RETT SYNDROME: UPDATE ON DIAGNOSIS MANAGEMENT AND RESEARCH

SAROJINI S. BUDDEN MD, FRCP(C)

Director Rett Syndrome Clinic

Associate Professor Pediatrics

Oregon Health Sciences University

Portland, Oregon

(Presented by Sue Gibson & Kylie Opperman 3/5/06)

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RETT SYNDROME

In 1954, Dr. Rett, a Viennese physician, first noticed this syndrome in two girls as they sat in his waiting room with their mothers. He observed these children making the same repetitive hand-washing motions. Curious, he compared their clinical and developmental histories and discovered they were very similar

In 1960, young female patients in Sweden with quite similar symptoms caught the eye of their own physician, Dr. Bengt Hagberg. Dr. Hagberg collected the records of these girls and put them aside, intending to return to them when he had more time to study this curious phenomenon.

But in 1983 an article on RS appeared in the mainstream, English-language journal, Annals of Neurology. Written by Dr. Hagberg and his colleagues, the report finally raised the profile of RS. This article was a breakthrough in communicating details of the disease to a wide audience, and the authors honoured its pioneering researcher by naming it Rett Syndrome.

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RETT SYNDROME

• Incidence of classic forms: 1:12000 - 1: 15000

• Incidence of atypical forms: 1: 45000

• In Australia, Rett Syndrome affects about 1 in 15,000 girls aged 5 to 18 years. Approx 12 girls per year, are diagnosed by the age of 12 years and10% of those with RS reside in South Australia. By 2002, there were about 250 girls throughout Australia who had been diagnosed with this condition.

• RS is most often misdiagnosed as autism, cerebral palsy or non-specific developmental delay.

• RS occurs in all races and ethnic groups.

• About 70% survive to age 35 years. The majority of deaths in RS are either sudden and unexpected, or secondary to pneumonia.

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RETT SYNDROME

X-linked dominant neurodevelopmental disorder.

NOT progressive, degenerative disorder as once thought

Predominantly affects females

Being identified in males

Sporadic in 99.5 % cases

Hereditary factors in 0.5 %.

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RETT SYNDROME – new class of genetic disease

In October of 1999, the discovery of a genetic mutation (MECP2 - methyl-cytosine binding protein) on the X chromosome (Xq28) provided significant insight into the cause of Rett syndrome.

This mutation has now been found in more than 95% of those meeting criteria for typical RS and more than 50% meeting those for atypical RS.

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MECP2 GENE

MECP2 encodes a protein called Mecp2 which regulates the expression of other genes by silencing them

Lack of properly functioning protein allows other genes to be expressed in an unregulated way

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• RS is classified as a developmental disease: it doesn’t cause the brain to degenerate. Rather, RS interferes with maturation of specific areas of the brain.

• The areas of the brain disrupted in RS are the frontal, motor, and temporal cortex, brainstem, basal forebrain, basal ganglia, which control many basic functions, such as movement. They are also critical to the normal development of the cortex, or higher brain centre, in late infancy. RS, therefore, ravages centres that control both motion and emotion.

• Barring illness or complications, survival into adulthood is expected. 

• Because of unusual X inactivation patterns, some females with MECP2 mutations may be normal or have mild learning disability and will not be identified unless they transmit the mutation to a daughter who develops RS.
  

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Diagnosis of Rett Syndrome

Diagnosed with Rett Syndrome if display a certain set of symptoms in their first 3 – 4 years.

