Gonadal mosaicism as a rare cause of autosomal recessive inheritance.

Autosomal recessive diseases are typically caused by the biparental inheritance of familial mutant alleles. Unusual mechanisms by which the recessiveness of a mutant allele is unmasked include uniparental isodisomy and the occurrence of a de novo chromosomal rearrangement that disrupts the other allele. Gonadal mosaicism is a condition in which a postfertilization mutation is confined to the gamete precursors and is not detected in somatic tissues. Gonadal mosaicism is known to give the impression of autosomal recessive inheritance when recurrence of an autosomal-dominant condition among offspring of phenotypically normal parents is observed. Here, we report an extremely rare event in which maternal gonadal mosaicism for a recessive mutation in COL4A4 caused the recurrence of Alport syndrome within a consanguineous family. Such rare occurrence should be taken into account when analyzing pedigrees both for clinical and research purposes.

Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss.

Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased urinary calcium solubility, and impaired bone physiology and growth. Two types of rdRTA have been differentiated by the presence or absence of sensorineural hearing loss, but appear otherwise clinically similar. Recently, we identified mutations in genes encoding two different subunits of the renal alpha-intercalated cell's apical H(+)-ATPase that cause rdRTA. Defects in the B1 subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with deafness and with preserved hearing, respectively. We have investigated 26 new rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity. In ATP6V1B1, one novel and five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4 kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4 mutations were found in "sporadic" cases. The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained. However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood. We show here that ATP6V0A4 is expressed within the human inner ear. These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time.

Infantile nephrotic syndrome and congenital glaucoma.

A case of infantile nephrotic syndrome (NS) with advanced membranoproliferative glomerulonephritis (MPGN), type I, and bilateral congenital glaucoma, is presented. The patient also had persistent thrombocytopenia and subclinical hypothyroidism. The parents were second-degree cousins and the affected infant had a sibling who was born with congenital glaucoma. His mother had an aunt and uncle on the maternal side who were born with congenital glaucoma. In addition, there was a history of infantile death in five family members of unknown causes (pedigree). To the best of our knowledge, the association of congenital glaucoma and infantile NS due to MPGN has not been reported previously.

Coexistent linear scleroderma and juvenile systemic lupus erythematosus.

We describe a girl who initially presented with linear scleroderma. Five and a half years later she developed systemic lupus erythematosus (SLE). Previous descriptions of the coexistence of linear scleroderma and SLE in childhood are reviewed.

Alport-like glomerular changes in a patient with nephrotic syndrome: report of a case.

We report a 17-year-old Saudi girl who presented with nephrotic syndrome at the age of 7 years. A renal biopsy revealed a mildly proliferative immune complex-mediated glomerulonephritis, which on ultrastructural examination revealed prominent thickening of the capillary basement membranes, along with marked splitting and lamellation of lamina densa resembling those seen in Alport syndrome. These changes were even more pronounced in renal biopsies performed 1 and 3 years later, respectively. Thorough clinical evaluations and follow-up of more than 10 years failed to reveal any evidence of Alport syndrome. Review of the literature revealed four similar cases reported previously. Diffuse and prominent Alport-like glomerular changes may rarely be seen in patients with nephrotic syndrome in the absence of Alport syndrome. Pathogenesis of these changes, however, remains to be understood.

Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing.

