Rett syndrome, a neurodevelopmental disorder affecting girls almost exclusively, was first described by Rett in 1966.
The disorder now bears his name and became widely known after a report of 35 cases by Hagberg et al. in 1983. The preva- lence is estimated to be 1/10,000 ~ 1/15,000 female births; over 95% of cases arise de novo due to the fact that most females with Rett syndrome do not reproduce. Rett syndrome is consid- ered to be one of the most common genetic causes of mental retardation in girls, second only to Down syndrome.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Sporadic cases (99.5%), occurring almost exclusively in females
i. A de novo mutation in the child with Rett syndrome
ii. Disease-causing mutation inherited from one parent who has somatic or germline mosaicism b. Several reports of familial recurrence support X-linked
dominant inheritance with lethality in hemizygous males
2. The region of interest has been localized to Xq28 by link- age analysis from available familial cases
3. Caused by mutations in the MECP2 (methyl-CpG-binding protein 2) gene in Xq28
a. Result in a loss of function by either disrupting the methylated DNA-binding properties of the protein or interfering with its association with transcriptional co-repressors
b. MECP2 mutations in sporadic or atypical cases i. Up to 80% of sporadic affected females ii. One third of the clinically atypical cases c. MECP2 mutations in familial cases (lower incidence)
i. Germline mosaic mothers
ii. Asymptomatic carrier mothers due to nonran- dom patterns of X-inactivation. The pattern of X-inactivation most likely protects the mutation carriers from expression of the disease by prefer- ential inactivation of the mutant MECP2 allele 4. Males with MECP2 mutations may suffer from severe
neonatal encephalopathy and die from breathing difficul- ties before their second year. The almost absence of men with classic Rett syndrome suggests a lethal effect of the MECP2 mutation in hemizygous affected men. However, males with Rett syndrome are not always lethal, although neurologic impairment is slowly progressive and much more severe in men than in women
a. Affected men have been reported in association with Klinefelter syndrome and somatic mosaicism b. Most MECP2 mutations have originated in the pater-
nal germline. The paternal X MECP2 never passed on from father to their sons
c. Only way for a male to have Rett syndrome is a de novo mutation of a maternal X or inheritance of a MECP2 gene mutation from his mother
d. Caution: some reported MECP2 mutations may actu- ally represent genetic variant rather than true patho- genetic novel mutations in the MECP2 gene in males
CLINICAL FEATURES
1. Normal prenatal and perinatal history 2. Appropriate head circumference
3. Apparently normal psychomotor development until about 6 to 18 months of life in affected girls
4. Developmental milestones afterwards beginning to slow down and regress with loss of skills already achieved a. Deterioration of communicative skills
b. Social withdrawal
c. Loss of purposeful hand movement 5. Continued deterioration over the next few years
a. Loss of language
b. Poor motor function (truncal and gait apraxia/ataxia) c. Stereotypic hand movements (hand wringing and
flapping)
d. Deceleration of head growth (acquired microcephaly) e. Autistic behavior
6. Period of stabilization
a. Severe psychomotor dysfunction
b. Some patients may make small recoveries in contact and communication skills
7. Breathing difficulties a. Periodic apnea b. Hyperventilation c. Breath holding
d. Forced explosion of air/saliva e. Bruxism
8. Swallowing difficulties
9. Dystonia and hand and foot deformities as affected girls grow older
10. Later development of scoliosis 11. Osteoporosis at risk for fractures
12. Seizures (epilepsy) in 50% affected females
13. Possible survival into adulthood without further deterioration 14. An increased risk for sudden, unexplained death
a. Longer corrected QT intervals b. T-wave abnormalities
c. Reduced heart rate
15. Rett syndrome variants (<10% of cases)
a. Patients with a milder clinical course (‘forme fruste’
phenotype): considered to be the most common vari- ant of nonclassical Rett syndrome
i. Less dramatic regression
ii. Mild learning disability
iii. Milder mental retardation
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iv. Preserved speech v. Ability to walk vi. Some hand use
vii. Usually without seizures
viii. No apparent symptoms observed in a few women who demonstrate skewed X chromo- some inactivation
b. Patients with a severe phenotype
i. Lack of normal postnatal developmental period ii. Congenital hypotonia
iii. Infantile spasms c. Patients with late regression d. Male patients with Rett syndrome
i. Males with XXY (Klinefelter syndrome) ii. Males with somatic mosaicism
iii. Males with XY (normal karyotype) 16. Clinical stages in classic Rett syndrome
a. Stagnation stage (6–18 months) i. Developmental arrest
ii. Deterioration of eye contact and possible loss of communication
b. Rapid destructive stage (1–4 years) i. Developmental deterioration ii. Loss of purposeful hand use iii. Stereotyped hand movements
iv. Autistic features v. Gait ataxia and apraxia
vi. Irregular breathing-hyperventilation
c. Pseudostationary stage (preschool-early school years) i. Mental retardation
ii. Decreased autistic features iii. Prominent gait ataxia and apraxia
iv. Gross motor dysfunction v. Seizures
d. Late motor deterioration stage (5–25 years) i. Decreased mobility
ii. Spasticity
iii. Improved emotional contact iv. Scoliosis
v. Cachexia and growth retardation vi. Staring, unfathomable gaze
17. Relatively restrictive international diagnostic criteria (Rett syndrome Diagnostic Criteria Work Group, 1988) a. Apparently normal prenatal and perinatal period*
b. Normal head circumference at birth
c. Apparently normal development through age six months*
d. Deceleration of head growth occurring anytime between ages three months and 48 months
e. Loss of acquired hand skills and purposeful hand use between ages five months and 30 months, with subsequent development of stereotyped hand movements
