Alkaptonuria: clinical manifestations and an updated approach to treatment of a rare disease

Alkaptonuria (AKU) is a rare autosomal recessive disorder with a global incidence of 1 in 250 000 to 1 million people worldwide. It results from a deficiency of the enzyme homogentisic acid (HGA) oxidase which when absent, leads to an accumulation of HGA. Without this enzymatic degradation, HGA deposits in connective tissues resulting in pigmentation (ochronosis), plaque formation and accelerated cartilage destruction. With this, many patients who suffer from AKU develop ochronotic arthropathies, tendon ruptures, fractures, and chronic joint pain. Similarly, patients can develop cardiac valvular dysfunction and interstitial renal disease. Our two cases highlight the array of pathologies seen in AKU and, in light of newly published research, give us a platform from which we can discuss the developments in management of this rare disease.

Black Aorta from Alkaptonuria

A-76-year old male with a past history of alkaptonuria with ochronosis (homogentisic acid deposition in tissues) had symptomatic aortic stenosis. Surgical replacement of the valve was undertaken, and he was noted to have a severely pigmented and porcelain aorta.

Preventive use of nitisinone in alkaptonuria

Alkaptonuria (AKU, OMIM 203500) is a rare congenital disorder caused by a deficiency of the enzyme homogentisate-1,2,-dioxygenase. The long-term consequences of AKU are joint problems, cardiac valve abnormalities and renal problems. Landmark intervention studies with nitisinone 10 mg daily, suppressing an upstream enzyme activity, demonstrated its beneficial effects in AKU patients with established complications, which usually start to develop in the fourth decade. Lower dose of nitisinone in the range of 0.2–2 mg daily will already reduce urinary homogentisic acid (uHGA) excretion by > 90%, which may prevent AKU-related complications earlier in the course of the disease while limiting the possibility of side-effects related to the increase of plasma tyrosine levels caused by nitisinone. Future preventive studies should establish the lowest possible dose for an individual patient, the best age to start treatment and also collect evidence to which level uHGA excretion should be reduced to prevent complications.

Alka Ptonuria Disorder

Alkaptonuria (AKU) is a rare disorder of autosomal recessive inheritance. It is caused by a mutation in a gene that results in the accumulation of homogentisic acid (HGA). Characteristically, the excess HGA means sufferers pass dark urine, which upon standing turns black. This is a feature present from birth. Over time patients develop other manifestations of AKU, due to deposition of HGA in collagenous tissue namely ochronosis and ochronotic osteoarthropathy. Although this condition does not reduce life expectancy, it significantly affects quality of life. The natural history of this condition is becoming better understood, despite gaps in knowledge. Clinical assessment of the condition has also improved along with the development of a potentially disease-modifying therapy. Furthermore, recent developments in AKU research have led to new understanding of the disease, and further study of the AKU arthropathy has the potential to influence therapy in the management of osteoarthritis.

Development of an effective therapy for alkaptonuria – Lessons for osteoarthritis

Osteoarthritis (OA) is one of the major causes of disability and pain worldwide, yet despite a massive international research effort, no effective disease-modifying drugs have been identified to date. In this review, we put forward the proposition that greater focus on rarer forms of OA could lead to a better understanding of the pathogenesis of more common OA. We have investigated the severe osteoarthropathy of the ultra-rare disease alkaptonuria (AKU). In addition to the progress made in finding a treatment for AKU, our research has revealed important lessons for more common OA, including the identification of high-density mineralized protrusions (HDMPs), new pathoanatomical structures which may play an important role in joint destruction and pain in AKU and in OA. AKU is an inherited disorder of tyrosine metabolism, caused by genetic lack of the enzyme homogentisate 1,2 dioxygenase (HGD), which leads to failure to breakdown homogentisic acid (HGA). While most HGA is excreted over time, some of it is deposited as a pigment in connective tissues, a process described as ochronosis. Ochronotic pigment alters the mechanical properties of tissues, leading to inevitable joint destruction and frequently to cardiac valve disease. Until recently, there was no effective therapy for AKU, but preclinical studies demonstrated that upstream inhibition of tyrosine metabolism by nitisinone, a drug previously used in hereditary tyrosinaemia 1 (HT1), completely prevented ochronosis in AKU mice. This was followed by successful clinical trials which have resulted in nitisinone being approved for therapy of AKU by the European Medicines Agency, making AKU the only cause of OA for which there is an effective therapy to date. Study of other rare causes of OA should be a higher priority for researchers and funders to ensure further advances in understanding and eventual therapy of OA.

