Continuing Education Activity

Alkaptonuria is a rare genetic inborn error of protein metabolism. It is the result of the deficiency of an enzyme (homogentisate 1,2 dioxygenase - HGD), leading to the accumulation of homogentisic acid in connective tissue leading to ochronosis. Most of the time, diagnosis is delayed as the patient remains asymptomatic during childhood. If treatment also delays, it leads to severe deformity of joints, spine, and organ dysfunction. Early diagnosis is the key to managing alkaptonuria effectively. This activity reviews the evaluation and treatment of alkaptonuria and highlights the role of pediatricians, physicians, orthopedic surgeons, and rehabilitation team in evaluating and treating patients with this condition.

Objectives:

• Describe the pathophysiology of alkaptonuria.
• Identify the gold standard diagnostic test to diagnose alkaptonuria.
• Outline the best current practice in the management of alkaptonuria.
• Summarize the importance of an interprofessional team in the management of alkaptonuria.

Introduction

Alkaptonuria is one of a rare autosomal recessive genetic disorder, which results from the deficiency of homogentisate 1,2 dioxygenase (HGD). HGD gene is expressed in the liver, kidney, prostate, small intestine, and colon.[1] This enzyme plays a role in the metabolism of tyrosine that converts homogentisic acid (HGA) into malate and acetoacetate. In the absence of HGD, homogentisic acid produced in excess by the liver oxidizes into ochronotic pigment polymer. Accumulation of this pigment in various tissues leads to systemic disease. This process is called ochronosis.

Alkaptonuria was amongst the first genetic disorders in humans that found to follow the principles of Mendelian recessive inheritance.[2] Historically, in 1908 it was used by Archibald Garrod in his Croonian lectures to illustrate the principles behind "inborn errors of metabolism." However, the Egyptian mummy Harwa believed to be the first clinical case of Alkaptonuria dating back as far as 1500 BC.[2] The term alkaptonuria originated from the Arabic word "alkali." Also, Boedeker created the name in 1859 after he noticed unusual decreasing properties in patient urine.[2] In 1866 ochronosis was discovered by Virchow, who noticed under microscopy when HGA pigment appeared to be a pale brownish yellow color (ochre-like).[2] 

Etiology

Homogentisate 1,2 dioxygenase (HGD)  expresses in various tissues in the body such as the kidney, liver, small intestine. HGD plays an important role in the tyrosine pathway by converting homogentisic acid (HGA) to maleylacetoacetate. HGD is a 445 amino based protein mapped to chromosome 3q13.33. Mutation in the HGD gene leads to a deficiency of the HGD enzyme resulting in the accumulation of homogentisic acid (HGA).

These mutations occur in specific parts of the exons. The normal HGD has a six subunit called a hexamer arranged in two trimers, each containing an iron atom. Various mutations may affect the function, structure, or solubility of HGD.  Rarely, this genetic disorder can be inherited in an autosomal dominant manner; other defects in other genes probably are responsible in these cases.[2] 

Epidemiology

Alkaptonuria is a rare disease with worldwide prevalence. The global prevalence of alkaptonuria is 1 per 100,000 to 250,000. The prevalence of the disease in the United States is 1 case in one million population.[2] According to the AKU Society and the DevelopAKUre Consortium, the number of alkaptonuria patients in the U.S. is 92.[2] It is mainly reported in the Dominican Republic and Slovakia.[2] It appears in all races with slightly more occurrence in the African population. The disease affects both men and women equally, although the disease severity is more in men.

Pathophysiology

The homogentisic acid oxidase is involved in the metabolism of the tyrosine and phenylalanine. Tyrosine is mainly necessary for specific functions, such as melanin, hormone, and several proteins, but the most majority is unused and finally generates acetoacetate and malate. In AKU, the HGD cannot form 4-maleylacetoacetate from homogentisic acid; therefore, the level of homogentisic acid in the blood will rise 100 times than normal, even though the kidneys eliminate a plentiful amount. The HGD converts to benzoquinone acetic acid, which produces polymers that match the skin pigment melanin. These accumulate in the collagen. This process of deposition is called ochronosis.[1] Ochronotic pigment deposits bind to connective tissues of various organs leading to the destruction of joints, valves, and intima of vessels. 

The pathological effects of ochronosis include arthritis,   increased incidence of renal, prostatic, gall bladder stones, ruptures of muscle, tendons, and ligaments.

