Welcome to the WCN 2021 Interactive Program

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    Please note that all sessions will run at their scheduled time and be followed by a LIVE Q&A/Discussion at the end

     The viewing of sessions, cannot be accessed from this conference calendar. All sessions are accessible via the Virtual Platform

Displaying One Session

Free Communication
Session Time
11:30 - 12:40
Room
Free Communication B
Chair(s)
  • Jo Wilmshurst (South Africa)
Free Communication

TRANS-ETHNIC FINE-MAPPING OF THE MHC REGION ON PARKINSON’S DISEASE IDENTIFIED SHARED GENETIC FEATURES ASSOCIATED WITH THE RISK

Session Type
Free Communication
Date
07.10.2021, Thursday
Session Time
11:30 - 12:40
Room
Free Communication B
Lecture Time
11:30 - 11:40
Presenter
  • Tatsuhiko Naito (Japan)

Abstract

Background and Aims:

Although different studies reported the genetic predisposition of human leukocyte antigen (HLA) to the risk of Parkinson’s disease (PD), the complex haplotype structure and highly polymorphic feature of the major histocompatibility complex (MHC) region has hampered a unified insight. In addition, the evidence for non-European populations was scarce. We conducted trans-ethnic fine-mapping for large cohorts to elucidate shared genetic features of the MHC region associated with the PD risk.

Methods:

We targeted European populations (14,650 cases and 1,288,625 controls) and East Asian populations (7,712 cases and 27,372 controls). We adopted a hybrid fine-mapping approach including: (1) HLA genotype imputation of GWAS genotype data using our novel imputation method, DEEP*HLA; and (2) direct imputation of HLA variant risk from the GWAS summary statistics.

Results:

The strongest association was observed at the protective effect of His13 in HLA-DRβ1 (P = 6.0 × 10−15), and this position explained the majority of the risk in HLA-DRB1. In silico prediction revealed that HLA-DRB1 alleles with His13 (protective) and Arg13 (risk) had significantly weaker and stronger binding-affinity to an α-synuclein epitope than other alleles (P = 9.6 × 10−4 and 1.0 × 10−3, respectively). Stepwise conditional analysis revealed additional independent associations at Ala69 in HLA-B (P = 1.0 × 10−7). We experimentally fine-mapped Alzheimer's disease risk, but the lead variants were not consistent.

Conclusions:

The current study highlights the genetic features of the MHC region associated with the risk of PD across ethnicities, enhancing our understanding of the immunologic pathophysiology of PD.

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Free Communication

HIGH EFFICIENCY AND CLINICAL RELEVANCE OF EXOME SEQUENCING IN THE DAILY PRACTICE OF NEUROGENETICS

Session Type
Free Communication
Date
07.10.2021, Thursday
Session Time
11:30 - 12:40
Room
Free Communication B
Lecture Time
11:40 - 11:50
Presenter
  • Quentin H. THOMAS (France)

Abstract

Background and Aims:

Exome Sequencing's (ES) relevance as a diagnostic tool in a real-life practice with heterogeneous cohort of patients presenting for neurogenetic evaluation is still debated and has yet to be assessed. Here, we report a prospective study using clinical ES (cES) as a first-tier test or after a non-contributive diagnostic odyssey in various progressive neurological disorders, regardless of age at onset, familial history or clinical spectrum, assessing the efficiency and relevance of cES in the daily practice of Neurology and Genetic Departments.

Methods:

Sixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labeled “other”) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) strategy depending on available samples and was analyzed with an in-house pipeline including software for CNV and mitochondrial-DNA variant detection.

Results:

In 29/67 individuals, cES identified clearly pathogenic variants leading to a 43% positive yield. When performed as a first-tier test, cES identified pathogenic variants for 53% of individuals (10/19). Difficult cases were solved including double diagnoses within a kindred or identification of a neurodegeneration with brain iron accumulation in a patient with encephalopathy of suspected mitochondrial origin.

Conclusions:

This study shows that cES is a powerful tool for the daily practice of neurogenetics offering an efficient (43%) and appropriate approach for clinically and genetically complex and heterogeneous disorders.

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Free Communication

DIAGNOSTIC YIELD OF CLINICAL EXOME TESTING IN NEUROLOGY PATIENTS OF FROM TERTIARY CARE CENTRE

Session Type
Free Communication
Date
07.10.2021, Thursday
Session Time
11:30 - 12:40
Room
Free Communication B
Lecture Time
11:50 - 12:00
Presenter
  • Piyush K. Anshu (India)

Abstract

Background and Aims:

Since last few years genetic testing has become easily available. In developing countries where cost may forbid testing, evaluating clinical exome sequencing(CES) might be financially more feasible than whole exome sequencing (WES) for heterogenous mendelian disorders. However there are few studies to assess diagnostic yield of CES.

Our study looked at diagnostic yield of clinical exome panel for phenotypic subgroup of neurological disorder with a presumed genetic aetiology.

