Sema Kalkan Uçar

Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.

Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-methylglutaconic aciduria. We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange. A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1 (where the species nomenclature denotes the number of carbon atoms in the two acyl chains:number of double bonds in the two acyl groups) and decreased concentrations of phosphatidylglycerol-36:1 species, resulting in an altered cardiolipin subspecies composition. We also detected low concentrations of bis(monoacyl-glycerol)-phosphate, leading to the accumulation of free cholesterol, as shown by abnormal filipin staining. Complementation of patient fibroblasts with wild-type human SERAC1 by lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1. Our data identify SERAC1 as a key player in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking.

The missing “link”: an autosomal recessive short stature syndrome caused by a hypofunctional XYLT1 mutation

Proteoglycan (PG) synthesis begins with the sequential addition of a “linker chain”, made up of four sugar residues, to a specific region of a core protein. Defects in the enzymes catalyzing steps two to four of the linker chain synthesis have been shown to cause autosomal recessive human phenotypes while no mutation has yet been reported in humans for the xylosyltransferases 1 and 2 (XT1 and XT2), the initiating enzymes in the linker chain formation. Here, we present a consanguineous Turkish family with two affected individuals presenting with short stature, distinct facial features, alterations of fat distribution, and moderate intellectual disability. X-rays showed only mild skeletal changes in the form of a short femoral neck, stocky and plump long bones and thickened ribs. Using a combination of whole-exome sequencing (WES), determination of homozygous stretches by WES variants, and classical linkage analysis, we identified the homozygous missense mutation c.C1441T in XYLT1, encoding XT1, within a large homozygous stretch on chromosome 16p13.12-p12.1. The mutation co-segregated with the phenotype in the family, is not found in over 13,000 alleles in the exome variant server and is predicted to change a highly conserved arginine at position 481 (p.R481W) located in the putative catalytical domain. Immunostaining of primary patient fibroblasts showed a loss of predominance of Golgi localization in mutant cells. Moreover, western blot analysis of decorin in cell culture supernatant demonstrated glycosylation differences between patient and control cells. Our data provide evidence that functional alterations of XT1 cause an autosomal recessive short stature syndrome associated with intellectual disability.

Clinical overview of children with mucopolysaccharidosis type III A and effect of Risperidone treatment on children and their mothers psychological status

Mucopolysaccharidosis IIIA (MPS IIIA) is a lysosomal storage disorder characterized by progressive mental deterioration and severe behavioral problems. We conducted an open-label, crossover study of the efficacy and safety of Risperidone on behavioral disorder in children with MPS IIIA. A total of 12 patients (5.5+/-2.2 years) with enzymatic diagnosis of MPS IIIA were randomly assigned to receive Risperidone (0.125-2mg/d) for 6 months. The hyperactivity and disruptive behavior level of children before and after treatment was evaluated regarding the scores from Turgay DSM IV Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S). Clinic Global Impression Scale - Severity (CGIS-S) was used for all cases for determining the psychiatric disorder severity. The anxiety and depression levels of mothers before and after treatment were evaluated using Hamilton Anxiety Scale (HAM-A) and Beck Depression Inventory (BDI). The adverse effects were evaluated by monitoring weight, serum prolactin, glucose and lipid levels. The response to the treatment was measured by decrease in values of CGI-S (from 6+/-1.12 to 2.91+/-0.66, p=0.001). According to T-DSM-IV-S scores the best improvement was observed in hyperactivity scores (16.25+/-8.57/11.58+/-7.26, p=0.001), followed by opposition/defiance (6.66+/-5.92/5.08+/-4.88, p=0.032), and conduct disorder scores (1.00+/-1.85/0.41+/-.99, p=0.67). No clinically relevant elevations in weight and serum prolactin, glucose or lipid levels have been documented (p>0.05). There was a significant decrease in anxiety and depression scores of mothers (HAM-A: 20.33+/-8.28/17.91+/-6.89, BDI: 23.58+/-7.14/20.5+/-5.93, p<0.001). To our knowledge, research on the pharmacological treatment of MPS IIIA with Risperidone has not been reported. According to our data, Risperidone appeared to be safe and effective in MPS IIIA patients.

