PubMed Health⌕ Search

Biomedical subjects

N Sakati

Publications and source records attributed to N Sakati.

At least 19 recordsLinked to original sources
PubMed1999

Sanjad-Sakati and autosomal recessive Kenny-Caffey syndromes are allelic: evidence for an ancestral founder mutation and locus refinement.

The Sanjad-Sakati syndrome (SSS; MIM241410), an autosomal recessive trait characterized by congenital hypoparathyroidism, growth and mental retardation, seizures, and a characteristic physiognomy, was recently linked to chromosome area 1q42-q43. SSS resembles the autosomal recessive form of Kenny-Caffey syndrome (KCS; MIM244460), with similar manifestations but lacking osteosclerosis. Since KCS was recently linked to the region 1q42-q43, the possibility that this disorder is allelic with SSS was considered. Eight Sanjad-Sakati families from Saudi Arabia were genotyped with polymorphic short tandem repeat markers from the SSS/KCS critical region. A maximum multipoint LOD score of 14.32 was obtained at marker D1S2649, confirming linkage of SSS to the same region as autosomal recessive KCS. Haplotype analysis refined the critical region to 2.6 cM and identified a rare haplotype present in all the SSS disease alleles, indicative of a common founder. In addition to the assignment of the Saudi SSS and Kuwaiti KCS syndromes to overlapping genetic intervals, comparison of the haplotypes unexpectedly demonstrated that the diseases shared an identical haplotype. This finding, combined with the clinical similarity between the two syndromes, suggests that the two conditions are not only allelic but are also caused by the same ancestral mutation.

Abnormalities, Multiple↗
PubMed1999

Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency.

Pyroglutamic aciduria (5-oxoprolinuria) is a rare autosomal recessive disorder caused by either glutathione synthetase deficiency (GSSD) or 5-oxoprolinase deficiency. GSSD results in low glutathione levels in erythrocytes and may present with hemolytic anemia alone or together with pyroglutamic aciduria, metabolic acidosis, and CNS damage. Five patients with pyroglutamic aciduria were studied. All presented with hemolytic anemia and metabolic acidosis. Two (brothers) also had Fanconi nephropathy, which is not seen in pyroglutamic aciduria. Molecular analyses of the GSS gene was performed in 3 patients. RT-PCR and heteroduplex analysis identified a homozygous deletion in 1 patient and a homozygous mutation in 2 others (brothers with Fanconi nephropathy). Sequencing of glutathione synthetase (GSS) cDNA from the first patient showed a 141-bp deletion corresponding to the entire exon 4, whilst the corresponding genomic DNA showed a G491 --> A homozygous splice site mutation. Sequencing of GSS cDNA from the Fanconi nephropathy patients showed a C847 --> T [ARG283 --> CYS] mutation in exon 9.

Female↗
PubMed1998

Different faces of non-autoimmune diabetes of infancy.

The aim of this report is to describe four cases of non-autoimmune diabetes that presented in infancy. Three had transient neonatal diabetes mellitus (TNDM) with diabetic ketoacidosis at onset, followed by complete remission after several months of insulin treatment. While the fourth case was initially diagnosed as TNDM, she had renal, hepatic and pancreatic dysplasia. These cases illustrate that diabetes in infants can be difficult to diagnose and that patients with TNDM can have a recurrence of diabetes several years later.

Blood Glucose↗
PubMed1998

Four contiguous amino acid substitutions, identified in patients with Laron syndrome, differently affect the binding affinity and intracellular trafficking of the growth hormone receptor.

