A condition, known commonly as "black urine disease" or Alkaptonuria is a rare genetic disorder involving protein metabolism, and it has its root in the mutation of the homogentisate 1,2-dioxygenase gene, which in turn causes homogentisic acid accumulation in the body. The appearance of dark urine after exposure to air is due to this kind of accumulation; however, a variety of symptoms can be expected, such as joint stiffness, changes in pigmentation, and other long-term health complications. Although the prevalence has been estimated to be between 1 in 250,000 and 1 in 1 million people in the United States, its effects are indeed high on those affected.

Alkaptonuria is an autosomal recessive disease, meaning that the child must inherit a defective copy of the HGD gene from both parents. If both parents are carriers, their offspring have a 25% chance of inheriting two faulty genes and developing alkaptonuria. The condition is genetic but is often not diagnosed for years because it progresses slowly and its early symptoms appear to be harmless.

Symptoms of Alkaptonuria

The most characteristic and common initial symptom of alkaptonuria is dark urine. The reason for this is due to the fact that excess HGA is excreted in the urine and upon oxidation in the presence of air, it gives the urine a brown or black color. Though it is often considered cosmetic, the long-term accumulation of HGA within the connective tissues produces more complicated health problems.

Progressive joint pain and stiffness: The accumulation of HGA in cartilage leads to early-onset osteoarthritis, making movement increasingly difficult over time.

Skin and eye pigmentation changes: Affected individuals may develop bluish or grayish discoloration of the sclera (white part of the eye) and the skin, particularly in areas exposed to friction.

Cardiovascular and respiratory problems: With age, HGA accumulation can lead to valve calcifications in the heart and stiffening of connective tissues in the respiratory tract, which can cause problems in middle and old age.

Decreased mobility and spinal problems: The spine may become stiff and painful due to chronic cartilage degeneration.

These symptoms usually begin to manifest during adulthood, leading to severe complications in a person's 40s or 50s and significantly affecting the quality of their life.

How is Alkaptonuria Diagnosed?

Because of its rarity, alkaptonuria is often mistaken or overlooked early in life. However, there are several ways to confirm the condition:

Urine Testing: The gold standard in the diagnosis is the testing of urine samples for high levels of homogentisic acid via gas chromatography. In case of oxidation, which changes the color of urine to black, it is indicative of alkaptonuria.

Genetic Testing: Confirmatory genetic testing reveals mutations of the HGD gene to diagnose the condition conclusively.

Blood Tests: High levels of HGA in the blood can be used as further evidence.

Imaging Studies: X-rays and MRIs will expose cartilage and joint damage characteristic of alkaptonuria.

Management of Alkaptonuria: Is There A Cure?

At present, there is no cure for alkaptonuria; however, various treatment approaches can reduce its symptoms and slow the disease's progress:

Nitisinone Therapy: Nitisinone is a drug that inhibits the production of HGA. It has been shown to reduce HGA levels and slow tissue damage. However, it needs to be taken under close medical supervision because of potential side effects.

Low-Protein Diet: Since HGA is a byproduct of protein metabolism, reducing protein intake—especially foods rich in tyrosine and phenylalanine—may help decrease HGA production.

Pain Management: OTC pain relievers and anti-inflammatory medications can be used to relieve joint pain and stiffness.

Physical Therapy: Exercise regularly, as it may improve mobility and strengthen muscles, thus reducing strain on affected joints.

Surgical Interventions: Most people with alkaptonuria develop severe osteoarthritis necessitating joint replacement in their old age. Also, some may require heart valve replacement surgery if cardiovascular complications develop.

Life with Alkaptonuria

Although alkaptonuria is not fatal, it severely affects the quality of life. The progressive deterioration of the joints and associated symptoms can make everyday activities difficult, requiring lifestyle changes and medical interventions. The disease may cause premature aging of the joints, requiring walking aids and mobility assistance earlier than expected.

Ongoing research will continue to work on improving the treatment options by focusing on gene therapy and alternative enzyme replacement therapies. However, because of its rarity, the clinical trials and research remain sparse.

As genetic research advances, more hope for better management and possible curative approaches for alkaptonuria exists. Scientists are searching extensively for enzyme replacement therapies and innovative drugs that can target the root cause of the disorder. Being aware and being diagnosed early helps individuals better their condition and ultimately have better long-term health outcomes.

Alkaptonuria is a striking example of how one gene mutation can have widespread effects on the body. Though still a rare and often misunderstood condition, growing awareness and advances in treatment are paving the way for better care. If you or a loved one suspect symptoms of alkaptonuria, it is essential to seek early diagnosis and medical guidance to manage the disease effectively and preserve quality of life.

At 22, the young woman had little reason to think she would soon be facing a major cardiac surgery. Newly married and otherwise healthy, she suddenly lost movement in her right arm and leg. Her family was devastated and struggled to understand how a young, healthy woman could have suffered a stroke.

