WNK1/HSN2 founder mutation in patients with hereditary sensory and autonomic neuropathy: A Japanese cohort study.

The clinical and genetic spectrum of hereditary sensory and autonomic neuropathy (HSAN) is still unknown in Japan. We collected a broad cohort of 33 unrelated patients with predominant sensory and/or autonomic dysfunctions, who were referred to our genetic laboratory. A gene panel sequencing targeting 18 HSAN-related genes was performed using a next-generation sequencing system. A recurrent frame shift mutation in the WNK1/HSN2 gene, c.3237_3238insT (p.Asp1080*), was detected in 5 patients. This mutation was homozygous in 4 cases and of a compound heterozygous genotype in 1 case. Geographic and haplotype analysis of all 5 patients suggested a founder event. In addition, a novel heterozygous nonsense variant, c.2615C>G (p.Ser872*), was identified. All the 5 patients presented with severe sensory and autonomic dysfunctions at birth or during adolescence. In 2 patients, an uncommon phenotype of acute pathological pain presented at ~50 years of age. Here, we present the first founder mutation of WNK1/HSN2, in addition to French Canadian, which accounts for ~15.2% of Japanese patients with HSAN in our cohort. We have also reviewed all previously described mutations in WNK1/HSN2 and reconciled their nomenclature strategy on the basis of the current longest transcript.

Carriers of recessive WNK1/HSN2 mutations for hereditary sensory and autonomic neuropathy type 2 (HSAN2) are more sensitive to thermal stimuli.

Hereditary sensory and autonomic neuropathy type 2 (HSAN2) is a rare recessive genetic disorder characterized by severe sensory loss affecting the tactile, thermal and nociceptive modalities. Although heterozygous carriers of nonsense mutations in the HSN2 gene, called with-no-lysine(K)-1 (WNK1), do not develop the disease, historical and experimental evidence suggests that these individuals might perceive somatosensory stimuli differently from others. Using the method-of-limits, we assessed the thresholds for warmth detection, cool detection, heat pain and cold pain in 25 mutation carriers and 35 controls. In group analyses, carriers displayed significantly lower warmth (p<0.001) and cool (p<0.05) difference thresholds, and also tended to report cold pain at higher temperatures (p=0.095), than controls. Similarly, matched-pair analyses showed that carriers are significantly more sensitive to warm stimuli (p<0.01) and cold pain stimuli (p<0.05), and tend to be more sensitive to cool stimuli (p=0.11). Furthermore, the differences between the warmth detection thresholds of the carriers and those of gender- and sex-matched wild types significantly increased with age (r=0.76, p=0.02), and in carriers cool detection thresholds did not increase with age (r=0.27, p=0.24) as expected and observed in controls (r=0.34, p=0.05). This study demonstrates that the carriers of a recessive mutation for HSAN2 display greater sensitivity to innocuous thermal stimuli, as well as for cold pain, suggesting a possible environmental adaptive advantage of the heterozygous state.

Familial sensory autonomic neuropathy with arthropathy in Navajo children.

Eight Navajo children had a neuropathy characterized by Charcot's joints and unrecognized fractures. Their reflexes were intact and they had normal strength. The sensory examinations in the group were variable. Many had no discernible sensory deficit. Others had subtle deficiency in deep pain sensation, temperature discrimination, and corneal sensitivity. Electromyography and nerve conduction velocities were normal in the seven studied; however, sural nerve biopsy revealed a marked reduction in small myelinated and unmyelinated nerve fibers. This sensory neuropathy, which we call "Navajo familial neurogenic arthropathy," differs from the acromutilating sensory neuropathy previously described by Appenzeller et al in Navajo children. It also differs clinically from a number of previously reported cases of hereditary sensory autonomic neuropathies in non-Navajos. The disorder in these eight children emphasizes the usefulness of pathologic investigation of the sural nerve in patients with Charcot's joints with minimal or no other neuropathic signs.

Asian hereditary neuropathy patients with peripheral myelin protein-22 gene aneuploidy.