• period of normal development

• slowed head growth

• severe impairment of expressive language

• loss of purposeful hand use, followed by repetitive hand movements eg clapping, tapping, wringing

• shakiness of the upper body

• unsteady walk

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Other effects of Rett Syndrome

• Breath holding, hyperventilation and air swallowing

• Sleep disturbances

• Spinal curvature, rigid muscles, joint contractures

• Seizures

• Bluish-red feet and legs because of poor circulation

• Teeth grinding and difficulty swallowing

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Variations in time of onset

• Early onset

• Onset with seizures

• Late onset

• Siblings can have differences in severity

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Stages of Rett Syndrome

• Early Onset (between 6 – 18 months)

• Rapid destructive phase – between 1 – 4 years

• Plateau Stage – symptoms get no worse or their intensity lessens

• Late motor deterioration – starts between 5 and 25 years of age and can last for decades

• Pre-Regression Stage- <1 Year

• Developmental Stagnation -
  9-24 months

• Stage of Regression
  1-4 years

• Early Post- Regression Stage-
  Preschool -early school years

• Late Post- Regression stage -
  5-15-25 Years ++

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CLINICAL FEATURES:
Pre-Regression Stage (<1 Year)

• Poor Suck*

• Weak cry*

• Poor grasp

• Low normal tone

• Random hand movements

• Deceleration head growth

(* ANS involvement)

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Developmental Stagnation (9-24 months)

• Immature hand function

• Unsteady immature ambulation

• Inconsistent social interaction

• Appropriate use of single words or phrases

• Intermittent transient strabismus*

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Stage of Regression
(1-4 years)

• Loss of hand function with hand stereotypes

• Loss of communication

• Inconsistent social interaction

• Agitation with panic like attacks*

• Ataxic /apraxic gait

• Dystonic movements/myoclonic jerks

• Vacant spells /sleep disturbances*

• Hyperventilation /apnea*

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Early Post- Regression Stage
(Preschool -early school years)

• Increasing rigidity noted in heel cords

• Abnormal tongue movements with chewing difficulties and teeth grinding

• Loss of transitional motor skills

• Onset of seizures

• Improved eye gaze

• Breath- holding/air swallowing*

• Vasomotor changes/ Growth delays*

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Late Post- Regression stage
(5-15-25 Years ++)

• Improved eye gaze

• Improved ability to communicate

• May gain some hand function and ambulation

• Increased rigidity with hand and foot deformities

• Scoliosis/kyphosis

• Improved seizures/sleep

• Less intense breath holding*

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Differential Diagnosis

EARLY STAGES

R/O progressive neurological, muscular metabolic and chromosomal disorders,

and Cerebral Palsy

LATE STAGES

R/O Autism,sensory disturbances, acquired CNS infections and Infantile Spasms

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Differential Diagnosis
Autism RS.

• M:F 5:1 Mainly females

• Inappropriate lang: Loss of acquired lang:

• Preserved hand use Loss of hand function

• Rarely Ataxic Ataxia common

• Normal chewing Abnormal chewing

• Seizures rare Seizures common

• Normal/large head Microcephaly

• Normal growth Growth failure

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RETT SYNDROME:
NEURODEVELOPMENTAL DISORDER

1. Brain immaturity due to developmental arrest

2. Immature autonomic nervous system

3. Growth failure

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Autonomic Dysfunction in Rett Syndrome

• Agitation

• Dyspraxia

• Slow responsiveness

• Disorganised breathing

• Vasomotor changes (blue hands and feet)

• Vacant spells

• “Sudden Infant Death” like syndrome

• Gastro-esophageal reflux

• Pupillary dilation

• Constipation 90%

• Abdominal distention (bloating) 50%

• Occasional urinary retention

• Panic like attacks

• Fluctuating mood

• Sleep disturbances

• Labile BP and HR

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Autonomic Dysfunction in Rett Syndrome

• Immature sleep patterns similar to those seen in infancy

• Sympathetic skin response and sleep wake rhythm abnormal in Rett Syndrome

• Poor sensory-motor integration

• Poor pain discrimination

• Reflex sympathetic dystrophy

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Growth Failure

• Microcephaly

• Short stature

• Organ size appropriate for height

• Poor weight gain inspite of good appetite

• Muscle mass low

• Osteoporosis as a result of very low rate of bone formation (decreased bone formation; normal numbers osteoclasts)

