Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease.

Mutations in the ganglioside-induced-differentiation-associated protein 1 gene (GDAP1) can cause Charcot-Marie-Tooth (CMT) disease with demyelinating (CMT4A) or axonal forms (CMT2K and ARCMT2K). Most of these mutations present a recessive inheritance, but few autosomal dominant GDAP1 mutations have also been reported. We performed a GDAP1 gene screening in a clinically well-characterized series of 81 index cases with axonal CMT neuropathy, identifying 17 patients belonging to 4 unrelated families in whom the heterozygous p.R120W was found to be the only disease-causing mutation. The main objective was to fully characterize the neuropathy caused by this mutation. The clinical picture included a mild-moderate phenotype with onset around adolescence, but great variability. Consistently, ankle dorsiflexion and plantar flexion were impaired to a similar degree. Nerve conduction studies revealed an axonal neuropathy. Muscle magnetic resonance imaging studies demonstrated selective involvement of intrinsic foot muscles in all patients and a uniform pattern of fatty infiltration in the calf, with distal and superficial posterior predominance. Pathological abnormalities included depletion of myelinated fibers, regenerative clusters and features of axonal degeneration with mitochondrial aggregates. Our findings highlight the relevance of dominantly transmitted p.R120W GDAP1 gene mutations which can cause an axonal CMT with a wide clinical profile.

PCR assays for the early detection of BKV infection in 125 Spanish kidney transplant patients.

BK virus (BKV) reactivation arises from immunocompromised conditions and can produce a tubulointerstitial nephropathy (BKVN) in kidney transplant recipients (KTR). Approximately 5% of KTR develop BKVN, and about 45% of these lose their graft. Therefore, using molecular tools to test for BKV may be helpful in early detection. A series of 125 Spanish KTR, originating from a single transplant center, were studied in relation to BKV infection in the first post-transplant year. First, we carried out a urinary cytological study, looking for decoy cells as a possible marker of virus replication. Secondly, in all positive cytological samples and in some negative cytological samples (selected at random), we performed qualitative polymerase chain reaction (PCR) assays in serum and urine amplifying two different genome regions (LT and VP1). A transcription control region (TCR)-BK polymorphism sequence analysis was also performed in those BK PCR positive cases. Twenty-three of 125 (18.4%) KTR presented decoy cells in at least one urinary cytological sample. Molecular studies revealed that 10 of 125 (8%) KTR were BK PCR-serum positive cases (seven LT+/VP1- and three LT+/VP1+); and 13 of 40 (32.5%) KTR were BK PCR-urine positive cases (five LT+/VP1- and eight LT+/VP1+). When we compared PCR-urine and cytological results in 40 KTR, only 15% (six cases) revealed simultaneous positivity in both studies. In the context of clinical graft dysfunction, three patients demonstrated BK DNA presence in the renal biopsy. Finally, sequence analysis of the TCR was performed in 13 BK-PCR positive cases determining the AS, JL, WW, and WW-like viral variants. TCR sequence analysis, allows us to demonstrate the possible implication of the donor in BK infection studying four BK-PCR positive patients paired by donor.

Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population.

BACKGROUND: Mutations in the dysferlin (DYSF) gene cause 3 different phenotypes of muscular dystrophies: Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal anterior compartment myopathy. OBJECTIVE: To present the results of clinical and molecular analysis of 8 patients with dysferlinopathy from 5 unrelated families. DESIGN: Clinical assessment was performed with a standardized protocol. A muscle biopsy specimen was obtained and studied by immunohistochemistry. Genetic analysis was performed using single-stranded conformation polymorphism and direct sequencing of genomic DNA. RESULTS: All the patients presented the R1905X mutation in the DYSF gene in homozygosity, and the haplotype analysis at the DYSF locus revealed that it was a novel and founder mutation. A C-to-T transition at nucleotide position 6086 changes an arginine into a stop codon, leading to premature termination of translation. This mutation was expressed as 3 different clinical phenotypes (limb-girdle muscular dystrophy type 2B, Miyoshi distal myopathy, and distal anterior dysferlinopathy), but only 1 phenotype was found in the same family. CONCLUSIONS: The new R1905X DYSF founder mutation produced the 3 possible dysferlinopathy phenotypes without intrafamilial heterogeneity. This homogeneous population in Sueca, Spain, should be helpful in studying the modifying factors responsible for the phenotypic variability.

