AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder.

Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH) due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a potentially treatable early-onset neurodegenerative disease.

The very low density lipoprotein receptor-associated pontocerebellar hypoplasia and dysmorphic features in three Turkish patients.

Pontocerebellar hypoplasia consists of a rare heterogeneous group of congenital neurodevelopmental disorders characterized by hypoplasia and atrophy of the cerebellar cortex, dentate and pontine nuclei, and inferior olives. The very low density lipoprotein receptor protein is an integral part of the reelin signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. Mutations in this receptor cause nonprogressive cerebellar ataxia, mental retardation, and cerebellar hypoplasia. In this report, we present 3 patients from 2 different families displaying very low density lipoprotein receptor-associated pontocerebellar hypoplasia, cortical dysplasia, mental retardation, and bipedal gait. One of the siblings has also displayed dysmorphic features, as we previously reported before the identification of the genetic defect in this family.

Exome sequencing can improve diagnosis and alter patient management.

The translation of "next-generation" sequencing directly to the clinic is still being assessed but has the potential for genetic diseases to reduce costs, advance accuracy, and point to unsuspected yet treatable conditions. To study its capability in the clinic, we performed whole-exome sequencing in 118 probands with a diagnosis of a pediatric-onset neurodevelopmental disease in which most known causes had been excluded. Twenty-two genes not previously identified as disease-causing were identified in this study (19% of cohort), further establishing exome sequencing as a useful tool for gene discovery. New genes identified included EXOC8 in Joubert syndrome and GFM2 in a patient with microcephaly, simplified gyral pattern, and insulin-dependent diabetes. Exome sequencing uncovered 10 probands (8% of cohort) with mutations in genes known to cause a disease different from the initial diagnosis. Upon further medical evaluation, these mutations were found to account for each proband's disease, leading to a change in diagnosis, some of which led to changes in patient management. Our data provide proof of principle that genomic strategies are useful in clarifying diagnosis in a proportion of patients with neurodevelopmental disorders.

MTHFR C677T polymorphism and its relationship to myocardial infarction in the Eastern Black Sea region of Turkey.

BACKGROUND AND AIMS: An association of homozygous MTHFR 677T genotypes with elevated plasma homocysteine level has been documented, but results are still controversial. We aimed to investigate prevalence of the C677T polymorphism in patients with acute myocardial infarction (MI) in the Eastern Black Sea region of Turkey. METHODS: We studied genomic DNA of 231 unrelated patients (aged 59 ± 13 years; 175 male, 56 female) with first anterior acute MI and 242 healthy controls (aged 54 ± 19 years; 182 male, 60 female) using real-time polymerase chain reaction kits for the MTHFR C677T mutation. RESULTS: Prevalence of MTHFR C677T mutant genotype was 49.1% (CT: 45.8%, TT: 3.3%) in controls and 48.45% (CT: 38.5%, TT: 9.95%) in patients with acute MI. The TT mutation was more frequent in patients with acute MI than in controls (9.95 vs. 3.3%) (OR; 3.23, 95% CI; [1.34-8.05], p = 0.003). CONCLUSIONS: The MTHFR gene homozygote TT mutation is a risk factor for patients with MI in the eastern Black Sea Turkish Population.

Distal femoral duplication and fibular agenesis associated with congenital cardiac defect.

A newborn, who had the congenital anomalies including protuberance on the right lower leg, bilateral equinovarus deformity of the feet, genu valgum with knee flexion deformity, syndactyly between the first and the second digit on the right, in addition with the absence of the fifth digit. Echocardiography revealed a secundum type atrial septal defect. The combination of these congenital defects associated with developmental anomalies of lower extremities. We discuss the clinical, radiological findings and pathogenesis of this lower extremity malformation.

Severe form of Cockayne syndrome with varying clinical presentation and no photosensitivity in a family.

We report six patients with Cockayne syndrome type B without photosensitivity. The patients are from the same inbred family and exhibit variable clinical features. The main clinical manifestations were progressive encephalopathy including intracranial calcification and white-matter lesions, dwarfism without growth hormone deficiency, senile appearance, mental and motor retardation, atrophy of subcutaneous fat tissue, severe pectus carinatus, and spasticity. Clinical photosensitivity was not observed in any patient. Other clinical findings were cataract, pigmentary retinopathy, and peripheral neuropathy. The onset of the disease was between 3 and 6 months of age. Molecular genetic analyses in the family established linkage to ERCC6, the gene responsible for Cockayne syndrome type B, confirming the clinical diagnosis.

Chromosomal abnormalities in 457 Turkish patients with MCA/MR.

