Genetics and Inheritance

Genetics of Rett Syndrome

The vast majority of cases of classic Rett syndrome are caused by mutations in the MECP2 gene. This gene, located in the Xq28 region, provides instructions for producing a protein (MeCP2) that is important for normal brain development and function. MeCP2 protein has several functions, including regulating other genes in the brain and maintaining connections (synapses) between nerve cells.

Using a battery of modern mutation detection assays, mutations in MECP2 can be found in 95–97% of individuals with typical RTT. Genotype-phenotype correlation studies have so far yielded inconsistent results.

Mutations in the CDKL5 gene, located in the Xp22 region, cause the early-onset seizure variant of Rett syndrome. The CDKL5 gene codes for a protein that is involved in brain development and appears to be essential for normal brain function. Although little is known about the protein's function, it may play a role in regulating the activity of other genes, including the MECP2 gene.

The congenital variant of Rett syndrome is caused by mutations in the FOXG1 gene, located in 14q12. The protein produced from this gene regulates several other genes involved in brain development.

 

Inheritance of Rett Syndrome

The MECP2 gene (as well as the CDKL5 gene) is located on the X chromosome.

MECP2 (and CDKL5)-related disorders are inherited in an X-linked dominant fashion (X-linked dominant is a dominant trait or disorder caused by a mutation in a gene on the X chromosome; in this case the phenotype is expressed in heterozygous females as well as in hemizygous males-having only one X chromosome but generally affected males tend to have a more severe phenotype than affected females).

Approximately 99.5% of RS are isolated cases within a family, occurring because of a de novo mutation within the child otherwise in the minority of cases from inheritance from a parent who has germ cell or somatic mosaicism. Families of girls with RS should be referred for genetic counseling to discuss recurrence and prenatal testing options.

Nutrition

Derangement of metabolic equilibrium is manifested in multiple organs in RTT. This often has a nutritional origin. There is very high-energy expenditure through increased motor activity, forceful breathing, Valsalva’s manoeuvre type of breathing, hyperventilation and perspiration. Daily energy and water requirements may be much higher than is often provided to persons with RTT. It is apparent that Forceful Breathers and the RTT population with the Valsalva’s manoeuvre type of breathing will require more than the normal amount of daily energy intake. It is also apparent that there is extra need for DNA and cell repair due to increased catabolism. This is usually carried out through the complex pathways of intracellular and extracellular membrane transport systems that are affected by the Reduction-oxidation (REDOX) status of the cell. The deranged carbon dioxide metabolism in RTT affects the REDOX status of the cell and therefore influences these cellular processes. 


Nutritional management in RTT must include evaluation and calculation of daily intake of food and energy requirements by a dietician. Measurements of Body Mass Index (BMI) and skin folds are useful for monitoring the progress of treatment. Clinical monitoring of blood total protein, albumin, protein electrophoresis, urea, creatinin and electrolytes like Na+, K+, Cl¯, Ca2+ and PO4 are useful in the assessment of nutritional status in RTT. Nutritional treatment must include high and condensed calorie diets. Poor responders may eventually require Percutaneous Endoscopic Gastrotomy, later replaced by small Mickey button, for supplementary feeding. Food supplements and extra micronutrients like glycoproteins, glycolipids and essential fatty acids are required. Glyconutrients are necessary for cellular and nucleic acid repairs .

Sleep disturbance

Sleep problems and night awakening are common in RTT. Management must include evaluation of the circadian rhythm or identification of problems in the initiation of sleep. Arousals due to breathing dysrhythmia should also be considered. Drug treatments recommended are Melatonin and or Pipamperon/Risperidon to restore the circadian rhythm, pipamperon if agitation is a major factor in the sleep disturbance, L-tryptophan if there is difficulty in the initiation of sleep. The CPAP (Continuous Positive Airway Pressure) system should be considered in cases where defence arousals are the major cause of the sleep disturbance.

Epileptic and non-epileptic paroxysms

Problematic epilepsy is common in the RTT population (14). However, autonomic events may simulate atypical seizures. Management must start with a clear clinical description of the fits, which is essential for the correct diagnosis of epilepsy. Signs of abnormal brainstem activity include blinking of the eyes and or facial twitching, non-epileptic vacant spells (atypical absence attacks without EEG evidence of epilepsy) with or without cyanosis and hypocapnic attacks with tetany. The abnormal brainstem activity can only be confirmed by monitoring both the brainstem and cortical activities synchronously and simultaneously in appropriate neurophysiological set up (6).
 
Treatment of epilepsy in RTT is aimed at reducing the excitability of neurones in the immature brain while at the same time trying to prevent the spread of seizures. We must not try to treat the EEG abnormalities in RTT, unless there is a clear clinical correlate. We have found a combination of Sodium Valproate (Epilim) and Lamotrigine useful for these purposes. There is a potential use of Gabapentin or Pregabalin for treatment of the very common abnormal brainstem autonomic paroxysms in RTT. The rationale of these drugs is neuronal membrane stabilisation. We also have limited
experience with left vagus nerve stimulation using implanted stimulators. The two treatment regimes are promising but require further clinical evaluation.

Agitation

Agitation in RTT is largely a consequence of unrestrained sympathetic activity. Typical symptoms and behaviour include very short attention span, increased physical activity, dilated pupils, excessive perspiration and transpiration, sudden screams or rage. Management must include identification of the trigger event or situation. Treatment must start with the avoidance or removal of the likely trigger.
Eventual use of time-out in sensory deprivation is reasonable. The drugs of choice are Risperidone or Pipamperon by mouth in low doses administered twice daily.