The multi-subunit H+-ATPase pump is present at particularly high density on the apical (luminal) surface of -intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification. The complete subunit composition of the apical ATPase, however, has not been fully agreed upon. Functional failure of -intercalated cells results in a group of disorders, the distal renal tubular acidoses (dRTA), whose features include metabolic acidosis accompanied by disturbances of potassium balance, urinary calcium solubility, bone physiology and growth. Mutations in the gene encoding the B-subunit of the apical pump (ATP6B1) cause dRTA accompanied by deafness. We previously localized a gene for dRTA with preserved hearing to 7q33-34 (ref. 4). We report here the identification of this gene, ATP6N1B, which encodes an 840 amino acid novel kidney-specific isoform of ATP6N1A, the 116-kD non-catalytic accessory subunit of the proton pump. Northern-blot analysis demonstrated ATP6N1B expression in kidney but not other main organs. Immunofluorescence studies in human kidney cortex revealed that ATP6N1B localizes almost exclusively to the apical surface of -intercalated cells. We screened nine dRTA kindreds with normal audiometry that linked to the ATP6N1B locus, and identified different homozygous mutations in ATP6N1B in eight. These include nonsense, deletion and splice-site changes, all of which will truncate the protein. Our findings identify a new kidney-specific proton pump 116-kD accessory subunit that is highly expressed in proton-secreting cells in the distal nephron, and illustrate its essential role in normal vectorial acid transport into the urine by the kidney.

Localization of a gene for autosomal recessive distal renal tubular acidosis with normal hearing (rdRTA2) to 7q33-34.

Failure of distal nephrons to excrete excess acid results in the "distal renal tubular acidoses" (dRTA). Early childhood features of autosomal recessive dRTA include severe metabolic acidosis with inappropriately alkaline urine, poor growth, rickets, and renal calcification. Progressive bilateral sensorineural hearing loss (SNHL) is evident in approximately one-third of patients. We have recently identified mutations in ATP6B1, encoding the B-subunit of the collecting-duct apical proton pump, as a cause of recessive dRTA with SNHL. We now report the results of genetic analysis of 13 kindreds with recessive dRTA and normal hearing. Analysis of linkage and molecular examination of ATP6B1 indicated that mutation in ATP6B1 rarely, if ever, accounts for this phenotype, prompting a genomewide linkage search for loci underlying this trait. The results strongly supported linkage with locus heterogeneity to a segment of 7q33-34, yielding a maximum multipoint LOD score of 8.84 with 68% of kindreds linked. The LOD-3 support interval defines a 14-cM region flanked by D7S500 and D7S688. That 4 of these 13 kindreds do not support linkage to rdRTA2 and ATP6B1 implies the existence of at least one additional dRTA locus. These findings establish that genes causing recessive dRTA with normal and impaired hearing are different, and they identify, at 7q33-34, a new locus, rdRTA2, for recessive dRTA with normal hearing.

Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption.

Epithelia permit selective and regulated flux from apical to basolateral surfaces by transcellular passage through cells or paracellular flux between cells. Tight junctions constitute the barrier to paracellular conductance; however, little is known about the specific molecules that mediate paracellular permeabilities. Renal magnesium ion (Mg2+) resorption occurs predominantly through a paracellular conductance in the thick ascending limb of Henle (TAL). Here, positional cloning has identified a human gene, paracellin-1 (PCLN-1), mutations in which cause renal Mg2+ wasting. PCLN-1 is located in tight junctions of the TAL and is related to the claudin family of tight junction proteins. These findings provide insight into Mg2+ homeostasis, demonstrate the role of a tight junction protein in human disease, and identify an essential component of a selective paracellular conductance.

A mutation in GLUT2, not in phosphorylase kinase subunits, in hepato-renal glycogenosis with Fanconi syndrome and low phosphorylase kinase activity.

Fanconi-Bickel syndrome is characterized by hepato-renal glycogenosis with severe renal tubular dysfunction and rickets. It has recently been found to be associated with GLUT2 mutations in three families. In another family, low activities of liver phosphorylase kinase (Phk) have been observed, suggesting that Fanconi-Bickel syndrome might be genetically heterogeneous. We have analyzed this family for mutations in the GLUT2 gene and in the three Phk subunit genes that can cause liver glycogenosis (PHKA2, PHKB, and PHKG2). The coding sequences of all three Phk genes are normal but we have identified a homozygous missense mutation (Pro417Leu) in GLUT2. The affected proline residue is completely conserved in all mammalian glucose permease isoforms and even in bacterial sugar transporters and is believed to be critical for the passage of glucose through the permease. Seven affected individuals from different branches of the same large consanguineous sibship all are homozygous for this mutation. These findings indicate that there is no specific subtype of genetic Phk deficiency giving rise to hepato-renal glycogenosis. Rather, they provide further evidence that Fanconi-Bickel syndrome is caused by GLUT2 mutations. The low Phk activity is probably a secondary phenomenon that contributes to the deposition of glycogen in response to the intracellular glucose retention caused by GLUT2 deficiency.