We have analyzed the GH receptor (GHR) gene in four individuals with Laron syndrome, and a missense mutation was identified for each patient in the extracellular domain of the GHR (D152H, I153T, Q154P, and V155G). The D152H mutation was previously reported. We have reproduced the three novel mutations in the GHR complementary DNA and analyzed their consequences in human 293 transfected cells. In cells expressing the I153T and V155G mutants, binding of [125I]human GH at the cell surface was very low, whereas binding to total membrane fractions was much less affected, suggesting impaired cell surface expression. Binding assays with cells expressing the Q154P mutant revealed severe defects both at the cell surface and in total particulate membrane fractions. Immunofluorescence experiments confirmed that cell surface expression of the three mutants was altered, and colocalization studies suggested that most of the mutant receptors are retained in the endoplasmic reticulum. Endoglycosidase H resistance tests also indicated that the majority of I153T and V155G GHRs are trapped in the endoplasmic reticulum. Thus, mutations on contiguous amino acids of the GHR result in various defects. The I153T, Q154P, and V155G mutations mainly affect intracellular trafficking and binding affinity of the receptor, whereas the D152H mutation affects receptor expression, dimerization, and signaling.

Adult↗
PubMed1997

A case of presumptive monosomy 21 re-diagnosed as unbalanced t(5p;21q) by FISH and review of literature.

By using fluorescence in situ hybridization (FISH), we demonstrate a case of monosomy 21 to result from an unbalanced translocation involving the short arm of chromosome 5 and the long arm of chromosome 21. Our case is compared to 3 similar cases of t(5p;21q) reported recently, which were also originally diagnosed as monosomy 21. The breakpoint on chromosome 5 in these cases occurred in the p13-p15 region, whereas the breakpoint on chromosome 21 was in the q21-q22 region. Comparison of the clinical findings in these patients demonstrated great similarities. Furthermore, a strong correlation between the clinical manifestations of these patients with cridu-chat syndrome patients was also noted. We suggest that cases with unbalanced t(5p;21q) represent a distinct syndrome which can be grouped under a new category of "5p/21q deletion syndrome."

Chromosomes, Human, Pair 21↗
PubMed1997

Gender reversal in 46XX congenital virilizing adrenal hyperplasia.

OBJECTIVE: To review the results of gender reversal in six patients with 46XX congenital virilizing adrenal hyperplasia (CVAH). PATIENTS AND METHODS: Fifty-one patients with 46XX CVAH were seen in an 8 year period; 45 were managed by conventional feminizing genitoplasty, but six underwent gender reversal and were managed as males. The clinical decision for gender reversal was made after appropriate counselling and was based primarily on parental choice, this being influenced significantly by a delayed diagnosis in four patients. Surgical management consisted of gonadectomy, excision of Müllerian structures and staged hypospadias repair/ chordee correction in four patients, and circumcision in two completely masculinized children. RESULTS: All six boys are well adjusted to their gender of rearing, with ages ranging from 3 years to 16.5 years (mean 8.5) at the time of review. Two children have normal penises and four have a satisfactory result after two-stage repair of hypospadias/chordee. CONCLUSION: Most patients with 46XX CVAH are preferably raised as females and require a feminizing genitoplasty. However, the clinical decision may be influenced by many factors, including delay in diagnosis, social bias and the premium on male rearing in certain communities. When male rearing is chosen, early gonadectomy and excision of Müllerian structures, together with staged hypospadias repair, gives satisfactory results.

Adolescent↗
PubMed1996

A novel mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor causes hereditary 1,25-dihydroxyvitamin D-resistant rickets.

