Hypophosphatasia: is it an underdiagnosed disease even by expert physicians?

INTRODUCTION: Hypophosphatasia (HPP) is caused by mutations in the ALPL that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (ALP). Clinical manifestations range from extreme life-threatening lethal forms to no signs or symptoms at all. MATERIALS AND METHODS: Consecutive 30,000 outpatients and inpatients with ALP data were screened retrospectively, out of which 1000 patients were found to have low levels of ALP more than once. Then, patients were evaluated for the symptoms and signs of HPP with further biochemical and genetic analyses. RESULTS: Thirty-seven patients who had severe musculoskeletal pain, recurrent fractures, and tooth anomalies were then screened with substrate and DNA sequencing analyses for HPP. It was determined that eight patients had variants in the ALPL gene. A total of eight different ALPL variants were identified in eight patients. The variants, namely c.244G > C (p.Gly82Arg), c.1444C > T (p.His482Tyr), c.1487A > G (p.Asn493Ser), and c.675_676insCA (p.Met226GlnfsTer52), had not been previously reported. DISCUSSION: Considering the wide spectrum of clinical signs and symptoms, HPP should be among the differential lists of bone, muscle, and tooth abnormalities at any age.

High incidence of co-existing factors significantly modifying the phenotype in patients with Fabry disease.

Fabry disease results from deficiency of the lysosomal enzyme alpha-galactosidase A. The families of 11 index cases were screened by enzyme and molecular assays. Further clinical and laboratory investigations were carried out in all cases. Including 33 new patients, a total of 28 females (Age 25,82 ±â€¯12,1 Range 8-46) and 16 males (Age 24,56 ±â€¯15,04 Range 2-48) were investigated. Ten different disease-causing variants were found two of them being novel. One patient had co-existing familial mediteranian fever, one had celiac disease and three had rheumatological disorders. Lipoprotein (a) levels were elevated in 17,6%, homocysteine in 22,2%, total and low density cholesterol in 12% and antithrombin 3 levels were elevated in 13,3%. One patient was found to be heterozygous for prothrombin p.G20210A disease-causing variant (5,8%) and two for factor V Leiden disease-causing variant (11,7%). Anticardiolipin IgM antibody was found to be positive in 11,7%. The patients with abnormal cranial imaging were also noticed to have additional risk factors for thrombosis. This study provides the largest data about Fabry patients from Turkey and implies that co-existing risk factors unrelated to Fabry Disease have significant association with the presence of clinical symptoms in females and might cause an early and severe clinical course in males.

Investigating the Impacts of Preoperative Steroid Treatment on Tumor Necrosis Factor-Alpha and Duration of Extubation Time underwent Ventricular Septal Defect Surgery.

BACKGROUND: Cardiopulmonary bypass is known to cause inflammatory events. Inflammation occurs due to many known important biological processes. Numerous mechanisms are known to be responsible for the development of inflammatory processes. Currently, there are many defined mediators as a tumor necrosis factor-α (TNF-α) playing an active role in this process. AIMS: This research was to investigate the effects of pre-operative steroid use on inflammatory mediator TNF-α and on time to extubation postoperatively in ventricular septal defect patients undergoing cardiopulmonary bypass surgery. STUDY DESIGN: Controlled clinical study. METHODS: This study included 30 patients. These patients were assigned into two groups, each containing 15 patients. 5 micrograms/kg methylprednisolone was injected intravenously 2 hours before the surgery to Group I, whereas there was no application to the patients in Group II. TNF-α (pg/mL) level was measured in arterial blood samples obtained at four periods including: the preoperative period (Pre TNF); at the 5(th) minute of cross-clamping (Per TNF); 2 hours after termination of cardiopulmonary bypass (Post TNF); and at the postoperative 24th hours in cardiovascular surgery intensive care unit (Post 24 h TNF). RESULTS: The mean cross-clamp time was 66±40 and 55±27 minutes in Group I and Group II respectively. No significant difference was found between the groups in terms of cross-clamp time (p>0.05). The mean time to extubation was 6.1±2.3 hours in Group I and 10.6±3.4 hours in Group II. Group I extubation time was significantly shorter than Group II. Group I TNF-α levels at Post TNF and Post24h TNF was lower than Group II. These differences are also statistically significant (p<0.05). CONCLUSION: There is a strong indication that preoperative steroid treatment reduced the TNF-α level together with shortens duration of postoperative intubation and positively contributes to extubation in ventricular septal defect patients operated in cardiac surgery with cardiopulmonary bypass. (ClinicalTrials.gov Identifier: TCTR20150930001).

Diagnosis of glycine encephalopathy in a pediatric patient by detection of a GLDC mutation during initial next generation DNA sequencing.

Early diagnosis for metabolic encephalopathy caused by inborn errors of metabolism is very important for the initiation of early treatment and also for prevention of sequela. Metabolic encephalopathy in the form of seizures can result from many inborn errors of metabolism and considering the large number of disorders causing metabolic encephalopathy, enzyme assays or conventional molecular tests are expensive and take considerably long period of time which results in delayed treatment. In our center we have used next generation DNA sequencing technology as an initial diagnostic test to look for about 700 disorders at the same time for the etiologic diagnosis of a 4-month-old female infant suffering from intractable seizures. The patient was found to have glycine encephalopathy resulting from a previously defined mutation in the GLDC gene. The diagnostic result was obtained much sooner than other conventional investigations. Up to our knowledge, this would be the first case with glycine encephalopathy in the literature who was approached by this novel panel method initially. Although currently, classical evaluation methods such as physical examination, biochemical and conventional molecular investigations are still accepted as the gold standards to clarify the etiology of the metabolic encephalopathy it is obvious that next generation sequence analysis will play a very significant role in the future.