PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia.

The glycophosphatidylinositol (GPI) anchor pathway plays an essential role in posttranslational modification of proteins to facilitate proper membrane anchoring and trafficking to lipid rafts, which is critical for many cell functions, including embryogenesis and neurogenesis. GPI biosynthesis is a multi-step process requiring the activity of over 25 distinct genes, most of them belonging to the phosphatidylinositol glycan (PIG) family and associated with rare neurodevelopmental disorders. PIGQ encodes the phosphatidylinositol glycan class Q protein and is part of the GPI-N-acetylglucosaminyltransferase complex that initiates GPI biosynthesis from phosphatidylinositol (PI) and N-acetylglucosamine (GlcNAc) on the cytoplasmic side of the endoplasmic reticulum (ER). Pathogenic variants in the PIGQ gene have been previously reported in 10 patients with congenital hypotonia, early-infantile epileptic encephalopathy, and premature death occurring in more than half cases. We detected a novel homozygous variant in PIGQ (NM_004204.5: c.1631dupA; p.Tyr544fs*79) by WES trio-analysis of a male patient with a neurodevelopmental disorder characterized by nonprogressive congenital ataxia, intellectual disability, generalized epilepsy, and cerebellar atrophy. Flow cytometry confirmed deficiency of several GPI-anchored proteins on leukocytes (CD14, FLAER). Clinical features of this case broaden the phenotypic spectrum of PIGQ-related GPI deficiency, outlining the importance of glycophosphatidylinositol (GPI) anchor pathway in the pathogenesis of cerebellar ataxia.

A clinical diagnostic algorithm for early onset cerebellar ataxia.

Early onset cerebellar Ataxia (EOAc) comprises a large group of rare heterogeneous disorders. Determination of the underlying etiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This may change the diagnostic work-up into a time-consuming, costly and not always rewarding task. In this overview, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society (CACG-EPNS) presents a diagnostic algorithm for EOAc patients. In seven consecutive steps, the algorithm leads the clinician through the diagnostic process, including EOA identification, application of the Inventory of Non-Ataxic Signs (INAS), consideration of the family history, neuro-imaging, laboratory investigations, genetic testing by array CGH and Next Generation Sequencing (NGS). In children with EOAc, this algorithm is intended to contribute to the diagnostic process and to allow uniform data entry in EOAc databases.

Mutations in the IRBIT domain of ITPR1 are a frequent cause of autosomal dominant nonprogressive congenital ataxia.

Congenital ataxias are nonprogressive neurological disorders characterized by neonatal hypotonia, developmental delay and ataxia, variably associated with intellectual disability and other neurological or extraneurological features. We performed trio-based whole-exome sequencing of 12 families with congenital cerebellar and/or vermis atrophy in parallel with targeted next-generation sequencing of known ataxia genes (CACNA1A, ITPR1, KCNC3, ATP2B3 and GRM1) in 12 additional patients with a similar phenotype. Novel pathological mutations of ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) were found in seven patients from four families (4/24, ∼16.8%) all localized in the IRBIT (inositol triphosphate receptor binding protein) domain which plays an essential role in the regulation of neuronal plasticity and development. Our study expands the mutational spectrum of ITPR1-related congenital ataxia and indicates that ITPR1 gene screening should be implemented in this subgroup of ataxias.

The SNPs in the human genetic blueprint era.

The analysis of human genetic variability can lead to the comprehension of medical issues and to the development of personalized therapeutic protocols. Single nucleotide polymorphisms, are the most common type of human genetic variation and have been associated to disease development and phenotype forecasting. The recent technologies for DNA sequencing and bioinformatic analysis are now giving the opportunity to develop new diagnostic and prevention approaches also through health promotion protocols. The genetic data management is at the same time underlining technical limitations and old ethical issues.

Systematic extended and saturation prostate biopsy: when and how.

The increasing incidence of prostate cancer is manly due to the improvement of systematic transrectal ultrasound-guided prostate biopsy techniques. The objective of this review is to analyze the different approaches and the most common schemes used to perform prostate biopsy, the role of the anesthetic procedures, of the complementary imaging methods and the histological evaluation of the biopsy results. The actual indications to perform prostate biopsy have been also critically reviewed. We performed a review of the literature by searching Medline Database with the following key words: prostate cancer, diagnosis, trans-rectal ultrasound (TRUS), prostate biopsy, anaesthesia and prognosis. Prostate biopsy is always performed under transrectal ultrasound guidance with both transrectal and transperineal approach, with a minimal core number of 10. The extended protocols include lateral peripheral zone cores and cores from lesions found on palpation or imaging. Saturation biopsies should be performed only in case of repeat biopsies. The refinement of effective local anesthesia has allowed to increase the number of biopsies without important side effects. Complementary imaging methods might be adopted in order to reduce the number of unnecessary procedures .The histological issues related to the number and the location of cores are still matter of debate as important prognostic factors. According to international guidelines, the factors most involved in performing prostate biopsy still include suspicious digital rectal examination and PSA. Both the transrectal and the transperineal approach in prostatic biopsy are valid in term of detection rate and low incidence of side effects. The initial biopsy scheme in mainly extended, saturation biopsy has to be considered only in the repeat setting, with the eventual help of the complementary imaging methods. The histological issues has to be considered about patient's prognosis.

