novel variant in the PAH gene causing phenylketonuria in an Iranian pedigree

Background: Phenylalanine hydroxylase [PAH] gene is the well-known causative gene for classic Phenylketonuria [PKU] [OMIM#261600] disease, with more than 500 reported mutations. Through this study, a novel mutation in the PAH gene in an Iranian pedigree with phenylketonuria was introduced

Methods: A consanguineous family with a 10-year old affected girl was referred for genetic analysis. Mutation screening of all exons and exon-intron boundaries was performed by Sanger sequencing, and mini haplotype analysis was carried out by genotyping of Short Tandem Repeat [STR] and Variable Number Tandem Repeat [VNTR] alleles

Results: Mutation analysis revealed a novel homozygous insertion of a single adenine nucleotide at position 335 in exon 3 of the PAH gene. Based on the American College of Medical Genetics and Genomics [ACMG] guidelines, the change is interpreted as a pathogenic mutation which produces a premature termination signal [TAA] at codon 113 according to in silico assessments. The mini haplotype analysis showed that this mutation was linked to STR [15] -VNTR [3]

Conclusion: In this study, a novel mutation was reported in a patient who had PKU symptoms without any previously reported mutations in the PAH gene [NM_000277.1: p.Asp112Glufs*2] that can be responsible for the classical PKU phenotype in the Iranian population. Detection of novel mutations indicates notable allelic heterogeneity of the PAH locus among this population

efficient trio-based mini-haplotyping method for genetic diagnosis of phenylketonuria

Objective: The phenylalanine hydroxylase [PAH] locus has high linkage disequilibrium. Haplotypes related to this locus may thus be considered sufficiently informative for genetic diagnosis and carrier screening using multi-allelic markers. In this study, we present an efficient method for haplotype analysis of PAH locus using multiplexing dyes. In addition, we explain how to resolve the dye shift challenge in multiplex short tandem repeat [STR] genotyping

Materials and Methods: One hundred family trios were included in this descriptive study. The forward primer of a tetra-nucleotide STR and the reverse primer of a variable number tandem repeat [VNTR] were labeled with three different non-overlapping dyes 5-carboxyfluorescein [FAM], 6-carboxy-N,N,N',N'-tetramethylrhodamine [HEX] and 6-carboxy-N,N,N',N'-tetramethylrhodamine [TAMRA]. The polymerase chain reaction [PCR] products from each family trio were multiplexed for capillary electrophoresis and results were analyzed using Peak Scanner software

Results: Multiplexing trio products decreased the cost significantly. The TAMRA labeled products had a significant predictable shift [migrated at a slower electrophoretic rate] relative to the HEX and FAM labeled products. Through our methodology we achieve, the less inter-dye shift than intra-dye shift variance. Correcting the dye shift in the labeled products, according to the reference allele size, significantly decreased the inter-dye variability [P<0.001]

Conclusion: Multiplexing trio products helps to detect and resolve the dye shift accurately in each family, which otherwise would result in diagnostic error. The dye system of FAM, HEX and TAMRA is more feasible and cheaper than other dye systems

randomized clinical trial of insulin Glargine and Aspart, compared to NPH and regular insulin in children with type 1 diabetes mellitus

Objective: Appropriate treatment of patients with Type 1 diabetes mellitus [T1DM] is necessary to avoid further complications. This study was performed to compare the efficacy of insulin Glargine and Aspart with NPH insulin and regular insulin regimen in a group of children with T1DM

Methods: Forty patients with T1DM were enrolled in this study. During run-in, all subjects were treated with conventional therapy consisting of twice-daily NPH and thrice-daily regular. Following randomization, 20 subjects received Glargine and Aspart and 20 subjects received NPH and Regular insulin

Findings: Mean HbA1c was 8.8% and 8.6% at first and 8.4% and 8.2% at the end of study for subjects randomized initially to Glargine and Aspart and for those randomized to NPH and Regular, respectively [P>0.05]. Mean fasting blood glucose [FBS] of the subjects randomized initially to Glargine and Aspart was 217+/-101 mg/dL, with no significant difference to 196+/-75 mg/dL for those randomized to NPH and Regular [P=0.48]. This was also true at the end of the study. The difference in total cholesterol and triglyceride between the two groups in the beginning of study and at the end did not show any significance

Conclusion: The current study showed no significant difference in glycemic control [Glycated hemoglobin [HbA1c] and FBS] and lipid profile [total cholesterol and triglyceride] between two regimes

