Relationship between biochemical bone markers and bone mineral density in patients with phenylketonuria under restricted diet

Most of phenylketonuria [PKU] develops bone turnover impairment and low bone mineral density [BMD]. Measurements of BMD reflect only bone mineral status but not the dynamics of bone turnover. Bone markers are a noninvasive tool useful for the assessment of bone formation and bone resorption processes. Our study was to assess the levels of bone markers in PKU in order to select a screen marker and detect the most specific marker which can be combined with BMD for appropriate follow up. Thirty three classic PKU patients were studied. BMD and bone mineral content [BMC] were measured. Total alkaline phosphatase [ALP], osteocalcin [OC] and carboxy-terminal propeptide of type I collagen [CICP], osteoprotegerin [OPG], receptor activator of nuclear factor kappa beta ligand [RANKL] and Deoxypyridinoline [DPD] were measured. Nineteen [57.6%] male and fourteen [42.4%] female PKU patients were involved in the current study. Their mean age was 8.4 +/- 4.6 yrs and the age range 3-19 yrs. The control group consisted of twenty two [52.4%] males and twenty [47.6%] females. Their mean age was 8.5 +/- 3.3 yrs and th age range 2-17 yrs. Using the Z score values, there was a significant decrease of total BMC [TBMC-Z], BMD of the femoral neck BMD-FN-Z, BMD of lumbar vertebrae [BMD-L-Z], BMD-FN and DPD while RANKL increased. There was a negative correlation between CICP and TBMC and between CICP and BMD-L in these patients. Also, a negative correlation between ALP and TBMC and between ALP and BMD-L was observed. It was concluded that the ALP provides a good impression of the new bone formation in the PKU patients and it has a highly significant negative correlation with the many parameters of the bone mineral status beside the wide availability of inexpensive and simple methods. So a screening test and/or follow up for the PKU patients using ALP would be available. Once the level of ALP decrease is detected, one can combine it with BMD to explore the bone mineral status and with specific bone markers [OC, RANKL and DBD], to verify the dynamics of bone turnover. This schedule will reduce the risk of exposure of these patients to the risk hazards of DXA and limit its use only to a limited number of the highly suspected cases

Clinical and molecular findings in eight Egyptian patients with suspected mitochondrial disorders and optic atrophy

Mitochondrial respiratory chain disorders [RCD] are a group of genetically and clinically heterogeneous diseases, caused due to defects of the respiratory chain. This study aimed to investigate the presence of common mtDNA point mutations in tRNALeu [UUR], tRNALys, MT-ATPase 6, MT-ND4, MT-ND1, MT-ND6 genes in eight Egyptian patients suspected to have mtDNA disease and optic atrophy. PCR-RFLP analysis was done for the detection of 3243A > G, 327IT > C, 8344A > G, and 8993T > G/C mtDNA point mutations. DNA direct sequencing was pursued for the detection of 11778G > A, 3460G > A and 14484T > C mtDNA point mutations. No point mutation of 3243A > G, 327IT > C, 8344A > G, and 8993T > G/C was detected in our group of patients. Four mtDNA polymorphisms in MT-ND1 and MT-ND4 genes [11467A > G, 11719G > A, 3348A > G and 3357G > A] were detected in three patients. Mitochondrial disorders are caused by a variety of genetic and racial factors, which differ among populations. The negative results of this study indicate that the chosen mutations might not be specific in Egyptians. Another explanation might be due to the low heteroplasmic levels of the mtDNA mutation. A registry for the different mtDNA mutations in Egyptian patients is highly recommended

impact of prenatal diagnosis in Egyptian families with Duchenne muscular dystrophy

Duchenne Muscular Dystrophy [DMD] is one of the most common lethal X-linked recessive genetic muscle disorders. It is caused by various mutations in the dystrophin gene. Due to the lack of efficient rehabilitation and treatment, prenatal diagnosis and proper genetic counseling of families with DMD are of great importance. This study aimed to evaluate an Egyptian prenatal molecular experience considering the impact of molecular information, the availability of prenatal diagnosis, and the changing attitude and choices of the Egyptian families with DMD. The study characterized the deletion patterns in 85 Egyptian patients with DMD and 32 fetuses from 27 mothers with previous history of DMD deletion mutations. Multiplex PCR amplification of 18 exons covering the two hotspots within the dystrophin gene was pursued to detect deletions in the probands. Detection of deletions in the fetal DNA was performed by using the targeted multiplex containing the deleted exons. Forty-six out of eighty-five probands [55%] had deletion mutations. Twenty-four out of the forty-six [52%] probands had multiple exons deletion and twenty-two [48%] showed single exon deletion. Out of the thirty-two amniotic fetal samples, fourteen fetuses inherited the same deletions present in the index cases while eighteen were normal. An emerging awareness of genetic information was observed and an apparent higher number of mothers seeking prenatal diagnosis was noticed. A change of attitude in favor of choosing the decision of abortion was apparent. Molecular diagnosis is an important tool for preventive medicine. It has an obvious impact on prenatal diagnosis and accurate genetic counseling. It also seems to have an impact on the attitude and choices of families in particular and society in general

