INTRODUCTION:

Alkptonuria is a rare autosomal recessive disorder that is due to a mutation in the homogentisate 1,2 dioxygenase (HDG) gene, resulting in abnormalities of tyrosine catabolism and tissue deposition homogenetisi. Alkaptonuria is a rare inherited disorder. It occurs when your body can’t produce enough of an enzyme called homogentisic dioxygenase (HGD). This enzyme is used to break down a toxic substance called homogentisic acid. When you don’t produce enough HGD, homogentisic acid builds up in your body. The buildup of homogentisic acid causes your bones and cartilage to become discolored and brittle. This typically leads to osteoarthritis, especially in your spine and large joints. People with alkaptonuria also have urine that turns dark brown or black when it’s exposed to air.¹

Definition:

A genetic metabolic disorder due to deficiency of the enzyme homogentisic acid (HGA) dioxygenase¹. Deficiency of this enzyme leads to the three cardinal features of alkaptonuria (the presence of homogentisic acid in the urine), ochronosis (bluish-black pigmentation in connective tissue), and arthritis.

Clinical manifestation:

Dark stains on a baby’s diaper are one of the earliest signs of alkaptonuria. There are few other symptoms during childhood. Symptoms become more obvious as you age¹. Your urine may turn dark brown or black when it’s exposed to air. By the time you reach your 20s or 30s, you may notice signs of early-onset osteoarthritis². For example, you may notice chronic stiffness or pain in your lower back or large joints. Other symptoms of alkaptonuria include:

· Dark spots in the sclera (white) of your eyes

· Thickened and darkened cartilage in your ears

· Blue speckled discoloration of your skin, particularly around sweat glands

· Dark-colored sweat or sweat stains

· Black earwax

· Kidney stones and prostate stones

· Arthritis (especially hip and knee joints)

· Alkaptonuria can also lead to heart problems.

· High blood pressure.

Pathophysiology:

All people carry in their DNA two copies (one received from each parent) of the gene HGD, which contains the genetic information to produce the enzyme homogentisate 1,2-dioxygenase (HGD) which can normally be found in numerous tissues in the body (liver, kidney, small intestine, colon, and prostate) (2). In people with alkaptonuria, both copies of the gene contain abnormalities that mean that the body cannot produce an adequately functioning enzyme.⁴ HGD mutations are generally found in certain parts (exons 6, 8, 10, and 13), but a total of over 100 abnormalities has been described throughout the gene.⁴ The normal HGD enzyme is a hexamer (it has six subunits) that are organized in two groups of three (two trimers) and contains an iron atom. Different mutations may affect the structure, function, or solubility of the enzyme.⁴ Very occasionally, the disease appears to be transmitted in an autosomal-dominant fashion, where a single abnormal copy of HGD from a single parent is associated with alkaptonuria; other mechanisms or defects in other genes possibly are responsible in those cases.⁴

Risk factors:

In most ethnic groups, the prevalence of alkaptonuria is between 1:100,000 and 1:250,000.² In Slovakia and the Dominican Republic, the disease is much more common, with prevalence estimated at 1:19,000 people.² As for Slovakia, this is not the result of a single mutation, but due to a group of 12 mutations in specific "hot spots" of the HGD gene.²The Slovakian clustering probably arose in a small area in the northwest of the country and spread after the 1950s due to migration.² Alkaptonuria is inherited in an autosomal recessive pattern, which means it is passed down from parents to their children. It was the first disease to be interpreted as a mendelian recessive trait by Garrod in 1902. If both parents carry one copy of the defective gene related to this condition, they typically do not show signs and symptoms but each of their children has a 25% chance of developing the disease.³

Causes:

Alkaptonuria is caused by a mutation on your homogentisate 1,2-dioxygenase (HGD) gene. It’s an autosomally recessive condition. This means that both of your parents must have the gene in order to pass the condition on to you⁴. Alkaptonuria is a rare disease. According to the National Institutes of Health, the condition affects about 1 in 250,000 to 1 million people worldwide, but is more common in Slovakia and the Dominican Republic, affecting about 1 in 19,000 people.

Diagnosis:

· Your doctor may suspect you have alkaptonuria if your urine turns dark brown or black when it’s exposed to air. They may also test you for the condition if you develop early onset osteoarthritis.

· Your doctor can use a test called gas chromatography to look for traces of homogentisic acid in your urine. They can also use DNA testing to check for the mutated HGD gene.

· Family history is very useful in making a diagnosis of alkaptonuria. However, many people don’t know they carry the gene. Your parents might be carriers without realizing it.

Standard therapies:

No treatment modality has been unequivocally demonstrated to reduce the complications of alkaptonuria. Main treatment attempts have focused on preventing ochronosis through the reduction of accumulating homogentisic acid. Such commonly recommended treatments include large doses of ascorbic acid (vitamin C) or dietary restriction of amino acids phenylalanine and tyrosine. However, vitamin C treatment does not have definitively proven effectiveness¹ and protein restriction (which can be difficult to adhere to) has not shown to be effective in clinical studies.¹

Several studies have suggested that the herbicide nitisinone may be effective in the treatment of alkaptonuria. Nitisinone inhibits the enzyme 4-hydroxyphenylpyruvate dioxygenase, responsible for converting tyrosine to homogentisic acid, thereby blocking the production and accumulation of HGA(5). Nitisinone has been used for some time at much higher doses in the treatment of type I tyrosinemia. Nitisinone treatment has been shown to cause a larger than 95% reduction in plasma and urinary HGA.¹ The main drawback is accumulation of tyrosine, the long-term risks of which are unknown; a particular concern exists about damage to the cornea of the eye. Long-term use requires frequent monitoring for complications.