Investigations revealed an unusual cause: a tumour in her heart, with a small piece believed to have broken away and travelled into the blood vessels supplying her brain. She was advised to undergo immediate open-heart surgery to remove the tumour.

But the prospect of open-heart surgery frightened her. Despite repeated counselling, she refused the procedure. Two months later, she suffered a second stroke. This time, she lost much of her ability to speak and eat, while her heart function had also fallen to 35%. Once again, open-heart surgery was advised. Once again, she refused.

Her Condition Worsened As Treatment Was Delayed

Over the next three months, her condition continued to deteriorate. She weighed only 35 kg, was weak and withdrawn, and required feeding through a Ryle's tube. Her husband continued looking for another option.

A neighbour eventually suggested that the family consult a doctor in Kolkata who performed robotic heart surgery. The family approached Dr Soumya Guha, Cardiothoracic and Vascular Surgeon, BM Birla Heart Hospital, initially through an online consultation, as the young woman was unwilling to visit a hospital.

This was an extremely high-risk case. She had already suffered two strokes, her heart function had come down to 35%, she was severely underweight at 35 kg and was physically very weak. The tumour was also large. Given her condition and the complexity of the surgery, I was initially reluctant to take up the case for robotic heart surgery. But the family was desperate, and we felt that if we could first improve her physical condition and prepare her psychologically, we could give her a chance. She needed to be built up before we could think of taking her safely through such a major procedure.

The team therefore spent time preparing her for surgery, working to improve her nutritional and physical condition while counselling her repeatedly to help her overcome her fear of surgery. Once she was considered ready, she was brought to Kolkata.

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Two Tumours Found During Robotic Heart Surgery

The surgery presented another unexpected finding. What had been thought to be a single cardiac tumour turned out to be two tumours in the heart. Both were removed using robotic heart surgery.

Given her small body size, weakness and small blood vessels, the procedure required additional precautions during cardiopulmonary bypass. The team used artificial conduits to establish bypass and employed NIRS monitoring along with multiple filtration modes to support her during the procedure.

Rehabilitation Helps Her Regain Movement, Speech And Swallowing

Her recovery was also a major part of the treatment. Following surgery, she underwent extensive physical rehabilitation along with speech and swallowing therapy. Nursing, intensive care, physiotherapy, dietary support and ward care were all part of the recovery process, with the hospital administration also providing financial assistance to the family.

Today, the young woman is able to stand and walk on her own. She has begun speaking a few words and has progressed from Ryle's tube feeding to eating small amounts of mashed food.

For her family, the change has been remarkable: from watching a young woman suffer two strokes and gradually lose her ability to speak and eat, to seeing her prepare to return home on her own feet.

The surgery was only one part of this patient's journey. Given how weak she was, getting her through the operation safely was important, but helping her regain movement, speech and swallowing afterwards was equally important. This required the efforts of the surgical and anaesthesia teams, perfusionists, nursing staff, ICU and ward teams, physiotherapists, speech and swallowing rehabilitation and the dietician. The support from the hospital administration also made a difference to the family. Every one of these teams had a role to play in getting her to where she is today.

While dementia is generally associated with older age, its onset can begin much earlier, including in middle age. A new study led by an international team of researchers found that muscle loss as people age may be an important warning sign for dementia risk.

The study, published in the International Journal of Food Sciences and Nutrition, also found a surprising difference in how obesity was linked to dementia depending on a person’s age.

What Did The Study Find?

Researchers analyzed more than 80 studies examining the links between body weight, body fat, muscle health and dementia.

They found that people with sarcopenia — the loss of muscle mass and strength — had a 42 per cent higher risk of dementia.

People with obesity in middle age, or before 65, had a nine per cent higher risk of dementia. In contrast, obesity in people aged 65 and over was linked to a 17 per cent lower risk.

The findings showed that body weight alone did not tell the full story when it came to dementia risk.

“It’s not just about how much you weigh – maintaining muscle strength and function also appears to be important as we age,” said lead researcher Dr Uraiporn Booranasuksakul from Burapha University, Thailand.

“Our findings suggest losing muscle could be an important warning sign for dementia risk.”

Why Muscle Health Matters

Sarcopenia is a condition where people lose a greater amount of muscle mass, strength and physical function, often as they get older.

Dr Booranasuksakul said the findings highlighted the importance of looking after muscle health throughout life.

“Maintaining muscle is an important part of healthy ageing, and regular physical activity and good nutrition can help support muscle strength and function,” she said.

Obesity And Dementia Risk Change With Age

Corresponding author Professor Mario Siervo from Curtin University’s School of Population Health said the findings also challenged the idea that dementia risk could be understood simply by looking at a person’s weight.