Prophylaxis of erectile function after radical prostatectomy with phosphodiesterase type 5 inhibitors.

Erectile dysfunction (ED) is one of the most challenging complications associated with radical prostatectomy (RP) for clinically localized prostate cancer. Currently, a broad spectrum of therapeutic options are available to improve sexual health after surgical treatment. Several basic science reports highlighted a potential role for phosphodiesterase type 5 inhibitors in the prevention of endothelial damage related to ischemia reperfusion and/or denervation following surgery. Recent studies have shown that pharmacological prophylaxis soon after RP can significantly improve the rate at which erectile function is recovered after surgery. Use of on-demand treatments for ED in patients who have undergone RP has been shown to be highly effective. In this context, pharmacological prophylaxis potentially may have a significantly expanded role in future strategies aimed at preserving postoperative erectile function. We analyzed the factors affecting erectile function after RP and evaluated the evidence suggesting the role of pharmacological prophylaxis and treatment of ED after surgery.

Mutations in the AP1S2 gene encoding the sigma 2 subunit of the adaptor protein 1 complex are associated with syndromic X-linked mental retardation with hydrocephalus and calcifications in basal ganglia.

Fried syndrome, first described in 1972, is a rare X-linked mental retardation that has been mapped by linkage to Xp22. Clinical characteristics include mental retardation, mild facial dysmorphism, calcifications of basal ganglia and hydrocephalus. A large four-generation family in which the affected males have striking clinical features of Fried syndrome were investigated for linkage to X-chromosome markers; the results showed that the gene for this condition lies within the interval DXS7109-DXS7593 in Xp22.2. In total, 60 candidate genes located in this region, including AP1S2, which was recently shown to be involved in mental retardation, were screened for mutations. A mutation in the third intron of AP1S2 was found in all affected male subjects in this large French family. The mutation resulted in skipping of exon 3, predicting a protein with three novel amino-acids and with termination at codon 64. In addition, the first known large Scottish family affected by Fried syndrome was reinvestigated, and a new nonsense mutation, p.Gln66X, was found in exon 3. Using CT, both affected patients from the French family who were analysed had marked calcifications of the basal ganglia, as previously observed in the first Scottish family, suggesting that the presence of distinctive basal ganglia calcification is an essential parameter to recognise this syndromic disorder. It may be possible to use this feature to identify families with X-linked mental retardation that should be screened for mutations in AP1S2.

Bilateral renal mass suggestive of cancer.

We present the case of a 44-year old man, presenting with acute left flank pain and gross haematuria, affected by bilateral renal mass and massive para-aortic and mediastinic lymphadenopathy, highly suspicious for metastatic renal cancer.

Oligophrenin 1 mutations frequently cause X-linked mental retardation with cerebellar hypoplasia.

BACKGROUND: Mutations of oligophrenin 1, one of the first genes identified in nonspecific X-linked mental retardation (MRX), have been described in patients with moderate to severe cognitive impairment and predominant cerebellar hypoplasia, in the vermis. OBJECTIVE: To further delineate the phenotypic and mutational spectrum of the syndrome, by screening oligophrenin 1 in two cohorts of male patients with mental retardation (MR) with or without known posterior fossa anomalies. METHODS: Clinical examination, cognitive testing, MRI studies, and mutational analysis (denaturing gradient gel electrophoresis and direct sequencing) on blood lymphocytes were performed in 213 unrelated affected individuals: 196 patients classified as MRX and 17 patients with MR and previously detected cerebellar anomalies. RESULTS: Four novel oligophrenin 1 mutations were identified. In the MRX group, two nonsense mutations were detected. In the MR group, two mutations were found: a deletion of exons 16 to 17 and a splice site mutation. All patients shared characteristic clinical, radiologic, and distinctive features with a degree of intrafamilial variability in motor and cognitive deficits. CONCLUSIONS: Oligophrenin 1 mutations were found in 12% (2/17) of individuals with mental retardatin and known cerebellar anomalies and in 1% (2/196) of the X-linked mental retardation group.

