Article: Rett syndrome

Rett syndrome (Rett syndrome, Rett's disorder) is a progressive neurological disorder. The symptoms of this disorder are easily confused with those of cerebral palsy. The clinical diagnosis specifies a small head and small hands and feet. Stereotypical repetitive hand movements such as mouthing or wringing of the hands are also included as diagnostic signs. Symptoms of the disease include learning disorders and a total inability to socialize. Girls with Rett syndrome are very prone to seizures and gastrointestinal disorders. They typically have no verbal skills, and about 50% of females are ambulatory.

Etiology

Rett syndrome (symbolized RTT) is X-linked dominant, affecting almost exclusively girls. Development is normal until 6-18 months, when language and motor milestones regress, purposeful hand use is lost and acquired microcephaly is seen. Hand-wringing and sighing are characteristic, and those affected develop autistic behavior. Rett syndrome is usually caused by a mutation in the gene encoding methyl-CpG-binding protein-2 (MECP2). MECP2 is found on chromosome band Xq28, near the long end of the X chromosome. Rett syndrome can also be caused by a mutation to the gene encoding cyclin-dependent kinase-like 5 (CDKL5). Rett syndrome affects one in every 12,500 female live births.

Gender and Rett syndrome

Most individuals with Rett syndrome are female. One explanation given for this was that the genetic defect that caused Rett syndrome in females caused embryonic lethality in males (that is, males with pathogenic MECP2 mutations died before they were born). While a plausible hypothesis, more recent research has contradicted this explanation.

Most males with a pathogenic MECP2 mutation suffer from neonatal encephalopathy and die within a year or so of birth. Males who have two X chromosomes and a Y chromosome (often called Klinefelter's syndrome), one with a mutated MECP2 gene, follow a similar development path to females with Rett syndrome. Males who have somatic mosaicism also have symptoms like females with Rett syndrome.

Some researchers (for example Masuyama et al 2005) have reported cases of males with Rett syndrome who have a pathogenic MECP2 mutation but do not have a somatic mosaicism or an extra chromosome.

Unlike most genetic diseases, many cases of Rett syndrome involve spontaneous mutations in one of the parent’s gonads. It has been argued that one cause of the majority of Rett syndrome individuals being female is that mutations to MECP2 are possibly more common in male gonads than female gonads, and only females can inherit a mutated MECP2 gene from fathers (males inherit a Y chromosome from fathers, which does not contain a copy of MECP2).

Development and Symptoms

Infants with Rett syndrome typically develop normally until they are 6-18 months old. Physioneurological development tends to plateau after this brief period of normal development, and is followed by deterioration of the high brain functions. Psychomotor and cognitive abilities rapidly decline between 1-2 years of age. Symptoms that develop are similar to those of autism, including mental retardation and poor growth. It is, hence, easy to mistakenly diagnose Rett syndrome for autism, or cerebral palsy.

Symptoms of Rett syndrome that are similar to autism:

• screaming fits
• panic attacks
• inconsolable crying
• avoiding looking into other people's eyes
• lack of social/emotional reciprocity
• general lack of interest
• marked impaired use of nonverbal behaviors to regulate social interaction
• delay of linguistic development
• loss of speech

Symptoms of Rett syndrome that are also present in cerebral palsy:

• short stature
• severe dementia
• mild learning disability
• hypotonia
• Delayed or absent ability to walk
• gait/movement difficulties
• ataxia
• microencephalopathy - abnormally small head, lack of head growth
• some forms of spasticity
  • wringing of hands
  • Chorea - spasmodic movements of hand or facial muscles
  • dystonia
  • bruxism - grinding of teeth

Symptoms may stabilize for up to a few decades before complications set in, such as epilepsy or seizure and spastic paraparesis (spasticity or paralysis of the lower limbs).

Treatment & Prognosis

Depending on the severity of psychomotoral and cognitive impairment, 2-15% of patients may achieve a nonretarded level of functioning through various rehabilitation methods. Marriage, success in achieving employment and independent living can be achieved during adulthood. Currently there is no cure for Rett syndrome.

Treatment of Rett disorder briefly includes:

• increasing the patient's communication skills
• counseling
• modifying social difficulties
• behavioral interventions

Treatment usually requires consultations from:

• speech and language therapist
• neuropsychologist/psychologist/counselor
• neurologist/neuropsychiatrist

Common drug prescriptions include:

• antidepressants
  • SSRIs
• antipsychotics
• beta-blockers
• opioid antagonists

Common assistive technology used:

• wheelchair
• standing frame

Mortality

Males with pathogenic MECP2 mutations usually die during infancy stage from severe encephalopathy, unless they have an extra X chromosome (often described as Klinefelter's syndrome), or have somatic mosaicism.

Females can live up to 40 years or more. Abnormal lab data values on Rett disorder may show:

• EEG abnormalities from 2 years of age
• atypical glycolipids
• elevated levels of beta-endorphins and glutamate
• reduction of substance P
• decreased levels of nerve growth factors

Mortality rate among children with Rett disorder is approximately at 1.2% per year.

High proportion of deaths are abrupt; due to:

• heart conduction problem - abnormally prolonged QT interval on ECG
• spontaneous brainstem dysfunction
• respiratory arrest