Genetics in the Third Millennium
Volume:4 Issue: 3, 2006

Spinal muscular atrophy (SMA) is a common neuromuscular disorder with progressive paralysis caused by the loss of α–motor neuron in the spinal cord. SMN is encoded by two genes, SMN1 and SMN2, which essentially differ by a single nucleotide in exon 7. The most frequent mutation is biallelic deletion of exon 7 of the SMN1 gene. A small percentage of SMA patients present compound heterozygosity with a point mutation on one allele and deletion on the other. In the remaining cases, the disease is unlikely to be related to SMN1 defects. In spinal muscular atrophy (SMA), SMN2 is not able to compensate for the loss of SMN1 due to exclusion of exon 7. The aim of our study was to estimate the frequency of the common exon 7 SMN1 deletion in the families who referred to our center for carrier detection and prenatal diagnosis. Between March 1999 and March 2006, one hundred sixty seven families with history of at least one affected member were referred to us. We performed detection of deletion exon 7 SMN1 for the patients and carrier detection for their parents, prenatal diagnosis in subsequent pregnancies to couples who previously had an affected child became possible (63 prenatal diagnosis). From 167 families, 139 categorized in type I of the disease, 21 in type II, and 7 in type III. Carrier detection for the parents indicated that in 96 families with history of affected member with type I SMA both parents carried the deletion in exon 7 and in 20 families, one of the parents was carrier. These rates were 16 to 1 for SMA type II, and 3 to 2 for type III SMA. Sixty-four children affected with SMA were studied, 58 of them were found to be homozygous for the loss of exon 7 of the SMN1 gene, except two patients who were heterozygote for exon 7 deletion (frequency of homozygocity: 90.7%). Eleven of sixty-three (17.5%) fetal samples were found to be affected and these pregnancies were terminated. The molecular analysis of the biallelic exon 7 of the SMN1 deletion is a standard and reliable test in cases of SMA.

Upon a scientific collaboration, families having affected offspring suspected for MPS disease were enzymaticaly analyzed. In 82 families the deficit enzymes were detected. Seventy prenatal diagnosis for parous at risk were performed, revealing 53 unaffected and 17 affected fetuses. All families with affected fetuses opted for pregnancy termination. The prenatal result of unaffected newborns confirmed the prenatal diagnosis findings. The summary of clinical findings and epidemiological distribution of MPS disorders and PND results are presented in this short report.

Peroxisomes are organelles present in all eukaryotic cells from yeast to human cells. It is now well known that approximately fifty different biochemical reactions occur within the peroxisome, including synthesis of bile acids, cholesterol, ether-phospholipids (plasmalogens), docosahexaenoic acid and catabolism of certain fatty acids, particularly very long chain fatty acids (VLCFAs). Proteins involved in peroxisomal function are known as peroxins. At least 29 peroxins are required for peroxisome membrane biogenesis, fission, and protein import. So far, mutations in 13 genes that encode peroxins are associated with human disease. Peroxisomal disorders currently falling into one of three groups peroxisome biogenesis disorders (PBDs), peroxisomal multi-enzyme disorders, and peroxisomal single-enzyme disorders. Infantile Refsum’s disease (IRD), neonatal adrenoleukodystrophy (NALD) and Zellweger’s syndrome (ZS) are different variants of a group of congenital diseases known as peroxisome biogenesis disorders. These disorders are characterized by the absence of normal peroxisomes in the cells of the body which mostly are fatal. Here we describe molecular events that cause these deficiencies and we introduce current molecular approaches for diagnosis of these disorders like mutation analysis and fibroblasts characterization derived from the patients.

Molecular studies have shown that several genes with various functions are induced by environmental stresses such as drought, high-salinity and low temperature in plants. Most of the dehydration responsive genes are induced by the plant hormone abscisic acid (ABA), but others are not. Expression analyses of dehydration-responsive genes have provided at least four independent regulatory systems (regulons) for gene expression in a model plant Arabidopsis thaliana. The cis- acting elements in the promoters of some genes that have a typical stress-inducible expression profile and the transcription factors that affect the expression of these genes have been analyzed. Transcription factors that bind to a DRE/CRT (Dehydration-responsive Element / C-Repeat) cis-acting element were isolated and termed DREB1/CBF (DRE-binding protein 1/ C-repeat Binding Factor) and DREB2 (DRE-binding protein 2). Overexpression of DREB1/CBF in transgenic Arabidopsis plants increased tolerance to freezing, drought and high salt concentrations. The DREB1/CBF genes have been successfully used to improve abiotic stress tolerance in a number of different crop plants. Studies on the other transcription factors associated with stress response are in progress. It is expected that the results of these studies will contribute to the sustainable food production in developing countries and help to prevent the global-scale environmental damage.