Mutations in the vitamin D receptor (VDR) result in hereditary 1,25-dihydroxyvitamin D3-resistant rickets (HVDRR), an autosomal recessive disease caused by target organ resistance to the action of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. In this study, we investigated the molecular basis of HVDRR in a child from Saudi Arabia who was previously shown to be resistant to 1,25-(OH)2D3 action, but whose cultured skin fibroblasts exhibited normal [3H]1,25-(OH)2D3 binding. Using the PCR, exons 2 and 3 of the VDR gene that encode the DNA-binding region of the receptor were amplified and sequenced. A novel point mutation at nucleotide 252 in exon 2 of the VDR was identified. This missense mutation (GGC to GAC) resulted in the conversion of glycine to aspartic acid at amino acid position 46 (G46D), located at the base of the first zinc finger. This single base change was introduced into wild-type VDR complementary DNA by site-directed mutagenesis, and the mutant VDR was then expressed in COS-1 cells. The expressed mutant VDR displayed a normal binding affinity (Kd = 1.2 x 10(-10) mol/L) for [3H]1,25-(OH)2D3 as determined by Scatchard analysis. However, the mutant VDR was shown to have reduced binding affinity for DNA by DNA-cellulose chromatography. In COS-7 cells cotransfected with a vitamin D response element-chloramphenicol acetyltransferase reporter construct and the mutant VDR complementary DNA expression vector, the mutant VDR was unable to activate gene transcription in cells treated with up to 100 nmol/L 1,25-(OH)2D3. Restriction fragment length polymorphism analysis using MwoI restriction digests of exon 2 demonstrated that the affected child is homozygous for the mutation, whereas the child's father is heterozygous and a carrier of the defective allele. In conclusion, a new mutation was identified in exon 2 of the VDR gene. This mutation, which occurs in the first zinc finger of the DNA-binding domain of the receptor, blocks 1,25-(OH)2D3 action and leads to the syndrome of HVDRR.

Base Sequence↗
PubMed1995

Persistent hyperinsulinemic hypoglycemia of infancy: experience with 28 cases.

Twenty-eight infants with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) were seen during a 10-year period. There were 13 males and 15 females. Their age at time of presentation ranged from a few hours to 6 months. Consanguinity was reported in 20 cases (71.4%). One family had two affected siblings and two affected cousins, another had three affected siblings and one affected cousin, and three others had lost siblings because of hypoglycemia and seizures. The primary clinical presentation was jitters and seizures in association with hypoglycemia. The diagnosis was suspected when the therapeutic glucose requirement was found to be more than 12 mg/kg/min and also when there was a good response to glucagon after exclusion of metabolic and storage diseases. A high insulin-to-glucose ratio was noted for all patients. Twenty-two had near-total (90%) pancreatectomy; the result was excellent in all but four, who required supplemental medical therapy. Five patients were treated medically, and one patient's family refused treatment. Twelve patients sustained moderate to severe brain injury before referral. There were no deaths, and only one patient had evidence of malabsorption after the pancreatectomy. PHHI correlates well with consanguinity and family history. Clinical awareness is essential to permit early diagnosis and prompt medical and supportive therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Bone marrow transplantation for infantile malignant osteopetrosis.

PURPOSE: Most patients diagnosed with malignant osteopetrosis die during infancy or early childhood from hemorrhage and infection due to bone marrow failure. Allogeneic bone marrow transplantation (BMT) has been reported to provide curative therapy for this disorder. We report our experience with eight patients with malignant osteopetrosis who underwent BMT. PATIENTS AND METHODS: Between May 1987 and August 1992, eight children with malignant osteopetrosis underwent allogeneic BMT. Median age at BMT was 9 months (range, 2-36 months). Six patients received marrow from HLA-identical sibling donors, one from phenotypically matched father, and one from a one antigen mismatched father. BMT conditioning for all patients was busulfan 16 mg/kg and cyclophosphamide 200 mg/kg each administered over 4 days. Graft versus host disease (GVHD) prophylaxis included cyclosporin A in six patients or cyclosporin A and methotrexate in two patients. RESULTS: Six patients, including those who received bone marrow from their father's, engrafted as documented by bone marrow biopsy showing an increase in osteoclasts in all cases and by chromosomal analysis in four patients. Two patients died without engraftment. Three out of six patients engrafted are alive and well at the follow-up of 48, 63, and 81 months. Serum calcium, alkaline, and acid phosphatase levels normalized within 2 months. These patients have full bone marrow reconstitution. Serial radiologic studies revealed bone marrow remodelling and a new nonsclerotic bone formation. Vision improved dramatically in the youngest patient. CONCLUSION: BMT offers cure to patients with malignant osteopetrosis with reconstitution of bone marrow and correction of metabolic disturbances. In our experience, reversibility in neurosensory deficit is possible when BMT is done at an early age.

