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

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Displaying One Session

Scientific Session: T (Topics)
Session Time
11:30 - 13:00
Room
Topic B
Chair(s)
  • Liying Cui (China)
Scientific Session: T (Topics)

HEREDITARY DEMYELINATING NEUROPATHIES IN THE DEVELOPING WORLD

Session Type
Scientific Session: T (Topics)
Date
06.10.2021, Wednesday
Session Time
11:30 - 13:00
Room
Topic B
Lecture Time
11:30 - 11:53
Presenter
  • Wilson Marques JR (Brazil)

Abstract

Abstract Body

HEREDITARY DEMYELINATING NEUROPATHIES IN THE DEVELOPING WORLD

At the Hospital das Clinicas, Faculty of Medicine of Ribeirão Preto, University of São Paulo we have categorized so far 1319 CMT1/CMT4 patients. At the beginning of our activities (1997), those patients suspected of having CMT were submitted to nerve conductions studies and those with upper limbs CV < 38 m/s or having intermediate values were initially submitted to the PMP22 duplication/deletion test. Gradually, we introduced PMP22, MPZ and GJB1 Sanger sequencing. More recently we initiated with target panels and exome sequencing.

Among the 1319 CMT1/CMT4 patients, there where 791 females, age at first consultation ranged from 1.8 to 71 years old (mean=31). There were 646 PMP22 duplications, 103 PMP22 deletions, 62 GJB1, 26 MPZ, 7 point mutations in PMP22 gene, 5 in LITAF, 2 in SH3TC gene and several other isolated mutations in other genes. Additional 294 patients do not have a known gene.

It is worth to know that at least 4 of our patients had an associated inflammatory neuropathy, respondeding well to treatment. Additional 5 patients presented a concomitant leprosy neuropathy.

In conclusion, our population of patients with inherited demyelinating neuropathies have a genotypic epidemiology that is very similar to studied populations from Europe and US. This is somewhat expected. Although the Brazilian population is extremely mixed, the European component is particularly strong at southeast region, where this study has been done. We still need to figure the genotypic distribution of other areas of the country with different ancestry.

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Scientific Session: T (Topics)

EMERGING TREATMENTS FOR HEREDITARY DEMYELINATING NEUROPATHIES

Session Type
Scientific Session: T (Topics)
Date
06.10.2021, Wednesday
Session Time
11:30 - 13:00
Room
Topic B
Lecture Time
11:53 - 12:16
Presenter
  • Kleopas A. Kleopa (Cyprus)

Abstract

Abstract Body

Inherited neuropathies known as Charcot-Marie-Tooth (CMT) disease are genetically heterogeneous, progressive disorders without effective therapy. Several demyelinating CMT types result from cell-autonomous loss of function mechanisms specifically in myelinating Schwann cells. Therefore, we have developed cell-targeted gene replacement or gene silencing approaches to treat demyelinating CMT. Using clinically relevant adeno-associated viral (AAV9) vectors and lumbar intrathecal injection we achieved widespread vector biodistribution throughout the PNS. Delivery of the GJB1 gene encoding the gap junction protein connexin32 (Cx32), which is associated with X-linked CMT (CMT1X), resulted in restoration of Cx32 expression in Schwann cells. GJB1 gene replacement in a model of CMT1X provided phenotypic improvement in motor performance, nerve conduction velocities, and peripheral nerve morphology both at pre- as well as post-onset stages of the neuropathy. Likewise, replacement of the SH3TC2 gene associated with recessively inherited CMT4C neuropathy in a model of the disease resulted in improvement of functional and morphological abnormalities. Finally, a gene silencing approach was used to treat an overexpressing model of CMT1A, the commonest demyelinating CMT type caused by PMP22 gene duplication. AAV9-mediated delivery of PMP22-targeting microRNA resulted in efficient silencing of PMP22 expression in PNS tissues, along with improvement of functional and morphological abnormalities. Treatment-responsive blood biomarkers of CMT neuropathies were identified and validated across different disease models. Our studies provide proof of principle for the therapeutic potential of gene replacement or gene silencing to treat demyelinating inherited neuropathies.

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Scientific Session: T (Topics)

UPDATE ON DIAGNOSIS OF HEREDITARY DEMYELINATING NEUROPATHIES

Session Type
Scientific Session: T (Topics)
Date
06.10.2021, Wednesday
Session Time
11:30 - 13:00
Room
Topic B
Lecture Time
12:16 - 12:39
Presenter
  • Mary M. Reilly (United Kingdom)

Abstract

Abstract Body

The hereditary demyelinating neuropathies are the most common form of Charcot Marie Tooth disease (CMT) and are defined as having upper limb motor conduction velocities below 38 m/s. They are classified into autosomal dominant (AD) forms (CMT1) and autosomal recessive (AR) forms (CMT4). The commonest cause of CMT1 is CMT1A due to a 1.4 megabase duplication of chromosome 17 containing the causative PMP22 gene but there are also multiple other genes that cause CMT1 and CMT4.

Once a clinical diagnosis of probable demyelinating CMT is made it may be possible depending on the family history to classify the patient as having CMT1 or CMT4.

As CMT1A is so common, it is usual to screen for CMT1A first by a technique that identifies genomic rearrangements such as MPLA. For routine testing most laboratories would then use next generation sequencing (NGS) techniques to screen multiple genes in a hereditary neuropathy panel which can be done in a number of ways including using whole exome sequencing (WES) and whole genome sequencing (WGS). For novel gene discovery WES and WGS are usually used.

The main challenge for clinicians is these NGS methods usually identify multiple variants which may be pathogenic and the investigation of these variants to identify the causative variant requires a combination of clinical and genetic expertise and is an increasing part of hereditary neuropathy clinical practice.

This talk will outline an approach to the diagnosis of hereditary demyelinating neuropathies and highlight both the rapid advances in genetic diagnosis and the challenges.

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Scientific Session: T (Topics)

LIVE Q&A

Session Type
Scientific Session: T (Topics)
Date
06.10.2021, Wednesday
Session Time
11:30 - 13:00
Room
Topic B
Lecture Time
12:39 - 13:00