Genome-wide association study of sensory disturbances in the inferior alveolar nerve after bilateral sagittal split ramus osteotomy.

BACKGROUND: Bilateral sagittal split ramus osteotomy (BSSRO) is a common orthognatic surgical procedure. Sensory disturbances in the inferior alveolar nerve, including hypoesthesia and dysesthesia, are frequently observed after BSSRO, even without distinct nerve injury. The mechanisms that underlie individual differences in the vulnerability to sensory disturbances have not yet been elucidated. METHODS: The present study investigated the relationships between genetic polymorphisms and the vulnerability to sensory disturbances after BSSRO in a genome-wide association study (GWAS). A total of 304 and 303 patients who underwent BSSRO were included in the analyses of hypoesthesia and dysesthesia, respectively. Hypoesthesia was evaluated using the tactile test 1 week after surgery. Dysesthesia was evaluated by interview 4 weeks after surgery. Whole-genome genotyping was conducted using Illumina BeadChips including approximately 300,000 polymorphism markers. RESULTS: Hypoesthesia and dysesthesia occurred in 51 (16.8%) and 149 (49.2%) subjects, respectively. Significant associations were not observed between the clinical data (i.e., age, sex, body weight, body height, loss of blood volume, migration length of bone fragments, nerve exposure, duration of anesthesia, and duration of surgery) and the frequencies of hypoesthesia and dysesthesia. Significant associations were found between hypoesthesia and the rs502281 polymorphism (recessive model: combined χ² = 24.72, nominal P = 6.633 × 10⁻7), between hypoesthesia and the rs2063640 polymorphism (recessive model: combined χ² = 23.07, nominal P = 1.563 × 10⁻6), and between dysesthesia and the nonsynonymous rs2677879 polymorphism (trend model: combined χ² = 16.56, nominal P = 4.722 × 10⁻5; dominant model: combined χ² = 16.31, nominal P = 5.369 × 10⁻5). The rs502281 and rs2063640 polymorphisms were located in the flanking region of the ARID1B and ZPLD1 genes on chromosomes 6 and 3, whose official names are "AT rich interactive domain 1B (SWI1-like)" and "zona pellucida-like domain containing 1", respectively. The rs2677879 polymorphism is located in the METTL4 gene on chromosome 18, whose official name is "methyltransferase like 4". CONCLUSIONS: The GWAS of sensory disturbances after BSSRO revealed associations between genetic polymorphisms located in the flanking region of the ARID1B and ZPLD1 genes and hypoesthesia and between a nonsynonymous genetic polymorphism in the METTL4 gene and dysesthesia.

[Roles of TRPA1 in Painful Dysesthesia].

Dysesthesia is an unpleasant abnormal sensation, often accompanied by pain, paresthesia (abnormal sensation), and numbness (decrease or loss of sensation). Dysesthesia has been associated with various conditions, although its underlying mechanisms are largely unknown. This study assessed the roles of transient receptor potential ankyrin 1 (TRPA1) in dysesthesia by utilizing three animal models of dysesthesia characterized by reductions in blood flow to the skin: a transient hindlimb ischemia/reperfusion model, characterized by spontaneous licking and tactile hypoesthesia of the ischemic hindpaw; a streptozotocin-induced diabetic neuropathy model in mice, characterized by cold hypersensitivity, which is likely parallel to the reduced skin blood flow of the hindpaw; and a hindlimb ischemia model. TRPA1 inhibition or deficiency blocked spontaneous licking in the transient hindlimb ischemia/reperfusion model and cold hypersensitivity in the diabetic mouse model mice. Consistent with these results, the nocifensive behaviors induced by intraplantar injection of a TRPA1 agonist were enhanced in the diabetic neuropathy and hindlimb ischemia models. Hypoxia enhanced H2O2-induced TRPA1 responses in human TRPA1-expressing cells and cultured mouse dorsal root ganglion neurons, with this hypoxia-induced TRPA1 sensitization to H2O2 being associated with hypoxia-induced inhibition of the hydroxylation of prolyl hydroxylases. These results suggest that dysesthesia following blood flow reduction is caused by the activation of TRPA1 sensitized by hypoxia and that hypoxia-induced TRPA1 sensitization plays a pivotal role in painful dysesthesia induced by peripheral blood flow reduction.

Autosomal-dominant locus for Restless Legs Syndrome in French-Canadians on chromosome 16p12.1.

