Families

TULP3-related disease is a rare inherited condition that causes progressive scarring, or fibrosis, of several major organs, mainly the liver, kidneys, and sometimes the heart. It develops slowly over many years, often beginning in childhood or early adulthood, and tends to worsen gradually throughout life.

The liver is usually the first organ affected. Early signs include abnormal liver blood tests, yellowing of the eyes or skin, itching, or tiredness. Over time, people may develop high pressure in the liver’s blood vessels (portal hypertension), an enlarged spleen, low platelet counts, fluid buildup, or bleeding from enlarged veins in the stomach or esophagus. As scarring advances, cirrhosis can develop, and some individuals eventually need a liver transplant.

Kidney problems tend to appear later. These may include small fluid-filled cysts, scarring of kidney tissue, or gradual loss of kidney function. A few people develop kidney failure and require dialysis or a kidney transplant. The heart can also be affected in adulthood, with some individuals developing a thickened heart muscle known as hypertrophic cardiomyopathy. This may cause shortness of breath, chest pain, or irregular heart rhythms, and heart scans often show fibrosis in the heart muscle.

The condition is inherited in an autosomal recessive manner. This means a person must inherit two faulty copies of the TULP3gene, one from each parent, to develop the disease. Parents who carry only one faulty copy are healthy. Each child of two carriers has a one in four chance of being affected, a one in two chance of being a carrier, and a one in four chance of inheriting no mutation.

The disease is extremely rare but it is probably underdiagnosed, as adults with slow-onset liver and kidney fibrosis may not have genetic testing. The cause is mutation of the TULP3 gene, which helps move important signalling proteins to a small cell structure called the primary cilium. When this transport fails, cells receive abnormal growth and repair signals that lead to scarring, and they may also lose the ability to repair DNA damage effectively.

Diagnosis is made by genetic testing, such as whole exome or genome sequencing, showing two faulty copies of TULP3. Supportive evidence comes from imaging or biopsy of the liver or kidneys showing fibrosis or small cysts, and from blood tests with persistent liver abnormalities. Biopsies usually show fibrosis but lack the typical features seen in other known fibrotic syndromes.

There is currently no cure, but treatment focuses on regular monitoring of the liver, kidney, and heart, management of complications such as portal hypertension or kidney disease, and organ transplantation when necessary. Family genetic counselling and testing for relatives are also recommended. The condition often progresses slowly, and some people remain well for many years before developing organ failure. Early diagnosis and careful long-term follow-up can help manage complications and improve quality of life.