Differences in the “egumi” taste of moso-bamboo shoots: research using chemical analysis and two types of taste sensors

We conducted our research with the aim of determining whether the “egumi” taste of moso-bamboo shoots differs depending on the production area and how the “egumi” taste of bamboo shoots from Yamagata Prefecture, which is near the northern limit of cultivation, differs. The investigation was conducted using conventional chemical analysis methods to quantitatively evaluate the presence and content of homogentisic acid and oxalic acid in bamboo shoots from different regions. In addition, qualitative evaluation, for which chemical analysis alone is insufficient, was conducted using taste sensors, which have rarely been used. As a result, chemical analysis showed that homogentisic acid was not identified among the two substances considered to be major components of egumi taste, while oxalic acid was identified in all samples. Therefore, it is highly likely that oxalic acid is responsible for the “egumi” taste in this study. In addition, qualitative analysis using taste sensors revealed that there is a difference in “egumi” taste depending on the origin of the bamboo shoot. It was suggested that bamboo shoots from Yamagata Prefecture, near the northern limit of cultivation, had a stronger “egumi” taste than those from Kyoto and Fukuoka Prefectures.

Aortic Valve Stenosis with Black Pigmentation Due to Alkaptonuria: A Case Report

We report about a 78-year-old woman with severe aortic valve stenosis (AS). She had heavily calcified and thickened aortic valve leaflets with black pigmentation. After excision of the aortic valve leaflets, biological aortic valve replacement (AVR) was performed. Alkaptonuria was diagnosed and confirmed based on increased urinary excretion of homogentisic acid. She has had no cardiovascular system-related symptoms for 3 years and no evidence of structural valve deterioration. Data on the long-term outcomes of AVR associated with structural valve deterioration that could regulate prosthetic valve selection in alkaptonuria are limited. Therefore, further research on the natural evolution of AS and the rate of structural valve deterioration after AVR is needed to provide an optimal prosthesis for these patients.

A Yarrowia lipolytica Strain Engineered for Pyomelanin Production

The yeast Yarrowia lipolytica naturally produces pyomelanin. This pigment accumulates in the extracellular environment following the autoxidation and polymerization of homogentisic acid, a metabolite derived from aromatic amino acids. In this study, we used a chassis strain optimized to produce aromatic amino acids for the de novo overproduction of pyomelanin. The gene 4HPPD, which encodes an enzyme involved in homogentisic acid synthesis (4-hydroxyphenylpyruvic acid dioxygenase), was characterized and overexpressed in the chassis strain with up to three copies, leading to pyomelanin yields of 4.5 g/L. Homogentisic acid is derived from tyrosine. When engineered strains were grown in a phenylalanine-supplemented medium, pyomelanin production increased, revealing that the yeast could convert phenylalanine to tyrosine, or that the homogentisic acid pathway is strongly induced by phenylalanine.

The Sardinian Bitter Honey: From Ancient Healing Use to Recent Findings

Sardinian bitter honey, obtained from the autumnal flowering of the strawberry tree (Arbutus unedo L.), has an old fame and tradition in popular use, especially as a medicine. Its knowledge dates back over 2000 years, starting from the Greeks and Romans to the present day. There are many literary references from illustrious personalities of the past such as Cicero, Horace, Virgil, and Dioscorides, until recent times, associated with the peculiar anomaly of its taste, which lends itself to literary and poetic metaphors. The curiosity of its bitter taste is also what led to the first studies starting in the late 1800s, aimed to reveal its origin. Other studies on its botanical source and characteristics have been carried out over time, up to the most recent investigations, which have confirmed its potential for use in the medical field, thanks to its antioxidant, antiradical, and cancer-preventing properties. These benefits have been associated with its phenolic component and in particular with the prevailing phenolic acid (homogentisic acid). Later, other strawberry tree honeys from the Mediterranean area have also shown the same properties. However, Sardinian bitter honey maintains its geographical and historical identity, which is recognized by other Mediterranean cultures.