SLCO1B1 Gene Polymorphisms (rs2306283 and rs4149056) and Statin-Induced Myopathy in Jordanian Diabetics.

BACKGROUND: The use of statins to lower high serum cholesterol levels may be associated with a number of adverse reactions, including severe myopathy. The solute carrier organic anion transporter 1B1 (SLCO1B1) gene, which encodes the organic anion-transporting polypeptide OATP1B1, is related to the intracellular transport of statins. The aim of this research was to study the association of rs2306283 and rs4149056 genetic polymorphism of the SLCO1B1 gene with the development of statin-induced myopathy in Jordanian diabetics receiving statins. METHODS: We included 413 patients attending the Diabetes Clinics of the National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan. The study was approved by the Institutional Review Board of NCDEG. Myopathy was defined as the elevation of creatine kinase more than 3 times the upper limit of normal. Every subject signed an informed consent form and donated 3-5 mL of venous blood. Genome DNA was extracted from lymphocytes of peripheral blood. Genotypes were identified using the Tetra Amplification Refractory Mutation System of SLCO1B1. RESULTS: The minor allele frequencies of rs2306283 [G] and rs4149056 [C] were 0.38 and 0.23, respectively. The two SNPs followed the Hardy-Weinberg equilibrium. The development of SIM was significantly associated with the homozygous and heterozygous minor allele genotype of rs4149056 (CC and CT), and the homozygous wild type allele genotype of rs2306283 (AA). There was no linkage disequilibrium between the two SNPs in the studied subgroups. CONCLUSION: Genetic polymorphism in the SLCO1B1 Gene is a risk factor for the development of SIM in Jordanian patients.

Assessment of segmental left ventricular thickening in diabetic type II obese patients with normal myocardial perfusion scan.

OBJECTIVE: The aim of this study is to investigate whether gated single photo emission tomography (gSPET) can be used to detect subclinical left ventricular systolic dysfunction (LVSD) in obese diabetic type II patients. SUBJECTS AND METHODS: We retrospectively reviewed gSPET images of 190 patients with diabetes mellitus type II (DM II) (137 females and 53 males) with normal myocardial perfusion and normal ejection fraction (EF). Standardized twenty segment polar maps of thickening and motion were generated. Correlation between body mass index (BMI) and thickening for each segment was performed. RESULTS: Statistically significant results were reported in female patients including: negative correlation between BMI and EF (-0.19, P=0.03). End diastolic volume (EDV) also significantly increased with increasing BMI (0.25, P<0.01). There was also statistically significant negative correlation between septal thickening and BMI segment 15 (-0.19, P=0.02), segment 16 (-0.22, P=0.01), segment 18 (-0.20, P=0.01), segment 19 (-0.25, P=0.003), segment 20 (-0.2, P=0.02)]. No statistical significant correlation was found between thickening and BMI in male patients. CONCLUSION: This is the first time where thickening as measured by gSPET has been used to demonstrate subclinical LVSD in DM II obese patients. The relationship between gender and obesity on cardiovascular function and structure needs further investigations.

Permanent neonatal diabetes mellitus in Jordan.

OBJECTIVE: Permanent neonatal diabetes mellitus (PNDM) is a rare heterogeneous form of diabetes that develops within the first 6 months of life. The objective of this study is to define the genetic etiology and incidence of permanent neonatal diabetes mellitus in Jordan. METHODS: This study was conducted in Jordan at the National Center of Diabetes, Endocrinology and Genetics, Amman, between 2006 and 2012. The study included 22 cases diagnosed with diabetes within the first year of life. RESULTS: The incidence of PNDM in Jordan was calculated as one case for every 203,221 live births. Mutations were found in six out of ten cases diagnosed before 6 months and included one homozygous ABCC8 p.R826W mutation, three cases with a heterozygous KCNJ11 p.R201C mutation, and two cases with a homozygous EIF2AK3 splicing mutation. CONCLUSION: The genetic etiology of PNDM in Jordan is different from that seen in European countries and more similar to other Arab countries.

N-acetyltransferase-2 genotypes among Jordanian patients with diabetes mellitus.

BACKGROUND: There are inconsistent reports concerning N-acetyltransferase 2 (NAT2) genotypes in diabetes mellitus (DM). OBJECTIVE: The objective of the study was to explore any association between NAT2 genotypes and Type 1 and Type 2 DM in Jordanians. METHODS: 106 Type 1 and 110 Type 2 DM patients attending the "National Center for Diabetes, Endocrinology and Genetics", Amman, Jordan, were included in the study. DNA was extracted from venous blood using a commercial DNA extraction kit. NAT2 genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The frequency of the genotype that encodes rapid acetylation (the wild-type genotype NAT2*4/4) was similar in the two types of diabetes mellitus. Those which encode intermediate acetylation (NAT2*4/5, NAT2*4/6, and NAT2*4/7) were higher in Type 2 diabetes (0.482) compared to Type 1 diabetes (0.339), while the frequency of genotypes which encode slow acetylation (NAT2*5/5, NAT2*5/6, NAT2*5/7, NAT2*6/6, NAT2*6/7, and NAT2*7/7) were higher in Type 1 diabetes (0.547) compared to Type 2 diabetes (0.418). CONCLUSION: There is excess of genotypes encoding intermediate acetylation in Type 2 DM and an excess of slow acetylator genotypes in Type 1 DM. Furthermore, NAT2*4/6 genotype (which encodes intermediate acetylation) was more prevalent in Type 2 DM. Type 1 DM behaved similar to non-diabetic controls in regard to acetylation status.

