Managing Alkaptonuria in Absence of Appropriate Medication: A Case Report and Review of Literature

Discussion

We have reported this case in accordance with CARE guidelines. In this report, we have present our case in which the patient suffered through worsening disease due to lack of appropriate treatment as well as lack of suitable replacement or backup drug. We have reviewed the current state of medical treatments of alkaptonuria to get a better picture of recommended diagnosis and treatment of the disease and compared our patient to cases seen in other literature.

Alkaptonuria is a disease with mutation of the enzyme homogentisic acid dioxygenase in the tyrosine degradation pathway causing accumulation of the intermediate homogentisic acid (HGA) in the pathway. Over time the pigment accumulates and deposits in connective tissue causing systemic disease.^1,2

Our patient suffered from disease worsening due to unavailability of nitisinone in Pakistan.^1-3 Nitisinone is being heralded as a treatment drug for alkaptonuria, as many clinical trials and studies have shown its effectiveness.^3,4 This is a rare disease, and at least 23 other cases of it have been identified in Pakistan.^5,6

Vitamin C and physiotherapy, although administered for this disease, especially in countries like Pakistan where nitisinone is generally unavailable, have not been seen to be effective in improving prognosis.^1,2 Regarding treatment efficacy, multiple case reports have demonstrated successful reduction of HGA levels^2,7,8 and disease improvement.

The diagnosis of alkaptonuria is achieved by identifying notable amounts of HGA in the urine (1-8 grams/day). This is considered to be the gold standard.⁹ Also for patients unable to afford the gold standard gas chromatography, or due to its unavailability especially in developing countries, Singh et al.¹ have proposed that biochemical studies be done on urine to diagnose the disease (Table 1). Generally, the decreased HGA levels in the body cause increased circulating tyrosine. Side effects of nitisinone treatment that have been seen mainly include keratopathy,^2,8 although urticarial skin rash has also been seen.⁸ This is postulated to be due to higher tyrosine levels due to nitisinone treatment,¹⁰ and uncontrolled protein intake in the diet. However, researchers at the National Institutes of Health postulated that only 5% of people develop this in response to tyrosine therapy, and they may very well be predisposed to it, because people with much higher tyrosine levels( up-to 1500 micromoles) have shown tolerance to it. Toxicity may also be due to a synergistic effect of nitisinone therapy and added tyrosine from their diet. Therefore, even with limited evidence, reducing dietary protein is recommended to err on the side of caution.⁸ Beyond this potential benefit, dietary restrictions of phenylalanine and tyrosine lack evidence.⁵ Vitiligo has also been seen as a side effect in very few cases, but the mechanism of development has been unclear.⁷

Since the disease is genetically linked, cases can be present in members of the family, too,¹¹ just as we suspect that our patient’s teenage daughter (who complains of joint pain but was not present at examination) has the disease also. In childhood the earliest and only symptom is bluish/black staining of the diaper on long standing after a child has urinated.¹² Our patient had a similar issue of diaper blackening since childhood, in addition to the arthritic complaints that became prevalent and cartilage discoloration he later developed.

It should be noted, however, that the main role of nitisinone is in the prevention of ochronosis by preventing HGA build up in the body, thus preventing HGA mediated changes.^3,13 Therefore, at this late stage into our patient’s disease where he has now developed progressive arthritic changes, nitisinone may not be as effective for him, as when it would have been if he had started it several years ago. Our patient had been suffering with the chronicity of this disease for a long time, without any hope of effective treatment. He has now moved to the United Kingdom to be treated with this drug. The initial travel restrictions due to the SARS-CoV-2 pandemic¹⁴ and the lack of availability of nitisinone in Pakistan,¹⁵ however, led to our patient’s condition constantly worsening. It is therefore suggested that nitisinone become available in developing countries like Pakistan, so that the few patients who actually have alkaptonuria can receive effective treatment early on in life to prevent the chronic systemic effects of it, as has been encouraged by published studies.³