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At a glance

A severe and global developmental disorder affecting the central nervous system (CNS) characterized by autism, dementia, ataxia, and loss of purposeful use of the hand. It is known as a uniform and striking progressive encephalopathy. Evolution in four phases after diagnosis is typical. Cardiac, respiratory, and gastrointestinal (GI) signs are associated.

Synonyms

RTS; Autism Dementia Ataxia and Loss of Purposeful Hand Use Syndrome.

History

First described by Andreas Rett, Austrian pediatrician in 1966; Hagberg in 1983 report 35 patients from France, Portugal, and Sweden.

Incidence

Only females are affected; incidence estimated at 1:15,000 to 1:20,000 in the general population. However, it has been suggested that the prevalence is about 1 in 10,000 to 15,000 female newborns in the United States, but most are not reported or misdiagnosed.

Genetic inheritance

X-linked dominant with 100% antenatal lethality in hemizygous male. All cases should be new mutations explicable on the basis of gonadal mosaicism or X-autosomal translocation in the mother.

Pathophysiology

Caused by mutation in the gene encoding methyl-CpG-binding protein-2 (MECP2) located on Xq28. Exact physiopathology is still unknown, but several reports have shown elevated endorphin levels in cerebrospinal fluid (CSF) and respiratory pattern is improved with opioid antagonists. The loss of function of MECP2 protein might intervene at the level of neurotransmitters and lead to cerebral hypoperfusion.

Diagnosis

Clinically evocated. Essential criteria are abnormal prenatal and perinatal period; an apparently normal psychomotor development until 6 months of age; a deceleration of head growth (between 5 months and 4 years of age); a loss of acquired purposeful hand skills with development of severely impaired speech associated with severe psychomotor retardation, stereotypic hand movements, and gait and truncal apraxia.

Clinical aspects

Usually normal development until age 1 year.

  • Stage 1: Regression of language milestones, with appearance of fine tremor of the hands, ataxic gait, and loss of purposeful movement of the hands, which may not appear until the girl is 2 to 3 years old.

  • Stage 2: Autistic behavior becomes evident at this stage. Rupture of head growth becomes evident and is known as “acquired” microcephalia. The disease is also marked with generalized tonic-clonic seizures that are well-controlled by antiepileptic drugs, peculiar sighing respiration, and periods of apnea. There are associated vasomotor disturbances of the legs. After the initial neurological degradation phase, the disease appears to plateau (between 6 and 18 months of age) followed by a rapid regression that stays for a few weeks to a few months.

  • Stage 3: Stabilization for a few years with some recovery of communication skills.

  • Stage 4: Long phase of motor deterioration with loss of ambulation, spasticity, dystonia, amyotrophy.

Other clinical features ...

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