Cystinosis

What is Cystinosis?

Cystinosis is a rare genetic disorder that results from changes or mutations in a gene called CTNS, which is responsible for making a protein called cystinosin. This disorder affects about 1 in 100,000 to 200,000 newborns globally, and leads to an over-accumulation of a substance called cystine within small parts of cells known as lysosomes, causing damage to almost all organs.

The most common issue seen in cystinosis patients is kidney-related and more specifically tied to ‘proximal tubulopathy’, which is a form of kidney damage. This condition is the leading cause of suffering and sadly, death in children who have a severe form of cystinosis called nephropathic or infantile cystinosis, and, over the long term, it typically causes kidney failure. It’s also important to know that cystinosis is the most common genetic reason for a kidney disorder known as Fanconi syndrome in children.

There are three known types of cystinosis: infantile (also called nephropathic), juvenile (including intermediate and late-onset forms), and adult (consisting of benign, ocular, and non-nephropathic variants). The infantile form is the most common and severe type, representing about 95% of all cases. By their early teens, children with this form often develop a serious kidney condition known as end-stage renal disease (ESRD).

To treat cystinosis, doctors often use a medicine called cysteamine, which helps to remove the excess cystine from the body. If the disease is recognized and treated early with cysteamine, it can delay the development of severe kidney disease and help improve the overall health and lifespan of affected individuals.

What Causes Cystinosis?

Cystinosis is a disorder caused by a faulty protein known as cystinosin. This protein’s job is to transport a substance called cystine out of a tiny cell part known as the lysosome. For understanding, lysosomes can be considered as the waste disposal system of the cell. This protein is created based on instructions from the CTNS gene located on a specific part of chromosome 17, named 17p13.2.

If there are mutations or changes in the CTNS gene, cystinosin might not be made correctly. Over 140 harmful mutations in this gene have been discovered and linked to cystinosis. The severity of cystinosis can depend on the type of mutation. Larger or more impactful mutations can cause a severe form of cystinosis which tends to appear in infancy (referred to as ‘nephropathic’ cystinosis). Meanwhile, those who have milder mutations, which still allow some cystine transport out of lysosomes, typically develop less severe forms of cystinosis either in childhood or adulthood.

Risk Factors and Frequency for Cystinosis

Cystinosis is a condition that affects about 1 in 200,000 newborns around the world. However, how common it is can greatly depend on where you live. The disease is inherited, meaning it’s passed down from parents to their children, and areas where families are closely related or share a common ancestor tend to have more cases. For example, in Brittany, France, it affects 1 in 26,000 newborns, while in Quebec, Canada, it affects 1 in 62,500 newborns.

• The region with the highest reported number of cystinosis cases is among the Pakistani ethnic group living in the West Midlands, UK, where it affects 1 in 3,600 births.
• Places where marriages between relatives are more common—like the Middle East and North Africa—also seem to have a higher number of cases, but we don’t have specific numbers for these areas.

Signs and Symptoms of Cystinosis

Infantile Cystinosis is the most common and severe type of cystinosis, making up about 95% of all cases. Symptoms usually start between 6 to 12 months of age. Common symptoms include failure to grow at the expected rate, excessive thirst and urination, imbalance of electrolytes, dehydration, vomiting, and constipation. If left untreated, serious conditions such as osteomalacia and osteoporosis can develop by the second decade of life. Protein in the urine is also an early sign of this disease.

A study showed that 93% of children with infantile cystinosis had growth issues. Between ages 3 and 4, children often experience light sensitivity due to a buildup of corneal crystals. Other common problems include liver enlargement, portal hypertension, and enlarged spleen. Hypothyroidism, hypogonadism, and diabetes typically develop by the second decade of life while difficulty walking, swallowing and legal blindness may occur by the third decade.

Juvenile or Late-Onset Nephropathic Cystinosis makes up about 5% of cases. This form usually begins between ages 5 and 20 with symptoms like discomfort in the eyes or light sensitivity. Unlike in the infantile form, growth retardation is typically not a feature of this form. Kidney disease typically progresses slower in this form.

Adult Cystinosis primarily presents with visual symptoms such as light sensitivity, usually in young adulthood to middle age. Other systemic symptoms are usually absent.

