Primary hyperoxaluria type 1 (PH1) is caused by deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is reduced or absent, glyoxylate is converted to oxalate, which cannot be metabolized and must be excreted by the kidneys. Insoluble calcium oxalate crystals form due to high urinary oxalate concentration. Urinary crystals aggregate, leading to nephrolithiasis (i.e., calcium oxalate kidney stones) in the renal pelvis / urinary tract; often the crystals deposit in kidney parenchyma (nephrocalcinosis). The age at presentation of PH1 ranges from infancy (age <12 months) in 10% of individuals, childhood/adolescence (age 1-17 years) in 70%, and adulthood (age =18 years) in 20%. The natural history of untreated PH1 is (1) progressive decline in kidney function due to complications of nephrolithiasis (e.g., urinary obstruction, infection) and nephrocalcinosis, and (2) in persons with advanced chronic kidney disease (CKD), high plasma oxalate concentrations result in other organ and tissue damage from calcium oxalate deposition (i.e., "oxalosis"), most commonly in the bones, heart, and retina. In the absence of treatment, progression of oxalosis results in death from kidney failure and/or other organ involvement.

Deficiency of antithrombin III is a major risk factor for venous thromboembolic disease. Two categories of AT-III deficiency have been defined on the basis of AT-III antigen levels in the plasma of affected individuals. The majority of AT-III deficiency families belong in the type I (classic) deficiency group and have a quantitatively abnormal phenotype in which antigen and heparin cofactor levels are both reduced to about 50% of normal. The second category of AT-III deficiency has been termed type II (functional) deficiency. Affected individuals from these kindreds produce dysfunctional AT-III molecules; they have reduced heparin cofactor activity levels (about 50% of normal) but levels of AT-III antigen are often normal or nearly normal (summary by Bock and Prochownik, 1987). The 2 categories of antithrombmin III deficiency have been classified further. Type I (low functional and immunologic antithrombin) has been subdivided into subtype Ia (reduced levels of normal antithrombin), and type Ib (reduced levels of antithrombin and the presence of low levels of a variant). Type II (low functional but normal immunologic antithrombin) has been subdivided into subtype IIa (functional abnormalities affecting both the reactive site and the heparin-binding site of AT3); subtype IIb (functional abnormalities limited to the reactive site); and subtype IIc (functional abnormalities limited to the heparin-binding site) (summary by Lane et al., 1992).