A novel NGFB point mutation: a phenotype study of heterozygous patients

Minde, Jan; Andersson, T.; Fulford, Martha; Aguirre, M. Carmen Fernández; Nennesmo, Inger; Remahl, Ingela Nilsson; Svensson, Olle; Holmberg, Monica; Toolanen, Göran; Solders, Göran

doi:10.1136/jnnp.2007.136051

Cited by 41 publications

(44 citation statements)

References 24 publications

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“…So far, only one homozygous missense mutation has been reported, in a recessive Swedish family (Einarsdottir et al ., 2004; Minde et al ., 2004). Detailed clinical, neurophysiological and genetic analysis of this family revealed that the heterozygous carriers presented with a variable but mild phenotype (Minde et al ., 2009). The main difference with CIPA was the absence of obvious mental retardation and less-pronounced anhidrosis.…”

Section: Discussionmentioning

confidence: 99%

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

Rotthier

Baets

Vriendt

et al. 2009

Brain

145

137

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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.

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Section: Discussionmentioning

confidence: 99%

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

Rotthier

Baets

Vriendt

et al. 2009

Brain

145

137

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“…Although not suffering from painless fractures, they can manifest Charcot arthropathies at single or multiple joints, particularly in the lower extremities. Cognitive functions and basic reflexes are normal in carriers (Einarsdottir et al 2004;Minde et al 2004Minde et al , 2006Minde et al , 2009. A list of the most relevant clinical features of R221W carriers is provided in Table 1.…”

Section: Methodsmentioning

confidence: 99%

“…This noninvasive method has been applied to quantify C-fiber loss in neuropathy secondary to diabetes and other etiologies (Einarsdottir et al 2004;Minde et al 2004Minde et al , 2006Minde et al , 2009Quattrini et al 2007;Tavakoli et al 2009Tavakoli et al , 2010Tavakoli et al , 2012. To further investigate the contribution of C-fiber density to clinical pain assessment scores and subjective pain evaluation, we also administered the Neuropathy Disability Score (NDS; Young et al 1993) and the Situational Pain Questionnaire (SPQ; Clark and Yang 1983).…”

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confidence: 99%

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Rare human nerve growth factor-β mutation reveals relationship between C-afferent density and acute pain evaluation

Perini

Tavakoli

Marshall

et al. 2016

Journal of Neurophysiology

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Perini I, Tavakoli M, Marshall A, Minde J, Morrison I. Rare human nerve growth factor-␤ mutation reveals relationship between C-afferent density and acute pain evaluation. J Neurophysiol 16: 425-430, 2016. First published May 4, 2016 doi:10.1152/jn.00667.2015The rare nerve growth factor-␤ (NGFB) mutation R221W causes a selective loss of thinly myelinated fibers and especially unmyelinated C-fibers. Carriers of this mutation show altered pain sensation. A subset presents with arthropathic symptoms, with the homozygous most severely affected. The aim of the present study was to investigate the relationship between peripheral afferent loss and pain evaluation by performing a quantification of small-fiber density in the cornea of the carriers, relating density to pain evaluation measures. In vivo corneal confocal microscopy (CCM) was used to quantify C-fiber loss in the cornea of 19 R221W mutation carriers (3 homozygous) and 19 age-matched healthy control subjects. Pain evaluation data via the Situational Pain Questionnaire (SPQ) and the severity of neuropathy based on the Neuropathy Disability Score (NDS) were assessed. Homozygotes, heterozygotes, and control groups differed significantly in corneal C-nerve fiber density, with the homozygotes showing a significant afferent reduction. Importantly, peripheral C-fiber loss correlated negatively with pain evaluation, as revealed by SPQ scores. This study is the first to investigate the contribution of small-fiber density to the perceptual evaluation of pain. It demonstrates that the lower the peripheral small-fiber density, the lower the degree of reported pain intensity, indicating a functional relationship between small-fiber density and higher level pain experience.nerve growth factor-␤ gene mutation; corneal confocal microscopy; pain evaluation; Situational Pain Questionnaire; C-fiber NEW & NOTEWORTHY

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“…To date only one NGFB point mutation has been described in a family with HSAN V (p.Arg221Trp) [4, 16], one family with HSAN IV was reported with a homozygous frameshift mutation due to a point mutation and two base pair deletion on the same allele (p.Val232fs) [1] and one patient with a sensory and autonomic neuropathy has been described with heterozygous deletion of 12 genes one of which was NGFB [5]. Although HSAN V is usually recessive, there is a suggestion that heterozygotes have a higher incidence of Charcot joints and neuropathy, as reported in a large family with p.Arg221Trp [15]. Our patient with a heterozygous duplication (p.Gly161_Glu162dup) has a similar phenotype; however, it is currently not possible to confirm whether this variant is pathogenic.…”

Section: Discussionmentioning

confidence: 99%

Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort

et al. 2012

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The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.

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A novel NGFB point mutation: a phenotype study of heterozygous patients

Cited by 41 publications

References 24 publications

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

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

Rare human nerve growth factor-β mutation reveals relationship between C-afferent density and acute pain evaluation

Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort

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