Genetic disorders of
mineral metabolism cause
urolithiasis, renal disease, and osteodystrophy. Most are rare, such that the full spectrum of clinical expression is difficult to appreciate. Diagnosis is further complicated by overlap of clinical features.
Dent's disease and
primary hyperoxaluria, inherited causes of
calcium urolithiasis, are both associated with
nephrocalcinosis and
urolithiasis in early childhood and
renal failure that can occur at any age but is seen more often in adulthood.
Bone disease is an inconsistent feature of each.
Dent's disease is caused by mutations of the CLCN-5 gene with impaired kidney-specific
CLC-5 chloride channel expression in the proximal tubule, thick ascending limb of Henle, and the collecting ducts. Resulting
hypercalciuria and proximal tubule dysfunction, including
phosphate wasting, are primarily responsible for the clinical manifestations. Low-molecular-weight
proteinuria is characteristic. Definitive diagnosis is made by
DNA mutation analysis.
Primary hyperoxaluria, type I, is due to mutations of the AGXT gene leading to deficient hepatic
alanine-glyoxylate aminotransferase activity. Marked overproduction of
oxalate by hepatic cells results in the
hyperoxaluria responsible for clinical features. Definitive diagnosis is by liver biopsy with measurement of
enzyme activity, with
DNA mutation analysis used increasingly as mutations and their frequency are defined. These disorders of
calcium urolithiasis illustrate the value of molecular medicine for diagnosis and the promise it provides for innovative and more effective future treatments.