Alkaptonuria

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: 

Connective tissue becomes weak and brittle as the result of homogentisic acid (HGA) accumulation.  The most disabling and chronic symptoms are secondary to joint cartilage damage especially in the spine.  Joint symptoms usually begin in the third or fourth decade and the degeneration of the ochonrotic 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.

The urine oxidizes and turns dark upon standing and parents may note staining of the diapers even in the newborn period.  The urine also becomes alkaline.  Plasma and urine levels of HGA are elevated.  Urolithiasis may occur.

Genetics

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 to the British physician Sir Archibald Garrod (who first reported this syndrome in 1902) that the pattern of inheritance of alkaptonuria was likely autosomal recessive 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.

Treatment
Treatment Options: 

Nitisinone reduces the production of HGA and can lower urinary levels up to 95% but may lead to elevated plasma tyrosine that rarely results in the deposition of corneal crystals.  Long-term benefits of nitisinone remain unknown. Others have tried dietary reduction of tyrosine and phenylalanine with reduction in HGA levels but the long term impact on the rate of tissue degradation remains unknown.    

Additional treatment is directed at specific damaged sites.  Calcified valves (often aortic) may need to be replaced.  Large joints such as hips, shoulders, and knees often require replacement for pain relief.  Stones in the urinary tract may need to be removed.  Ophthalmologists should keep such patients under observation for progressive astigmatism and the risk of elevated intraocular pressure.

It may be prudent to avoid contact sports and minimize heavy weight lifting to limit trauma to joint cartilage.

References
Article Title: 

Natural history of alkaptonuria

Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick DL, Anderson PD, Huizing M, Anikster Y, Gerber LH, Gahl WA. Natural history of alkaptonuria. N Engl J Med. 2002 Dec 26;347(26):2111-21.

PubMed ID: 
12501223

The molecular basis of alkaptonuria

Fernandez-Canon JM, Granadino B, Beltran-Valero de Bernabe D, Renedo M, Fernandez-Ruiz E, Penalva MA, Rodriguez de Cordoba S. The molecular basis of alkaptonuria. Nat Genet. 1996 Sep;14(1):19-24.

PubMed ID: 
8782815

References

Lindner M, Bertelmann T. On the ocular findings in ochronosis: a systematic review of literature. BMC Ophthalmol. 2014 Jan 30;14:12.

PubMedID: 24479547

Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick DL, Anderson PD, Huizing M, Anikster Y, Gerber LH, Gahl WA. Natural history of alkaptonuria. N Engl J Med. 2002 Dec 26;347(26):2111-21.

PubMedID: 12501223

Fernandez-Canon JM, Granadino B, Beltran-Valero de Bernabe D, Renedo M, Fernandez-Ruiz E, Penalva MA, Rodriguez de Cordoba S. The molecular basis of alkaptonuria. Nat Genet. 1996 Sep;14(1):19-24.

PubMedID: 8782815