Subclinical ochronosis features in alkaptonuria: a cross-sectional study

Abstract

BackgroundAlkaptonuria (AKU) is present from birth, yet clinical effects are considered to appear later in life. Morbidity of AKU, considered irreversible, is secondary to ochronosis. Age of ochronosis onset is not clearly known. Nitisinone profoundly lowers homogentisic acid (HGA), the metabolic defect in AKU. Nitisinone also arrests ochronosis and slows progression of AKU. However, tyrosinaemia post-nitisinone has been associated with corneal keratopathy, rash and cognitive impairment in HT 1. The optimal time to start nitisinone in AKU is unknown.MethodsIn an open, cross-sectional, single-site study, 32 patients with AKU were to be recruited. The primary outcome was presence of ochronosis in an ear biopsy. Secondary outcomes included analysis of photographs of eyes/ears, serum/urine HGA, markers of tissue damage/inflammation/oxidation, MRI imaging, gait, quality of life and Alkaptonuria Severity Score Index (qAKUSSI).ResultsThirty patients, with mean age (SD) 38 (14) years, were recruited. Percentage pigmentation within ear biopsies increased with age. Ear pigmentation was detected in a 20-year-old woman implying ochronosis can start in patients before the age of 20. Gait and qAKUSSI were outside the normal range in all the patients with AKU.ConclusionsOchronosis can be present before age 20 years.

<p>Alkaptonuria: Current Perspectives</p>

“…Thirty patients from different age-groups (from 16 years) were recruited and several outcomes evaluated: ochronosis on ear biopsy, visible ochronosis quantification in eyes and ears, MRI examination, deviation in gait, modified questionnaire Alkaptonuria Severity Score Index (qAKUSSI), circulating and urine HGA, biomarkers of inflammation, cartilage damage, bone and other tissue, and quality of life. 12 Pigmentation within ear biopsy was detected in a 20-year -old female, providing evidence that ochronosis can start in AKU patients before the age of 20 years. Eye ochronosis increased with age, and was first detected at age 22 years.…”

“…Interestingly, the inflammation biomarkers SAA and serum protein thiols increased with age, with no significant difference between AKU patients and controls. 12 Despite the lack of change in the spine and joints at ages <30 years (as MRI analysis showed), gait analysis was abnormal early on, since young patients had meandeviation profiles indicating that the gait had been affected at an early age. 12 Analysis also showed that quality of life appears to deteriorate seriously from the third decade.…”

“…Externally visible ear ochronosis was detected only after age 34 years. 12 TIM, a marker of MMP-mediated titin degradation reflecting a remodeling of the cardiac sarcomere, could be an indirect marker of ochronosis of the cardiac valve, since it was increased with age in AKU patients, but not in controls. Interestingly, the inflammation biomarkers SAA and serum protein thiols increased with age, with no significant difference between AKU patients and controls.…”

Ochronotic pigmentation is caused by homogentisic acid and is the key event in alkaptonuria leading to the destructive consequences of the disease—A review

“…The earliest pigment in articular cartilage is seen in calcified cartilage cells at the junction between the calcified cartilage and subchondral bone . Similarly, OP is found in intervertebral discs and adjacent articular cartilage …”

“…However, direct detection of OP in vivo by Raman spectroscopy is possible. Such a technique has been validated in ex vivo tissue and is being adapted as an in vivo technique using ear cartilage and Achilles tendon, both tissues with little subcutaneous tissue …”