Transient neonatal diabetes as a presentation of fanconi- bickel syndrome

Fanconi- Bickel Syndrome [FBS] is a rare type of glycogen storage disease [GSD] Characterized by hepatomegaly, proximal renal tubular acidosis [RTA] and marked growth retardation. We report a case of FBS presenting with diabetic ketoacidosis and transient neonatal diabetes. A female infant, product of consanguineous marriage presented with diabetic ketoacidosis at age 33 days, and was treated as neonatal diabetes with insulin. At age 14 months, insulin was discontinued. She presented with short stature, hepatomegaly, RTA and hypophosphatemic rickets at age 4 and [FBS] was diagnosed. Diagnosis was confirmed by mutation analysis, showing mutation in SLC2 A2 gene. In conclusion,: neonatal diabetes or diabetic ketoacidosis may be the first presentation of infants with FBS

Female sex as a risk factor for glycemic control and complications in Iranian patients with type one diabetes mellitus

The aim of this study was to evaluate the influence of sex on glycemic control, diabetes complications and associated abnormalities in patients with type one diabetes mellitus. In a cross-sectional study in 309 patients [156 females and 153 males within the age range of 3-16 years] with type one diabetes mellitus referred to endocrinology clinic in Children's Medical Center in Tehran from March 2005 to March 2007 gender differences in diabetes control were analyzed. Mean glycosylated hemoglobin [HbA1c], was significantly higher in females [9.25 vs. 8.01]. Insulin dose per kilogram of body weight was significantly more in girls [0.91 +/- 0.31 vs. 0.74 +/- 0.37, P<0.001] self monitoring of blood glucose was performed significantly more in boys. Frequency of Diabetic ketoacidosis, height growth problems and dyslipidemia were significantly higher in girls. 1.20 +/- 0.86 vs. 0.93 +/- 0.55, P=0.004], [-0.05 +/- 1.20 vs. -0.41 +/- 1.17, P=0.015], [134.60 +/- 44.43 vs. 110.56 +/- 20.72, P=<0.001] respectively. Female sex is a risk factor in glycemic control and complications of diabetes type I and females should be managed more seriously regarding self monitoring of blood glucose, nutritional and psychological factors and puberty issues

Wolfram syndrome: endocrinological features in a case series study and review of the literature

Wolfram syndrome [WFS] is a rare and complex genetic disorder referred to as DIDMOAD [diabetes insipidus, diabetes mellitus, optic atrophy and deafness]. All insulin dependent diabetic patients presented over a period of 10 years, who had optic atrophy or a positive family history of WFS, were enrolled in the study. Criteria for the diagnosis of WFS were the presence of insulin dependent diabetes mellitus [IDDM] along with optic atrophy unexplained by any other disease and/or some other abnormalities associated with WFS. WFS has been diagnosed in sixteen patients, 9 males and 7 females aged 5.5 to 22yr [median age of 13.4 yr]. Nine patients [more than half] came from consanguineous marriages. The earliest manifestation of WFS was IDDM [at a median age of 5.4yrs]. All patients developed non-autoimmune IDDM before the age of 8 years old. Only two cases were ketoacidotic. Common diabetic complications of proliferative retinopathy, glomerulosclerosis and neuropathy were remarkably absent in our patients even with long-lasting diabetes mellitus. Antidiuretic hormone [ADH]-responsive diabetes insipidus was confirmed by water deprivation test in 8 patients [50%]. The incidence of diabetes insipidus in our patients was lower compared to other studies. Growth retardation, as short stature and a weight below the 5th percentile for age and gender, was found in 13 [81%] and 5 [31%] patients respectively. Early diagnosis and proper treatment aimed at relieving the symptoms and preventing the future complications are of paramount value and importance

Attention deficit hyperactivity disorder and growth

Attention deficit hyperactivity disorder [ADHD] is a common neuropsychiatric syndrome of childhood and adolescence in which stimulant medications are used to treat it. The evidence clearly indicates a temporary retardation in the rate of growth in weight and stature, with no effect on adult height. In this article we present a case with ADHD on stimulant therapy that had a catch up growth after the discontinuation of therapy, then review the literature on possible growth, and suppressing effects of these medications in the long term treatment. Most of the previous studies suggest that the stimulant-associated height deficits in ADHD are temporary and early manifestation of ADHD itself and not complication of therapy, and the small risk of lost centimeters may be a price worth paying for many children to gain improved learning and social function