Fatih Kardas

Novel mutations of ABCA1 transporter in patients with Tangier disease and familial HDL deficiency

The objective of the study was the characterization of ABCA1 gene mutations in 10 patients with extremely low HDL-cholesterol. Five patients (aged 6 months to 76 years) presented with splenomegaly and thrombocytopenia suggesting the diagnosis of Tangier disease (TD). Three of them were homozygous for novel mutations either in intron (c.4465-34A>G) or in exons (c.4376delT and c.5449C>T), predicted to encode truncated proteins. One patient was compound heterozygous for a nucleotide insertion (c.1758_1759insG), resulting in a truncated protein and for a nucleotide substitution c.4799A>G, resulting in a missense mutation (p.H1600R). The last TD patient, found to be heterozygous for a known mutation (p.D1009Y), had a complete defect in ABCA1-mediated cholesterol efflux in fibroblasts, suggesting the presence of a second undetected mutant allele. Among the other patients, four were asymptomatic, but one, with multiple risk factors, had severe peripheral artery disease. Three of these patients were heterozygous for known mutations (p.R130K+p.N1800H, p.R1068C, p.N1800H), while two were carriers of novel mutations (c.1195-27G>A and c.396_397insA), predicted to encode truncated proteins. The pathogenic effect of the two intronic mutations (c. 1195-27G>A and c.4465-34A>G) was demonstrated by the analysis of the transcripts of splicing reporter mutant minigenes expressed in COS-1 cells. Both mutations activated an intronic acceptor splice site which resulted in a partial intron retention in mature mRNA with the production of truncated proteins. This study confirms the allelic heterogeneity of TD and suggests that the diagnosis of TD must be considered in patients with an unexplained splenomegaly, associated with thrombocytopenia and hypocholesterolemia.

Cardiometabolic Risk Factors Related to Vitamin D and Adiponectin in Obese Children and Adolescents

Obesity-related diseases are becoming the most important causes of mortality worldwide. Several studies have suggested an association between low levels of vitamin D and obesity. In addition, plasma adiponectin levels have been found to be lower in obese subjects. We evaluated the association of metabolic risk factors with both adiponectin and vitamin D levels and that between adiponectin and vitamin D levels. The study consisted of 114 obese and healthy subjects. 25-Hydroxy vitamin D [25(OH)D] levels were positively correlated with adiponectin and HDL-cholesterol (HDL-C) and inversely correlated with body mass index (BMI), LDL-cholesterol (LDL-C), total cholesterol (T-C), triglyceride (TG), fasting glucose, homeostasis model assessment of insulin resistance (HOMA index), systolic blood pressure (SBP), and diastolic blood pressure (DBP). The mean 25(OH)D levels in the obese and nonobese groups were 22.5 ± 5.7 and 32.3 ± 5.8 ng/mL, respectively (P < 0.0001). The mean adiponectin level in the obese group was lower than that in the nonobese group (P < 0.0001). Lower vitamin D and adiponectin levels were strongly associated with metabolic risk factors and obesity in Turkish children and adolescents.

Increased Serum Phthalates (MEHP, DEHP) and Bisphenol A Concentrations in Children With Autism Spectrum Disorder The Role of Endocrine Disruptors in Autism Etiopathogenesis

The aim of this study was to investigate the relationship between autism spectrum disorders development and exposure to mono-(2-ethylhexyl)-phthalate (MEHP), di-(2-ethylhexyl)-phthalate (DEHP), and bisphenol A (BPA), 1 of the endocrine disruptors, among phthalates. The study included 48 children with autism spectrum disorder (27 boys, 21 girls) and 41 healthy subjects (24 boys, 17 girls) as controls. Serum MEHP, DEHP, and BPA levels were measured by using high-performance liquid chromatography. Children with autism spectrum disorder had significantly increased serum MEHP, DEHP, and BPA concentrations (0.47 ± 0.14 µg/ml, 2.70 ± 0.90 µg/ml, 1.25 ± 0.30 ng/ml) compared to healthy control subjects (0.29 ± 0.05 µg/ml, 1.62 ± 0.56 µg/ml, 0.88 ± 0.18 ng/ml) respectively (P = .000). The fact that higher serum MEHP, DEHP, and BPA were found levels in the autism spectrum disorder group compared to healthy controls suggests that endocrine disruptors may have a role in the pathogenesis of autism spectrum disorders.

Hemophagocytic syndrome in a 4‐month‐old infant with biotinidase deficiency

Hemophagocytic syndromes such as hemophagocytic lymphohistiocytosis (HLH) are life‐threatening hyperinflammatory conditions caused by inherited or acquired immune disorders. Awareness of the clinical symptoms and diagnostic criteria for hemophagocytic syndromes is crucial to start timely life‐saving therapy. We present a case of a 4‐month‐old boy presenting with HLH. However, the patient was subsequently diagnosed with biotinidase deficiency and was successfully treated with biotin‐replacement therapy, upon which the hemophagocytic syndrome ceased. Subsequent laboratory evaluations revealed normal lymphocyte cytotoxicity and no mutations in genes associated with familial HLH were found. Biotinidase deficiency should be considered as a differential diagnosis of patients fulfilling HLH criteria. Pediatr Blood Cancer 2012; 59: 191–193.

Primary adrenal failure due to viral infection in an infant.

Acquired primary adrenal insufficiency is a rare disorder in childhood. The most common cause is autoimmune adrenalitis, especially as a part of polyendocrinopathy syndromes. Impaired adrenal function is seen in patients infected with HIV. In adult patients with AIDS, cytomegalovirus (CMV)-associated adrenal insufficiency is a well-known condition, whereas CMV infection as a causing adrenal insufficiency in children is very rare. Here, we report an infant with transient adrenal insufficiency associated with CMV infection but without HIV. She was treated successfully with steroid replacement and ganciclovir. Early diagnosis and treatment is lifesaving in these patients.

