User:Tony22221v/sandbox

Summary
xxx

a. Genotype: how is the disorder inherited?
x

b. Phenotype: how is the disorder diagnosed? Signs and symptoms / characteristics across the life span
x

c. Effect on cognitive development
Research on cognitive development within Alkaptonuria is limited. “To date there are no reports of altered cognitive functioning or central neurotransmitter metabolism in AKU patients”, (Davison, AS et al,. 2022). This is due to the unethical and impractical nature of Alkaptonuria being a recessive gene in which limits the amount of participants evolved in the practice of assessing the central neurotransmitter metabolism through cerebrospinal fluid or a brain biopsy. Concerns of AKU patients' health inevitably arise as the AKU patients have a significantly weaker musculoskeletal. However that does not mean suggestions cannot be made based on pathophysiology of AKU. The accumulation of HGA in the body can result in oxidative stress and inflammation, ensuing neurons being damaged thus disrupting neural pathways. This may cause cognitive development and impairments as metabolic pathways cannot function properly.

d. Effect on fertility
Regarding fertility to AKU, there is no direct association or evidence suggesting that AKU causes infertility towards men and women. However, the possibility of other health issues associated with AKU depending on severity of AKU can cause issues in the activity of production in men and the potential of hormonal secretion within women. Due to the nature of AKU in bone deterioration because of Ochronotic in connective tissue, hips or pelvis movement may become difficult to assume certain positions during intercourse and at times may even feel painful and cause discomfort. In women hypothyroidism may occur, and result in infertility at low levels of thyroid hormone.

''' e. What is the morbidity / mortality of the disease? '''

Alkaptonuria is a rare condition that  occurs globally in 1 in 250000 people opposed to 1 in 1 million people worldwide. Moreover about 1 in 100,000 to 250,000 in the general population with more prevalence occurring in Slovakia   tracing back to Kysuce region in the Carpathian mountains, domiancian republic and the middle east , seen to be due to founder effects. Consequently, 5 in 500,000 in Slovakia, the Dominican Republic, and the Middle East. The high prevalence is Dominican republic is due to a mutation in the c120W gene. The cause of the morbidity is due to accumulation of homogentisic acid (HGA) due to the ineffective HGD enzyme which is responsible for converting HGA into maleylacetoacetic acid, the excess forms in connective tissue causing multiple problems that result in  ochronotic arthropathies, tendon ruptures, fractures, and chronic joint pain as well as cardiac valvular dysfunction and interstitial renal disease. This is because excess HGA  is oxidized to  benzoquinone acetic acid which is then converted to a melanin-like pigment. This is the course of the ruptures, fractures, and weakness. Ochronosis occurs over time due to this excessive HGA production, which leads to hyperpigmentation and progressive degeneration, but differ in location and severity. All resulting in various problems. Mortality is not seen to be effected by the disease itself but  there are serval complication that can arise which impact ones health. The most detrimental of the disease’s effects include Debilitating arthritis and sight-threatening ocular complications. As such, “Early identification and diagnosis of the disorder are imperative for management and treatment as complications can be sight-threatening, including astigmatism, central vein occlusion, glaucoma, and blindness”. Since ocular symptoms are the first symptoms to arise with this disease, with a mean age of 15 years. Thus, treatment can be used earlier to minimise the profound effect.

''' f. Can we prevent the disease? '''

Yes, you can prevent complication of the disease through medical interventions such as Nitisinone10 mg daily for those presenting with complications. It suppresses enzyme activity from converting tyrosine to HGA. But lower dosage (i.e. between 0.2-2 mg) can be used to prevent complications from arising by reducing hga production by greater than 90%, whilst also limiting side effects of Nitisinone. other interventions like low protein intake can help with the side effects of Nitisinone due ot the increase tyrosine plasma and tissue concentrations. Low protein intervention alone can be used in children younger than 12 years to significantly reduce hga excretion in urine. Potential preventions could be Crispr Cas 9 to edit the homogentisate 1,2-dioxygenase enzyme gene.

a. What is the typical age of onset of signs and symptoms?
x

b. How does the sufferer’s disease affect their ability to interact with society?
x

c. What special requirements might they need?
x

a. What are possible therapies?
Currently, there is no cure for alkaptonuria, however there are 3 main therapies that focus on minimising symptoms and preventing or slowing the progression of the condition.

Physical Therapies are most common in dealing with AKU later in life. The severe deformity of joints that progresses can have a significant impact on movement, especially on the hip and knee. Surgical interventions will be necessary to considerably improve the quality of life.

Dietary modifications in a low protein diet can reduce the amount of tyrosine in the body. However, compliance to the strict low protein diet has become difficult.

Nitisinone is an enzyme that inhibits production of 4-hydroxyphenylpyruvate dioxygenase (HPPD) which directly corresponds to the production of HGA. This significantly improves symptoms such as joint pain and stiffness and slows down AKU however, it is not widely accepted treatment as it is still in clinical trials for alkaptonuria. Concerns for potential liver damage and eye problems can occur and long term effects of nitisinone have not been fully understood. More research is needed to determine the optimal dosage and duration of treatment for it to be applied for more practical use.

b. What is the long-term prognosis with or without treatment?
Without treatment to alkaptonuria, considerable effects can occur to quality of life as symptoms of joint movement can significantly impact individual lifestyle. Consequently, compared to an individual who is compliant towards his diet and nitisinone treatment can achieve a normal life without ongoing noticeable stiffness and movement impairment. Surgical interventions are most considerable to be the most effective measure in restoring quality of life as long term benefit exceeds losses.

c. Recent research on therapies / management of the condition.
Nitisinone is the most recent and continued research in AKU management, as it directly prevents production of HGA as a replacement pathway of breaking down HGA. Nitisinone is still in the clinical trial phase until long term effects are fully understood. Research on AKU is very limited thus nitisinone research has become more prevalent.

5. References
x