RETT SYNDROME
Rett syndrome (RTT; Online Mendelian Inheritance in Man [OMIM]: phenotype #312750; gene/locus #300005) is a neurodevelopmental disorder first noted about 1960 by the Austrian developmental pediatrician Andreas Rett and the Swedish child neurologist Bengt Hagberg. RTT is the leading genetic cause of severe intellectual disability in females. Its incidence is approximately 1:10,000 female births.
After a normal pregnancy and
delivery, early development is apparently normal through age 6 months; however,
retrospectively, subtle deviant patterns occur, including deceleration of
acquired head growth. Developmental progress stalls between 6 and 18 months,
followed by frank regression of fine motor skills and communication function,
including loss of acquired language with poor visual and aural interactions
suggesting autism.
Concomitantly, stereotyped hand
movements appear during wakefulness: hand-wringing, hand-mouthing,
hand-clapping or patting, or unusual finger movements. Each girl develops her
own repertoire, generally evolving over time. Subtle stereotypies occur in the
feet and circumorally. Although gait is acquired in about 80%, approximately
20% of Rett children require assistance. It is subsequently lost in about 25%
to 35%, becoming considerably dyspraxic in the remainder, with broad-based,
semipurposeful patterns, toe-walking, or retropulsion. Overall, about 70% are
able to walk, 20% of whom require assistance.
After the early period of
autistic-like behaviors, an increasingly interactive phase emerges, typically
by age 3 to 5 years. Here the child becomes very responsive to external
stimuli, with intensive eye gaze and markedly improved receptive communication
skills. However, expressive language remains poor. Their inability to speak or
engage in volitional fine motor functions makes intellectual assessment
difficult. Improved communication is possible through picture boards and
advanced computer-based technologies. Although cognitive function remains
stable, gradual slowing of motor skills occurs in adulthood, with increasing
rigidity and dystonic posturing of ankles and feet.
There are common associated medical
problems. Periodic breathing consists of breath-holding,
hyperventilation, or a combination. This is prominent between ages 5 and 15
years, being exacerbated by unfamiliar or stressful circumstances, including large
crowds or new surroundings. Gastrointestinal dysfunction includes disordered chewing and swallowing, gastroesophageal
reflux, delayed stomach emptying, constipation, gall-bladder dysfunction, and
impaired growth, all related to the neurologic underpinnings of Rett syndrome.
Epilepsy and scoliosis are increasingly common throughout childhood and
adolescence, ultimately occurring in 80%.
Seizures are infrequent before age 2
years, may be generalized or partial and usually easily managed. Many girls
have unusual behaviors (“vacant spells”) that are difficult to distinguish from
epilepsy, thus requiring video electroencephalographic monitoring. Scoliosis
becomes evident by age 4 years, with greater severity in hypotonic children
lacking ability to maintain independent upright posture. Surgery is required in
12% to 14%, often improving quality of life. Bracing is employed with greater
frequency; its effectiveness is inadequately
evaluated. Feet and hands are generally small, unusually cold, and discolored.
Unexplained sudden death occurs,
possibly related to unwitnessed seizures, respiratory failure, or prolonged QT
syndrome; average survival is 50+ years. With increasing appreciation of the
underlying medical issues, general well-being has improved remarkably.
PATHOPHYSIOLOGY
At present, 95% or more of those
with features consistent with RTT have a mutation in the MECP2 gene
(coding for methyl-CpG-binding protein 2), located at Xq28. MECP2, a member of
a family of methyl-binding proteins, is an epigenetic regulator of a large and
increasing number of genes, including BDNF (brain-derived neurotrophic
factor) and CRH (corticotrophin- releasing hormone). Reduced growth of
dendrites and their spines are present throughout the cerebral hemispheres (an
explanation for deceleration of head growth) and brainstem. All
neurotransmitter function is impaired, with an imbalance between excitatory
(principally glutamatergic) and inhibitory (chiefly GABAergic) expression.
Conditional knockout mouse models indicate the diverse functional impact in
specific neural centers. For example, knockout of
GABAergic function in the forebrain, sparing the brainstem, results in an
absence of periodic breathing abnormalities.
In general, RTT is a sporadic
condition with recurrence in the family being <<0.1%. In 75% or more, new
mutations derive from paternal germ lines. In the small number of familial
cases, the mother carries the gene but is normal or shows mild cognitive
impairment or a learning disability due to favorable skewing of X-chromosome
inactivation. The differential diagnosis includes autism, Angelman syndrome,
and the neuronal ceroid lipofuscinoses.
Males with mutations in MECP2 have
a progressive disorder, the abnormal gene being expressed in all cells.
Duplication of MECP2 produces another distinctive disorder that is
modified by the involvement of other genes. These males are quite abnormal,
whereas their mothers, 70% (or more) of whom carry the same duplication, appear
normal yet have significant obsessive- compulsive behaviors.
At present, substantial research is
being conducted in mouse models of RTT/MECP2 mutants, and a number of
clinical trials are ongoing or in planning stages. Despite this, specific
treatment designed to provide a cure remains
elusive.
