Environmental influences on familial discordance of phenotype in people with homocystinuria: a case report

<p>Abstract</p> <p>Introduction</p> <p>Non-heritable factors may have an influence on the clinical expression of monogenic inherited metabolic diseases.</p> <p>Case presentation</p> <p>This is a case report of a man whose mother had been diagnosed late in childhood with pyridoxine responsive homocystinuria with lens dislocation and neurodevelopmental delay. These severe complications were not observed in her son who was pyridoxine unresponsive but who had been treated appropriately since early infancy.</p> <p>Conclusion</p> <p>The phenotype of people with homocystinuria can be discordant within a family, with variability in metabolic and clinical expression depending upon both the genotype and therapeutic interventions. Offspring of people with homocystinuria should be screened in early infancy and, if positive, treated appropriately whether they have pyridoxine responsive or unresponsive disease.</p

Newborn Screening for Homocystinuria Revealed a High Frequency of MAT I/III Deficiency in Iberian Peninsula

Acessível em: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375120/Homocystinuria due to cystathionine β-synthase deficiency or "classical homocystinuria" is a rare autosomal recessive condition resulting in altered sulfur metabolism with elevated methionine and homocysteine in plasma and homocystine in urine. This condition is characterized by a high clinical heterogeneity, which contributes to late clinical diagnosis, usually only made after irreversible damage has occurred. Treatment is effective if started before clinical symptoms. The analysis of methionine levels by tandem mass spectrometry (MS/MS) allows the newborn screening for homocystinuria, but false-positive results can be frequently obtained and lead to the unwanted identification of methionine adenosyl transferase (MAT I/III) deficiency. This latter condition is biochemically characterized by isolated persistent hypermethioninemia, accompanied in some individuals with slightly elevated levels of homocysteine in plasma. A dominant form of MAT I/III deficiency, associated with mutation p.R264H, seems to be very frequent in the Iberian Peninsula and usually has a clinically benign course. Both these metabolic disorders are screened in Galicia and Portugal since the introduction of the MS/MS technology, in 2000 and 2004, respectively, resulting in the identification of three patients with classical homocystinuria and 44 patients with MAT I/III deficiency. All but one heterozygous parent of MAT I/III patients, identified with the p.R264H mutation, are healthy adults around the age of 30/40. The implementation of a second-tier test for homocysteine in dried blood spots would considerably reduce the number of MAT I/III-deficient patients identified and improve the specificity and positive predictive value for classical homocystinuria screening

Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI-GOIM): A randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX

Background: Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. Patients and methods: We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progressionfree survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. Results: Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056]. Conclusions: Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials

PTPN22 R620W polymorphism in the ANCA-associated vasculitides

Objectives. PTPN22 is involved in T-cell activation and its R620W single-nucleotide polymorphism ( SNP) has been shown to predispose to different autoimmune diseases. The aims of this study were to investigate the role of the PTPN22 R620W SNP in conferring susceptibility to the ANCA-associated vasculitides (AAVs), and to explore potential associations between the PTPN22 genotype and the disease manifestations. Methods. PTPN22 R620W SNP was genotyped in a cohort of 344 AAV patients [143 with granulomatosis with polyangiitis (Wegener's) (GPA), 102 with microscopic polyangiitis (MPA) and 99 with Churg-Strauss syndrome (CSS)] and in 945 healthy controls. Results. The frequency of the minor allele (620W) was significantly higher in GPA patients than in controls [P = 0.005, chi(2) = 7.858, odds ratio (OR) = 1.91], while no statistically significant association was found with MPA or CSS. Among GPA patients, the 620W allele was particularly enriched in ANCA-positive patients as compared with controls (P = 0.00012, chi(2) = 14.73, OR = 2.31); a particularly marked association was also found with ENT involvement (P = 0.0071, chi(2) = 7.258, OR = 1.98), lung involvement (P = 0.0060, chi(2) = 7.541, OR = 2.07) and skin manifestations of all kinds (P = 0.000047, chi(2) = 16.567, OR = 3.73). Conclusion. The PTPN22 620W allele confers susceptibility to the development of GPA (but not of MPA or CSS), and particularly of its ANCA-positive subset

What to Say and What to Omit? Strategies and Self-Narratives for Obtaining a Diagnosis in Gender Transition

In gender transition, psychological and diagnostic assessment is essential for accessing medical treatment and gaining legal recognition. This puts the psychologist in the role of gatekeeper and places the diagnosis at the center of the clinical relationship, despite recent guidelines' depathologizing orientation. This study investigates how trans people approach and prepare for psychological interviews, what they report and what they tend to conceal to optimize the chances of being diagnosed as Gender Dysphoric. Thematic analysis of transcripts of two focus groups involving 13 people brought to light several narrative strategies aimed at assuring the saturation of the clinical criteria needed for the release of the diagnosis, among them the (more or less intentionally) forced adherence to gender binarism in the definition of Self and attempts to hide or affirm aspects of themselves in the clinical encounter. The perception of vexatiousness and imbalance of power in the relationship also emerged as a prominent theme. Between the many implications, the most important relates to the risk that the psychological pathway can be exploited to obtain the diagnosis and, once set up like this, it may lose other functions and meanings. The study can contribute to directing professional practice towards trans people's actual needs to promote health and gender affirmation