Bone Marrow Transplantation↗
PubMed1994

Ethylmalonic aciduria: an organic acidemia with CNS involvement and vasculopathy.

Five infants from 3 families, one Egyptian, two Yemeni, are described with a progressive encephalopathy, four of whom have been studied in detail. All patients showed vascular lesions of the skin, characterized by waxing and waning petechiae and ecchymoses. Acrocyanosis was present in three patients. All patients showed retinal lesions characterized by tortuous veins. Protracted diarrhea was not a consistent finding, although they had metabolic crisis in association with diarrhea. They did not show failure to thrive. The neurologic symptoms were indicative of a progressive pyramidal tract disease. Three patients died following sudden emergence of severe basal ganglia, putaminal and head of caudate lesions. In one patient the CT changes in brain were suggestive of infarction. The patients who died manifested pulmonary congestion, or wet lung, and respiratory difficulties during the terminal stage of the disease. In all patients before and during the terminal event, mild-to-moderate hematuria, and in two RBC in CSF, was observed. In one patient there was mild hemoperitoneum at the terminal event. The urine organic acids indicated increased excretion of ethylmalonic, methylsuccinic, glutaric, and adipic acids. The patients invariably showed lactic acidosis, but no ketosis, during and in between the acidotic attacks of the disease. The acylcarnitine profile in blood of two patients showed a pronounced increase in C4 and C5 carnitine esters. In three patients, biopsies from petechiae indicated absence of an immune event, showing only fresh hemorrhage. An immunologic study in one patient was normal for the suppressor:cytotoxic lymphocyte ratio and concentration of interleukin-2 receptor during and in between hemorrhagic attacks. The cytochrome c oxidase activity in fibroblasts was normal. The rate of oxidation of glucose, leucine, isoleucine, valine, propionate and butyrate by fibroblasts was normal. The disease is not responsive to treatment with riboflavin, ascorbic acid, vitamin E, glycine, or carnitine. One patient remained stable on prolonged large doses of methylprednisolone. The biochemical defect leading to ethylmalonic aciduria in this disease remains unknown.

Acidosis↗
PubMed1994

Familial growth hormone deficiency: a model of dominant and recessive mutations affecting a monomeric protein.

Two families with familial isolated GH deficiency (IGHD) were studied, type II (autosomal dominant) and type I (autosomal recessive), whose GH1 genes exhibit cosegregation with IGHD. DNA sequencing of the GH1 genes of the first family (IGHD II) demonstrated heterozygosity for a T-->C transition in the sixth base of the donor splice site of intron III. The GH1 gene mutation in the second family (IGHD I) was found, in a previous study, to be a G-->C transversion altering the first base of the donor splice site of intron IV. Interestingly, analysis of the transcripts derived from the mutant IGHD II allele revealed that the sequences corresponding to exon III were absent due to an exon skip that causes the loss of amino acids 32-71 from the mature GH protein. In contrast, the IGHD I mutation activates a cryptic donor splice site 73 bases upstream of the normal exon IV donor splice site causing loss of amino acids 103-126 of exon IV followed by a reading frameshift and synthesis of 94 novel amino acids before chain termination 88 nucleotides downstream of the normal GH stop codon. It is hypothesized that, because of the loss of protein sequences derived from exons IV and V, the IGHD I mutation products are not transported to secretory granules and thus cannot perturb secretion of the normal monomeric GH protein. In contrast the T-->C IGHD II mutant allele product retains these sequences and is transported to secretory granules where it can interact with the normal allele product producing a dominant-negative effect at the protein level.

Adolescent↗
PubMed1993

Heterogeneous growth hormone (GH) gene mutations in familial GH deficiency.

