Sodium channel mutations as a possible cause for primary dysautonomia

Active Project Grant Awarded Last action

Award ID
R01NS126398
Recipient
Awarding agency
Obligated
$4,943,588

Award facts

Completion date 76% complete
Place of performance
Baltimore, MD 21205, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Primary dysautonomia (PD), distinct from the entity called familial dysautonomia, is a multifactorial condition that runs in families in which the autonomic nervous system (ANS) does not function correctly leading to a range of disabling disease symptoms. Despite the known fact that PD exhibits mendelian inheritance patterns, underlying genetic origins have not been identified. Treatments are solely based on alleviating symptomatology and there is no rationale for effectuating a cure. To help fill this knowledge GAP and start identifying contributing factors to PD, we closely followed sixty-nine families with a dominant mendelian inheritance pattern of multiple shared symptoms including (I) chronic orthostatic intolerance, (II) chronic fatigue, (III) primary focal hyperhidrosis, (IV) chronic itch, and (V) generalized anxiety. We initiated whole-exome sequencing (WES) of the probands in these families with resulting data suggesting a causal relationship between PD and an autosomal dominant inheritance pattern of mutations in genes encoding voltage-gated sodium (NAV) channels. This outcome is strengthened by the fact that we have treated family members with NAV channel modulators which resolved many of their complaints. Based on preliminary results, we hypothesize that what appears to pathophysiologically link diffuse autonomic symptoms, is a disease model in which NAV channel mutations can transform the ANS into an oversensitive nervous system that over time develops incapacitating and persistent disease. To start investigating the involvement of NAV channel mutations in PD, we devised a strategy to help elucidate the link between our targets and anomalous activation of the sympathetic nervous system in patients. Our approach will culminate in the creation of a validated animal model with autonomic dysfunction in which human therapeutics can be tested. Successful completion will provide new insights into genetic causes of PD, a vital step towards understanding the multifactorial nature of this disorder.

Transactions

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Original award $530,798
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Subawards

Subrecipient Amount Awarded
Vrije Universiteit Brussel Sodium channel mutations as a possible cause for primary dysautonomia $188,578
Universiteit Gent $227,747

Quick answers

Who received award R01NS126398?

R01NS126398 was awarded to The Johns Hopkins University by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on February 15, 2023.

How much is award R01NS126398 worth?

$4,943,588 has been obligated on R01NS126398.

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