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 days every 2 to 3 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 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
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.
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 decade and progress to incapacitating spondylosis,
arthropathy, and fractures by the sixth to eighth decades. Cardiac valve deterioration and
renal and prostrate 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 scores of different mutations have been defined. Only symptomatic treatment is
available. We propose to investigate up to 200 alkaptonuric patients, particularly adults,
during 5-day admissions, to define the disorder using current medical techniques. We will use
our expertise in this disease to advise the population in terms of prognosis and therapy.
Mutation analysis with correlation of genotype and phenotype, will be performed as a
secondary goal. Finally, we will use this protocol to recruit patients into protocol
05-HG-0076. "Long-term Clinical Trial of 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 examine patients, measure baseline
excretion of homogentisic acid on repeated 24-hour urines, and characterize the signs and
symptoms of alkaptonuria at different ages. This protocol will also serve as the "mother"
protocol from which other alkaptonuria studies emanate.
- INCLUSION CRITERIA:
All patients entering this study will carry the diagnosis of alkaptonuria, although we will
confirm this diagnosis during the admission.
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