Rare Genetic Diseases: Rett Syndrome

Occurring in 1:10,000 of female births, Rett syndrome (RS) is a rare genetic disease which influences the patient’s metabolism. How many of you have heard about a rare genetic disease that involves gastrointestinal problems?

RS is a neurological disorder with metabolic components. The syndrome is caused by mutation in the X-linked gene methyl-CpG-binding protein 1 (MECP2). This transcriptional regulator is ubiquitously expressed in all human tissues. The syndrome occurs almost exclusively in girls, as the majority of the boys suffering from this condition die shortly after birth. The diagnosis is based on the symptoms and can be confirmed with a genetic test.

Following a period of normal neurological and physical development during the first 6–18 months of life, the first features of RS start to manifest and appear progressively over several stages.

1. Stagnation: occurs between the 6th and 18th month of life, during which the infant shows less eye contact and is less interested in it’s toys.
2. Rapid progression: takes place within the first four years of the patient’s life. This stage is characterized by the loss of purposeful hand skills and spoken language and lasts only for a couple of weeks, however the symptoms do not go away.
3. Pseudo Stationary Phase: appears after the fourth year and can potentially last until the patient’s death. Apraxia (difficulty with motor planning to carry out tasks), motor problems and seizures are prominent during this stage.
4. Late motor deterioration: onsets during the 10th year of life and lasts for lifetime. The characteristic features of this stage include reduced mobility, curvature of the spine and muscle weakness.

Symptoms include loss of acquired speech and motor skills, repetitive hand movements, as well as breathing irregularities and seizures. The patient may suffer from sporadic episodes of gastrointestinal problems, early onset osteoporosis (bone weakening), bruxism (excessive teeth grinding or jaw clenching) and screaming spells. Many children suffering from this disorder have reduced brain volume due to the small neuronal body size and a denser packing of cells. A number of patients also present with dyslipidaemia (abnormal amount of lipids in the blood), elevated ammonia and inflammation of the gallbladder (an organ which stores bile for fat digestion).

RS patients have increased levels of sphingolipid metabolites, which support the growth, survival, and maturation of the nerve cells. Due to the dysregulation of the cholesterol pathway in the brain, the patients have elevated cholesterol synthesis early in the disease, which is followed by a sharp downregulation of cholesterol synthesis as the disease progresses.

As it was already mentioned, the MECP2 gene is located at q28 on the human X chromosome. It encodes a protein of 498 or 468 amino acids, depending on the use of alternative splice variants, with MECP2B being the predominant isoform in the brain. MECP2 is important for the function of several types of cell, including nerve cells (neurons). Less than one percent of the patients have inherited the gene mutation from their parents.This type of mutation is called the germline mutation. Majority of the patients suffer from the disease due to the sporadic mutation, which occurs on the X chromosome of the male. The principle why the mutation occurs in the sperm is unknown.

Due to the lack of knowledge about the principles of the disease, the treatment is purely focused on relieving the symptoms.