuromielite óptica. Os dados foram coletados por meio de um questionário semiestruturado para espasmos tônicos, mediante a avaliação retrospectiva dos prontuários e a análise dos dados clínicos Resultados: Todos os pacientes com neuromielite óptica exceto um apresentaram espasmos tônicos. Os principais fatores desencadeantes foram movimentos bruscos e fatores emocionais. Espasmos foram frequentemente associados a perturbações sensoriais e se agravaram durante a fase aguda da doença. A carbamazepina foi utilizada frequentemente para tratar os sintomas, com boa resposta. Conclusões: Os espasmos tônicos são manifestações clínicas frequentes em pacientes com neuromielite óptica. .

Paroxysmal dystonia and neuromyelitis optica / Distonia paroxística e neuromielite óptica

Paroxysmal dyskinesias (PD) are thought to be rare movement disorders. The overwhelming majority of reported cases are primary. Secondary PD has seen reported to occur in some conditions, mainly in multiple sclerosis and head trauma. The anatomic origin of the lesion is also rarely seen at the spinal cord. Our objective was to describe four patients with paroxysmal dystonia secondary to spinal lesions during the recovering phase of a neuromyelitis optica (NMO) bout. In the reviewed literature, we do not find any report of PD related to NMO.

Discinesias paroxísticas (DP) são distúrbios do movimento raros. A maioria dos casos relatados é de origem primária. DP secundárias têm sido relatadas em algumas condições, principalmente na esclerose múltipla e no trauma craniano. A origem anatômica da lesão também é raramente observada na medula. O objetivo deste trabalho foi descrever quatro pacientes com distonia paroxística secundária a lesões medulares, ocorrida durante a fase de recuperação do surto de neuromielite óptica (NMO). Na literatura consultada, não encontramos qualquer relato de DP secundárias à NMO.

A Case of Nocturnal Paroxysmal Dystonia

Nocturnal paroxysmal dystonia is characterized by brief, abrupt, dystonic or dyskinetic movement during NREMsleep. It has been considered as a form of nocturnal frontal lobe epilepsy. A 35-year-old man complained of sleep disturbance and abnormal movement during sleep. In video-polysomnography recordings, he showed frequent stereotyped abnormal dystonic movements in upper and lower extremities. The dystonic movements occurred during stage IV sleep. He was treated with carbamazepine and the symptoms improved. (J Korean Neurol Assoc 19(3):305~308, 2001)