Familial Juvenile Hyperuricemic (or Gouty) Nephropathy (FJHN) is an inherited kidney disorder characterized by renal urate hypoexcretion, hyperuricemia, and frequent, precocious gout predating the onset of kidney disease ¹. Individuals with FJHN experience progressive loss of renal function that, without appropriate treatment, may result in life-threatening complications. Medullary Cystic Kidney Disease Type II (MCKD2) is also associated with gout and kidney failure. Despite its name, affected family members may or may not have medullary cysts.

Mutations in two exons of the Uromodulin gene (UMOD), have been recently shown to cause FJHN and MCKD2 ^1-3. The UMOD gene encodes the Tamm-Horsfall glycoprotein⁴, the most abundant protein excreted in normal urine ^3,4.

Athena Diagnostics, Inc. is now pleased to offer bi-directional DNA sequencing of the two exons of UMOD that have been shown to harbor disease-causing alterations. Order the Hereditary Interstitial Kidney Disease assay (Unit Code 770) for the diagnosis of MCKD2 and FJHN.

Indications for Testing

• Chronic interstitial renal disease
• Chronic interstitial renal disease of unknown cause
• Familial kidney disease of unknown cause
• Gout predating and associated with kidney failure
• Prior to transplant in living-related donors

FJHN and MCKD2 are inherited as autosomal dominant genetic traits and have similar clinical presentations ⁵. The age of onset of gout and kidney failure varies greatly within and among families, but hyperuricemia develops in most individuals early in life. Beginning in the teens and early 20's, renal insufficiency due to tubulo-interstitial disease (absence of significant proteinuria) develops, and many, but not all, affected individuals develop gout. Renal insufficiency usually proceeds to end-stage renal disease in the third through eighth decades of life ³.

In 2001, Dahan et al. suggested that FJHN and MCKD2 were, in fact, differing manifestations of the same disease ⁵. Further support for FJHN and MCKD2 being allelic disorders comes from more recent work by Hart, et al ². These authors identified mutations in UMOD that segregated with disease in three families with FJHN and one family with MCKD2. Importantly, they point out that “The primary clinical features of MCKD2 and FJHN vary in presence and severity, complicating the diagnosis of these conditions, particularly in milder cases.”

Early treatment with allopurinol may prevent the development of severe gout and in some families, may slow or prevent the progression of kidney disease ⁶.

Screening of family members is important prior to transplant donation when signs of the disease may not be present ².

REFERENCES

1. Bleyer AJ, et al.: Clinical characterization of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene. Kidney Int. 2003 Jul;64(1):36-42.
2. Hart TC et al.: Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J. Med. Genet. 39:882-892, 2002.
3. Bleyer AJ et al.: Renal manifestations of a mutation in the uromodulin (Tamm Horsfall protein) gene. Am. J. Kidney Dis. 2003 42(2):1-7.
4. Tamm I, Horsfall FL: Characterization and separation of an inhibitor of viral hemagglutination present in urine. Proc. Soc. Exp. Biol. Med. 1950 74:108-114.
5. Dahan K, et al.: Familial juvenile hyperuricemic nephropathy and autosomal dominant medullary cystic kidney disease type 2. Two facets of the same disease? J. Am. Soc. Nephrol. 2001 12:2348-2357.
6. Fairbanks L, et al.: Early treatment with allopurinol in familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease. QJM. 2002 Sep;95(9):597-607.