Methods:

Retrospective analysis of all patients who were subjected to CES between 2016 and 2019 at neurology department of KEM hospital was done. It was done in patients in whom clinical picture was highly suggestive of genetic aetiology. CES data was generated at standard genetic laboratory

Results:

Exome data from 95 adult and child neurological patients were analysed. Likely or definite causative variants were found in 52 individuals, achieving an overall diagnostic rate of 55%. Molecular diagnosis could be established in 34/47 (72%) patients with neuromuscular disease, 6/24 (25%) with epileptic disorders, 6/14 (43%) with movement disorders and 6/10 (60%) with suspected intellectul disability and delay. In 20(21%) patients the management changed in terms of specific drugs and diet.

Conclusions:

Diagnostic CES identified underlying genetic defect definitively or likely in 55% of neurological patients. Highest diagnostic yield was achieved in neuromuscular group (72%). Diagnostic yield was high because of stringent selection of patients. Confirmation of diagnosis by genetics paves way for genetic counselling, avoids invasive diagnostic tests and decreases economic burden to family.

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Free Communication

SELF-REPORTED POSTURAL SYMPTOMS PREDICT VESTIBULAR DYSFUNCTION AND FALLS IN MITOCHONDRIAL DISEASE PATIENTS WITH MULTI-SENSORY IMPAIRMENT

Session Type
Free Communication
Date
07.10.2021, Thursday
Session Time
11:30 - 12:40
Room
Free Communication B
Lecture Time
12:00 - 12:10
Presenter
  • Nehzat Koohi (United Kingdom)

Abstract

Background and Aims:

Mitochondrial diseases (MD) are a genetically heterogenous group of conditions. Large phenotypic variations are seen in people with MD, with presentations ranging from single organ involvement to multisystem disorders, which commonly give rise to multi-sensory impairment including ataxia, neuropathy, myopathy and vestibular dysfunction. We investigated the relative contributions of sensory impairment to postural control in patients with MD as a human model of multi-sensory dysfunction and explore how these impairments relate to falls risk.

Methods:

We recorded clinical data of 130 patients with a confirmed genetic and/or clinicopathological diagnosis of MD, who attended an out-patient MD clinic at the National Hospital for Neurology and Neurosurgery. We specifically recorded the presence of ataxia, peripheral neuropathy, myopathy, hearing loss and vestibular dysfunction, in addition to symptoms of dizziness and imbalance.

Results:

Of the patients who presented with ataxia, 52% reported that they had experienced falls. Similarly, 52% of patients with confirmed vestibular dysfunction reported falls, versus 38% with neuropathy and 30% with myopathy. Eighty percent of MD patients with confirmed vestibular dysfunction reported imbalance, 56% reported dizziness and 52% reported falls.

Conclusions:

Whilst ataxia is an established cause of falls, and a recognised feature of MD, but dizziness symptoms and vestibular dysfunction may be more prevalent than is currently reported. Patients with objective evidence of vestibular dysfunction were at greater risk of imbalance, dizziness, and falls. Dizziness and imbalance are useful self-reported indicators of vestibular dysfunction in patients with multisensory impairment, and highly predictive of falls.

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Free Communication

THE PUZZLING FINDING OF DISTURBED NEUROMUSCULAR TRANSMISSION IN GAUCHER DISEASE: A CASE REPORT AND REVIEW OF THE LITERATURE

Session Type
Free Communication
Date
07.10.2021, Thursday
Session Time
11:30 - 12:40
Room
Free Communication B
Lecture Time
12:10 - 12:20
Presenter
  • Francesca Beretta (Italy)

Abstract

Background and Aims:

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by glucocerebrosidase deficiency. Type 2 GD manifests in early infancy with failure to thrive, progressive neurological deficits and systemic findings. It is invariably fatal, with death usually occurring within the second year of life.

Methods:

We describe a 7-month-old infant referred to the clinical neurophysiology department of our hospital under the suspicion of a congenital myasthenic syndrome. She presented with hypotonia, convergent strabismus, failure to thrive and dysphagia. She had findings of abnormal neuromuscular transmission on repetitive nerve stimulation and single-fiber EMG, associated with initial clinical benefit from pyridostigmine. The final diagnosis of GD, genetically verified, was unexpected.

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Results:

In the literature, neuropathy and myopathy were previously described in GD and unexplained “multifactorial fatigue” is frequently reported by patients with both type 1 and type 3 GD. However, there were no descriptions of neuromuscular transmission failure.

In vitro studies indicate a neurotoxic effect of glucosylsphingosine, a metabolite of glucosylceramide, connected to reduced neuronal acetylcholine content. Altered calcium homeostasis has been proposed as additional pathogenetic mechanism. All these mechanisms could potentially explain neuromuscular transmission impairment.

Conclusions:

To our knowledge, this is the first report of disturbed neuromuscular transmission in GD.

Neuromuscular transmission failure could be an overlooked feature, either overshadowed by more severe neurological symptoms or subclinical in more attenuated phenotypes. As symptomatic therapy exists, we believe that further studies are warranted to establish its contribution to disease burden.

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Free Communication

LIVE Q&A

Session Type
Free Communication
Date
07.10.2021, Thursday
Session Time
11:30 - 12:40
Room
Free Communication B
Lecture Time
12:30 - 12:40