Dura mater involvement in ochronosis (alkaptonuria)

Archives of Pathology & Laboratory Medicine, Jul 2001 by Liu, Wendy, Prayson, Richard A

Ochronosis refers to the systemic deposition of "ochrecolored" pigment in collagen-rich regions. About half of patients with alkaptonuria demonstrate evidence of ochronosis.3 Often, patients remain asymptomatic until renal function deteriorates later in life, resulting in elevated homogentisic acid levels. Homogentisic acid is an intermediate in phenylalanine-tyrosine metabolism. Patients with ochronosis lack the enzyme homogentisic acid oxidase, which cleaves homogentisic acid into its end product, maloylacetoacetic acid. In patients with alkaptonuria, excess homogentisic acid is oxidized and polymerized by polyphenol oxidase into benzoquinone acetic acid, which binds to collagen irreversibly.4 There is some suggestion that in experimental chick embryo models homogentisic metabolites inhibit lysyl hydroxylase activity, which results in poor collagen cross linking.- Collagen may be damaged by pigment deposition. It also appears that pigment deposition may be enhanced by prior collagen damage. This is evidenced in the current case by the fact that prominent pigmentation was noted in the heart at the site of previous valve surgery. The renal failure that developed in the patient in this report exacerbated the accumulation of homogentisic acid to an extraordinarily high level, which may have accounted for its deposition in the dural region, a site not typically described as being involved by this process.

The most classic clinical manifestations of ochronosis include arthritis with pigment deposition in cartilage and intervertebral disks, black-discolored urine, cortically pigmented renal stones, cutaneous pigmentation, and cardiovascular involvement.4,6 Cardiac disease often involves the valves and is associated with calcifications and valvular stenosis.7 Scleral involvement of the eye is noted in most patients. Autopsy involvement of other organ systems, including breast, lymph nodes, bone marrow, thyroid, and teeth, has been documented to occur less frequently.6, 11,9

The elevated urinary excretion of pyroglutamic acid in our patient raises the possibility of hawkinsinuria. Hawkinsinuria is a rare disorder of tyrosine metabolism. It is transmitted as an autosomal dominant trait with variable clinical expression and is typically associated with a defect of the 4-hydrophenylpyruvate dioxygenase enzyme.10 A subset of patients with this disorder present with metabolic acidosis and failure to thrive early in life. However, documented cases of patients who are biochemically involved but clinically asymptomatic have been reported.10 The patient in the current study fits this latter profile. The significance of this finding and its contribution, if any, to the ochronosis in this current case are unknown.

This case expands the list of conditions that may result in increased dural pigmentation to include ochronosis.

Special thanks to Denise Egleton for her help in the preparation of this article.

References

1. Pollak MR, Chou YHW, Cerda Jj, et al. Homozygosity mapping of the gene for alkaptonuria to chromosome 3q2. Nat Genet. 1993;5:201-204.