The purpose of this study is to gain a better understanding of alkaptonuria and collect medical data on patients who may later participate in new drug trials for this rare genetic disease. In alkaptonuria, a pigment called homogentisic acid collects in bone and connective tissue, causing arthritis and eventually bone fractures, and also causes discoloration in the ears and whites of the eyes. Some patients also develop kidney stones and heart valve problems. Alkaptonuria has not been studied for decades; and scientists expect to gain comprehensive clinical information using current medical techniques.

Patients with alkaptonuria who are at least one month old may be eligible for this study. Participants will be evaluated at NIH's Clinical Center for 5 to 7 days every 1 to 2 years. They will have a medical history, physical examination, routine blood and urine tests. Blood may also be collected to measure a type of collagen that indicates new bone formation and to analyze DNA for genetic studies. 24-hour urine collections will be done to measure organic acids and homogentisic acid excretion, assess overall kidney function, and evaluate bone metabolism. A total of 89.5 ml (about 6 tablespoons) of blood will be drawn for these studies in adults and 51 ml (about 3 tablespoons) in children.

Patients will also have a skin biopsy (removal of a small piece of skin, done under local anesthetic), bone X-rays, kidney ultrasound, brain and chest computerized tomography (CT) scans, magnetic resonance imaging (MRI) scans of affected joints, electrocardiograms, echocardiogram, lung function tests, and a hearing test. Photographs of the face and full body (with underwear on) will be taken.

Patients will also have consultations with dentistry and ophthalmology, with physical therapy and rehabilitation medicine for arthritis management, and with cardiology for heart valve evaluation. When appropriate, patients may also have dermatology, pulmonology and neurology consultations.

The information from this study will enable doctors to better advise patients with alkaptonuria about their disease and treatment options. It will also prepare the way for clinical studies of a new drug that blocks production of homogentisic acid.

Condition
Alkaptonuria

Further Study Details: 

Expected Total Enrollment:  120

Alkaptonuria is a rare autosomal recessive disorder in which homogentisic acid accumulates and destroys connective tissue and bone, creating a condition called ochronosis. Symptoms generally begin in the third or fourth decades and progress to incapacitating spondylosis, arthropathy, and fractures by the sixth to eighth decades. Cardiac valve deterioration and renal calculi also occur. Diagnosis is made by measurement of gram quantities of urinary homogentisic acid, which turns black on alkali treatment or exposure to oxygen. In the body, homogentisic acid forms a characteristic blue color in the cartilage of the ear and brown color in the sclera of the eye. The gene for homogentisic acid oxidase was isolated in 1996, and 67 different mutations have been defined. Only symptomatic treatment is available. We propose to investigate up to 120 alkaptonuric patients, particularly adults, every 2-3 years during 5-7-day admissions, to define the disorder using current medical techniques. We plan to acquire expertise in this disease in order to advise the population in terms of prognosis and therapy. Mutation analysis with correlation of genotype and phenotype, will be performed. Finally, we will use this protocol t make contact with patients who may be interested in participating in protocol 97-HG-0201. (Therapy Use if Nitisinone in Alkaptonuria.) Nitisinone is a very promising drug which inhibits the formation of homogentisic acid. The present protocol does not include treatment with nitisinone. Instead, we will collect patients, measure baseline excretion of homogentisic acid on repeated 24-hour urines, and determine which signs and symptoms to employ as clinical outcome parameters for our upcoming a treatment protocols.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
All patients entering this study will carry the diagnosis of alkaptonuria, Although we will confirm this diagnosis during the admission.
EXCLUSION CRITERIA:
Patients will be excluded if they cannot travel to the NIH due to their medical condition, are less than two years old, or are in imminent danger of death due to, e.g., cardiac involvement.

Maryland
      National Human Genome Research Institute (NHGRI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  000141; 00-HG-0141
Record last reviewed:  May 12, 2004
Last Updated:  November 23, 2004
Record first received:  June 13, 2000
ClinicalTrials.gov Identifier:  NCT00005909
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08