(mentions CMT 2B) Genes for hereditary sensory and autonomic neuropathies: a gen

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Brain. 2009 Aug 3.

Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype

correlation.

Rotthier A, Baets J, Vriendt ED, s A, Auer-Grumbach M, Lévy N,

Bonello-Palot N, Kilic SS, Weis J, Nascimento A, Swinkels M, Kruyt MC, Jordanova

A, De Jonghe P, Timmerman V.

1 Peripheral Neuropathy Group, VIB Department of Molecular Genetics, University

of Antwerp, Antwerpen, Belgium.

Hereditary sensory and autonomic neuropathies (HSAN) are clinically and

genetically heterogeneous disorders characterized by axonal atrophy and

degeneration, exclusively or predominantly affecting the sensory and autonomic

neurons. So far, disease-associated mutations have been identified in seven

genes: two genes for autosomal dominant (SPTLC1 and RAB7) and five genes for

autosomal recessive forms of HSAN (WNK1/HSN2, NTRK1, NGFB, CCT5 and IKBKAP).

We performed a systematic mutation screening of the coding sequences of six of

these genes on a cohort of 100 familial and isolated patients diagnosed with

HSAN. In addition, we screened the functional candidate gene NGFR (p75/NTR)

encoding the nerve growth factor receptor. We identified disease-causing

mutations in SPTLC1, RAB7, WNK1/HSN2 and NTRK1 in 19 patients, of which three

mutations have not previously been reported. The phenotypes associated with

mutations in NTRK1 and WNK1/HSN2 typically consisted of congenital insensitivity

to pain and anhidrosis, and early-onset ulcero-mutilating sensory neuropathy,

respectively.

RAB7 mutations were only found in patients with a Charcot-Marie-Tooth type 2B

(CMT2B) phenotype, an axonal sensory-motor neuropathy with pronounced

ulcero-mutilations. In SPTLC1, we detected a novel mutation (S331F)

corresponding to a previously unknown severe and early-onset HSAN phenotype. No

mutations were found in NGFB, CCT5 and NGFR. Overall disease-associated

mutations were found in 19% of the studied patient group, suggesting that

additional genes are associated with HSAN.

Our genotype-phenotype correlation study broadens the spectrum of HSAN and

provides additional insights for molecular and clinical diagnosis.