f. Severe impairment of expressive and receptive lan- guage together with severe psychomotor retardation g. Development of gait apraxia and truncal ataxia
between ages 12 months and 48 months
18. Modified diagnostic criteria (proposed by Clarke in 1996) a. Necessary criteria
i. Normal prenatal and perinatal development ii. Loss of acquired skills such as communication
and speech
iii. Normal head circumference at birth with acquired microcephaly
iv. Marked developmental delay v. Loss of hand skills
vi. Autistic features vii. Gait apraxia
viii. Stereotypic hand movements b. Supportive criteria
i. Seizures ii. Abnormal EEG iii. Apnea
iv. Hyperventilation
v. Breathing dysfunction with breath holding vi. Scoliosis
vii. Growth retardation viii. Cold feet
ix. Spasticity with muscle wasting
19. Wide spectrum of clinical features associated with an MECP2 mutation
a. Male patients with early-onset lethal encephalopathy b. Adult cases with severe mental retardation
c. Female cases i. Asymptomatic
ii. Mildly mentally retarded
iii. Severe variant of Rett syndrome with congenital onset
DIAGNOSTIC INVESTIGATIONS
1. Mutational analyses of MECP2 gene
a. Sequence analysis and mutation scanning
b. Mutations detected in 35–90% of patients (detected in almost every patient with classical Rett syndrome) c. Wide spectrum of mutations of the MECP2 gene d. Mutations extending to phenotypes that are not easily
recognized as Rett syndrome
e. No significant correlation exists between the clinical course and mutation type
f. MECP2 mutations have been identified in patients previously diagnosed with the following conditions:
i. Autism
ii. Mild learning disability
iii. Clinically suspected but molecularly unconfirmed Angelman syndrome
iv. Mental retardation with spasticity or tremor 2. X-chromosome inactivation pattern: not tested routinely 3. EEG: not specific
4. CT and MRI
a. Cortical atrophy predominantly in the frontal area b. No abnormalities in the white matter, basal ganglia,
thalamus, or hippocampus
c. Narrowing of the brain stem in some patients 5. Photon emission CT
a. Lower cerebral blood flow in the prefrontal and tem- poroparietal association regions with sparing of the sensorimotor regions
*Clinical criteria “a” and “c” may not be applicable to severely
affected females; other criteria will not apply to those who are
mildly affected and are identified as having mutations in MECP2.
b. The flow distribution in Rett patients
i. Similar to that observed in infants of a few months of age
ii. Suggesting a neurodevelopmental abnormality rather than a neurodegenerative process
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. 50% risk to sibs of inheriting MECP2 allele from the carrier mother
ii. Low risk to sibs when a mutation present in the proband is not identified in a parent, provided germline mosaicism is not present in either parent b. Patient’s offspring
i. Unlikely to have offspring due to mental retarda- tion and other handicaps
ii. Reproduction reported in mildly affected females a) Each offspring of a carrier female with 50% risk of inheriting the disease-causing mutation
b) Daughters who inherit the mutation are at high risk of developing classic Rett syndrome, although skewed X chromosome inactivation may result in a milder phenotype
c) Sons who inherit the mutation may suffer a severe neonatal encephalopathy or severe mental retardation in those who survive beyond the first year of age
iii. Healthy sisters of a girl with Rett syndrome a) Possibility of being carriers of the MECP2
mutation but with little or no symptoms because of favorable skewed X chromosome inactivation
b) At risk of transmitting the disease-causing MECP2 mutation to their own children iv. No male with a MECP2 mutation known to
reproduce 2. Prenatal diagnosis
a. Amniocentesis or chorionic villus sampling available to pregnancies at risk for women with a known MECP2 mutation identified in a family member b. Appropriate to offer prenatal diagnosis to couples
who have had a child with Rett syndrome or mental retardation due to a MECP2 mutation, whether or not the disease-causing mutation has been identified in a parent, since germline mosaicism cannot be excluded in either parent
c. A male fetus with the mutation
i. May suffer from a severe neonatal encephalopathy ii. May survive with a severe mental retardation
syndrome
d. A female fetus with the mutation
i. Difficult to predict the phenotype in a female fetus with a MECP2 mutation which can range from apparently normal to severely affected ii. At high risk of developing classic Rett syn-
drome, although skewed X chromosome inacti- vation may result in a milder phenotype
3. Management
a. No treatment is known to improve the neurologic out- come of Rett patients
b. Supportive and symptomatic therapies i. Anticonvulsants for seizures ii. Chloral hydrate for agitation iii. Carbidopa and levodopa for rigidity
iv. Melatonin for sleep disturbances
v. Nutritional management to insure adequate caloric and fiber intake
vi. Management of gastroesophageal reflux a) Antireflux agents
b) Smaller and thickened feedings c) Positioning
c. Occupational and physical therapies i. Maintain function
ii. Prevent scoliosis and deformities d. Augmentative communication
e. Therapeutic horseback riding, swimming, and music therapy
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Fig. 1. A girl with Rett syndrome.
Fig. 2. A girl with Rett syndrome who has MECP2 mutation (R106W).
Fig. 3. A 33-year-old female with Rett syndrome showing severe psy- chomotor retardation and hand wringing so severe that the part of the hand and fingers are red, rough, and swollen from constant irritation by stereotypic hand movement. She was normal developmentally until about 18 months of age when she started to have hand washing/
wringing, tip toe walking, fell easily, and lost the skills she already attained. Shortly after, she started to loose eye contact with people and have seizures. DNA sequence analysis identify a nucleotide change of 763C>T in one copy of the MECP2 gene which predicts an amino acid change of arginine to a premature translation stop at codon 255 (R255X). This nonsense mutation was previously identi- fied in multiple Rett syndrome patients as a disease-causing MECP2 mutation.