Contribution of radioiodine uptake measurement and thyroid scintigraphy to the differential diagnosis of thyrotoxicosis.

Both clinical and subclinical thyrotoxicosis can result from a wide range of disorders. Establishing the correct etiology underlying thyrotoxicosis is essential to direct treatment towards its specific pathophysiologic process. Based on clinical experience and guideline recommendations, radioiodine iodine uptake (RAIU) measurement and scintigraphy are often requested as the first-line investigation in thyrotoxic patients; however, their specific individual contribution to the differential diagnosis of thyrotoxicosis has not been previously investigated. In our study we aimed at evaluating the diagnostic role of RAIU measurement and scintigraphy in the management of thyrotoxicosis. A total of 108 patients with clinical and 42 patients with subclinical thyrotoxicosis were included in this retrospective study. All patients had RAIU measured at 24 hours after (131)I-iodide administration, followed by thyroid scintigraphy. Based on the combination of RAIU and scintigraphy, patients were classified as having diffuse toxic goiter (DTG) in 44% (the most common diagnosis), toxic adenoma in 15.9%, thyroiditis in 14%, and toxic multinodular goiter in 2.7%, while the pattern was inconclusive in 22.7% of all patients. When considering only patients with clinical thyrotoxicosis, the scan was inconclusive in 12.9% of patients whereas it was inconclusive in 47.6% of patients with subclinical thyrotoxicosis. There was a highly significant association between thyrotoxic status and scan result, with a statistically significant better performance of RAIU and scintigraphy in patients with clinical thyrotoxicosis when compared to patients with subclinical thyrotoxicosis considered as a whole (P<0.001). Instead, no statistically significant difference was observed between patients with subclinical thyrotoxicosis and TSH <0.1 mU/L and patients with TSH between 0.1 mU/L and 0.4 mU/L (P=0.191). In conclusion, we confirm the key role of RAIU and scintigraphy in the management of thyrotoxicosis and document its better performance in patients with clinical thyrotoxic status.

Sleepwalking associated with hyperthyroidism.

OBJECTIVE: To report several cases of hyperthyroidism in patients presenting with the unusual symptom of sleepwalking and to discuss the possible pathophysiologic basis for this novel association. METHODS: After encountering and reporting the first case of new-onset somnambulism in a patient presenting with thyrotoxicosis at our institution, we routinely inquired about the sleep history of patients with thyrotoxicosis, questioning both the patients and family members when applicable. Those patients who actually had sleepwalking episodes coinciding with the onset of thyrotoxicosis underwent close follow-up, and the relationship between the sleepwalking and the results of thyroid function tests was analyzed. In addition, we reviewed the literature on psychiatric disorders and sleep problems, and the pathophysiologic rationale for a cause-and-effect relationship is discussed. RESULTS: We collected 8 cases of patients with new-onset sleepwalking episodes that coincided with the start of thyrotoxicosis. The disappearance of the sleepwalking with successful achievement of euthyroidism supports a cause-and-effect relationship. This hypothesis is further supported by the absence of a family history, the adult onset, and the relapse of sleepwalking in 2 of the patients when their thyrotoxicosis became poorly controlled as a result of noncompliance with medications and its subsequent disappearance with reachievement of euthyroidism. Of note, such a presentation was seen only in patients with thyrotoxicosis caused by diffuse toxic goiter or Graves' disease and never in patients with other causes of thyrotoxicosis. CONCLUSION: New-onset sleepwalking could be caused by thyrotoxicosis or, more specifically, by thyrotoxicosis resulting from diffuse toxic goiter. The mechanism is hypothesized to be related to the combination of prolongation of non-rapid eye movement sleep and the associated fatigue. Specific inquiry about this unusual presentation of thyrotoxicosis is encouraged, and more studies are needed to confirm and evaluate its extent.

Clinical and inheritance profiles of Kallmann syndrome in Jordan.

BACKGROUND: Proper management of patients with Kallmann syndrome (KS) allows them to attain a normal reproductive health. The purpose of this study is to demonstrate the presentation modalities, phenotypes and the modes of inheritance among 32 patients with Kallmann syndrome in Jordan. Recognition of the syndrome allows for prompt proper management and provision of genetic counselling. SUBJECTS: Over a period of five years (1999-2004), the clinical and inheritance profiles of 26 male and 6 female patients with Kallmann syndrome from 12 families were evaluated at the National Center for Diabetes, Endocrinology and Genetics in Jordan. RESULTS: The patients belonged to twelve Jordanian and Palestinian families and their age at presentation ranged from 4 - 46 years. Nine boys aged 4-14 years presented with cryptorchidism and microphallus, all other males presented with delayed puberty, hypogonadism and/or infertility. The main presentation among six female patients was primary amenorrhea. Intrafamilial variability in clinical phenotype was specifically evident for renal abnormalities and sensorineural hearing impairment. Familial KS was diagnosed in 27 patients belonging to five families with the X-linked mode of inheritance and two families with the autosomal recessive mode of inheritance. CONCLUSIONS: (1) the majority of cases in this study represented the X-linked form of KS, which might point to a high prevalence of Kal 1 gene in the population. (2) Genetic counselling helps these families to reach a diagnosis at an early age and to decide about their reproductive options. (3) Children presenting with cryptorchidism and microphallus in our population should be investigated for KS.