Molecular characterization of 21 hydroxylase deficiency congenital adrenal hyperplasia in Egyptian children: a pilot study

Defective steroid synthesis due to derangements of 21-hydroxylase gene [CYP21] constitutes the most frequent cause of congenital adrenal hyperplasia [CAH] and is one of the most frequent inborn errors of metabolism world wide. The molecular basis of CYP21 mutations is complicated. During meiosis gene conversion occurs and transfers deleterious point mutations from the inactive [CYP21P] to the corresponding sequence of the CYP21 gene causing either complete or partial inactivation of 21-hydroxylase activity. Allele specific polymerase chain reaction [ASPCR] was used for the detection of the 4 most common mutations in CYP21 gene: Intron 2 splice mutations [IVS2-13], 8bp deletion in exon 3 [del-8bp], I172N mutation in exon 4 and V281L mutation in exon 7, in 11 salt wasting SW-CAH Egyptian infants. In the examined 22 alleles, 2 alleles were carrying del-8bp, 3 were carrying IVS2-13 mutation, 4 with I172N, 4 with V281L. In the present study the percentage of undetectable mutations was 50%. The wide range of genetic mutations reported for CYP21 gene reconfirm the marked heterogeneity of the disorder among Egyptian and calls for more extensive molecular work

Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density in postmenopausal Egyptian women

Low bone mineral density is a major risk factor for development of osteoporosis. The estrogen receptor alpha gene is a candidate locus for genetic influence on bone mass. The possible association between two polymorphisms in the first intron of this gene, independently or in combination, and bone mineral density was widely studied in different population. In the present study, the relationship of TC [Pvull] and AG [Xbal] polymorphisms to variability in bone mineral density [BMD] was determined in 69 unrelated postmenopausal Egyptian women aged 43-75 years. All of the participants were non-smoker with no history of medication affecting bone loss or bone turnover. Hepatic and renal investigations were evaluated to ensure normal functions. BMD at the calcaneous bone was measured by peripheral computed tomography and expressed as t-values for the corresponding age. Analysis of the TC [Pvull] and AG [Xbal] polymorphisms revealed that BMD was significantly lower in women with homozygous absence of the restriction sites, in other words, women with the PP genotype showed significant reduction in their bone mass than in those with the pp genotype. And women with the XX genotype showed significant lowered BMD compared to those with Xx then xx genotypes. Analysis of combined genotypes in the same sample revealed that BMD was significantly lower in Egyptian women with the PPXX genotype [ANOVA, P= 0.002] than in those with the PpXx genotype [ANOVA, P= 0.022]. The xxpp genotype did not exhibit any significance association with the reduced BMD in either the osteoporotic or osteopenic groups. The overall distribution of ER Pvull and Xbal genotypes frequency identified in the present study: Pp 55%, pp 20%, PP 17%, Xx 55%, xx 30%, XX 10% is consistent with that found in the postmenopausal American white women, and postmenopausal Italian women, as the heterozygous [ +/- ] Pvull or Xbal genotype is the most prevalent one then the homozygous presence of restriction site, [+/+] genotype, followed by the homozygous absence of the restriction sites, [-/-] genotype is the least prevalent one. Identified allele frequencies [P= 0.52, p= 0.48 and X= 0.42, x= 0.58] at the two polymorphisms are in Hardy-Weinberg equilibrium. Results of the present analysis, which to the best of our knowledge is the first one in our population, suggest that testing for ER Pvull and Xbal restriction fragment length polymorphisms might be useful in screening and identifying postmenopausal Egyptian women at risk for developing osteoporosis, PPXX followed by PpXx genotypes were found to be associated with reduction in BMD in our population

Allele profiles of short tandem repeat loci in Egyptians

In this study, relative allele frequencies of 4 short tandem repeats [STR] loci in 47 unrelated subjects from Egyptian population as a primary step for forming a nationwide database was reported. The sample represented various geographical, ethnic and religious backgrounds that constituted contemporary Egyptian population. DNA was extracted from whole blood using salting out method. The allele patterns in Egyptian sample showed high levels of heterozygosity over 74% in 3 loci. The interpopulation differences were least detected with Caucasians and most with Asian and Hispanic Americans