“We found that obesity in middle age was linked to a higher risk of dementia, but this relationship changed in later life,” Professor Siervo said.

“This does not mean people should gain weight as they get older. Rather, it shows us that the relationship between body weight, ageing and dementia is complex.”

What About Sarcopenic Obesity?

The researchers also looked at sarcopenic obesity, where a person has both low muscle mass or function and excess body fat.

Only four studies met the criteria for this part of the analysis, and researchers found no statistically significant link between sarcopenic obesity and dementia.

Professor Siervo said more research was needed to understand whether the combination of muscle loss and excess body fat affected dementia risk.

“There is still a lot we don’t know about how changes in muscle and body fat interact over time,” Professor Siervo said.

“More long-term research is needed to understand whether having both low muscle mass and excess body fat increases dementia risk.”

A Lifelong Approach To Healthy Ageing

The researchers said the findings reinforced the importance of taking a lifelong approach to maintaining healthy body composition, including preventing unhealthy weight gain during middle age and maintaining muscle strength and function as people get older.

India has a target to eliminate dog-mediated rabies by 2030. It has strengthened access to post-exposure prophylaxis for people exposed to rabid animals, but controlling transmission among dogs still remains a challengge.

India's National Action Plan for dog-mediated rabies elimination rests on human-health component, which focuses on post-exposure prophylaxis and awareness among bite victims, and the animal-health component, which focuses on vaccinating and sterilising stray dogs.

In a conversation with HealthandMe, Dr Hanul Thukral, Veterinary Epidemiologist, South Asia Field Epidemiology & Technology Network (SAFETYNET), formerly with the Centre for One Health, National Centre for Disease Control (NCDC), Ministry of Health & Family Welfare, Government of India, says that the human-health side of the programme is strong. The bigger challenge lies in giving the animal-health side enough resources, coordination and accountability.

The Gap Of Animal Health Component In Rabies

Dr Thukral talks about an unusual problem at the heart of India's rabies-control efforts. He speaks about the ownership of stray dogs and that they do not fall under any single ministry.

“Stray dogs also do not come under a particular ministry. They do not come under the animal husbandry ministry, the health ministry or the wildlife ministry. They are under the purview of local bodies, including municipal corporations and rural local bodies,” he said.

This is a larger issue as the animal-health component of rabies elimination depends on sustained vaccination and sterilisation campaigns. Dr Thukral said the country currently lacks dedicated funding and resources for this part of the effort.

For India to move faster towards the 2030 goal, he said local bodies need to be given greater financial and operational support, including resources to capture rabid dogs, sterilise stray dogs and vaccinate them.

He added, “There should be an incentive-based model for local bodies like Swachh Bharat. Financial or non-financial incentives could be offered to local bodies for their rabies efforts, including recognition for those that prevent the majority of deaths.”

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Treatment Is Available But The Patient May Seek Treatment Late

India's human-health response is strong. Dr Thukral said the health ministry has increased access to rabies vaccination and rabies immunoglobulins, with a goal of making vaccines available up to the PHC level and immunoglobulin available up to the CHC level.

Yet the first break in the prevention chain can occur before the health system even knows a bite has happened.

“The prevention chain breaks down where it actually starts. It starts with the awareness of dog-bite victims,” Dr Thukral said. “A person bitten by a dog has to recognise the danger and seek care before the health system can intervene. According to a recent estimate cited during the interview, only around 20-25% of dog-bite victims receive post-exposure prophylaxis, while 60-65% do not. Of those who receive it, only 50% complete it.”

Dr Thukral stressed that these are not definitive figures. “These are just estimates based on a subset of the population,” he said.

That gap can lead to delayed treatment. “In rabies, time is everything,” he said, adding, “If we don't get post-exposure prophylaxis immediately after the dog bite, after 10 hours or after 24 hours, it has virtually no use.”

The 70% Dog-Vaccination Challenge

Human treatment can prevent death after exposure, but elimination requires the transmission cycle to be interrupted among dogs. Around 70% vaccination coverage among dogs is needed to interrupt the transmission chain.

The problem, Dr Thukral said, is that India does not have reliable nationwide data showing what proportion of its stray-dog population is actually vaccinated.

He said, “A nationwide stray-dog census was only recently conducted, counting almost 1 crore 50 lakh stray dogs across the country. Local bodies and panchayats conduct surveys and organise vaccination campaigns within their jurisdictions, but the current effort is very scattered and very non-uniform.”

He added, “If I achieve 70% vaccination in a particular block, the dogs of that block are protected. But there is always a chance that unvaccinated dogs from the periphery or neighbouring blocks can enter that block.”

