MKS1-related disorders

What are MKS1-related Disorders?

Mutations in MKS1 can cause a spectrum of inherited disorders known as ciliopathies, which affect tiny hair-like parts of a cell (cilia).

Meckel-Gruber Syndrome

Meckel-Gruber syndrome is caused by mutations in at least 13 different genes, including MKS1. Meckel-Gruber syndrome is an inherited genetic condition that causes central nervous system (CNS) malformations, fluid-filled sacs (cysts) in the kidney, and polydactyly (extra fingers and toes). Other birth defects, including defects of the heart, cleft lip and cleft palate, and abnormalities of the liver and genitalia, are also features of Meckel-Gruber syndrome. Due to the severity of symptoms, those affected with Meckel-Gruber syndrome are stillborn or die soon after birth. The common birth defects associated with Meckel-Gruber syndrome can often be seen on prenatal ultrasound.

Bardet-Biedl Syndrome 13

In some cases, mutations in this gene may cause a condition called Bardet-Biedl syndrome (BBS13). BBS13 is an inherited disease that causes vision problems, kidney abnormalities, genital anomalies, extra fingers or toes (polydactyly), and mild obesity, among other symptoms. About half of individuals with the disease have developmental delay or intellectual disability.

Joubert Syndrome 28

Mutations in MKS1 can also cause Joubert syndrome. To date, 34 genes are known to cause this disease. The defining characteristic of Joubert syndrome is a distinctive brain malformation known as the molar tooth sign. Features include intellectual disability, respiratory issues, abnormal motor function, abnormal eye movements, retinal dystrophy, and extra fingers or toes (polydactyly), among others. MKS1 is associated specifically with Joubert syndrome 28 (JBTS28), which is a relatively mild form of the disease.

How common are MKS1-related disorders?

Meckel-Gruber syndrome affects an estimated 1 in 13,250 to 1 in 140,000 people in the general population and approximately 7% of these cases are attributed to the MKS1 gene. It is more common in certain specific populations such as the Finnish (1 in 9,000) and Belgians (1 in 3,000).

BBS13 is rare, affecting about 1 in 100,000 in North America and 1 in 125,000 in Europe. It is more or less common in specific populations such as Kuwaiti Bedouins (1 in 13,500), residents of Newfoundland, Canada (1 in 17,500), and the Swiss (1 in 160,000). It is estimated that MKS1 accounts for 4.5% of all BBS13 cases.

The incidence of Joubert syndrome is estimated to range from 1 in 80,000 to 1 in 100,000 live births. Approximately 2-6% of Joubert syndrome cases are caused by MKS1.

How are MKS1-related Disorders treated?

There is no cure for Meckel-Gruber syndrome. For those affected, treatment is supportive.

For those individuals affected with BBS13, extra fingers and toes can often be surgically removed in childhood. The vision and kidney problems associated with the disease can be treated via standard protocols by medical specialists. If kidney problems reach life-threatening levels, dialysis and/or kidney transplantation may be necessary. Diet and exercise can help control obesity. In women, vaginal malformations can be surgically corrected.

Individuals affected with Joubert syndrome should be monitored for respiratory issues, including apnea, and treated if necessary. Occupational, physical, and speech therapy may address developmental delays. Liver, kidney, and vision problems can be treated by medical specialists with surgical or other methods of intervention, including organ transplant.

What is the prognosis for an individual with an MKS1-related Disorder?

Meckel-Gruber syndrome is a lethal condition, and prognosis is poor. Those affected are either stillborn or die in the first few hours or days of life.

Kidney disease is a major cause of early death for individuals with BBS13. However, the majority of affected individuals may have a normal or near-normal life expectancy with some impairments.

The prognosis for individuals with Joubert syndrome depends on the severity of the disease. The most common causes of death are respiratory failure in young children and kidney or liver failure later in life. JBTS28 has been reported to be a milder form of Joubert syndrome.