Histopathology

Histopathological examination shows hyperkeratosis, hypergranulosis with fibro-elastic degeneration of collagen. Increased levels of homogentisic acid (HMA) shows intracellular and extracellular ochronotic pigmentation on electron microscopy.[1]

History and Physical

History

Alkaptonuria is an autosomal recessive disorder; familial genetic analysis shows no other affected member. The typical presentation of alkaptonuria is the darkening of the urine upon standing for longer time or dark urine stains on the diaper to the oxidation and polymerization of homogentisic acid; this could be the only feature suggestive of alkaptonuria in the pediatric age group. A significant amount of people with AKU may not present with black urine, which can be unreliable. The most frequent symptoms are one of the arthritic features confined mainly to the spine, hips, and knees. Practically all people with AKU eventually experience Arthritis. The onset of lumbar back pain, thoracic back pain, or both is frequent, especially around age 30. Progressive kyphoscoliosis, reduced disc space, spinal stenosis, and compressive myelopathy can occur with advancing age.

Physical Findings

Alkaptonuria has multiple clinical spectrums. Ochronosis, homogenistic aciduria, and ochronotic osteoarthropathy are called the triad of alkaptonuria. Ochronosis commonly presents in the third or fourth decade, which develops as the deposition of benzoquinone acetate in both extra- and intra-cellularly connective tissue. Finally, ochronotic arthropathy develops as an accumulation of Homogentisinic acid polymer within hyaline articular cartilage.[2]

 The clinical features are secondary to ochronosis:[2][3][4]

• General: Grey pigmentation in the ear cartilage or the sclerae, also skin discoloration
• Bone and joint: Lumbar pain (ankylosis), arthritis leading to joint effusions, decreased joint mobility, impaired spinal, and thoracic mobility may lead to disability. There is also an increase in the prevalence of fractures secondary to osteopenia.
• Respiratory: Decreased respiratory reserve and restrictive lung disease.
• Cardiac: Valvular heart disease like aortic stenosis(more common), aortic regurgitation, mitral valve stenosis; cardiac arrhythmias; heart failure, and an increase in the incidence of coronary artery disease.
• Neurological: Peripheral neuropathy, tinnitus, diplopia, and an increase in the incidence of stroke.
• Metabolic: Increase in the incidence of renal, gallbladder, and prostatic stones.

Evaluation

The diagnosis and evaluation of AKU can be established based on the severity scoring system.

AKU Severity Score Index (AKUSSI): is a clinical scoring system of an objective measurement of severity. It is based on a quantitative validated multidisciplinary assessment.

system.[5]

The clinical objectives include,

• Pigmentation of eye and ear
• Prostate and salivary stone
• Osteopenia
• stroke
• Aortic valvular heart disease, heart failure, atrial fibrillation

Laboratory Diagnosis

1. The urine test for HGA is the gold-standard test to diagnose alkaptonuria. The amount of homogentisic acid in the 24-hour urine is detected via gas chromatography-mass spectrometry (GC-MS) analysis. The amount of HGA excreted each day in patients with AKU is usually between 1 and 8 grams. The change in urine color is non-specific.
2. Molecular genetic testing can identify the biallelic abnormalities in HGD and other mutations that can help in family counseling.
3. Various imaging modalities like CT scan or MRI help in assessing the severity of joint involvement.
4. 2D-Echocardiography can detect valvular abnormalities.
5. CT Angiogram can detect calcification of coronary vessels.

Treatment / Management

Despite being one of the first discovered genetic disorders that are supposed to follow Mendelian law, to date, there is no effective treatment for AKU. Therefore, the management of alkaptonuria remains palliative, which includes pain control, physiotherapy, and joints surgery. Additionally, the main focus of the treatment is to reduce the deposition of HGA. 

Ascorbic acid(Vit-C)

Commonly recommended therapy involves ascorbic acid, which known as vitamin C due to the effect on reducing the conversion of homogentisic acid to benzoquinone acetic acid by oxidation. However, it does not affect the urinary excretion of homogentisic acid.[2]

Low Protein Diet

A low protein diet can reduce tyrosine load and reduce the severity of the disease, but compliance with dietary requirements is not easy. Efficacy is unproven.

Disease-modifying Agents

Many studies have suggested that nitisinone, a triketone herbicide has a significant impact on the treatment of AKU. The enzyme 4-hydroxyphenylpyrvute dioxygenase believed to play a role in converting the hydroxyphenylpyruvate to HGA. Therefore, nitisinone inhibits the conversion of tyrosine to homogentisic acid. Also, nitisinone therapy(2 mg/day )has shown to produce a reduction in urinary and plasma HGA larger than 95% hence, increase the levels of tyrosine in the body. Other serious side effects associated with raised plasma tyrosine levels rather than corneal irritation include leukopenia, thrombocytopenia, and porphyria.[1][6][2]

Differential Diagnosis

• Osteoarthritis[2]
• Ochronosis
• Melanosarcoma[7]
• Rheumatoid arthritis
• Valvular heart disease[8]
• Acute porphyria
• Ankylosing spondylitis

Prognosis

This disorder does not seem to affect life expectancy. However, the significant impact is on the patient's quality of life; for example, lots of people with AKU have experienced symptoms such as lack of sleep, pain, and difficulty breathing. These features begin in the fourth decade.[1]

Complications

• Renal and prostate stones[9]
• Gallbladder stone[10]
• Salivary gland stones[2]
• Ruptures of tendons, and ligaments[2]
• Osteopenia and fractures[2]
• Aortic valvular calcification, and stenosis[8]
• Amyloidosis[11]

Deterrence and Patient Education

Patient awareness is a crucial element of patient care. Education about the disorder process, signs, and symptoms to lifestyle and diet modification, including a low protein diet, lifestyle counseling may improve long-term outcomes in people with AKU. Also, referred for genetic counseling for all family members is very important. Some of the patients may need surgical interventions like knee and hip replacement, which can significantly improve the quality of life.

