Rare mutations in ATL3, SPTLC2 and SCN9A explaining hereditary sensory neuropathy and congenital insensitivity to pain in a Brazilian cohort

Cintra, Vívian Pedigone; Dohrn, Maike F.; Tomaselli, Pedro J.; Figueiredo, Fernanda Barbosa; Marques, Sandra Elisabete; Camargos, Sarah Teixeira; Barbosa, Luiz C. A.; Rebelo, Adriana P.; Abreu, Lisa; Danzi, Matt C.; Marques, Wilson; Züchner, Stephan

doi:10.1016/j.jns.2021.117498

Cited by 9 publications

(13 citation statements)

References 20 publications

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“…Since we did not include families without cough, no conclusions on sensitivity and specificity of this feature can be drawn. Nevertheless, approximately 90% of HSAN cases remain genetically unsolved, and thus the diagnostic yield of 75% is strikingly high [1][2][3].…”

Section: Discussionmentioning

confidence: 99%

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RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia

Beijer

Dohrn

Winter

et al. 2022

Euro J of Neurology

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Background and purpose Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a group of diseases of mostly unknown genetic cause. Biallelic repeat expansions in RFC1 are associated with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). This study aimed to investigate the prevalence of RFC1 repeat expansions in a cohort of HSAN patients. Methods After unremarkable whole‐exome sequencing (WES) analysis, we performed repeat‐primed PCR to detect intronic RFC1 expansions in 12 HSAN families, who all presented with chronic cough. Results In these patients, 75% carried biallelic expansions of the pathogenic AAGGG motif. Compared with RFC1−/− cases, RFC1+/+ cases presented more consistently with positive sensory and autonomic symptoms. Afferent ataxia was more severe in the RFC1+/+ cohort and cerebellar ataxia was a common feature (21%). Conclusions We demonstrate that RFC1 is a frequent cause of (WES‐negative) HSAN with chronic cough and ataxia. The diagnostic yield of RFC1 repeat‐primed PCR was surprisingly high, given that HSAN is genetically poorly understood. This combination of HSAN, ataxia, and chronic cough symptoms represents a new nosological entity within the neuropathy‐ataxia spectrum.

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Section: Discussionmentioning

confidence: 99%

“…Hereditary sensory and autonomic neuropathies (HSAN) are a rare subgroup of inherited peripheral neuropathies, characterized by sensory loss, neuropathic pain, trophic and autonomic disturbances, for which the underlying cause remains unknown in approximately 80% to 90% of patients [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia

Beijer

Dohrn

Winter

et al. 2022

Euro J of Neurology

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“…However, very few studies involving whole-exome sequencing (WES) or whole-genome sequencing (WGS) screening have been conducted, so current knowledge is incomplete. WGS of 23 unrelated Brazilian families with familial sensory neuropathy detected pathogenic variants in ATL3 , SPTLC2 and SCN9A in 12 patients from 5 unrelated families 50. There is also increasing understanding that more-common non-deterministic variants—for instance potentially affecting energy metabolism and immune responses—almost certainly contribute, but will require genotyping thousands of well phenotyped cases and healthy controls to identify them.…”

Section: Clinical Featuresmentioning

confidence: 99%

“…Specifically, gain of function mutations in Na v 1.7, Na v 1.8 and Na v 1.9 alpha subunits encoded by SCN9A (OMIM *603415), SCN10A (OMIM *604427) and SCN11A (OMIM *604385), respectively, are associated with heterogenous clinical phenotypes, which can include painful small fibre neuropathy, small-fibre dysautonomia and other small-fibre symptoms and other concerns 58. A recent Brazilian study using WGS identified two new mutations 50. Very rarely, patients have pathogenic variants in the auxiliary beta, rather than the alpha, sodium channel subunits or loss-of-function variants associated with reduced pain sensitivity that can be lethal 59 60.…”

Section: Clinical Featuresmentioning

confidence: 99%

Advances in diagnosis and management of distal sensory polyneuropathies

Silsby

Feldman

Dortch

et al. 2023

J Neurol Neurosurg Psychiatry

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Distal sensory polyneuropathy (DSP) is characterised by length-dependent, sensory-predominant symptoms and signs, including potentially disabling symmetric chronic pain, tingling and poor balance. Some patients also have or develop dysautonomia or motor involvement depending on whether large myelinated or small fibres are predominantly affected. Although highly prevalent, diagnosis and management can be challenging. While classic diabetes and toxic causes are well-recognised, there are increasingly diverse associations, including with dysimmune, rheumatological and neurodegenerative conditions. Approximately half of cases are initially considered idiopathic despite thorough evaluation, but often, the causes emerge later as new symptoms develop or testing advances, for instance with genetic approaches. Improving and standardising DSP metrics, as already accomplished for motor neuropathies, would permit in-clinic longitudinal tracking of natural history and treatment responses. Standardising phenotyping could advance research and facilitate trials of potential therapies, which lag so far. This review updates on recent advances and summarises current evidence for specific treatments.

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“…Mild signs of upper motor neuron involvement have been reported in these families, suggesting an ATL1-associated disease spectrum 64,65 . Missensemutations in the homologous ATL3 can cause autosomal-dominant HSAN1 as well [66][67][68][69] , characterized by delayed wound healing, adult onset painless chronic ulcerations and fractures of the metatarsals, which may result in severe bone destruction. Homozygous loss-of-function mutations in ARL6IP1 can cause a complicated form of HSP with the typical signs of HSAN in terms of pain loss and acromutilations [70][71][72][73][74][75] .…”

Section: [H2] Epigenetics and Transcriptionmentioning

confidence: 99%

Genetic pain loss disorders

Lischka

Laššuthová

Çakar

et al. 2022

Nat Rev Dis Primers

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Rare mutations in ATL3, SPTLC2 and SCN9A explaining hereditary sensory neuropathy and congenital insensitivity to pain in a Brazilian cohort

Cited by 9 publications

References 20 publications

RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia

RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia

Advances in diagnosis and management of distal sensory polyneuropathies

Genetic pain loss disorders

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