Autosomal-dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation.

We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole-exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A > G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations.

Autonomic neuropathy in mixed cryoglobulinemia.

A retrospective, cross-sectional study was performed on a series of HCV-related mixed cryoglobulinemia (HCV-MC) patients to assess autonomic neuropathy (AN) and its relation to peripheral neuropathy (PN). Thirty consecutive patients affected by HCV-MC underwent clinical, neurological and electrodiagnostic examinations. Autonomic nervous system (ANS) involvement was assessed by functional cardiovascular tests and sympathetic skin response (SSR) evaluation. Sural nerve biopsy was performed in 10 patients with PN. All patients received steroids, 15 also received recombinant interferon-alpha2b (RIfn-alpha2b). PN occurred in 27 patients (90.0%) and AN in 4 (13.3 %) all with signs of PN. SSR was the autonomic test more frequently altered. Biopsy disclosed axonal degeneration more evident in the 4 patients with AN. Three out of 4 patients with AN received steroids and rIFN-alpha2b and 1 steroids alone. In our study on HCV-MC, it was concluded that AN can occur also without dysautonomic symptoms, SSR appears to be one of the optional tests to use together with dysautonomic tests to identify AN and finally PN and AN do not seem to be positively influenced by addition of rIFN-alpha2b to steroid treatment.

Peripheral nervous system involvement in Klippel-Trenaunay syndrome.

Klippel-Trenaunay syndrome (KTS) is a rare congenital malformation of unknown etiology characterized by cutaneous hemangiomas, venous varicosities and bony and soft tissues hypertrophy usually affecting one limb. Several complex anomalies involving various organs and systems have been described, whereas involvement of the peripheral nervous system has rarely been reported in KTS. We describe the case of a 67-year-old woman with KTS and peripheral neuropathy related to the presence of epineurial microscopic arteriovenous anastomoses (AVA) and endoneurial vascular coils in sural nerve biopsy from both hypertrophic and non-hypertrophic limb. The maintenance of AVA has been proposed to be the cause of the hypertrophy. The observation in our patient of AVA in non-hypertrophic limb contrasts with this hypothesis.

Chordomas: a histological and immunohistochemical study of cases with and without recurrent tumors.

Chordomas are rare, slow-growing and often recurrent neoplasms being composed of various cell types (physaliferous, epitheloid, chondroid), thus, showing a wide range of histological features. To study the relationship between histological and immunohistochemical pattern and biological behavior according to different cell types, the authors studied 33 specimens of 17 patients with and without recurrent tumors. Additionally, the histological features according to nuclear atypia and mitotic activity of both groups were analyzed and compared with each other. Predominance of one cell type was observed in 19 specimens (10 were composed mainly of physaliferous, 8 of the epitheloid and one of chondroid cell type). In 7 cases, areas of chondroid differentiation were present. MIB proliferation index tended not to be higher in recurrent tumors but in cases with nuclear atypia and nuclear pleomorphism seems to be predictive for recurrency. Immunohistochemically, nearly all cell types (physaliferous, epithelial-like and cells of chondroid differentiation) of both recurrent and non recurrent chordomas stained positive for epithel membrane antigen (EMA), cytokeratins (KL1, AE1/AE3), S100, vimentin and negative for HMB45 and desmin. Positive staining for NSE was observed in 70% of cases, however, the chondroid componente stained negative in every case.

[Peripheral nervous system involvement in HCV-related mixed cryoglobulinemia] / Interessamento del sistema nervoso periferico nella crioglobulinemia mista HCV-correlata.

In HCV-related mixed cryoglobulinemia (MC) a peripheral neuropathy (PN) may occur. To evaluate the prevalence and the characteristics of PN, 133 consecutive patients with HCV-MC (117 type II, 16 type III) were studied. Neurologic evaluation was performed according to the guidelines of Italian Group for the Study of Cryoglobulinemias, using a neurological disability score and a neurological symptom score. In 52/133 patients an electrophysiologic study (ENG) of ulnar, peroneal and sural nerves was performed. For 27/52 patients ENG data registered at different times (interval 12-96 months) were available. In 11 patients a sural nerve biopsy was obtained. An overt PN, mostly as sensory asymmetrical or symmetrical nerve impairment, was found in 107/133 patients (80.4%). ENG abnormalities-reduction or absence of sensory and sometimes of motor action potential, normal or slightly impaired nerve conduction velocity, consistent with axonal damage- were detected in 48/52 patients (92.3%). In 26 out of the 27 patients observed at different times an evolution of PN was found. Nerve biopsies showed a prevalent axonal damage, swollen endothelial cells in epi- and perineurial vessels and scarce mononuclear perivascular infiltrates. No leukocytoclastic vasculitis was observed. Immunoglobulins and complement in sub-perineurial vessel wall were detected. CONCLUSIONS: In HCV-MC a PN is frequent. It is mostly a sensory and progressively worsening axonopathy. Different mechanisms may be involved in the pathogenesis of this disorder and a direct role of HCV cannot be excluded.

European surveillance on Creutzfeldt-Jakob disease: a case-control study for medical risk factors.

Medical risk factors for Creutzfeldt-Jakob disease (CJD) were analyzed in a prospective ongoing case-control study based on European CJD surveillance. Detailed data on past and recent medical history were analyzed in 405 cases and controls matched by sex, age, and hospital. Data were correlated with polymorphism at codon 129 of the prion protein gene. Our analysis did not support a number of previously reported associations and failed to identify any common medical risk factor for CJD. Although not statistically significant, brain surgery was associated with an increased risk of CJD. A detailed medical history should be obtained in every suspected CJD case in order to identify iatrogenic sources of CJD.

Identification and characterization of a novel member of the dystrobrevin gene family.

A new member of the dystrobrevin gene family was identified using a bioinformatics approach. Sequence analysis indicates that this gene, named DTN-B, is highly homologous to the rabbit A0, the previously described dystrobrevin (DTN), Torpedo 87 kDa and to the C-terminus of dystrophin. The coiled-coil domain, shown to be the site of interaction between dystrobrevins and dystrophin, is highly conserved. Immunostaining studies indicate that DTN-B and DTN expression is absent in affected muscle fibers from DMD patients and carriers.

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.

Paramedian hourglass epidermoid extending above and below the tentorium.

The case of a 22-year-old woman with a large hourglass epidermoid tumor extending both below and above the tentorium is presented. The tumor was located in the suprasellar region, left middle cranial fossa, and posterior fossa on the left side. Conventional computerized tomographic (CT) scanning was inconclusive as to the actual extension of the tumor, whereas air encephalography was more helpful. The subtemporal transtentorial approach made it possible to achieve a seemingly radical excision of the tumor. Nevertheless, the CT scan one year later showed the presence of a small tumor mass. The diagnostic and surgical implications are discussed in light of few similar cases reported in the literature.