There’s no specific treatment for alkaptonuria. Instead, treatment is focused largely on managing symptoms⁹. There are many therapies that have been tried, but unfortunately they haven’t been proven to be effective, and may be harmful or unhelpful in the long term. However, The National Institutes of Health Trusted Source warns that long-term use of vitamin C can sometimes increase the production of kidney stones and has generally proven ineffective for long-term treatment of this condition⁶. Other treatments for alkaptonuria are focused on preventing and relieving possible complications, such as: arthritis, heart disease, kidney stones.

The World Institutes of Health Trusted Source reports adults can experience a buildup of homogentisic acid in cartilage, resulting in arthritis. As a result those with alkaptonuria may need a shoulder, knee, or hip replacement. You may also require surgery to replace your aortic or mitral heart valves, if they stop working properly⁶. In some cases, you may need surgery or other therapies to treat chronic kidney or prostate stones.

Investigational therapies:

Researchers are studying the use of a drug known as nitisinone (Orfadin®) as a potential treatment for alkaptonuria. Nitisinone, which received orphan drug status in 2001 from the Food and Drug Administration (FDA), has been approved for the treatment of a metabolic disorder known as tyrosinemia¹⁰. In earlier studies, nitisinone was shown to significantly reduce accumulations of homogentisic acid in individuals with alkaptonuria. However, more research is necessary to determine whether nitisinone given to younger patients can prevent the symptoms of alkaptonuria as well as to determine the long-term safety and effectiveness of the drug for individuals with alkaptonuria⁴.

Complication:

· Homogentisic acid also can build up on the heart valves, especially the mitral valve.

· Coronary artery disease may develop earlier in life in people with alkaptonuria.

· Kidney stones and prostate stones may be more common in people with alkaptonuria.⁵

· Damage to the cornea of the eye

Progonosis:

The life expectancy for people with alkaptonuria is fairly normal. However, the disease puts you at much higher risk of certain disorders, including:

· Arthritis in your spine, hips, shoulders, and knees

· Tearing of your Achilles tendon

· Hardening of your heart’s aortic and mitral valves

· Hardening of your coronary arteries

· Kidney and prostate stones

· Some of these complications can be delayed with regular checkups. Your doctor will want to monitor you regularly. Tests to monitor the progress of your condition might include:

· spinal X-rays to check for disk degeneration and calcification in your lumbar spine

· chest X-rays to monitor your aortic and mitral heart valves

· CT (computed tomography) scans to find signs of coronary artery disease.

· Alkaptonuria does not appear to affect life expectancy, although the last study on the topic is from 1985.¹ The main impact is on quality of life; many people with alkaptonuria have disabling symptoms such as pain, poor sleep, and breathing symptoms. These generally start in the fourth decade. The typical age at requiring joint replacement surgery is 50–55 years.¹

CONCLUSION:

Alkaptonuria is a congenital disorders and it can transfer from parents to children through DNA which can found in numerous tissue in the body. It affect the childhood period of children. AKU thrives on deliberately annoying other people. It has very rare condition but it affect the child very badly throughout the life the child suffering from many complication .The life expectancy was fairly normal but its puts higher risk of certain disorders ,regular checkups with consultant delayed the complication so prevention is the best out come to prevent from further complication in Alka ptonuria.

REFERENCES:

1. https://www.healthline.com/health/alkaptonuria#treatment

2. Lindner, Moritz; Bertelmann, Thomas (2014-01-30). "On the ocular findings in ochronosis: a systematic review of literature". BMC Ophthalmology. 14 (1): 12. doi:10.1186/1471-2415-14-12. ISSN 1471-2415. PMC 3915032. PMID 24479547.

3. https://flipper.diff.org/app/items/info/6243

4. ntrone WJ, Perry MB, Troendle J, et al. A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Gene Metab. 2011; 103:307-314. http://www.ncbi.nlm.nih.gov/pubmed/21620748

5. Petit SJ, Fisher M, Gallagher JA, Ranganath LR. Cardiovascular manifestations of alkaptonuria. J Inherit Metab Dis. 2011; [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/21506017

6. https://www.google.com/search?rlz=1C1GNAM_en-GBIN688IN688&sxsrf=ALeKk00UZX-XYCZJ17-fPJ3rKPX19iZPEA:1611926312003&q=complications+OF+ALKAPTONURIA&spell=1&sa=X&ved=2ahUKEwjziey5ncHuAhXH4jgGHc8SDyEQBSgAegQIChAw&biw=1366&bih=625

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

8. Speeckaert R, Van Gele M, Speeckaert MM, Lambert J, van Geel N (July 2014). "The biology of hyperpigmentation syndromes". Pigment Cell Melanoma Res. 27(4): 512–24. doi:10.1111/pcmr.12235. PMID 24612852.

9. Speeckaert R, Van Gele M, Speeckaert MM, Lambert J, van Geel N (July 2014). "The biology of hyperpigmentation syndromes". Pigment Cell Melanoma Res. 27(4): 512–24. doi:10.1111/pcmr.12235. PMID 24612852.

10. Zatkova A (December 2011). "An update on molecular genetics of Alkaptonuria (AKU)". J. Inherit. Metab. Dis. 34 (6): 1127–36. doi:10.1007/s10545-011-9363-z. PMID 21720873

Received on 03.02.2021 Modified on 11.03.2021

Int. J. Nur. Edu. and Research. 2021; 9(3):364-366.

DOI: 10.52711/2454-2660.2021.00084