The GH1 genes of probands of two families with familial isolated GH deficiency (IGHD) were sequenced. Double stranded sequencing of the polymerase chain reaction (PCR) amplification products from genomic DNA of two affected cousins in a consanguineous Turkish family revealed a G-->A transition in the 20th codon of the GH1 signal peptide. This substitution converts a TGG (Trp) to a TAG (stop) codon and generates a new AluI recognition site. PCR amplification of the GH1 alleles of family members, followed by AluI digestion, revealed that the G-->A transition segregated with the IGHD phenotype. In a Saudi Arabian family, a G-->C transversion was found that alters the first base of the donor splice site of intron IV. This substitution should perturb mRNA splicing, resulting in an altered protein product which should be unstable or bioinactive. This transversion also destroys an HphI site, which was used to assay samples from relatives. Digestion of PCR amplification products with HphI demonstrated cosegregation of the G-->C transversion with IGHD. These results demonstrate that familial IGHD is a heterogeneous disease that perturbs different steps in the expression of the GH1 gene.

Base Sequence↗
PubMed1992

Saudi variant of multiple sulfatase deficiency.

We describe eight patients with multiple sulfatase deficiency (MSD, or Austin's disease) who differ phenotypically from classic neonatal-, childhood-, or juvenile-onset MSD. The age of onset was in childhood. The patients presented with somatic and facial features of mucopolysaccharidosis reminiscent of Maroteaux-Lamy and Morquio syndromes. They differed from classic MSD by the presence of corneal cloudiness, macrocephaly, severe dysostosis multiplex, and gibbus and the absence of ichthyosis, retinal degeneration, severe deafness, severe mental retardation, and dementia. The main neurologic presentation was cervical cord compression due to axis abnormalities. Despite neuroradiologic evidence of white-matter changes, neurologic presentation was not like metachromatic leukodystrophy. The sulfatase deficiencies were more marked than in the classic juvenile form of MSD, but less marked than in the classic childhood-onset form of MSD. Steroid sulfatase activity was spared except in one patient. This Saudi variant of MSD accounts for 5% of all lysosomal storage diseases in the Cell Repository Registry of our Inborn Errors of Metabolism Laboratory.

Child↗
PubMed1992

Unknown dysmorphic syndromes and development delay in Saudi Arabia.

Forty-four Saudi Arabian patients with unknown dysmorphic syndromes were studied with respect to their level of cognitive delay. The relationship between such delay and particular patterns of dysmorphic features, as well as various demographic and historical data, were also investigated. Prognostication and genetic counseling are difficult for this group because little is known about morbidity or other factors. These concerns, along with broader issues, stimulated this study. Significant associations were found between level of cognitive function and consanguinity, abnormal motor and language milestones, and abnormal electroencephalograms. No significant relationship was found between various dysmorphic feature clusters and measured cognition. Concerns were expressed about demands on family and community for these children, as well as possible larger issues in this heavily consanguineous society. Further research, including epidemiologic studies, was recommended.

Abnormalities, Multiple↗
PubMed1991

Osteodysplastic variant of primordial dwarfism.

A patient with intrauterine growth retardation and marked postnatal retardation of growth had microcephaly and the orofacial and dental characteristics of the Seckel phenotype. In addition she had short forearms, metaphyseal flare, especially of the distal femora, triangular distal femoral epiphyses, and pseudoepiphyses of the hands, all characteristics of an osteodysplastic variant. Parental consanguinity suggests autosomal recessive inheritance.

Abnormalities, Multiple↗
PubMed1989

Cystic fibrosis in Saudi Arabia.

Cystic fibrosis (CF) is generally believed to be rare or nonexistent in Saudi Arabia. The aim of this report is to document the occurrence of CF in Saudi Arabia. Thirteen Saudi children were diagnosed as having CF, evidenced by typical clinical features and elevated sweat chloride concentrations (greater than 60 mmol/l). Duration of symptoms prior to diagnosis varied from 1 month-5 years (mean 23 months). The main clinical manifestations of the children were abdominal distention, failure to thrive, steatorrhoea, hepatomegaly, rectal prolapse and recurrent respiratory infections, often with Pseudomonas aeruginosa. In addition, eight patients with symptoms and a family history highly suggestive of CF, but without confirmatory sweat test results are presented. We hope that this report will increase the awareness of CF and ensure an earlier diagnosis of the disease in Saudi Arabia.

Child, Preschool↗