Primary hyperoxaluria type 1 and brachydactyly mental retardation syndrome caused by a novel mutation in AGXT and a terminal deletion of chromosome 2.

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder caused by mutations in the alanine:glyoxylate aminotransferase (AGXT) gene, located on chromosome 2q37. Mutant AGXT leads to excess production and excretion of oxalate, resulting in accumulation of calcium oxalate in the kidney, and progressive loss of renal function. Brachydactyly mental retardation syndrome (BDMR) is an autosomal dominant disorder, caused by haploinsufficiency of histone deacetylase 4 (HDAC4), also on chromosome 2q37.

Genetic determinants of urolithiasis.

Urolithiasis affects approximately 10% of individuals in Western societies by the seventh decade of life. The most common form, idiopathic calcium oxalate urolithiasis, results from the interaction of multiple genes and their interplay with dietary and environmental factors. To date, considerable progress has been made in identifying the metabolic risk factors that predispose to this complex trait, among which hypercalciuria predominates.

Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis.

Background And Objectives: Primary hyperoxaluria types I and II (PHI and PHII) are rare monogenic causes of hyperoxaluria and calcium oxalate urolithiasis. Recently, we described type III, due to mutations in HOGA1 (formerly DHDPSL), hypothesized to cause a gain of mitochondrial 4-hydroxy-2-oxoglutarate aldolase activity, resulting in excess oxalate.

Design, Setting, Participants, & Measurements: To further explore the pathophysiology of HOGA1, we screened additional non-PHI-PHII patients and performed reverse transcription PCR analysis.

Cardiac abnormalities in primary hyperoxaluria.

Background: In patients with primary hyperoxaluria (PH), oxalate overproduction can result in recurrent urolithiasis and nephrocalcinosis, which in some cases results in a progressive decline in renal function, oxalate retention, and systemic oxalosis involving bone, retina, arterial media, peripheral nerves, skin, and heart. Oxalosis involving the myocardium or conduction system can potentially lead to heart failure and fatal arrhythmias.

Methods And Results: A retrospective review of our institution's database was conducted for all patients with a confirmed diagnosis of PH between 1/1948 and 1/2006 (n=103).

Mutations in DHDPSL are responsible for primary hyperoxaluria type III.

Primary hyperoxaluria (PH) is an autosomal-recessive disorder of endogenous oxalate synthesis characterized by accumulation of calcium oxalate primarily in the kidney. Deficiencies of alanine-glyoxylate aminotransferase (AGT) or glyoxylate reductase (GRHPR) are the two known causes of the disease (PH I and II, respectively). To determine the etiology of an as yet uncharacterized type of PH, we selected a cohort of 15 non-PH I/PH II patients from eight unrelated families with calcium oxalate nephrolithiasis for high-density SNP microarray analysis.

Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene.

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive, inherited disorder of glyoxylate metabolism arising from a deficiency of the alanine:glyoxylate aminotransferase (AGT) enzyme, encoded by the AGXT gene. The disease is manifested by excessive endogenous oxalate production, which leads to impaired renal function and associated morbidity. At least 146 mutations have now been described, 50 of which are newly reported here.

Phenotypic and functional analysis of human SLC26A6 variants in patients with familial hyperoxaluria and calcium oxalate nephrolithiasis.

Background: Urinary oxalate is a major risk factor for calcium oxalate stones. Marked hyperoxaluria arises from mutations in 2 separate loci, AGXT and GRHPR, the causes of primary hyperoxaluria (PH) types 1 (PH1) and 2 (PH2), respectively. Studies of null Slc26a6(-/-) mice have shown a phenotype of hyperoxaluria, hyperoxalemia, and calcium oxalate urolithiasis, leading to the hypothesis that SLC26A6 mutations may cause or modify hyperoxaluria in humans.

Comprehensive mutation screening in 55 probands with type 1 primary hyperoxaluria shows feasibility of a gene-based diagnosis.

Mutations in AGXT, a locus mapped to 2q37.3, cause deficiency of liver-specific alanine:glyoxylate aminotransferase (AGT), the metabolic error in type 1 primary hyperoxaluria (PH1). Genetic analysis of 55 unrelated probands with PH1 from the Mayo Clinic Hyperoxaluria Center, to date the largest with availability of complete sequencing across the entire AGXT coding region and documented hepatic AGT deficiency, suggests that a molecular diagnosis (identification of two disease alleles) is feasible in 96% of patients.

Glyoxylate reductase activity in blood mononuclear cells and the diagnosis of primary hyperoxaluria type 2.

Background: Primary hyperoxaluria type 2 (PH2) is a rare monogenic disorder characterized by an elevated urinary excretion of oxalate. Increased oxalate excretion in PH2 patients can cause nephrolithiasis and nephrocalcinosis, and can, in some cases, result in renal failure and systemic oxalate deposition. The disease is due to a deficiency of glyoxylate reductase/hydroxypyruvate reductase (GRHPR) activity.

International registry for primary hyperoxaluria.

Background/aims: Primary hyperoxaluria (PH) is an inherited disorder that causes calcium urolithiasis and renal failure. Due to its rarity, experience at most centers with this disease is limited.

Methods: A secure, web-based, institutional review board/ethics committee and American Health Insurance Portability and Accountability Act (HIPAA)-compliant registry was developed to facilitate international contributions to a data base.

Implications of genotype and enzyme phenotype in pyridoxine response of patients with type I primary hyperoxaluria.

Background: Marked hyperoxaluria due to liver-specific deficiency of alanine:glyoxylate aminotransferase activity (AGT) characterizes type I primary hyperoxaluria (PHI). Approximately half of PHI patients experience improvement in the degree of hyperoxaluria following pyridoxine (VB6) treatment. Recently, we showed an association between VB6 response and the commonest PHI mutation G170R, with patients possessing one or two copies showing 50% reduction or complete to near complete normalization of oxaluria, respectively.

Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele.

Background: Pyridoxine (VB6) response in type I primary hyperoxaluria (PHI) is variable, with nearly equal numbers of patients showing partial to complete reductions in oxaluria, and resistance. Because high urine oxalate concentrations cause stones and renal injury, reduction in urine oxalate excretion is deemed favorable. Mechanisms of VB6 action on hepatic alanine:glyoxylate aminotransferase (AGT), the deficient enzyme in PHI, and VB6 dose response have not been well-characterized.

Potential mechanisms of marked hyperoxaluria not due to primary hyperoxaluria I or II.

Background: Hyperoxaluria may be idiopathic, secondary, or due to primary hyperoxaluria (PH). Hepatic alanine:glyoxylate aminotransferase (AGT) or glyoxylate/hydroxypyruvate reductase (GR/HPR) deficiency causes PHI or PHII, respectively. Hepatic glycolate oxidase (GO) is a candidate enzyme for a third form of inherited hyperoxaluria.