Primary hyperoxaluria type 1: An underestimated cause of nephrocalcinosis and chronic renal failure in Saudi Arabian children.

BACKGROUND: Primary hyperoxaluria type I (PHI) is a rare metabolic disease caused by deficiency or abnormalities of the peroxisomal enzyme alanine-glyoxylate aminotransferase. In the majority of patients, the clinical expression of PHI is characterized by recurrent calcium oxalate urolithiasis, nephrocalcinosis and renal failure. PATIENTS AND METHODS: Sixteen children aged 5 months to 14 years were diagnosed as PHI over a 10-year period ending in June 1997. The diagnosis was established by quantitative urinary oxalate excretion, or by a high urine oxalate/creatinine ratio on spot urines. RESULTS: The majority of patients had nephrolithiasis (13/16) and/or nephrocalcinosis (12/16). Four patients already had advanced chronic renal failure at the time of diagnosis. Altogether, PHI accounted for 20% of nephrocalcinosis and 6% of end-stage renal disease. Two patients had a complete response to pyridoxine therapy, while four patients had a partial response. Eight patients underwent organ transplantation, three underwent kidney transplantation, three received combined liver/kidney transplantation for end-stage renal disease, and two received isolated preemptive liver transplantation. CONCLUSION: Combined organ transplantation provided the best long-term results.

Spectrum of glomerular disease among children in saudi arabia.

A total of 376 renal biopsies performed in several hospitals in Riyadh, on children with glomerulonephritis were reviewed. Focal segmental glomerulosclerosis (FSGS) was the most common glomerulopathy found and accounted for 120 cases (31.9%), followed by mesangial proliferative glomerulonephritis in 99 (26.3%). Minimal change nephrotic syndrome was seen in 55 (14.6%), membranoproliferative glomerulonephritis in 30 (8.0%), membranous glomerulonephritis in 18 (4.8%), IgA nephropathy in 15 (4.0%), post-infectious glomerulonephritis in 15 (4.0%), Alport syndrome in 14 (3.7%) and rapidly progressive glomerulonephritis in 10 (2.7%). Our findings show a high prevalence of FSGS in comparison with most international renal pathological studies published in children. At the same time, there is a relatively low prevalence of IgA nephropathy as compared to some other Asian countries. Additional, more comprehensive, clinical and pathological studies on Saudi children with glomerular diseases are needed to confirm or negate these findings. Environmental and genetic factors have to be explored and studied for their role related to these differences. Also, there is an urgent need to establish a glomerulonephritis registry for children in Saudi Arabia.

Congenital chloride diarrhea: A single center experience with ten patients.

Congenital chloride diarrhea (CCD) is a rare autosomal recessive disorder characterized by life-long watery diarrhea with a high fecal chloride concentration. We report the clinical and laboratory data in 20 Saudi infants with CCD admitted to our center between January 1986 and December 1991. In addition to diarrhea, there was a history of maternal polyhydramnios, low birth weights, abdominal distention and failure to thrive. The mean serum and stool chloride concentrations were 71 and 146 mmol/L respectively. Diagnosis was frequently delayed in spite of the early symptoms and the unique association of diarrhea with hypochloremic alkalosis. Treatment with NaCl and KCI solutions in amounts titrated to correct their electrolyte depletion and metabolic alkalosis resulted in marked clinical improvement and growth catch-up. Congenital chloride diarrhea should be suspected in patients with watery stools starting in teh neonatal period or early infancy. The diagnosis is confirmed by the presence of a high fecal chloride concentration and the concomitant hypochloremic alkalosis.

