Sergio Alejandro Rodríguez-Quiroga

Ataxia plus myoclonus in a 23-year-old patient due to STUB1 mutations.

More than 1,000 mutations mapping to 60 different loci have been recognized as the cause of hereditary ataxias. However, almost 50% of the cases are still genetically uncharacterized, with etiology remaining to be identified.1 Diagnosis and research in rare diseases such as ataxia has been significantly improved with the recent availability of next-generation sequencing technologies.2 In order to expand the phenotype recently described in ataxia due to STUB1 mutations and to illustrate the utility of clinical genomics in the diagnosis of ataxias, we present a 23-year-old patient who had ataxia plus myoclonus in whom exome sequencing revealed novel compound heterozygous mutations in the STUB1 gene.

Tonic spasms are a common clinical manifestation in patients with neuromyelitis optica

UNLABELLED 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.

Hemimasticatory spasm: report of a case and review of the literature†.

Background Hemimasticatory spasm is a very rare movement disorder characterized by unilateral, involuntary, paroxysmal contractions of the jaw-closing muscles, causing clinically brief twitches and/or spasms. Case Report A 62-year-old female consulted us with a 30-year history of unusual involuntary twitches in the preauricular region and spasms that hampered jaw opening. During these spasms, she could not open her mouth. On physical examination, we also observed hypertrophy of the masseter and temporalis muscles, which can be features of hemimasticatory spasm. She was treated with botulinum toxin type A, with excellent response. Here, we present her case and review the literature. Discussion Hemimasticatory spasm is a rare movement disorder. Given the excellent response to botulinum toxin type A treatment, it should be considered within the spectrum of facial spasms.

Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders

Neuronal migration disorders are a clinically and genetically heterogeneous group of malformations of cortical development, frequently responsible for severe disability. Despite the increasing knowledge of the molecular mechanisms underlying this group of diseases, their genetic diagnosis remains unattainable in a high proportion of cases. Here, we present the results of 38 patients with lissencephaly, periventricular heterotopia and subcortical band heterotopia from Argentina. We performed Sanger and Next Generation Sequencing (NGS) of DCX, FLNA and ARX and searched for copy number variations by MLPA in PAFAH1B1, DCX, POMT1, and POMGNT1. Additionally, somatic mosaicism at 5% or higher was investigated by means of targeted high coverage NGS of DCX, ARX, and PAFAH1B1. Our approach had a diagnostic yield of 36%. Pathogenic or likely pathogenic variants were identified in 14 patients, including 10 germline (five novel) and 4 somatic mutations in FLNA, DCX, ARX and PAFAH1B1 genes. This study represents the largest series of patients comprehensively characterized in our population. Our findings reinforce the importance of somatic mutations in the pathophysiology and diagnosis of neuronal migration disorders and contribute to expand their phenotype-genotype correlations.

Neurogenetics in Argentina: diagnostic yield in a personalized research based clinic.

As a whole neurogenetic diseases are a common group of neurological disorders. However, the recognitionand molecular diagnosis of these disorders is not always straightforward. Besides, there is a paucity of informationregarding the diagnostic yield that specialized neurogenetic clinics could obtain. We performed a prospective,observational, analytical study of the patients seen in a neurogenetic clinic at a tertiary medicalcentre to assess the diagnostic yield of a comprehensive diagnostic evaluation that included a personalizedclinical assessment along with traditional and next-generation sequencing diagnostic tests. We included a cohortof 387 patients from May 2008 to June 2014. For sub-group analysis we selected a sample of patientswhose main complaint was the presence of progressive ataxia, to whom we applied a systematic moleculardiagnostic algorithm. Overall, a diagnostic mutation was identified in 27·4% of our cohort. However, if weonly considered those patients where a molecular test could be performed, the success rate rises to 45%. Weobtained diagnostic yields of 23·5 and 57·5% in the global group of ataxic patients and in the subset of ataxicpatients with a positive family history, respectively. Thus, about a third of patients evaluated in a neurogeneticclinic could be successfully diagnosed.

Huntington’s disease masquerading as spinocerebellar ataxia

Huntington’s disease (HD) is a neurodegenerative disorder of the central nervous system characterised by the presence of choreic abnormal movements, behavioural or psychiatric disturbances and dementia. Noteworthy, despite atypical motor symptoms other than chorea have been reported as initial presentation in some patients, a very few number of HD patients, presenting at onset mostly cerebellar dysfunction masquerading dominant spinocerebellar ataxias (SCA), were occasionally reported. We report the case of a 42-year-old man with a 5-year history of gait disturbance, dysarthria and cognitive impairment and familial antecedents of dementia and movement disorders. Initially the clinical picture suggested the diagnosis of a dominant SCA, but finally a diagnosis of HD was made based on the molecular evidence of abnormal 39 Cytosine-Adenine-Guanine (CAG) repeats in exon 1 of Huntingtin gene. The authors highlight the importance of suspecting HD in the aetiology of spinocerebellar ataxias when dementia is a prominent feature in the proband or their family.

Whole exome sequencing in neurogenetic odysseys: An effective, cost- and time-saving diagnostic approach

Background Diagnostic trajectories for neurogenetic disorders frequently require the use of considerable time and resources, exposing patients and families to so-called “diagnostic odysseys”. Previous studies have provided strong evidence for increased diagnostic and clinical utility of whole-exome sequencing in medical genetics. However, specific reports assessing its utility in a setting such as ours- a neurogeneticist led academic group serving in a low-income country—are rare. Objectives To assess the diagnostic yield of WES in patients suspected of having a neurogenetic condition and explore the cost-effectiveness of its implementation in a research group located in an Argentinean public hospital. Methods This is a prospective study of the clinical utility of WES in a series of 40 consecutive patients selected from a Neurogenetic Clinic of a tertiary Hospital in Argentina. We evaluated patients retrospectively for previous diagnostic trajectories. Diagnostic yield, clinical impact on management and economic diagnostic burden were evaluated. Results We demonstrated the clinical utility of Whole Exome Sequencing in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%) among a diverse group of neurological disorders. The average age at the time of WES was 23 (range 3–70). The mean time elapsed from symptom onset to WES was 11 years (range 3–42). The mean cost of the diagnostic workup prior to WES was USD 1646 (USD 1439 to 1853), which is 60% higher than WES cost in our center. Conclusions WES for neurogenetics proved to be an effective, cost- and time-saving approach for the molecular diagnosis of this heterogeneous and complex group of patients.

Commentary on neuromyelitis optica associated with painful paroxysmal dystonia: case report and literature review

Dr Bălasa has provided an interesting description of the presence of paroxysmal dystonia in a patient with neuromyelitis optica [1]. The paroxysmal dystonia, also called Tonic Spasms, was the most frequent movement disorder described in patients with multiple sclerosis [2]. However, based on recent studies, it is stated that paroxysmal dystonia could be more commonly seen in patients with neuromyelitis optica spectrum disorders compared to patients with multiple sclerosis. This has led to consider that transverse myelitis, typically longitudinally extensive (more than 3 vertebral segments), followed by tonic spasms is a signature clinical feature of neuromyelitis optica [3]. In our experience, in a recent study, we found the presence of paroxysmal dystonia in 95 % (18 of 19) of a group of patients with clinical and radiological criteria for NMO spectrum disorders [4]. The principal features of our patients were the occurrence of a somesthetic aura associated with the paroxysmal dystonia in 18 of 19 patients, as well as the worsening of the movement disorders during the acute phases of the disease. Almost all patients had a dramatic response to the use of carbamazepine or acetazolamide, as seen in the case described by Dr Bălasa and consistent with previous reports [2, 5]. We believe that one of the reasons for an increasing incidence of paroxysmal dystonia in our NMO patients could be explained due to the fact that we employed a structured questionnaire to find signs and symptoms that suggested the presence of paroxysmal dystonia and because of a long follow-up period in most of the evaluated subjects. Based on our experience, we support the hypothesis that paroxysmal dystonia could be a common movement disorder in patients with neuromyelitis optica. The recognition of this clinical picture is relevant because we can offer a medical therapy that could relieve the symptoms.

Dramatic Improvement of Parkinsonism While Dancing Tango

Keywords: Parkinson disease; tango; rehabilitation; gait disturbance; quality of life