Since eye abnormalities are often the earliest signs of cystinosis, an eye examination is crucial for diagnosis. Corneal cystine accumulation with crystal formation is typically the first finding, which can cause light sensitivity and eye spasms from mid-childhood to early adolescence.

Neurological examinations may reveal common issues such as tremors, low muscle tone, motor impairment, speech delays, behavioral issues, and brain diseases. Progressive muscle wasting and weakness are also often observed.

• Coarse facial features
• Congenital hypopigmentation, including light skin and blond hair, due to impaired melanin production
• Slow growth rate
• Liver enlargement
• Hypogonadism
• Premature skin aging

Testing for Cystinosis

If you are urinating a lot, measured as more than 2 litres per day for each square meter of your body surface, it could be a sign of cystinosis. Cystinosis is a condition where certain types of amino acids accumulate in various organs of the body, causing damage. If you are suspected to have this condition, the doctor will check the levels of different substances in your urine, such as electrolytes, bicarbonate, glucose, and protein. This is because cystinosis is the most common inherited cause of a condition called Fanconi syndrome in children, which affects the kidneys’ ability to absorb these substances.

There are several common signs and symptoms that a doctor may look for when diagnosing cystinosis. These include low levels of electrolytes like potassium, phosphate, calcium, sodium, and bicarbonate in the blood; low concentration, presence of sugar and certain proteins and high levels of phosphate and bicarbonate in the urine; an imbalance of acids and bases in the blood; signs of an underactive thyroid; persistent high blood sugar levels indicated by a high hemoglobin A1c (HbA1c) level; low testosterone levels; elevated liver enzymes; low levels of a certain type of vitamin D; low bone density; and calcium deposits in the kidneys.

Usually, a doctor will use two specific tests to confirm the diagnosis of cystinosis – leukocyte cystine levels and genetic testing for pathogenic CTNS variants. These levels are generally measured in a specialized laboratory. If the levels of cystine (a type of amino acid) in the white blood cells are usually greater than 2 nanomoles of half-cystine per milligram of protein, it might suggest cystinosis. When these levels range between 5 to 15 nanomoles, it might indicate infantile cystinosis, whereas levels ranging between 3 to 6 nanomoles could suggest juvenile cystinosis. For individuals without cystinosis, these levels are typically below 0.2 nanomoles. Additionally, a comprehensive eye examination is also very important in evaluating cystinosis.

Treatment Options for Cystinosis

Cysteamine is a common treatment to lower the levels of cystine in your body. This chemical interaction forms compounds that are safely transported out of certain cellular structures, leading to a reduction in the complications of cystinosis. Cystinosis is a condition that causes an abnormal buildup of a certain amino acid (cystine) in various organs of the body. Doing this can significantly slow down the progression of the disease and lessen its impact. However, it’s important to start treatment early, as this can not only slow down the progression of the condition but also improve growth and reduce other complications.

Although cysteamine is not a cure, it’s important to note that patients will need to stay well-hydrated, nourished, and their electrolyte and bicarbonate levels need to be maintained. Major studies have shown that early treatment in infants can help maintain normal levels of these crucial bodily components.

Cysteamine comes in two forms: immediate release and delayed release. Your doctor may monitor your leukocyte cystine levels (a measure of certain amino acids in your white blood cells) regularly to adjust your treatment plan. The intent is to keep this level below a certain threshold.

Unfortunately, cysteamine can cause some unpleasant side effects like nausea, vomiting, diarrhea, lack of appetite, abdominal pain, headache, bad breath, body odor, hallucinations, nervousness, fever, and skin rash. It may also increase the secretion of stomach acid, potentially leading to digestive complications. To manage the side effects, your doctor may prescribe other helpful drugs or recommend dietary supplements.

For eye problems caused by cystinosis, eye drops that directly apply cysteamine to the eye can help prevent and reduce the buildup of cystine in the cornea, the clear outer layer of the eye. It is essential to note that these eye drops need to be applied several times daily.

Prostaglandin inhibitors, a type of medication, have had some success in treating symptoms of the condition Fanconi syndrome that are also seen in cystinosis, such as loss of water and electrolytes.