The evaluation of multiple congenital abnormalities and/or mental retardation (MCA/MR) is always a challenge to clinicians. The recognition of specific physical or behavioral characteristics can vastly improve diagnostic yield. Chromosomal abnormalities account for a high percentage in the etiology of MCA/MR. In this study, frequency of chromosomal abnormalities was 4.81% of 457 patients. Chromosomal abnormalities and polymorphisms were detected in 65 (14.21%) (structural and numerical chromosomal abnormalities in 22 patients and polymorphisms in 43) of 457 MR and/or MCA patients. Our results show that chromosomal abnormalities contribute much to the causation of multiple malformations and/or MR. It is essential that fluorescence in situ hybridization (FISH) be used in conjunction with standard methods in order to maximize obtainable information for better management of patients with MR and/or MCA.

A comparison of sister chromatid exchanges in lymphocytes of anesthesiologists to nonanesthesiologists in the same hospital.

An increased incidence of sister chromatid exchanges (SCEs) in peripheral lymphocytes of operating room personnel exposed to waste anesthetic gases has been reported. We investigated whether the increase of SCEs in anesthesiologists was reversible. Twenty-five anesthesiologists exposed to waste anesthetic gases such as sevoflurane and nitrous oxide were compared with nonexposed internists working in the same hospital. The concentrations of sevoflurane and nitrous oxide in the operating rooms were measured. The incidence of SCE was measured in lymphocytes cultures of anesthesiologists before and after a 2-mo leave from the operating room. These values of SCE were compared with those of nonexposed physicians. Occupational exposure to sevoflurane and nitrous oxide in the operating rooms were above the threshold values. There was a significant difference in SCE values of the anesthesiologists compared with the nonexposed physicians (11.9 +/- 4.4 versus 4.2 +/- 1.1, P < 0.001). After a 2-mo leave from the operating room, the SCE values of the anesthesiologists were significantly lower compared with those taken before the leave (4.8 +/- 1.8 and 11.9 +/- 4.4, respectively, P < 0.001). We conclude that the increase of SCE in anesthesiologists exposed to increased environmental concentrations of waste anesthetics gases, such as sevoflurane and nitrous oxide, are reversible if they work free from exposure for 2 mo.

The frequency of chromosomal abnormalities in patients with reproductive failure.

OBJECTIVE: To investigate the ratio of chromosomal abnormalities in recurrent fetal wastage. STUDY DESIGN: We conducted a study of the cytogenetic data of 645 couples (1290 patients) with recurrent fetal wastage examined at the Department of Medical Biology and Genetics, Trabzon, Turkey. Couples who had first trimester miscarriages/abortion, preceded or followed by a second or third trimester fetal death/fetal abnormalities were recruited from Obstetrics and Gynecology Clinics for cytogenetics analysis. RESULTS: Chromosome abnormalities were found in 25 (3.86%) patients. The chromosomal abnormalities were structural (3.71%) and numerical (0.15%). Polymorphisms of heterochromatin blocks and inv(9) were shown in 115 (17.51%) patients. CONCLUSIONS: Chromosome analyses are an important and necessary part of the etiological research in couples with recurrent fetal wastage.

Detection of chromosomal aberrations in prostate cancer by fluorescence in situ hybridization (FISH).

PURPOSE: Fluorescence in situ hybridization (FISH) is a powerful tool for quantitative analysis of chromosomes and genes and can be applied in a variety of specimens, including cell cultures, isolated nuclei from fresh and fixed tissues, and histological tissue sections. For detection of numerical chromosome aberrations, we examined prostatic cancer samples at our department. In addition, we also observed primary and secondary aberrations taking part in the initiation and progression of tumours. MATERIALS AND METHODS: FISH using chromosome-specific alpha-satellite DNA probes for chromosomes 7, 8, 9, 10, 17, X and Y was performed on 19 prostatic cancer and 19 benign prostatic hyperplasia (BPH) samples obtained from transurethral resection (TUR) and archival paraffin-embedded blocks. RESULTS: Numerical aberrations were observed in 41% of the tumours studied. A range of aberrant copy numbers of chromosome 9 (68%), 7 (63%), 8 (58%), 17 (37%), Y (32%) and 10 (26%) was observed. We did not observe significant aberrations in BPH samples. In prostate cancer patients, chromosomes 7 (47%), 8 (58%) and 9 (63%) were monosomic by FISH. Monosomy 8 and 9 were significant differences (p>0.05) between prostate cancer and BPH patients. CONCLUSIONS: FISH analysis could be observed an one of strongest methods of analysis in detecting numerical aberrations of individual chromosomes with application to paraffin-block samples, metaphase and, interphase nuclei. To our knowledge, this analysis is firstly studied in Turkish patients. Therefore, results of this analysis may be important for Turkish patients.