A VERTICAL (PSEUDODOMINANT) PATTERN OF INHERITANCE IN THE AUTOSOMAL RECESSIVE DISEASE PRIMARY HYPEROXALURIA TYPE-1 - LACK OF RELATIONSHIP BETWEEN GENOTYPE, ENZYMATIC PHENOTYPE, AND DISEASE SEVERITY

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disea se caused by a deficiency of alanine:glyoxylate aminotransferase (enco ded by the AGXT gene). Primary hyperoxaluria type 1 is characterized b y the elevated urinary excretion of oxalate and glycolate, and the dep osition of insoluble calcium oxalate in the renal parenchyma and urina ry tract. In the present study, we investigated an unusual family cont aining four affected individuals in two different generations, Based o n our genetic, enzymic, metabolic, and clinical analyses, we have come to the following conclusions. First, although the pattern of inherita nce of PH1 is usually horizontal (ie, all patients in the same generat ion), as expected for an autosomal recessive disease, it can sometimes show a vertical (pseudodominant) pattern of inheritance (ie, patients in more than one generation) due to the segregation within a family o f three, rather than two, mutant AGXT alleles, Second, affected member s of such a family can manifest very different clinical phenotypes bot h within and between generations, Although the clinical differences be tween generations might be at least partly due to differences in AGXT genotype, differences can equally occur within the same generation in individuals who possess the same AGXT genotype, Finally, individuals w ith PH1 at the level of the AGXT genotype might remain asymptomatic an d undiagnosed for many years, The consequences of these findings for t he clinical management and genetic counseling of families with PH1 are profound and wide-ranging. (C) 1997 by the National Kidney Foundation , Inc.