We describe an autosomal-dominant locus for Restless Legs Syndrome (RLS) in a French-Canadian (FC) pedigree. Genome-wide microsatellite scan and linkage analysis were used in this study. The locus maps to chromosome 16p12.1 and spans 1.18 Mega bases. The maximum multipoint LOD scores are of 3.5 over the total of 10 markers. Evidence for the same locus was also found in a smaller FC pedigree sime095. The analysis of the sequence of 8 annotated genes within the region did not reveal any pathogenic mutations. Copy number variation and karyotype analyses did not reveal any chromosomal abnormality in the region. Further analyses of the region are necessary to find the genetic cause of RLS in this family.

Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations.

Mutations in POLG gene are responsible for a wide spectrum of clinical disorders with altered mitochondrial DNA (mtDNA) integrity, including mtDNA multiple deletions and depletion. Sensory ataxic neuropathy with ophthalmoparesis (SANDO) caused by mutations in POLG gene, fulfilling the clinical triad of sensory ataxic neuropathy, dysarthria and/or dysphagia and ophthalmoparesis, has described in a few reports. Here we described five cases of adult onset autosomal recessive sensory ataxic neuropathy with ophthalmoplegia. All patients had ataxia, neuropathy, myopathy, and progressive external ophthalmoplegia (PEO). The muscle pathology revealed ragged-red and cytochrome c oxidase (COX) negative fibers in three patients. However, deficiencies in the activities of mitochondrial respiratory chain enzyme complexes were not detected in any of the patients' muscle samples. Multiple deletions of mtDNA were detected in blood and muscle specimens but mtDNA depletion was not found. Due to these diagnostic difficulties, POLG-related syndromes are definitively diagnosed based on the presence of deleterious mutations in the POLG gene.

Hereditary neuropathy with liability to pressure palsies: description of seven patients without known family history.

OBJECTIVES: Hereditary neuropathy with liability to pressure palsies (HNPP) is an inherited disorder resulting in a polyneuropathy with particular involvement at sites of entrapment, and is often underdiagnosed or misdiagnosed. We report findings on seven patients referred for evaluation of focal mononeuropathies or polyneuropathies of undetermined etiology, in whom we established a diagnosis of HNPP. MATERIALS AND METHODS: We retrospectively reviewed clinical, electrophysiological and laboratory data for patients diagnosed with HNPP over a 4-year period at our institution. RESULTS: All patients had transient or recurrent neurological symptoms, some with residual deficits. No patients had a family history of any neuropathy. Electrodiagnostic studies revealed abnormal conduction findings at symptomatic and asymptomatic sites. Testing for the Peripheral Myelin Protein (PMP22) deletion was positive in all patients. CONCLUSIONS: A high index of clinical suspicion and thorough electrodiagnostic evaluation can lead to correct diagnosis of HNPP, despite the absence of a positive family history.

Familial meralgia paresthetica with an autosomal dominant trait.

Familial occurrence of Meralgia paresthetica is uncommon. Only few familial case studies have been reported up to now. The author presents a family with Meralgia in four generations, suggesting a distinctly autosomal dominant trait.

[Early acroparesthesia in females: a sign disclosing heterozygote Fabry disease]. / Acroparesthésies féminines précoces: signe révélateur d'une maladie de Fabry à l'état hétérozygote.

Heterozygous Fabry's disease has an inconstant expression and very few complications. The theory of X-chromosome inactivation which, according to Lyon, occurs hazardly, is illustrated by the fact that the disease is expressed even in hemizygous women. Ophthalmic manifestations, as detected by the slit lamp method, are almost constant, 80 p. 100 of women with the disease having a verticillate cornea. Angiokeratoma is present in 20 p. 100 of the cases. Episodes of paraesthesia of the hands and feet are less common; in most cases they are attributed to the disease retrospectively, during family investigations. In two girls aged 10 and 11 years respectively and without history of Fabry's disease the only symptom suggestive of the diagnosis was paroxysmal acroparaesthesia. In one of the girls acroparaesthesia was associated with acrocyanosis, livedo and acro-osteolysis, but concordance was the only argument in favour of a link with Fabry's disease. Alterations of the extremities have been reported in this disease, including palmar erythema and a bluish discoloration of the palms due to dilatation of the superficial veins. Only two cases of livedo have been published. Acrosteolysis has never been documented in Fabry's disease, and its presence must be confirmed in further cases. The diagnosis of heterozygous Fabry's disease in these 2 girls was confirmed by the finding of ceramide trihexoside in urine and by leucocyte alpha-galactosidase levels that were 25 to 30 p. 100 of values obtained in controls. A study of the family of one of the girls showed that the father was involved; this hemizygous type of the disease with a 10 p. 100 alphagalactosidase level was totally asymptomatic.(ABSTRACT TRUNCATED AT 250 WORDS)

Testicular cancer survivorship: research strategies and recommendations.

