Atypical Rett Syndrome

A rare genetic neurological disorder characterized by the presence of two or more of the main criteria for classic Rett syndrome (loss of acquired purposeful hand skills, loss of acquired spoken language, gait abnormalities, stereotypic hand movements), a period of regression followed by recovery or stabilization, and five out of eleven supportive criteria (breathing difficulties, bruxism, impaired sleep pattern, abnormal muscle tone, peripheral vasomotor disturbances, scoliosis/kyphosis, delayed growth, small cold hands and feet, inappropriate laughter or screaming spells, decreased pain sensation, and intense eye communication). Like classic Rett syndrome, it almost exclusively affects girls, while the disease course may be either milder or more severe.

Epidemiology

Based on reports that up to 32% of RTT cases show an atypical phenotype, the prevalence of atypical RTT is estimated at around 1/45,000. Like classic RTT, atypical RTT syndrome predominantly affects girls.

Clinical description

Atypical forms may present with either a milder or more severe clinical picture than that seen in typical RTT. Several subvariants of atypical RTT have been defined. i) The early-onset seizure type (Hanefeld variant) is characterized by seizures in the first months of life with subsequent development of RTT features. ii) The congenital variant (Rolando variant) is the most severe form of atypical RTT, with onset of classic RTT features during the first three months of life. iii) The 'forme fruste' is a milder variant with onset in early childhood and an incomplete and protracted course. iv) The late childhood regression form is characterized by a normal head circumference and by a more gradual and later onset (late childhood) regression of language and motor skills. v) The preserved speech variant (PSD or Zappella variant) is marked by recovery of some verbal and manual skills.

Etiology

The early-onset seizure type (Hanefeld variant) is frequently caused by mutations in the X-linked CDKL5 gene (Xp22). A translocation involving the NTNG1 gene (1p13.2-p13.1) has also been identified in a patient with early seizures and atypical RTT. The congenital variant (Rolando variant) is generally caused by mutations in the FOXG1 gene (14q11-q13). A microdeletion syndrome involving a 14q12 interstitial deletion has also been described with a similar phenotype but with the additional feature of facial dysmorphism. The preserved speech variant (PSD or Zappella variant) is caused in at least some cases by mutations in the MECP2 (Xq28) gene, which is also responsible for the majority of cases of classic RTT.

Diagnostic methods

Diagnosis relies on clinical evaluation using the diagnostic criteria for atypical RTT originally defined by Hagberg in 1994: an atypical case must meet at least three of the six main criteria and at least five of the eleven supportive criteria. Molecular analysis may allow confirmation of the diagnosis.

Differential diagnosis

Differential diagnoses include Angelman syndrome, autism, cerebral palsy, inborn errors of metabolism and severe intellectual deficit (see these terms).

Genetic counseling

Genetic counseling should be proposed and prenatal testing is available for female relatives of an index case, who may asymptomatic due to skewed X-inactivation.

Management and treatment

At present, there is no specific cure for atypical RTT. Treatment is symptomatic and supportive. Medication may be needed for breathing irregularities, sleep disturbances (melatonin), agitation (risperidone), rigidity (carbidopa, levodopa) and motor difficulties, and antiepileptic drugs may be used to control seizures. Anti-reflux agents may also be required.

Prognosis

The course of atypical Rett syndrome, including the age of onset and the severity of symptoms, varies from child to child. Despite the range of symptoms, most individuals with RTT continue to live well into middle-age and beyond.