RESUMEN
Two distinct genomic disorders have been linked to Xq28-gains, namely Xq28-duplications including MECP2 and Int22h1/Int22h2-mediated duplications involving RAB39B. Here, we describe six unrelated patients, five males and one female, with Xq28-gains distal to MECP2 and proximal to the Int22h1/Int22h2 low copy repeats. Comparison with patients carrying overlapping duplications in the literature defined the MidXq28-duplication syndrome featuring intellectual disability, language impairment, structural brain malformations, microcephaly, seizures and minor craniofacial features. The duplications overlapped for 108 kb including FLNA, RPL10 and GDI1 genes, highly expressed in brain and candidates for the neurologic phenotype.
Asunto(s)
Duplicación Cromosómica , Cromosomas Humanos X , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteína 2 de Unión a Metil-CpG/genética , Proteínas de Unión al GTP rab/genética , Adolescente , Adulto , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Niño , Facies , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética , Masculino , Linaje , Fenotipo , Adulto JovenRESUMEN
X-linked Charcot-Marie-Tooth disease (CMT Type X1, OMIM: 302800) represents a frequent cause of hereditary peripheral motor and sensory neuropathies and is associated with mutations in GJB1 encoding the gap junction beta 1 protein connexin 32 (Cx32). Studying an Argentinean family of Italian origin with seven affected males in three generations exhibiting clinical signs of CMT, eight obligate female carriers were identified genealogically. DNA sequencing of exon 2 and adjacent regions of the GJB1 gene in two symptomatic males whose respective maternal grandfathers, both affected, were brothers, revealed mutations in GJB1/Cx32. Surprisingly, each of the two affected patients had a different mutation in hemizygous state at the same nucleotide position: c.383C>T (p.S128L) and c.383C>A (p.S128X). In both cases, the identified mutation was present in heterozygous state in the corresponding maternal genomic DNA. Furthermore, X-chromosomal microsatellite analysis showed identical marker alleles in both patients. Together with the genealogical information, these molecular data imply that a primarily mutated allele mutated for a second time. In conclusion, two different mutations at the same nucleotide position in this Argentinean family represent a finding with a very low probability of occurrence.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Conexinas/genética , Alelos , Argentina , Enfermedad de Charcot-Marie-Tooth/etnología , Femenino , Haplotipos , Humanos , Masculino , Repeticiones de Microsatélite , Mutación , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , Proteína beta1 de Unión ComunicanteRESUMEN
BACKGROUND: The serotonin receptor 2A (HTR2A) has been described as an important facilitation mediator of spinal nociceptive processing leading to central sensitization (CS) in animal models of chronic pain. However, whether HTR2A single nucleotide variants (SNVs) modulate neuropathic pain states in patients has not been investigated so far. The aim of this study was to elucidate the potential association of HTR2A variants with sensory abnormalities or ongoing pain in neuropathic pain patients. METHODS: At total of 240 neuropathic pain patients and 253 healthy volunteers were included. Patients were phenotypically characterized using standardized quantitative sensory testing (QST). Patients and controls were genotyped for HTR2A g.-1438G > A (rs6311) and c.102C > T (rs6313). Genotype-related differences in QST parameters were assessed considering QST profile clusters, principal somatosensory components and sex. RESULTS: There was an equal distribution of rs6313 and linked rs6311 between patients and controls. However, the rs6313 variant was significantly associated with a principal component of pinprick hyperalgesia and dynamic mechanical allodynia, indicating enhanced CS in patients with sensory loss (-0.34 ± 0.15 vs. +0.31 ± 0.11 vs., p < .001). In this cluster, the variant allele was also associated with single QST parameters of pinprick hyperalgesia (MPT, +0.64 ± 0.18 vs. -0.34 ± 0.23 p = .002; MPS, +0.66 ± 0.17 vs. -0.09 ± 0.23, p = .009) and ongoing pain was increased by 30%. CONCLUSIONS: The specific association of the rs6313 variant with pinprick hyperalgesia and increased levels of ongoing pain suggests that the HTR2A receptor might be an important modulator in the development of CS in neuropathic pain. SIGNIFICANCE: This article presents new insights into serotonin receptor 2A-mediating mechanisms of central sensitization in neuropathic pain patients. The rs6313 variant allele was associated with increased mechanical pinprick sensitivity and increased levels of ongoing pain supporting a contribution of central sensitization in the genesis of ongoing pain providing a possible route for mechanism-based therapies.
Asunto(s)
Dolor Crónico , Neuralgia , Animales , Sensibilización del Sistema Nervioso Central , Humanos , Hiperalgesia/genética , Neuralgia/genética , Receptor de Serotonina 5-HT2A/genéticaRESUMEN
Hereditary motor-sensory neuropathy (HMSN) Type 1/CMT 1 is a disorder of the peripheral nervous system. The underlying genetic cause is heterogeneous, and mutations in LITAF (Lipopolysaccharide-induced TNF-alpha factor) represent a rare cause of CMT Type 1. In this report, a novel missense mutation is presented in the LITAF gene (c.430G>A p.V144M) in a German CMT family exhibiting typical electrophysiological features of a demyelinating neuropathy with conduction blocks and variable age at onset. Molecular genetic characterization of demyelinating HMSN should therefore include screening of the LITAF gene if typical signs of a non-homogenous demyelinating neuropathy combined with dominant familial occurrence are evident.