A molecular genetic analysis of childhood nephrotic syndrome in a cohort of Saudi Arabian families.

Nephrotic syndrome (NS) is a renal disease characterized by heavy proteinuria, hypoalbuminemia, edema and hyperlipidemia. Its presentation within the first 3 months of life or in multiple family members suggests an underlying inherited cause. To determine the frequency of inherited NS, 62 cases (representing 49 families with NS) from Saudi Arabia were screened for mutations in NPHS1, NPHS2, LAMB2, PLCE1, CD2AP, MYO1E, WT1, PTPRO and Nei endonuclease VIII-like 1 (NEIL1). We detected likely causative mutations in 25 out of 49 families studied (51%). We found that the most common genetic cause of NS in our cohort was a homozygous mutation in the NPHS2 gene, found in 11 of the 49 families (22%). Mutations in the NPHS1 and PLCE1 genes allowed a molecular genetic diagnosis in 12% and 8% of families, respectively. We detected novel MYO1E mutations in three families (6%). No mutations were found in WT1, PTPRO or NEIL1. The pathogenicity of novel variants was analyzed by in silico tests and by genetic screening of ethnically matched control populations. This is the first report describing the molecular genetics of NS in the Arabian Peninsula.

Long-term follow up of carbonic anhydrase II deficiency syndrome.

OBJECTIVE: To describe the long term clinical, biochemical and radiological features of 35 Saudi Arabian children with carbonic anhydrase II deficiency syndrome who have been followed at King Faisal Specialist Hospital and Research Center, Riyadh since 1979. METHODS: The records of these patients were retrospectively evaluated. The diagnosis was based on the clinical and the radiological evidence of the disease. Carbonic anhydrase II level was measured in 9 patients. RESULTS: Clinically, these patients had typical facial features, growth failure and varying degrees of psychomotor retardation. Biochemically, all children had renal tubular acidosis that was of distal type in the majority of them. Radiologically, this syndrome was characterized by metyphyseal osteopetrosis and intracranial calcification that was progressive in 2 patients. Five patients were blind secondary to optic nerve entrapment and 2 patients developed anemia and secondary erythropoesis due to bone marrow involvement. Nineteen patients had attained the final adult height; the mean adult height was 146 cm (-3 standard deviation) in 11 females and 152 cm (-4 standard deviation) in 8 males. Two patients were married and had clinically and radiologically normal children. CONCLUSION: The syndrome of carbonic anhydrase II deficiency is usually benign in nature and compatible with long term survival, however it can progress and involve the cranial nerves. Close clinical and neurological assessment of these patients is mandatory to early detect and manage potential serious complications.

Characterization of CTNS mutations in Arab patients with cystinosis.

BACKGROUND: Cystinosis is an autosomal recessive disease characterized by impaired transport of free cystine out of lysosomes with resulting renal and ophthalmic manifestations. Mutations in CTNS, encoding cystinosin, are the only known cause of this autosomal recessive disorder with more than 85 different mutations described so far. PURPOSE: To identify CTNS mutations in Arab cystinosis patients. METHODS: In this study, we have analyzed the mutational spectrum of CTNS in a population of 21 patients from 13 families of Arab origin. The entire coding region and flanking intronic regions of CTNS were analyzed by direct sequencing. RESULTS: Eight mutations were identified, four of which are novel (c.530A>G, c.681G>A, 1013T>G, and c.1018_1041del). CONCLUSION: These alleles will provide the basis for routine molecular diagnosis of cystinosis in the region.

Novel mutations underlying nephrogenic diabetes insipidus in Arab families.

PURPOSE: Nephrogenic Diabetes Insipidus (NDI) is genetically heterogeneous and may be inherited in an X-linked or autosomal recessive manner. We aimed to investigate the molecular basis of NDI among Arab families. METHODS: Direct sequencing of coding regions for AQP2 and AVPR2 was used to identify underlying mutations. One large deletion required Southern blot analysis and a PCR-based strategy to identify deletion junctions. RESULTS: We identified two novel missense mutations (AQP2:p.Gly100Arg and p.Gly180Ser) in AQP2 and one novel missense mutation (AVPR2:p.Gly122Asp), one previously reported missense mutation (AVPR2:p.Arg137His) and one novel contiguous deletion (AVPR2:c.25 + 273_ARHGAP4o:2650-420del) affecting AVPR2. We also describe evidence of lyonization associated with the novel deletion. CONCLUSIONS: Two novel mutations were identified in each of AVPR2 and AQP2 underlying CNDI in Arab families. Identification of these mutations will facilitate early diagnosis of CNDI, counseling of families and provide opportunities for early intervention aimed at reducing morbidity. The presence of affected females and consanguinity, as is often observed in Arab communities should not be used to rule out AVPR2 as a candidate when considering diagnostic testing. Careful observation of phenotypic heterogeneity should be used in referring such families for both AQP2 and AVPR2 molecular genetic testing.

Post renal transplantation tubulopathies in children: a 9-year experience at a tertiary care centre.

To evaluate the incidence of tubulopathies in the long-term follow-up of children post renal transplantation, we reviewed the records of 43 patients from 1987-1996. There were 24 (56%) boys. The age of patients at the time of transplant ranged from 2.7 to 15 years. Eighteen children (78%) had transplantation from cadaver donors (CAD). Thirty-two (74%) patients were transplanted in Saudi Arabia and 11(26%) were transplanted abroad. Significant tubular dysfunction developed in 72% of patients. Renal Tubular Acidosis (RTA) occurred in 23/43 (53%) patients. The patients who received CAD grafts required higher mean dose of bicarbonate and longer duration of therapy compared to living related donors (LRD) recipients ( mean dose of 1.7 Vs 0.5 meq/kg/day and mean duration of 18 Vs 3 (1/2) months, respectively). Hypophosphatemia of various degrees of severity (0.4-0.8 mmol/1) was detected in 12 (28%) patients. Those who received CAD grafts required higher mean dose of phosphate and longer period of therapy than those who received LRD grafts. Hypomagnesemia requiring supplemental magnesium therapy occurred in 4 (9%) patients, all received tacrolimus therapy. In four patients with hypomagnesemia, this was mild and transient. Hypokalemia was found in 5 (11.5%) patients; all had CAD grafts. We conclude that tubulopathies were a frequent complication post renal transplantation in our population. They were more severe in the patients who received CAD grafts. However, the defects were controllable and transient.