The ageing male and erectile dysfunction.

Erectile dysfunction is common in the ageing man and reliable therapies are needed. The pathophysiology of erectile dysfunction in this group mainly includes chronic ischaemia, which triggers the deterioration of cavernosal smooth muscle and the development of corporeal fibrosis. Assessing the ageing man with erectile dysfunction who seeks medical treatment should comprise a thorough medical and sexual history, a systemic and focused physical examination and selected blood tests. Oral drug therapy represents a safe and effective option for most ageing men.

X-linked congenital ataxia: a clinical and genetic study.

We report on a family in which two males are affected with X-linked congenital ataxia (XCA). Clinical manifestations include severe hypotonia at birth, delay of early motor development, slow eye movements, and nonprogressive cerebellar ataxia. The neurological examination excluded a neuromuscular disease, mental retardation, and pyramidal tract involvement. Neuroimaging showed global cerebellar atrophy in both patients that was not evident in the first years of life. The clinical findings in this family are very similar to those in a Russian pedigree [Illarioskin et al., 1996: Ann Neurol 40:75-83] and outline a recognizable phenotype. Linkage studies in our family, using 28 highly polymorphic Généthon microsatellite markers evenly distributed along the X chromosome, excluded a 24 cM interval between DXS990 and DXS424 located within the previous candidate region of 54 cM, reducing the critical interval.

Clinical and molecular aspects of the Simpson-Golabi-Behmel syndrome.

The Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth/multiple congenital anomalies/dysplasia syndrome caused by a mutant X-linked gene. The spectrum of its clinical manifestations is broad, varying from very mild forms in carrier females to infantile lethal forms in affected males. A typically affected male will show tall stature, "coarse" face, supernumerary nipples, congenital heart defect, and generalized muscular hypotonia. Mental development is normal in most cases. There is an increased risk of neoplasia in infancy, especially Wilms tumor. The SGBS gene spans 500 kilobases in the Xq26 region and contains eight exons. It encodes an extracellular proteoglycan, designated glypican 3 (GPC3), capable of interacting with the insulin-like growth factor IGF2. At present, only deletions of various sizes have been found in a number of affected families.

HCV and monoclonal gammopathies.

OBJECTIVE: To determine the prevalence of antibodies against HCV in monoclonal gammopathies with and without cryoglobulinemic activity. METHODS: 201 patients were divided into two groups: (I) 94 patients with monoclonal gammopathies with cryoglobulinemic activity, and (II) 107 with monoclonal gammopathies without cryoglobulinemic activity. Cryoglobulins were characterized by immunofixation; HCVAb were detected using second-generation ELISA and RIBA methods; in 38 cases the presence of HCV in peripheral blood mononuclear cells was evaluated by PCR. RESULTS: The HCVAb prevalence, as evaluated by RIBA, in Group I was 69.1% while in Group II it was only 14.9%. Histological and immunohistochemical study of the bone marrow in Group I patients frequently showed signs of nodular B-cell clonal expansion. CONCLUSIONS: Our data confirm the existence of a close correlation between HCV infection and the monoclonal gammopathies with cryoglobulinemic activity. HCV-positive cryoglobulinemic is characterized by self-limiting IgM monoclonal expansion associated with histological aspects of bone marrow lymphoid nodules that do not expand in the course of the disease like classic evolving lymphoproliferative processes.

Cryoglobulinemia in HCVAb+ patients on chronic hemodialysis.

OBJECTIVE: Striking evidence of HCV infection has been found in mixed cryoglobulinemia (MC) and HCV has been hypothesized to be the causative agent of this disease. To assess the association of C virus infection and cryoglobulinemia we studied cryoglobulin levels in 66 patients on maintenance hemodyalisis who were selected on the basis of HCVAb positivity and not because they were affected by liver disease. The control group was made up of 45 patients also on hemodyalisis but without HCV infection. RESULTS: Circulating cryoglobulins were found in 34 (52%) of 66 HCV+ patients: the cryocrit was < 1% in 20, 1 to 5% in 12, and > 5% in 2 patients. The cryoglobulins were classified by immunofixation as type II in 8 and type III in 8 others; identification was not possible in 18 cases. In the HCVAb- control group untypable cryoglobulins were detected in 9% of the patients at < 1% by volume. No correlation was found between these data and the liver disease detected by biohumoral tests. CONCLUSIONS: Our data confirm the close link between HCV infection and cryoglobulins; the prevalence of circulating cryoglobulins in uremic HCVAb+ patients is very close to that found in HCV-related liver disease.