Low density lipoprotein apheresis in pediatric patients with homozygous familial hypercholesterolemia.

The aim of the present study is to clarify the low density lipoprotein apheresis procedure for pediatric patients with homozygous familial hypercholesterolemia (FH) in terms of efficacy, adverse effects and difficulties. The follow‐up was carried out using an open, prospective uncontrolled clinical design. Data were collected from 10 patients (with an average age of 8.4 ± 4.7 years) with FH treated with double filtration plasmapheresis. The total time span of follow‐up covered five years (30.2 ± 17.8 months [range 9–60 months]) and more than 600 sessions (62.1 ± 35.5 sessions per patient [range 18–120 sessions]) were evaluated. The mean low density lipoprotein cholesterol (LDL‐C) pre‐treatment value was 375.5 ± 127.5 mg/dL, and the post‐treatment value was 147.5 ± 73.9 mg/dL. This corresponded to a 62.8 ± 10.3% (43–73%) acute reduction of LDL‐C, while the mean high density lipoprotein cholesterol losses amounted to 41%. The chronic reduction in LDL‐C ranged from 18 to 52%, with a mean level of 36.4 ± 11.7%. The most frequently occurring technical problems were related to blood lines: puncture difficulties (4.5%), insufficient blood flow (3.5%), and obturation of the blood lines (2.4%). The main clinical adverse effects were hypotension (0.2%), chills/feeling cold (0.1%), and nausea and vomiting (0.2%). We observed that the low pediatric patient tolerance is the main problem in compliance with treatment. In conclusion, LDL apheresis, started under the age of eight years, combined with lipid‐lowering drugs, provides a safe and effective lowering of the mean LDL‐C levels in pediatric homozygous FH; and there are more problems with compliance for pediatric LDL apheresis than in the adult population.

An association among iron, copper, zinc, and selenium, and antioxidative status in dyslipidemic pediatric patients with glycogen storage disease types IA and III.

Dyslipidemia in patients with glycogen storage disease types Ia (GSD Ia) and III (GSD III) does not lead to premature atherosclerosis. The aim of this study was to investigate the association among serum copper (Cu), zinc (Zn), iron (Fe), and selenium (Se) concentrations, and their carrier proteins: ceruloplasmin, albumin, and related antioxidant enzyme activities [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), paraoxonase (PON), and arylesterase (ARYL)] in 20 GSD Ia and 14 III patients compared to age and sex matched 20 healthy subjects. Erythrocyte oxidative stress was measured by erythrocyte thiobarbituric acid reactive substances (eTBARSs). Hypertriglyceridemia [333 (36-890)mg/dL] in GSD Ia and hypercholesterolemia with elevated LDL-cholesterol [188 (91-313)mg/dL] and decreased HDL-cholesterol [32(23-58)mg/dL] levels in GSD III were found. Serum Cu, Fe, and Zn showed no significant differences between groups. However, Se 60 (54-94), 81 (57-127) microg/L, ceruloplasmin 21 (10-90), 27 (23-65) microg/L, and albumin 2.4 (1.7-5.1), 2.8 (1.8-4.06)g/dL levels were decreased in GSD Ia and III groups, respectively, in comparison with the controls [Se 110 (60-136) microg/L, ceruloplasmin 72 (32-94) microg/L, and albumin 4.4 (4-4.8)g/dL)]. In spite of high oxidative stress in erythrocyte detected by elevated eTBARS/Hb levels in GSD group [674.8 (454.6-948.2) for GSD Ia, 636.3 (460.9-842.1) for GSD III, and 525.6 (449.2-612.6)], the activities of CAT, SOD, ARYL, and PON in GSD patients were not different from the controls. GPx activity was decreased in GSD Ia [3.7 (1.8-7.1)U/mL] and GSD III [4.2 (2.2-8.6)U/mL] compared with healthy controls [7.1 (2.9-16.2)U/mL]. In conclusion, this study supplied the data for trace elements, their carrier, and antioxidative enzymes in the patients with GSD Ia and III. The trace elements and anti-oxidative enzyme levels in GSD patients failed to explain the atherosclerotic escape phenomenon reported in these patients.

Chitotriosidase as a possible marker of clinically evidenced atherosclerosis in dyslipidemic children.