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Treatment Alone Can Prevent Deaths, But Not Eliminate Rabies

Dr Thukral says saving people from rabies and eliminating rabies are not the same goal. He said, “One estimate suggests that if India continues increasing post-exposure prophylaxis coverage while carrying out suboptimal dog vaccination, around 400 deaths could be prevented over the next 10 years.”

Another estimate cited by Dr Thukral puts the figure at about 400-500 deaths over the next 10 years, with spending about 5 to 10 crores. But preventing those deaths would still fall short of elimination. “That’s it. We cannot achieve elimination,” Dr Thukral said.

“Humans are not the source of the infection,” he explained. “In this case, dogs or other animals are the source of infection. Unless we target them, we do not move closer to elimination.”

India Does Not Have Reliable Data For Vaccinated Stray Dogs

The same data problem extends to the Animal Birth Control programme, which combines sterilisation with anti-rabies vaccination. The expert says that there is no nationwide figure showing how many stray dogs have been vaccinated or sterilised. The information exists, but it sits across individual municipal corporations and panchayats rather than in one comprehensive national dataset.

“Vaccinating stray dogs doesn't come under the purview of the health ministry or the animal husbandry ministry,” he said. That makes it difficult to answer a seemingly basic question: what proportion of India's stray dogs is vaccinated at any given time? “We do not have nationwide data,” Dr Thukral said.

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Reliable 'One Health' Approach

Rabies is not a problem that can be solved by hospitals alone. At the district level, Dr Thukral said an effective One Health system would require health departments, municipalities, animal husbandry authorities, veterinary services and welfare bodies to have clearly defined responsibilities, adequate resources and a mechanism to coordinate.

He said, “The health department would focus on post-exposure prophylaxis, animal-bite management and awareness. Local bodies would handle dog vaccination, sterilisation and solid-waste management. The animal husbandry department could provide technical support, while welfare bodies could promote responsible dog ownership. Let every department do its job and establish coordination among them.”

That coordination also becomes important after an individual bite. Municipal or animal-health authorities need to communicate with the health department because one reported bite may indicate that additional people have been exposed.

How To Recognise A Rabid Dog?

Another challenge is recognising rabid animals. Dr Thukral said that after a dog is bitten by another rabid dog, it can take up to three months for symptoms to develop. However, he stressed that this does not mean the animal transmits the virus throughout that entire period.

“It will transmit the virus about 10 days before it starts showing symptoms,” he said. He also described several behavioural and neurological changes that can raise concern.

A dog that suddenly becomes aggressive, unusually quiet, or behaves differently from its normal pattern may warrant attention. Other signs described by Dr Thukral include seizures, excessive drooling, and changes in vocalisation.

“The basic thing we need to look out for if we get a dog bite or exposure from a potentially rabid animal is, most importantly, change in the animal's behaviour,” he said.

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India’s Surveillance Gaps

India's surveillance recorded 54 rabies deaths in 2024, according to the Press Information Bureau. But an independent study cited during the discussion put the number at more than 5,700, and estimated that India may have between 3,000 and 7,000 deaths annually.

Dr Thukral said that India's human rabies surveillance system is well equipped to detect, diagnose and report suspected and confirmed cases. But the bigger vulnerability, he said, may occur before a suspected case enters the health system.

“If there are scattered cases, such as one bite or a couple of bites, unless that patient reports to a health facility for potential post-exposure prophylaxis, the health system will most probably fail to capture it,” he said.

In other words, surveillance can only record what comes into contact with the system. Community awareness and care-seeking behaviour therefore remain critical.

The Biggest Challenge In India’s Rabies Elimination Goal

Dr Thukral believes the health component of India's rabies programme is comparatively strong. Post-exposure prophylaxis is accessible, almost free and cost-effective, he said. But it becomes more difficult when the focus shifts to dogs.

“Sterilising and vaccinating a dog currently takes around Rs 1,500 per stray dog to vaccinate it and sterilise it,” he said.

With a stray-dog population of around 1.5 crores, the scale of resources required becomes enormous. According to Dr Thukral, local bodies generally do not have that kind of money to dedicate to rabies control.

“So, yes, our system is very much in place and very strong to detect human rabies cases and treat them and provide them with the necessary care,” Dr Thukral said. “But for elimination, we need to target the source of the infection, which is obviously these stray dogs.”

For India to reach its 2030 goal, he said, the pace needs to pick up in terms of resources, manpower and political intention.

India's rabies challenge is therefore not confined to what happens after a person is bitten. It begins much earlier. With awareness, timely care-seeking, dog vaccination, sterilisation, waste management, reliable data and coordination between agencies working across the human and animal-health systems.

The country can continue expanding access to post-exposure prophylaxis and prevent more deaths. But, as Dr Thukral emphasises, that alone cannot deliver elimination. The question for the next four years is whether India can move from responding to individual exposures to systematically interrupting transmission at its source. As the expert said, “We need to target the source.”