OMIM ID:
Alkaptonuria
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
Ocular signs of this disease are present in two out of three patients. Black or bluish pigmented patches may be noted in the sclerae by the fourth decade. The pigmentation is most evident just anterior to the insertion of the medial and lateral rectus muscles. It is claimed that brown pigment spots resembling ‘oil drops’ near the opaque portion of the limbus are diagnostic but they are often not present until the 4th or 5th decades. Nevertheless, these ocular signs on average precede systemic signs by about 15 years and are therefore diagnostically useful. The pigmentation has no impact on vision. Hyperpigmentation of the anterior chamber angle with elevated intraocular pressure has been reported. An increased incidence of central vein occlusion has been suggested. Progressive astigmatism is sometimes seen. Staining of the tarsal plates may be seen in the eyelids.
Systemic Features
Ochronosis (dark pigmentation in connective tissue) as the result of homogentisic acid (HGA) accumulation is a useful sign but does not appear until the 4th decade. As a result the joint cartilage becomes fragile leading to disabling and chronic symptoms of arthritis especially in the spine and large joints. Symptoms usually begin in the third or fourth decade and the degeneration of the ochronotic intervertebral disks may result in significant loss of height. Back pain, kyphosis, and decreased lumbar flexion are common. Usually smaller joints such as those of the digits are not affected sufficiently to cause symptoms.
Tendons, ligaments, and other fibrous tissue such as sclerae and heart valves are all susceptible to degenerative changes. The discoloration in skin hue can also be seen in the axillae, nail beds, pinnae, forehead, tympanic membranes, genital areas, and buccal mucosa. Clothing may become stained from discolored perspiration.
HGA in the urine oxidizes and turns dark and parents may note staining of diapers in the newborn period. The urine also becomes alkaline. Plasma levels of HGA are also elevated. Urolithiasis may occur.
Genetics
Inheritance
This metabolic disease is among the first inborn errors of metabolism described. Virchow had early described the yellowish discoloration of connective tissue seen under the microscope. William Bateson at the beginning of the 20th century suggested the heritability of this condition to the British physician Sir Archibald Garrod who then described this syndrome in 1902 as the first human disease whose transmission pattern conformed to mendelian autosomal recessive inheritance based on his understanding of Mendel’s laws.
Homozygosity of mutations in the HGD gene (3q13.33) coding for homogentisate 1,2-dioxygenase is responsible for the phenotype.
Pedigree
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.