RESUMO
BACKGROUND: Neuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of SCN9A, SCN10A and SCN11A variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening. METHODS: Between September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for SCN9A, SCN10A and SCN11A variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared. RESULTS: Among 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for SCN9A, 3.7% (n=42/1139) for SCN10A and 2.9% (n=33/1139) for SCN11A. Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants. CONCLUSION: (Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of SCN9A, SCN10A and SCN11A should be considered in patients with pure SFN, independently of clinical features or underlying conditions.
Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7/genética , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Neuropatia de Pequenas Fibras/genética , Idoso , Feminino , Testes Genéticos , Variação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.9/genética , Valor Preditivo dos Testes , Estudos Retrospectivos , Neuropatia de Pequenas Fibras/complicações , Neuropatia de Pequenas Fibras/diagnósticoRESUMO
INTRODUCTION: Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour-bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle-specific alterations associated with human lung cancer cachexia. METHODS: Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour-bearing group. Syngeneic lung epithelium-derived adenocarcinoma cells (K-rasG12D ; p53R172HΔG ) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis. RESULTS: Two-third of the tumour-bearing mice developed cachexia based on predefined criteria. Final body weight (-13.7 ± 5.7%; P < 0.01), muscle mass (-13.8 ± 8.1%; P < 0.01) and muscle strength (-25.5 ± 10.5%; P < 0.001) were reduced in cachectic mice compared with sham controls and median survival time post-surgery was 33.5 days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (Fbxo32 and Trim63) and autophagy-lysosomal pathway (Gabarapl1 and Bnip3), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E-BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin-2 (P < 0.001) and CXCL1/KC (P < 0.01) expression levels in blood plasma and increased mRNA expression of IκBα (P < 0.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal muscle strongly mirrored alterations observed in muscle biopsies of patients with lung cancer cachexia. CONCLUSIONS: We developed an orthotopic model of lung cancer cachexia in immune competent mice. Because this model simulates key aspects specific to cachexia in lung cancer patients, it is highly suitable to further investigate the underlying mechanisms of lung cancer cachexia and to test the efficacy of novel intervention strategies.
Assuntos
Caquexia , Neoplasias Pulmonares , Animais , Masculino , Camundongos , Biomarcadores/metabolismo , Caquexia/metabolismo , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Força Muscular , Músculo Esquelético/patologia , Atrofia Muscular/metabolismoRESUMO
Loss-of-function mutations of GLI2 are associated with features at the mild end of the holoprosencephaly spectrum, including abnormal pituitary gland formation and/or function, and craniofacial abnormalities. In addition patients may have branchial arch anomalies and polydactyly. Large, microscopically visible, interstitial deletions spanning 2q14.2 have been reported in patients with multiple congenital anomalies and intellectual disability. We report here on a patient with a mild holoprosencephaly spectrum phenotype (bilateral cleft lip and palate and abnormal pituitary gland formation with panhypopituitarism) and normal psychomotor development, who was found to carry a 1.3 Mb submicroscopic heterozygous deletion in 2q14.2, encompassing the GLI2 gene. We review the genotype and phenotype of previously published probands with GLI2 aberrations. Our findings confirm the association of haploinsufficiency of GLI2 and mild HPE spectrum features. Consistent with prior reports, we observed incomplete penetrance of the deletion in the family, illustrating the multifactorial etiology of holoprosencephaly spectrum features. In addition to the holoprosencephaly spectrum features, the proband had heterotaxy of the abdominal organs. Mutations in the known heterotaxy genes (NODAL, ZIC3 and CFC1) were excluded. The deletion contains five genes, in addition to GLI2, including the EPB4.1l5 gene. Based on findings in Epb4.1l5 mutant mice we hypothesize that Epb4.1l5 is a candidate gene for the heterotaxy observed in the proband.
Assuntos
Deleção Cromossômica , Deleção de Genes , Síndrome de Heterotaxia/genética , Holoprosencefalia/genética , Fatores de Transcrição Kruppel-Like/genética , Proteínas Nucleares/genética , Criança , Cromossomos Humanos Par 2/genética , Variações do Número de Cópias de DNA , Feminino , Triagem de Portadores Genéticos , Haploinsuficiência , Humanos , Hipopituitarismo/genética , Lactente , Imageamento por Ressonância Magnética , Análise em Microsséries , Mutação , Linhagem , Fenótipo , Proteína Gli2 com Dedos de ZincoRESUMO
OBJECTIVE: Screening for Fabry disease in patients with small fiber neuropathy has been suggested, especially since Fabry disease is potentially treatable. However, the diagnostic yield of testing for Fabry disease in isolated small fiber neuropathy patients has never been systematically investigated. Our aim is to determine the presence of Fabry disease in patients with small fiber neuropathy. METHODS: Patients referred to our institute, who met the criteria for isolated small fiber neuropathy were tested for Fabry disease by measurement of alpha-Galactosidase A activity in blood, lysosomal globotriaosylsphingosine in urine and analysis on possible GLA gene mutations. RESULTS: 725 patients diagnosed with small fiber neuropathy were screened for Fabry disease. No skin abnormalities were seen except for redness of the hands or feet in 30.9% of the patients. Alfa-Galactosidase A activity was tested in all 725 patients and showed diminished activity in eight patients. Lysosomal globotriaosylsphingosine was examined in 509 patients and was normal in all tested individuals. Screening of GLA for mutations was performed for 440 patients, including those with diminished α-Galactosidase A activity. Thirteen patients showed a GLA gene variant. One likely pathogenic variant was found in a female patient. The diagnosis Fabry disease could not be confirmed over time in this patient. Eventually none of the patients were diagnosed with Fabry disease. CONCLUSIONS: In patients with isolated small fiber neuropathy, and no other signs compatible with Fabry disease, the diagnostic yield of testing for Fabry disease is extremely low. Testing for Fabry disease should be considered only in cases with additional characteristics, such as childhood onset, cardiovascular disease, renal failure, or typical skin lesions.