Abstract A correlation has been clearly shown between inflammation markers and subclinical atherosclerosis markers in the early stages of atherogenesis in subjects with familial hypercholesterolemia (FH). The aim of this study was to investigate potential inflammation markers in the diagnosis of atherosclerosis in children with FH. A total of 48 dyslipidemic children and 24 healthy age-matched control subjects were taken into study. Inflammation and macrophage activation markers (hsCRP, myeloperoxidase, chitotriosidase, YKL-40, TNF-α, IL-6, IL-18, MMP-1 and MMP-9) and lipid parameters of all patients were measured. Carotid intima-media thickness (cIMT) and flow-mediated dilation (FMD) levels were determined. Our data suggested that clinically evidenced (by cIMT and FMD levels) atherosclerosis starts in the early ages in hypercholesterolemic children. Higher cholesterol levels strongly correlated with macrophage activation markers (ChT, YKL-40 and myeloperoxidase). ChT and YKL-40 seem to be the more predictable markers of atherosclerosis even in early ages (<6 years old) than other classical inflammation markers such as hs-CRP, IL-6 and TNF-α.

Alpha-galactosidase A activity levels in Turkish male hemodialysis patients.

Fabry disease is an X‐linked lysosomal storage disorder due to deficient activity of alpha‐galactosidase A (α‐Gal A) leading to renal insufficiency in males. The aim of present study was to investigate the level of α‐Gal A activity and to determine the prevalence of Fabry disease in a Turkish male hemodialysis population. The activity of plasma α‐Gal A was measured in a group of 808 male hemodialysis patients using fluorimetric methods. Patients with low α‐Gal A activity were evaluated clinically and genetic testing was carried out. A correlation with creatinine, uric acid, urea, white blood cell (WBC), and high sensitivity (hs)CRP and α‐Gal A activity was also investigated. Plasma α‐Gal A activity among this male population undergoing hemodialysis was 7.88 ± 5.18 µM/hour/L (0.40–55.72), significantly lower when compared to controls. No influence of creatinine, uric acid, WBC, or hsCRP on measured α‐Gal A activity was reported. Two new Fabry disease patients were identified. Both were previously diagnosed with diabetes mellitus type 2. These findings provide, for the first time, data regarding the prevalence of α‐Gal A deficiency (0.24%) in Turkish males receiving hemodialysis.

A cross-sectional, mono-centric pilot study of insulin resistance in enzyme replacement therapy patients with Gaucher type I without overweight

Insulin resistance have been demonstrated in untreated patients with Gaucher type I disease. It was implied in overweight enzyme replacement therapy (ERT) treated patients with Gaucher type I disease. In present study we investigate whether insulin resistance is presented in fourteen ERT treated patients with Gaucher type I disease and without overweight in comparison to normal subjects. This work illustrates the presence of insulin resistance in non-overweight ERT treated patients with Gaucher type I disease.

Unexpected clinical features in a female patient with proopiomelanocortin (POMC) deficiency.

Abstract Background/aims: Loss of function mutations of proopiomelanocortin (POMC) gene results in adrenal insufficiency, early-onset hyperphagic obesity, and red hair. However, neuromotor retardation with POMC deficiency has not been reported before. Case report: We report a female patient whose initial diagnosis was neurometabolic disease because of motor mental retardation, ataxia, and bilateral hyperintense lesions in the basal ganglia in cranial magnetic resonance imaging, increased lactate-lipid peak in proton magnetic resonance spectroscopy. She was consulted due to rapid weight gain, obesity, and episodes of hypoglycemia and homozygous mutation (c.64delA) in POMC gene was found. Conclusion: Severe motor mental retardation and cranial magnetic resonance imagingpathology in patients with POMC deficiency have not been reported previously in the literature. Bilateral hyperintense lesions in the basal ganglia and the increased lactate-lipid peak was thought to be the result of recurrent hypoglycemia.

The Burden Endured by Caregivers of Patients With Morquio A Syndrome: Results From an International Patient-Reported Outcomes Survey

This international survey performed by direct personal interview or mail evaluated the global burden among primary caregivers of patients with Morquio A syndrome. Collected outcomes included self-r...