Tumor de células granulares de piel mamaria. Estudio morfológico de dos casos mostrando inmunorreactividad frente alfa-inhibina / Granular cell tumor of the mammary skin. Morphological study of two cases showing immunoreactivity against alfa-inhibin

Introducción: El tumor de células granulares (TCG) es una lesión infrecuente en la mama, representando solo el 6-8 por ciento de los TCG, comprometiendo a menudo a la piel mamaria. Pacientes y métodos: Se revisa la casuística de TCG mamarios del Hospital Universitario La Fe de Valencia en un período de 19 años, con un total de 8000 especímenes biópsicos mamarios con 2200 diagnósticos de cáncer, realizando de forma retrospectiva un estudio morfológico (óptico, inmunohistoquímico y ultraestructural) a partir de material incluido en parafina. Resultados: Se detectan dos casos de TCG con afectación de piel mamaria con distinta presentación clínica (TCG como nódulo tumoral único y TCG como lesión tumoral múltiple en relación a una cicatriz de mastectomía previa). En ambas observaciones se comprobó, junto a otros datos ya conocidos (PAS + citoplásmica granular diastasa resistente, positividad a S-100, VT, CD68 y ultraestructura con numerosos cuerpos densos lisosomiales) la presencia de una reactividad inmunohistoquímica frente a alfa-inhibina. Conclusiones: Los TCG de glándula mamaria muestran reactividad inmunohistoquímica frente a alfa-inhibina, aspecto éste que amplia la aplicabilidad de este anticuerpo, sumándose al panel existente de inmunomarcadores en el diagnóstico de los TCG (AU)

Clinical, electrophysiological and morphological findings of Charcot-Marie-Tooth neuropathy with vocal cord palsy and mutations in the GDAP1 gene.

Three Spanish families with an autosomal recessive severe hereditary motor and sensory neuropathy, showing mutations in the ganglioside-induced-differentiation-associated protein 1 (GDAP1) gene in the Charcot-Marie-Tooth (CMT) type 4A locus were studied. The disorder started in the neonatal period or early infancy with weakness and wasting of the feet and, subsequently, involvement of the hands, causing severe disability. By the late teens, some patients developed a hoarse voice and vocal cord paresis. Peripheral motor nerve conduction velocity (MNCV) could not be measured in many cases because of the absence of muscle response due to distal atrophy. However, latencies to proximal muscles were in the normal range; median MNCV was >40 m/s in those cases in which it could be measured. Sural nerve biopsy from two patients showed a pronounced depletion of myelinated fibres, regenerative clusters and signs of axonal atrophy. Additionally, a small proportion of thin myelinated fibres and proliferation of Schwann cells forming onion bulb structures were also found. Unmyelinated fibre population was markedly increased. These findings are indicative of a predominant axonal degeneration with some demyelinating features. These Spanish families share in the severe CMT clinical phenotype with some Tunisian families who also presented mutations in the GDAP1 gene and to which the CMT4A locus was originally assigned. However, our families differ in the presence of laryngeal involvement and values of MNCV and pathological features are more in line with CMT2 type. The possibility that GDAP1 gene mutations could be expressed under different phenotypes is a question to be resolved.

The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.

We identified three distinct mutations and six mutant alleles in GDAP1 in three families with axonal Charcot-Marie-Tooth (CMT) neuropathy and vocal cord paresis, which were previously linked to the CMT4A locus on chromosome 8q21.1. These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes.