The odyssey of complex neurogenetic disorders: From undetermined to positive.

The genetic and phenotypic heterogeneity of neurogenetic diseases forces patients and their families into a "diagnostic odyssey." An increase in the variability of genetic disorders and the corresponding gene-disease associations suggest the need to periodically re-evaluate the significance of variants of undetermined pathogenicity. Here, we report the diagnostic and clinical utility of Targeted Gene Panel Sequencing (TGPS) and Whole Exome Sequencing (WES) in 341 patients with suspected neurogenetic disorders from centers in Buenos Aires and Cincinnati over the last 4 years, focusing on the usefulness of reinterpreting variants previously classified as of uncertain significance. After a mean of ±2years (IC 95:0.73-3.27), approximately 30% of the variants of uncertain significance were reclassified as pathogenic. The use of next generation sequencing methods has facilitated the identification of both germline and mosaic pathogenic variants, expanding the diagnostic yield. These results demonstrate the high clinical impact of periodic reanalysis of undetermined variants in clinical neurology.

Argentinian clinical genomics in a leukodystrophies and genetic leukoencephalopathies cohort: Diagnostic yield in our first 9 years.

INTRODUCTION AND OBJECTIVES: Leukodystrophies and genetic leukoencephalopathies constitute a vast group of pathologies of the cerebral white matter. The large number of etiopathogenic genes and the frequent unspecificity on the clinical-radiological presentation generate remarkable difficulties in the diagnosis approach. Despite recent and significant developments, molecular diagnostic yield is still less than 50%. Our objective was to develop and explore the usefulness of a new diagnostic procedure using standardized molecular diagnostic tools, and next-generation sequencing techniques. MATERIALS AND METHODS: A prospective, observational, analytical study was conducted in a cohort of 46 patients, evaluated between May 2008 and December 2016, with a suspected genetic leukoencephalopathy or leukodystrophy. A diagnostic procedure was set up using classical monogenic tools in patients with characteristic phenotypes, and next-generation techniques in nonspecific ones. RESULTS: Global diagnostic procedure yield was 57.9%, identifying the etiological pathogenesis in 22 of the 38 studied subjects. Analysis by subgroups, Sanger method, and next-generation sequencing showed a yield of 64%, and 46.1% respectively. The most common pathologies were adrenoleukodystrophy, cerebral autosomal-dominant arteriopathy with subcortical infarcts (CADASIL), and vanishing white matter disease. CONCLUSIONS: Our results confirm the usefulness of the proposed diagnostic procedure expressed in a high diagnostic yield and suggest a more optimal cost-effectiveness in an etiological analysis phase.

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.

[The broad phenotypic spectrum of SCA-3: hereditary spastic paraplegia]. / Amplio espectro fenotípico de la SCA-3: paraparesia espástica hereditaria.

Machado-Joseph disease (MJD) is the most frequent dominantly inherited spinocerebellar ataxia. A marked phenotypic variability is a characteristic of this disorder that could involve non-cerebellar presentations. Based on several case reports describing pyramidal dysfunction as the main symptom at onset, a clinical form resembling hereditary spastic paraplegia has been proposed. We report here two further cases of MJD patients whose initial clinical presentation suggested hereditary spastic paraplegia, and a summary of the main findings of previously similar published reports. Our findings lent support to the proposal of a MJD subtype distinguished by a marked pyramidal dysfunction at onset, simulating a clinical picture of hereditary spastic paraplegia.

Social concepts and the cerebellum: behavioural and functional connectivity signatures in cerebellar ataxic patients.

Neurocognitive research on social concepts underscores their reliance on fronto-temporo-limbic regions mediating broad socio-cognitive skills. Yet, the field has neglected another structure increasingly implicated in social cognition: the cerebellum. The present exploratory study examines this link combining a novel naturalistic text paradigm, a relevant atrophy model and functional magnetic resonance imaging. Fifteen cerebellar ataxia (CA) patients with focal cerebellar atrophy and 29 matched controls listened to a social text (highlighting interpersonal events) as well as a non-social text (focused on a single person's actions), and answered comprehension questionnaires. We compared behavioural outcomes between groups and examined their association with cerebellar connectivity. CA patients showed deficits in social text comprehension and normal scores in the non-social text. Also, social text outcomes in controls selectively correlated with connectivity between the cerebellum and key regions subserving multi-modal semantics and social cognition, including the superior and medial temporal gyri, the temporal pole and the insula. Conversely, brain-behaviour associations involving the cerebellum were abolished in the patients. Thus, cerebellar structures and connections seem involved in processing social concepts evoked by naturalistic discourse. Such findings invite new theoretical and translational developments integrating social neuroscience with embodied semantics. This article is part of the theme issue 'Concepts in interaction: social engagement and inner experiences'.

Clinical next generation sequencing in developmental and epileptic encephalopathies: Diagnostic relevance of data re-analysis and variants re-interpretation.

Developmental and epileptic encephalopathies (DEE) are complex pediatric epilepsies, in which heterogeneous pathogenic factors play an important role. Next-generation-sequencing based tools have shown excellent effectiveness. The constant increase in the number of new genotype-phenotype associations suggests the periodic need for re-interpretation and re-analysis of genetic studies without positive results. In this study, we report the diagnostic utility of targeted gene panel sequencing and whole exome sequencing in 55 Argentine subjects with DEE, focusing on the utility of re-interpretation and re-analysis of undetermined and negative genetic diagnoses. The new information in biomedical literature and databases was used for the re-interpretation. For re-analysis, sequencing data processing was repeated using updated bioinformatics tools. Initially, pathogenic variants were detected in 21 subjects (38%). After an average time of 29 months, 25% of the subjects without a genetic diagnosis were re-categorized as diagnosed. Finally, the overall diagnostic yield increased to 53% (29 subjects). In consequence of the re-interpretation and re-analysis, we identified novel variants in the genes: CHD2, COL4A1, FOXG1, GABRA1, GRIN2B, HNRNPU, KCNQ2, MECP2, PCDH19, SCN1A, SCN2A, SCN8A, SLC6A1, STXBP1 and WWOX. Our results expand the diagnostic yield of this subgroup of infantile and childhood seizures and demonstrate the importance of re-evaluation of genetic tests in subjects without an identified causative etiology.

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.

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.

Molecular Diagnosis in an Argentinean Mitochondrial Disorders Cohort

Abstract Mitochondrial diseases are multisystemic disorders characterized by an impairment of the mitochondrial respiratory chain. Diagnosis requires an approach that involves a high index of suspicion, molecular techniques and a careful selection of the tissue to be studied. Our goal was to develop and implement local strategies for diagnosing mitochondrial disorders, by standardizing procedures of molecular biology and nucleic acid sequencing. A prospective, analytical, observational study was conducted in a cohort of, a total of 82 patients with suspected mitochondrial disorder who were treated at our hospital between May 2008 and June 2019. We developed molecular diagnostic tools that included classical monogenic techniques and Next Generation Sequencing. We characterized the neurological and extra neurological manifestations noted in our cohort. Following the proposed algorithm, we obtained a molecular diagnostic performance of 54%, identifying mutations in 44 patients. mtDNA mutations were identified in 34 patients. Structural rearrangements in mitochondrial genome were found in 3 and 7 in nuclear genes, respectively. Our results confirm the utility of the proposed algorithm and the molecular tools used, as evidenced by a high diagnostic performance. This is of great value to a more efficient and comprehensive medical care of patients and families affected by mitochondrial disorders.

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.

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.

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.