Japanese hereditary neuropathy with liability to pressure palsy (HNPP) patients have a deletion of one peripheral myelin protein-22 (PMP22) gene region in distal chromosome band 17p11.2 as do Caucasian patients. Japanese and Asiatic Indian CMT1A patients have a PMP22 gene duplication that results in Charcot-Marie-Tooth disease type IA (CMT1A; HMSNIA) in patients of European and Middle Eastern ancestry. About 70% of Japanese CMT1 patients have a PMP22 duplication as do Caucasians, while Japanese CMT1B, CMT2 and Dejerine-Sottas patients to not have PMP22 gene region aneuploidy. Although HNPP and CMT1A genotypes are generated simultaneously by unequal recombination that results in PMP22 gene aneuploidy in each daughter cell, only 3 Japanese HNPP probands with PMP22 deletion from a large patient population were referred to a single center compared to 18 referred CMT1A probands with PMP22 duplication. This lower HNPP frequency more likely reflects lower HNPP reproductive fitness than patient ascertainment bias because disease severity and variation in severity is about the same in CMT1A and HNPP patients and because all patients of both types were referred regardless of disease severity. These results, along with an apparently high de novo CMT1A mutation rate, suggest that common ancestors of Japanese, Asian Indians, and Caucasians carried PMP22 geneflanking sequences that enhance unequal crossing over.

Distal truncation of KCC3 in non-French Canadian HMSN/ACC families.

BACKGROUND: Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a severe and progressive autosomal recessive polyneuropathy. Mutations in the potassium-chloride cotransporter 3 gene (KCC3) were identified as responsible for HMSN/ACC in the French Canadian (FC) population. In the present study, the authors were interested in finding new mutations in non-FC populations, assessing the activity of mutant proteins and refining genotype-phenotype correlations. METHODS: The authors screened KCC3 for mutations using direct sequencing in six non-FC HMSN/ACC families. They then assessed the functionality of the most common mutant protein using a flux assay in Xenopus laevis oocytes. RESULTS: The authors identified mutations in exon 22 of KCC3: a novel mutation (del + 2994-3003; E1015X) in one family, as well as a known mutation (3031C-->T; R1011X) found in five unrelated families and associated with two different haplotypes. The function of the cotransporter was abolished, although a limited amount of mutant proteins were correctly localized at the membrane. CONCLUSIONS: KCC3 mutations in exon 22 constitute a recurrent mutation site for hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), regardless of ethnic origin, and are the most common cause of HMSN/ACC in the non-French Canadian (FC) families analyzed so far. Therefore, for genetic analysis, exon 22 screening should be prioritized in non-FC populations. Finally, the R1011X mutation leads to the abrogation of KCC3's function in Xenopus laevis oocytes, likely due to impaired transit of the cotransporter.

Familial amyloidotic polyneuropathy: description of an Italian kindred.

Familial amyloidotic polyneuropathy (FAP) is a heterogeneous group of genetic disorders characterized by progressive systemic deposition of extracellular amyloid fibrils, mainly affecting the peripheral nervous system (PNS). These disorders, inherited as an autosomal dominant trait, have frequently been described in various ethnic groups, but have rarely been reported in Italy. A 42 year-old man came to our observation for loss of pain and temperature sense in his legs. Clinical and laboratory data pointed to an amyloidotic polyneuropathy. This led us to discover a large italian kindred in which 19 members were affected by FAP. The diagnosis, established in 8 members on the clinical and laboratory findings, was ana-catamnestic in other 11. In this kindred the onset of the disease ranges from 35 to 50 years of age and the course is progressive and often fatal. The early symptoms are mainly related to autonomic disturbances and to peripheral neuropathy. Cardiac and renal involvement occurs frequently and may be life-threatening.

Molecular genetics of amyloid neuropathy in Europe.

The Portuguese type of familial amyloid polyneuropathy (FAP type I), a disabling autosomal dominant disorder with onset in early adult life, is caused by a point mutation in the transthyretin (TTR; previously known as prealbumin) gene. DNA analysis in thirteen European families (one British, two French, one Italian, one Greek, and eight Cypriot) showed that members of all those from Cyprus and Greece, and one from France, carried the FAP type I mutation. Patients from seven of these ten kindreds were not known to have a genetic disease before this study, which demonstrated the mutation in 16 of 43 clinically unaffected relatives. 2 of these were aged over 50 years. TTR gene analysis has useful applications in genetic counselling, including prenatal diagnosis, in identifying the cause of seemingly sporadic cases of amyloid neuropathy, and in epidemiological studies of FAP.

Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1.

The hereditary ataxias represent a clinically and genetically heterogeneous group of neurodegenerative disorders. Various classification schemes based on clinical criteria are being replaced as molecular characterization of the ataxias proceeds; so far, seven distinct autosomal dominant hereditary ataxias have been genetically mapped in the human genome. We report linkage to chromosome 16q22.1 for one of these genes (SCA4) in a five-generation family with an autosomal dominant, late-onset spinocerebellar ataxia; the gene is tightly linked to the microsatellite marker D16S397 (LOD score = 5.93 at theta = .00). In addition, we present clinical and electrophysiological data regarding the distinct and previously unreported phenotype consisting of ataxia with the invariant presence of a prominent axonal sensory neuropathy.