Treatment of cystinosis-related conditions may include providing adequate fluids, supplements such as phosphate, potassium, and alkali to compensate for losses, growth hormone therapy for children experiencing growth failure, and thyroid hormone replacement as needed.

Testosterone replacement therapy may be necessary in male patients, as cystinosis can lead to decreased androgen and sperm production. For female patients, their fertility may be impacted due to chronic kidney disease and the potential need for kidney transplantation.

If the disease has progressed to the point where a patient’s kidneys are failing, they might be offered a kidney transplant. The new kidney will not suffer the same damage, and long-term results of transplantation are generally good.

There are potential future treatments being investigated, such as various disease-modulating therapies, but these are not yet available.

What else can Cystinosis be?

Fanconi syndrome, a kidney condition, can be caused by a variety of factors. Some of these include:

• Tyrosinemia
• Galactosemia
• Glycogen storage disorders
• Wilson disease
• Lowe syndrome
• Hereditary fructose intolerance
• Mitochondrial disorders
• Monoclonal gammopathy
• Dent disease

Exposure to heavy metals can also lead to Fanconi syndrome, particularly:

• Lead (majorly in children)
• Cadmium
• Mercury
• Platinum
• Uranium

Other conditions that cause growth retardation along with kidney-related symptoms or periodic dehydration include:

• Renal tubular acidosis (proximal and distal)
• Bartter syndrome
• Gitelman syndrome
• Diuretic abuse

Finally, certain genetic factors can cause a specific form of rickets that is resistant to vitamin D. These include vitamin D–dependent rickets types 1A, 1B, 2A, and 2B.

What to expect with Cystinosis

In the past, most people with a condition called cystinosis didn’t live into adulthood due to complications from the disease. However, an early treatment using a medicine named cysteamine has now made it possible for patients to live much longer.

Unfortunately, cystinosis still causes serious health problems and increases the risk of death. While cysteamine therapy can delay complications and reduce the severity of these health problems, there is currently no treatment that can ensure a completely normal and healthy life.

One of the main health problems caused by cystinosis is related to the kidneys, which often leads to an increase in the severity of the disease and the need for a kidney transplant. When a patient with cystinosis gets a new kidney through a transplant, cystine (a substance that builds up and causes problems in cystinosis) does not build up in the new kidney.

Gene therapy, specifically using a procedure called hematopoietic stem cell transplantation, is a potential future treatment for cystinosis, but there is currently limited clinical experience with this.

Possible Complications When Diagnosed with Cystinosis

Cystinosis is a disease that can impact almost every part of the body, but it most often affects the kidneys. Early signs can include a condition known as proximal renal tubular acidosis, where multiple substances leak from the kidneys which leads to a disease called Fanconi syndrome. Over time, the ability of the kidneys to filter blood effectively can decrease, a symptom often noted by high levels of protein in urine. Eventually, this condition may progress to a stage of kidney disease where dialysis or a kidney transplant is needed.

Here are some of the potential complications:

• Kidney-related complications: Fanconi syndrome, dehydration, low blood potassium levels, metabolic acidosis, a form of rickets due to low phosphate, and severe kidney disease requiring replacement therapy.
• Eye-related complications: Deposits in the cornea, causing symptoms such as watery eyes, sensitivity to light, eyelid spasm, and retinal hemorrhage.
• Hormone-related complications: Stunted growth, underactive thyroid, diabetes, and a condition affecting the gonads and their function.
• Neurological and muscle-related complications: Gradual loss of speech, memory, and cognitive function; deposits of calcium in the brain; and muscle disease leading to difficulty swallowing and walking.
• Bone-related complications: Rickets, osteoporosis, a bone disease linked with kidney disease, and fragility fractures.

Preventing Cystinosis

Cystinosis is a genetic disorder that is inherited from both parents. It follows a predictable pattern and there’s a 25% chance of passing it onto children. It’s really important that people are made aware of this disorder; genetic counseling can help to prevent it from occurring within families and the wider community.

Besides prevention, catching the disorder early and starting treatment with a medicine called cysteamine can greatly reduce the negative health effects and delay death. Managing any other health problems that might come with this disorder, as well as referring for a kidney transplant in a timely manner can greatly improve the quality of life for families affected by this disorder. The medicine, cysteamine, alongside these measures, can offer a signifcantly positive impact.