6th February 2024

Alkaptonuria

Alkaptonuria, also known as black urine disease, is a rare genetic disorder affecting the metabolism of amino acids, tyrosine and phenylalanine. Autosomal recessively inherited mutations in the HGD gene cause defects in the enzyme homogentisate 1, 2 dioxygenase, which breaks down an intermediate of tyrosine metabolism known as homogentisic acid. Deficiency or loss of function mutations leads to the accumulation of homogentisic acid within the body.

Clinical features 

Patients with alkaptonuria classically first notice the darkening of urine, which occurs when homogentisic acid is oxidised and turns black upon exposure to air. This discolouration is not present at birth but becomes apparent by late childhood. Other body fluids, such as sweat, tears, and tissues, can also become darker and may lead to blue-black pigmentation in various body parts, such as the ears, sclerae and connective tissues.

Alkaptonuria may also affect the musculoskeletal system, with homogentisic acid accumulating in the joints, leading to ochronosis. This condition is characterised by progressive degeneration of the cartilage and connective tissues, leading to arthritis-like symptoms with stiff, painful joints that show a reduced range of motion. These features are most commonly observed in the spine, hips and knees. When they affect the ribs and thoracic spine, they can interfere with ventilatory mechanisms, leading to shortness of breath. 

Homogentisic acid can be deposited in various organs. In the urinary tract, this causes stone formation in the kidney, bladder and prostate. In the heart, deposits affect the valves, causing stenosis, whereas atherosclerotic changes can be seen in blood vessels. 

Diagnosis

Alkaptonuria is typically diagnosed with a urine test that detects homogentisic acid or a genetic test identifying a mutation in the HGD gene.

Management

Alkaptonuria requires lifelong symptom control and support with regular monitoring of joint function and pain management as the mainstays of treatment. Some medications, such as nitisinone, have shown the potential to reduce homogentisic acid levels, slowing down the progression of ochronosis. 

Genetic counselling may be recommended for affected individuals and their families to understand the inheritance pattern and assess the risk of the condition in future generations. 

Patients with pain and stiffness from alkaptonuria can benefit from regular exercise to strengthen joints and muscles. Sometimes, if joints are damaged and need replacement, or where heart valves become stenotic, there is also a role for surgery in these individuals.

Cystinosis

Cystinosis is a rare genetic disorder affecting the transport of amino acid, cystine, within cells. It is subsequently characterised by the accumulation of cystine crystals within various organs and tissues throughout the body. Cystinosis is caused by mutations in the CTNS gene, which encodes a protein called cystinosis.

In healthy individuals, cysteine is transported out of lysosomes, aided by cystinosis. However, impaired cystinosis function in affected individuals causes cystine accumulation within the lysosomes. Over time, excess cystine forms crystals that damage tissues and organs.

Three main types of cystinosis are described and classified based on the age of onset and severity of symptoms:

• Nephropathic infantile cystinosis
  • This is the most severe form, usually diagnosed in infancy (before age 2). It represents 95% of all cases and primarily affects the kidneys with accumulation and deposition of cystine within nephrons. If untreated, this leads to kidney dysfunction, renal Fanconi syndrome, and eventually end-stage renal disease. Patients with Fanconi syndrome exhibit impaired kidney reabsorption, resulting in excessive loss of amino acids, glucose, electrolytes and other vital molecules in the urine.
• Nephropathic juvenile cystinosis
  • Usually, later onset in childhood or adolescence shares some characteristics with nephropathic infantile cystinosis but is usually less severe and has a slower progression. Kidney dysfunction and Fanconi syndrome may still occur.
• Non Nephropathic or Ocular Cystinosis
  • This is the rarest form (representing only 1-2% of all cases), primarily affecting the eyes with deposition of cystine crystals in the cornea. Symptoms typically manifest in adulthood, including eye pain, blurred vision, and photophobia.

Cystinosis can affect many other organs and tissues, including the liver, muscles, thyroid gland, pancreas and the brain. Progression and severity are variable amongst individuals.

Clinical features

Clinical manifestation of cystinosis includes:

• Kidneys
  • Parents initially notice extreme thirst, excessive urination, vomiting, difficulty feeding, and failure to thrive in the young infant. This usually reflects Fanconi syndrome, in which the kidneys fail to absorb essential substances.
• Eyes
  • Cystine crystal deposition in the cornea can cause painful eyes, blurred vision and photophobia.
• Musculoskeletal
  • Renal failure resulting from Fanconi syndrome causes severe vitamin deficiency, ultimately resulting in rickets in the growing child. Crystal deposition can also cause weakness and wasting of the muscles; in the limbs, this can cause reduced mobility; in the chest, it may predispose to breathing difficulty; and in the larynx, it may manifest as swallowing/feeding difficulties.
• Other organs
  • Deposition of cystine crystals within the pancreas can lead to diabetes, whilst thyroid involvement can lead to an underactive thyroid with associated sequelae.

Diagnosis 

Cystinosis is diagnosed with genetic testing to identify mutations in the CTNS gene. Measurement of cystine levels in white blood cells or tissue biopsies can also play a role.

Management

Cystinosis is a chronic condition requiring lifelong management. Early diagnosis and initiation of treatment are crucial to minimise organ damage and improve long-term outcomes. 

Mainstays of management involve treating symptoms and preventing complications with cystine-depleting medications such as cysteamine. Other treatments may include supportive measures such as electrolyte replacement and nutritional support, with a role for kidney transplantation reserved for severe cases of renal failure. 

Patients must undergo regular monitoring by a multidisciplinary medical team, including nephrologists, ophthalmologists and other specialists. Genetic counselling is also crucial for individuals and families affected by cystinosis to understand the inheritance pattern and assess the risk of passing the condition on to future generations.