Testicular cancer represents the most curable solid tumor, with a 10-year survival rate of more than 95%. Given the young average age at diagnosis, it is estimated that effective treatment approaches, in particular, platinum-based chemotherapy, have resulted in an average gain of several decades of life. This success, however, is offset by the emergence of considerable long-term morbidity, including second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems. Data on underlying genetic or molecular factors that might identify those patients at highest risk for late sequelae are sparse. Genome-wide association studies and other translational molecular approaches now provide opportunities to identify testicular cancer survivors at greatest risk for therapy-related complications to develop evidence-based long-term follow-up guidelines and interventional strategies. We review research priorities identified during an international workshop devoted to testicular cancer survivors. Recommendations include 1) institution of lifelong follow-up of testicular cancer survivors within a large cohort setting to ascertain risks of emerging toxicities and the evolution of known late sequelae, 2) development of comprehensive risk prediction models that include treatment factors and genetic modifiers of late sequelae, 3) elucidation of the effect(s) of decades-long exposure to low serum levels of platinum, 4) assessment of the overall burden of medical and psychosocial morbidity, and 5) the eventual formulation of evidence-based long-term follow-up guidelines and interventions. Just as testicular cancer once served as the paradigm of a curable malignancy, comprehensive follow-up studies of testicular cancer survivors can pioneer new methodologies in survivorship research for all adult-onset cancer.

Histochemistry of the amyloid substance from familial amyloidotic polyneuropathy.

The histochemical properties of the amyloid substance from familial amyloidotic polyneuropathy (FAP) were studied. The results showed differences among the FAP amyloid and the others amyloid substance. The main difference being that FAP amyloid substance was free of or only contain a small amount of protein. It contains acid and neutral glycidic substances, constituting its major part.

Restless legs syndrome and nocturnal myoclonus: initial clinical manifestation of familial amyloid polyneuropathy.

Restless legs syndrome was the first isolated clinical manifestation in four siblings of a family with familial amyloid polyneuropathy. Clinical and electrophysiological evidence of peripheral neuropathy appeared after a variable time interval. Polysomnography showed abnormal sleep patterns and nocturnal myoclonus in all patients. The restless legs syndrome responded favourably to clonazepam.

Studies on familial amyloid polyneuropathy in Ogawa Village, Japan.

A newly discovered large concentration of familial amyloid polyneuropathy (FAP) in Japan is clinically outlined. The importance of the urinary secretion of IgA in these cases is stressed. Dimethyl sulfoxide administration to these patients induced clinical improvements accompanied by increased excretion of low molecular weight proteins. Amino acid composition of amyloid protein of the Ogawa village-type FAP cases was similar to that of primary amyloidosis.

Current perception threshold testing in Fabry's disease.

We investigated 16 patients with Fabry's disease (eight hemizygous men and eight heterozygous women) in one family. We used constant current perception threshold (CPT) testing, which evaluated three major sensory nerve fiber populations, to assess subjective complaints of pain and paresthesias. We also examined clinical and biochemical features and compared the values of CPTs and nerve conduction studies (NCS) in detecting the sensory neuropathy. Our results showed that CPT testing at low frequencies (5 and 250 Hz) was significantly more sensitive than at a higher frequency (2 kHz) and NCS in detecting sensory neuropathy in patients with Fabry's disease. However, there was no correlation between CPT testing and clinical symptom scores, duration of disease, creatinine clearance (Ccr) values or alpha-galactosidase A (AGA) activities in either hemizygous or heterozygous patients. Hemizygous patients clinically demonstrated more severe symptom scores, poorer renal function, and higher prevalence of hypohidrosis and corpora angiokeratomas than did heterozygous patients, which indicates that detailed clinical examinations can differentiate the clinical status of hemizygous men from heterozygous women. There were no associations between the biochemical levels of serum AGA activity and renal function (Ccr values) or the symptom scores (grading of acroparesthesia), indicating that biochemical parameters do not predict clinical severity.