A novel homozygous GALC mutation: Very early onset and rapidly progressive Krabbe disease

A clear cut genotype-phenotype correlation for Krabbe disease is not available. Therefore, it is important to identify new mutations and their associated phenotypes to predict the prognosis of the disease. The aim of this study is to identify the causative mutation(s) in a family with Krabbe disease. After a clinical evaluation and suspicion of Krabbe disease galactocerebrosidase activity was analyzed and GALC gene mutation analysis was performed. The galactocerebrosidase enzyme activity was 0.01 nmol/mg/h protein (normal range 0.8-4). For further investigation mutation screening was performed by Sanger sequencing across the 17 exons of GALC gene. A novel homozygous mutation c.727delT (p.S243QfsX7) was found. In this study we present the clinical findings along with a novel GALC mutation in a consanguineous Turkish family. Although the relationship between the various genotypes and phenotypes in Krabbe disease has not been fully elucidated an accurate genetic family study is helpful for genetic counseling follow-up and therapy of Krabbe disease. Also, it is important to identify new mutations in order to clarify their clinical importance, to assess the prognosis of the disease, and to suggest either prenatal diagnosis or preimplantation genetic diagnosis to the effected families.

The Effects of Ketogenic Diet on Seizures, Cognitive Functions, and Other Neurological Disorders in Classical Phenotype of Glucose Transporter 1 Deficiency Syndrome

OBJECTIVES The purpose of this study was to characterize patients who were diagnosed with glucose transporter protein 1 deficiency syndrome (Glut1D), and also to assess the efficacy of ketogenic diet (KD) therapy on seizure control, cognitive functions, and other neurological disorders. PATIENTS AND METHODS We studied six unrelated patients with the classical phenotype of Glut1D, focusing on clinical and laboratory features, the KD therapy and outcome over the 25-month follow-up period. RESULTS Five patients became seizure-free with the onset of ketosis, and anticonvulsants were discontinued. Other neurological features such as ataxia, spasticity, and dystonia showed a less striking improvement than seizure control. There was no significant change in the intelligence quotient (IQ) level or microcephaly. In all patients, alertness, concentration, motivation, and activity resulted in a moderate improvement of variable degree. The early-onset adverse effects of KD were observed in five patients. The KD regimen failed in one patient, therefore, his diet was changed with an alternative to KD. CONCLUSIONS Treatment with KD resulted in a marked improvement in seizures and cognitive functions but its effect appeared to be less striking on the other neurological disorders of the patients. When the classic KD is not tolerated, an alternative to KD may be helpful.

Clinical, Electrodiagnostic, and Genetic Features of Tangier Disease in an Adolescent Girl with Presentation of Peripheral Neuropathy.

Tangier disease (TD) is a rare, autosomal recessive inherited disorder caused by a mutation in the adenosine triphosphate-binding cassette transporter 1 (ABCA1) gene, which results in a decrease in plasma high-density lipoprotein (HDL) levels. Peripheral neuropathy can be seen in approximately 50% of patients with TD, which usually occurs after the age of 15 years, and is characterized by relapsing-remitting mono- or polyneuropathy or syringomyelia-like neuropathy. Herein, we report a 16-year-old female patient who was initially diagnosed with peripheral neuropathy at the age of 13 years. Whole exome sequencing was performed, and a nonsense mutation (p.Arg1817X) in ABCA1 was identified. The patient was investigated for systemic findings of TD after the genetic diagnosis was made, and low (< 5 mg/dL) levels of HDL cholesterol were detected by lipid electrophoresis. Other family members were reexamined after the diagnosis of the proband, and asymptomatic sister of the proband was diagnosed with TD. We would like to emphasize that TD should be considered in the differential diagnosis of pediatric patients presenting with peripheral neuropathy; furthermore detection of HDL levels by lipid electrophoresis is a simple but indicative diagnostic test.

Phenylketonuria with acute myeloblastic leukemia in a 9-year-old boy: reporting a rare case.

Phenylketonuria is a genetic metabolic disorder resulting in phenylalanine accumulation in blood. Phenylacetate, which is an abnormal phenylalanine metabolities, was hypothesized to have anticancer activity. Two-years-old boy was diagnosed with classical phenylketonuria because of mental motor retardation. When the patient was 9-year-old, he developed acute myeloblastic leukemia. Here, we present the case with phenylketonuria and acute myeloblastic leukemia because of its extreme rarity.

Tyrosinemia type II: Novel mutations in TAT in a boy with unusual presentation.

Tyrosinemia type II is a rare autosomal recessive disorder caused by deficiency of tyrosine aminotransferase (TAT). It may occur with ocular and cutaneous symptoms with or without mental retardation, but epileptic seizure is a rare presentation of this disease. Herein we report the clinical, biochemical and genetic features of a 4‐year‐old boy who presented with afebrile seizure and photophobia. Genomic DNA was obtained from peripheral blood leukocytes from the whole family. Sequencing analysis was performed using the MiSeq next‐generation sequencing platform. Sequencing of TAT indicated two new homozygous mutations p.L312P (c.935T>C) and p.T408M (c.1223C>T) for the proband and his asymptomatic sister. During a 2 year follow‐up period, the patient had overall poor compliance with protein‐restricted diet, but his asymptomatic sister had good compliance with the diet. Cognitive function of the patient worsened steadily, but his asymptomatic sister maintained normal mental status. Tyrosinemia type II should be considered in the differential diagnosis of children presenting with epileptic seizure and photophobia; furthermore, early diagnosis and protein‐restricted regimen are important to reduce the risk of long‐term complications of tyrosinemia type II such as mental disability.