Early amniocentesis is a new context in prenatal diagnosis. However, the consequences of this procedure are not known clearly. We compared cytogenetic results of 655 amniotic fluid samples obtained at 12-14 gestational weeks (early amniocentesis, EA) and 804 samples at 15-18 gestational weeks (mid-trimester amniocentesis, MA). The rate of chromosomal abnormalities for early amniocentesis was 3.2% (21 cases) and for mid-trimester amniocentesis was 5.3% (43 cases) (p=0.047). True mosaicism was seen in 2 cases MT group (p=1.000). We did not have maternal cell contamination in either group. The ratio of repeat amniocentesis was 0.6 percent in the EA group compared with 0.2 percent in MA group (p=0.417). Procedure-related early abortion (within the first 30 days after amniocentesis) was seen in 4 cases of EA (2.2%) and 3 cases of MA (1.5%) (p=0.719). Hemorrhage occured in the same ratio. Intra-uterine fetal death (IUFD) was seen in 7 cases of MA, but not in any cases of EA (p=0.015). Our findings showed comparable outcome in two method of amniocentesis, except for lower chromosomal abortion rate and IUFD.

Peroxisomes are responsible for a number of very important metabolic reactions, including synthesis of glycerol ethers, shortening very long chain fatty acids (VLCFAs C24:O and C26:O), and oxidation of the side chain of cholesterol needed for bile acid production. Peroxisomal biogenesis disorders (PBDs) are genetically and phenotypically related disorders that involve enzymatic activities of peroxisomes. They are rare mostly autosomal recessive diseases characterized by multi-systemic structural and functional abnormalities. A number of biochemical abnormalities have been described in PBD patients including decreased levels of plasmalogens, and increased levels of VLCFAs and cholestanoic acid derivatives. More than 25 different entities have been diagnosed and reported in the last two decades. The most severe condition is the Zellweger syndrome, a condition due to the absence of functional peroxisomes. Affected patients are severely ill, and show multiple congenital anomalies and neurological aberrations. Chondrodysplasia punctata is another example they are genetically heterogeneous group of dysplasias having stippling of the epiphyses in infancy as a common feature. Peroxisomal abnormalities only found in the rhizomelic type I. There are specific biochemical tests for evaluating peroxisomal functions. The diagnoses on suspected cases can now be confirmed precisely by detailed biochemical evaluation and molecular analysis in some metabolic centers. Accumulation of certain VLCFAs (C24:0, and C26:0) deficiency of plasmalogens, and elevation of phytanic acid are some of them. Herein we report 10 Iranian families with 15 affected cases of Zellweger syndrome and rhizomelic type I chondrodysplasia punctata (RCDP I).

Freeman-Sheldon syndrome is a morphologically well-defined syndrome that results in a dysmorphic status combining bone anomalies and joint contractures with characteristic facies. FSS (Freeman-Sheldon Syndrome) is also known as craniocarpotarsal dysplasia (or dystrophy), distal arthrogryposis type IIA (DAIIA), whistling face syndrome, and whistling face-windmill vane hand syndrome. The syndrome is an autosomal dominant trait and characterized by flattened, mask-like facies, microstomia, protruding lips (as in whistling), deep-set eyes with hypertelorism, and camptodactyly with ulnar deviation of the fingers and talipes equinovarus. We are reporting 6 cases with this syndrome that were referred to our genetic center from 2000 to 2006 for cytogenetic study and clinical genetic counseling.

We report a case of complete tetraploidy in amniotic fluid culture obtained at 14 weeks of pregnancy. Amniocentesis was performed in this pregnancy because of high maternal age and history of offspring with meningomyelocele. Ultrasonography at that time, revealed a single fetus with normal fetal activity and heart beat. Amniotic fluid volume was normal. The amniotic fluid obtained was yellow and clear. It was cultured in two flasks. Growth was very slow in one culture with no growth in the other. Harvest was possible after 3 weeks which revealed tetraploidy in all studied plates. Alpha feto protein of amniotic fluid was 24.1 KIU/m (normal range 11.1-48, for 15 weeks). A repeat culture was performed at 18 weeks of gestation and a FISH analysis was performed using X and Y centromeric probes. Repeat culture revealed 46, XY pattern in 89 out of 90 studied plates. Only one plate revealed tetraploidy. Two hundred interphase cells were studied for the FISH analysis and 98% had one single X and one single Y signal. Ultrasonography at 18 weeks of pregnancy revealed no abnormality. A healthy male infant was born at term and is doing well. We conclude that abnormal karyotypes in poor growth cultures could be misleading and have to be confirmed with repeat cultures.

Fabry disease is an X-Linked lysosomal storage disease, caused by deficient activity of lysosomal enzyme α-galactosidase A. The accumulation of globotriaosylceramide (GL-3) in the lysosomes causes lysosomal and cellular dysfunction and this in turn triggers the cascade of cells and tissue ischemia and fibrosis. The classic phenotype of Fabry disease is seen in most males with no enzyme activity and it affects multiple organ-systems. The early clinical manifestation of the disease occur in childhood with episodes of severe pain in the extremities (acroparesthesia), hypohidrosis, corneal and lenticular changes, and skin lesions (angiokeratoma). The renal failure, cardiovascular disease and stroke are the major causes of morbidity and mortality occurring later in life. Due to random chromosome X inactivation (Lyonization), the carrier females of Fabry disease may experience Fabry disease-related symptoms including acroparesthesia, gastrointestinal complains, renal and cardiac disease and/or strokes. In this article, after brief review of clinical presentations and diagnostic tests for the disease, we review the present therapeutic approaches and future directions in management of patients with Fabry disease.