Pearls and Other Issues

• Alkaptonuria (AKU) is an iconic rare igenetic diorder.
• Objective assessment of severity by using clinical scoring like AKUSSI may improve outcomes.
• Nitisinone therapy is promising.
• Enzyme replacement by gene replacement therapy would be ideal.

Enhancing Healthcare Team Outcomes

• Alkaptonuria has systemic repercussions. Besides, there is no effective treatment for AKU, which is also can lead to severely diminished life-quality of the patients. furthermore, organs involved in AKU are the cardiovascular system, large joints, kidney, glands, large joints.[2]
• Early diagnosis is the key to treat alkaptonuria successfully.
• The management of AKU is ideally done by the healthcare professional team that involves a nurse, ophthalmology, biochemical geneticist, physical therapist, rheumatologist, orthopedic surgeon, a cardiologist for older patients, pain specialist, pharmacist, and an internist.
• Screening and genetic counseling should take place to diagnose the disease at the earliest in the community.
• A multi-disciplinary approach aimed at improving the quality of life and reducing morbidity should be the priority in treating AKU patients.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Ranganath LR, Jarvis JC, Gallagher JA. Recent advances in management of alkaptonuria (invited review; best practice article). J Clin Pathol. 2013 May;66(5):367-73. [PubMed: 23486607]

2.

Mistry JB, Bukhari M, Taylor AM. Alkaptonuria. Rare Dis. 2013;1:e27475. [PMC free article: PMC3978898] [PubMed: 25003018]

3.

Fisher AA, Davis MW. Alkaptonuric ochronosis with aortic valve and joint replacements and femoral fracture: a case report and literature review. Clin Med Res. 2004 Nov;2(4):209-15. [PMC free article: PMC1069096] [PubMed: 15931360]

4.

Gottschalk BH, Blankenstein J, Guo L. Ochronosis of Mitral Valve and Coronary Arteries. Ann Thorac Surg. 2018 Jul;106(1):e19-e20. [PubMed: 29501639]

5.

Langford B, Besford M, Hall A, Eddowes L, Timmis O, Gallagher JA, Ranganath L. Alkaptonuria Severity Score Index Revisited: Analysing the AKUSSI and Its Subcomponent Features. JIMD Rep. 2018;41:53-62. [PMC free article: PMC6122049] [PubMed: 29654544]

6.

Davison AS, Norman BP, Ross GA, Hughes AT, Khedr M, Milan AM, Gallagher JA, Ranganath LR. Evaluation of the serum metabolome of patients with alkaptonuria before and after two years of treatment with nitisinone using LC-QTOF-MS. JIMD Rep. 2019 Jul;48(1):67-74. [PMC free article: PMC6606987] [PubMed: 31392115]

7.

SKINSNES OK. Generalized ochronosis; report of an instance in which it was misdiagnosed as melanosarcoma, with resultant enucleation of an eye. Arch Pathol (Chic). 1948 Apr;45(4):552-8. [PubMed: 18891026]

8.

Olive JK, Alnajar A, Gnanashanmugam S, Lamelas J. Transcatheter Aortic Valve Replacement for Alkaptonuria-Associated Aortic Stenosis. Ann Thorac Surg. 2019 Dec;108(6):e377-e379. [PubMed: 31181205]

9.

Keller JM, Macaulay W, Nercessian OA, Jaffe IA. New developments in ochronosis: review of the literature. Rheumatol Int. 2005 Mar;25(2):81-5. [PubMed: 15322814]

10.

Taylor AM, Wilson PJ, Ingrams DR, Helliwell TR, Gallagher JA, Ranganath LR. Calculi and intracellular ochronosis in the submandibular tissues from a patient with alkaptonuria. J Clin Pathol. 2010 Feb;63(2):186-8. [PubMed: 20154043]

11.

Millucci L, Ghezzi L, Bernardini G, Braconi D, Lupetti P, Perfetto F, Orlandini M, Santucci A. Diagnosis of secondary amyloidosis in alkaptonuria. Diagn Pathol. 2014 Sep 26;9:185. [PMC free article: PMC4189149] [PubMed: 25567001]

Disclosure: Alaa Sharabi declares no relevant financial relationships with ineligible companies.

Disclosure: Raghavendra Goudar declares no relevant financial relationships with ineligible companies.