Kidney transplantations at King Faisal Specialist Hospital and Research Centre.

During the five year period from 1987G to 1991G, 161 kidney transplantations were performed at King Faisal Specialist Hospital and Research Centre (KFSH&RC); 79 from cadaveric donors (CD) and 82 from living related donors (LRD). All cadaveric kidneys except one were harvested within Saudi Arabia and 67% were from Saudi nationals. The immunosuppresive protocol was a triple drug regimen comprising cyclosporin-A (CyA), azathioprine (Aza), and prednisone. The actuarial graft survival rates at one and three years were 85% and 76% for the cadaveric donor transplants and 96% and 91%, respectively for the living related donor transplants (P<0.01). The corresponding patient survival rates for cadaveric donor transplants (CDTxs) were 97% and 94% and for the living related donor transplants (LRDTxs), 99% and 97% (NS). These results compare well with the best results in the Western world. The most serious surgical complications were vascular thromboses (five cases) and infections of the arterial anastomosis line with bleeding (two cases), all leading to loss of the cadaveric graft. The most common causes of death were virus infection, varicella, cytomegalovirus, and hepatitis B and C. The organ donation rate, from cadaveric donors as well as living related donors, is stil low in Saudi Arabia. Lack of organs is the main obstacle to an expansion of this promising transplantation activity. Continuous education of the multinational medical profession as well as the lay population is necessary to improve the situation.

Clinical and serologic responses of Saudi children to Hemophilus influenzae type B capsular polysaccharide diphtheria toxoid conjugate vaccine.

Sixty-eight Saudi children, 17 to 19 months of age, were enrolled in a study to evaluate the safety and immunogenicity of Hemophilus influenzae type B capsular polysaccharide diphtheria toxoid (PRP-D) conjugate vaccine. Adverse reactions to the vaccine were determined through a questionnaire administered to the parents. Local and systemic reactions to the vaccine were mild and resolved within 24 to 48 hours. PRP antibody levels were measured prior to and one to two months following immunization. PRP antibody levels in the pre-immunization sera of 77% of subjects were below the level associated with immediate protection (>/=0.15 microg/ml), and 88% were below the level associated with long-term protection (>/=1 microg/ml) from Hemophilus influenzae type B (HIB) disease. After one dose of PRP-D vaccine, 100% of recipients achieved antibody levels of >/=0.15 microg/ml, and 85% achieved levels of >/=1 microg/ml. The geometric mean level of antibody after immunization (5.66 microg/ml) was significantly higher than that before immunization (0.098 microg/ml). All subjects had a twofold or greater increase in antibody level in response to the vaccine. We conclude that PRP-D is a safe and highly immunogenic vaccine in this age group of Saudi children.

FK 506 associated disorders in liver transplantation.

Immunosuppressive regimens are usually required for patients receiving organ transplants. The development of a post-transplant lymphoproliferative disorder is an infrequent complication of such therapy. FK 506 is a new immunosuppressant agent that has recently been used in patients receiving organ transplantation. This report describes a 20 month old Saudi child who developed post-transplant lymphoproliferative disorder while receiving FK 506 following liver transplantation. Such a complication has been recognized with cyclosporine but has not been well addressed as yet with FK 506. The child also developed progressive renal complications. There was also a difficulty in interpreting the results for IgM antibodies to different viruses. The overall features of progressive renal toxicity and those of lymphadenopathy, hepatosplenomegaly, fever, neutropenia and thrombocytopenia reversed following discontinuation of FK 506 therapy. It is concluded that all the above complications, though reversible, may well be linked to the new immunosuppressant agent FK 506.