FAMILY HYPERURICEMIA WITH RENAL FAILURE – A NEW MUTATION Ilze Andersone a Vladimirs Strazdins a Karl Lhotta b Florian Kronenberg c a Nephrology Department, University Hospital for Children, Riga, Latvia b Clinical Division of Nephrology, Innsbruck Medical University, Austria c Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Austria

Prepublicized presentation, Riga & Innsbruck Introduction We present the family case characterized by: Hyperuricemia Renal failure Caused by new (previously unknown) UMOD gene mutation February 8, 2007 Prepublicized presentation, Riga & Innsbruck

Prepublicized presentation, Riga & Innsbruck The Father The historically first patient in the family was father (KS). Diagnosed with terminal renal failure and started on HD in 1998, renal biopsy not performed. Supposed ESRD cause recorded as chronic glomerulonephritis. Tx in 2000, failed in 3 years. HD restarted in 2004. Hyperuricemia was never diagnosed. February 8, 2007 Prepublicized presentation, Riga & Innsbruck

Prepublicized presentation, Riga & Innsbruck The Daughter Part 1 Elder daughter (age 22, lives in Austria) from the KS’s first wife. Presented in 1999 at age 15 with episodic macrohematuria. Primary investigations showed renal failure (GFR 39,68 ml/min/1,73 m2) and anemia (Hb 9,3 g/dl). Subcutaneous Erythropoietin alpha, oral iron and ACEI for renoprotection were started. Renal biopsy performed in early 2000 showed only tubulo-interstitial lesion with intact glomeruli. February 8, 2007 Prepublicized presentation, Riga & Innsbruck

Prepublicized presentation, Riga & Innsbruck The Daughter Part 2 July 2002: surgery due to pain and swelling of the left big toe (described by surgeons as "lymphoma"). X-ray December 2002: multiple cystic lesion at the same location. Surgery February 2003: the biopsy of the removed cystic tissues showed multiple uric acid crystal deposits. Blood chemistry: hyperuricemia 679,6 mcmol/l. Diagnosed as familial juvenile goat nephropathy, Allopurinol added. February 8, 2007 Prepublicized presentation, Riga & Innsbruck

Prepublicized presentation, Riga & Innsbruck The Elder Son Elder son (age 12) from the KS’s second wife (AS) presented in May 2003 at age 9 with serum urea 10,2 mmol/l, creatinine 85 mcmol/l, GFR 62,14 ml/min/1,73 m2, uric acid 521,4 mcmol/l. Allopurinol and Captopril started. Additional anamnesis discovered microhematuria episodes from the early childhood. No further investigation done at the time. February 8, 2007 Prepublicized presentation, Riga & Innsbruck

Prepublicized presentation, Riga & Innsbruck The Younger Son Younger son (current age 4) from the KS’s second wife (DS) was first investigated in October 2006. Serum urea, creatinine and uric acid were within the normal range. 24-hour urine showed more than two-fold uric acid excretion. Allopurinol started. February 8, 2007 Prepublicized presentation, Riga & Innsbruck

Prepublicized presentation, Riga & Innsbruck Genetic Check Performed in Innsbruck to all family members: Unknown UMOD mutation found. The mutation is present in the father and all three children. It is a G/T-SNP and leads to substitution of ASP to TYR on position 196. It is a “hot spot” where other mutations have been described. February 8, 2007 Prepublicized presentation, Riga & Innsbruck

Prepublicized presentation, Riga & Innsbruck Discussion The case is somewhat anecdotal, since Uricopathy was first diagnosed in the daughter accidentally while evaluating the bone biopsy after the orthopedic surgery, though renal failure was already present. The father was diagnosed only retrospectively when the daughter's diagnosis was confirmed. Suggestion. The routine uric acid testing in all CKD cases is advocated. February 8, 2007 Prepublicized presentation, Riga & Innsbruck

Prepublicized presentation, Riga & Innsbruck Comments The father’s Tx failure might also be caused by untreated hiperuricemia. Colleagues were warned on Allopurinol and UA check necessity. The mutation seems to be autosomal dominant. There seem to be a high risk of family recurrence also in further generations. February 8, 2007 Prepublicized presentation, Riga & Innsbruck