• Fertility not affected

• Precocious puberty in < 2%

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Medical management

• Diagnosis and genetic counseling

• Hypotonia (Use of Oral Carnitine )

• Seizure management

• Sleep disturbances

• Feeding difficulties and nutritional management

• Drooling

• Agitation - Apnea - Hyperventilation

• Dystonic spasms

• Osteoporosis/ Orthopaedic care

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Seizure Management

• Anticonvulsant medications

• Consider Ketogenic Diet ( High Fat and protein)

• Vagal Nerve Stimulator in intractable seizures

• Effectiveness of VNS on Seizures N=10

50% (5/10) 100% reduction in seizures

30% (3/10) 90% reduction in seizures

20% (2/10) 60-70% reduction in seizures

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Sleep Disturbances
Medications for Sleep

• Melatonin

• Chloral hydrate

• Clonidine

• Ativan

• Trazadone

• Remeron

• Cyproheptadine

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Feeding / Nutrition

• Determine oral- motor and oral- pharyngeal function

• Involuntary tongue movements / chewing

• Positioning and neck posture / scoliosis

• Increased rigidity

• Gastro-esophageal reflux and dysmotility

• Complete nutritional history and caloric intake, types of foods textures/ consistencies

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Management of Drooling

• Oral – motor treatment

• Use of extract rubbed over the oral mucosa

• 1% Atropine ophthalmic drops _ use 1 drop orally once a day

• Robinol (Glycopyrolate) .01- .22mg/kg/day oral

• Botox injections orally used once in 3 months

• Surgical (Tympanic plexus , Partial Removal of salivary glands, Redirect the salivary ducts)

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Management of Agitation

• Find cause ( reflux, constipation, infections, gall stones, seizures, headache, fractures, change of school or placement, abuse )

• Treat cause

• Use frequent snacks, music, massage, warm baths.

• Medications - Tranxene, Naltraxone, (antiopioid), Resperdol, Ativan, Seroquel, Buspar.

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Management of Respiratory problems

• Usually no treatment

• If there is central apnea use Naltrexone

• For shallow breathing use Theophylline

• If girl hyperventilates and has alkalotic tetany use a bag to breathe into.

• There is no good basis for continuous use of oxygen

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Management of dystonic spasms and rigidity

• Massage

• Warm baths

• Swimming

• Medications – Valium, Klonopin, Neurontin, Artane, Baclofen, Sinemet, Zanaflex

• Botox injections

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Management of Osteoporosis

• Be aware that it is common

• Fractures may result: Inform parents, therapists and teacher

• Proper nutrition

• Do not add excessive calcium if levels are normal

• Treat with Vitamin D, Phosphorous and calcium

• Fosamax , IV Pamidronate

• Maintain muscle use and strength

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Interventions

Treatment and therapies should be based on the rationale that Rett Syndrome is NOT a degenerative disease

Each individual has potential to develop new skills

Receptive communicative skills are far better than expressive

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Interventions

• Therapies should be aimed at maintaining or improving ambulation and balance, maintaining full range of movement or at least functional movement, preventing deformities, promoting and improving the use of the hands, and promoting communication and choice making.

• As Rett Syndrome is considered a neuro-developmental disorder, it is thought that, if individuals with Rett Syndrome are given the opportunity, they may demonstrate the capacity to learn new skills

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Therapeutic Interventions

COVENTIONAL APPROACHES – physiotherapy, occupational therapy, speech pathology

OTHER EFFECTIVE THERAPIES-

• Hydrotherapy

• Hippotherapy/ horse back riding

• Music therapy

• Massage

Factors interfering with communication - Cognitive impairment, delayed latency of response, delayed auditory processing, oral- motor dyspraxia,

dysarthria

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Lessons Learned

• Speech and hand function can improve

• Receptive language better than expressive speech

• Scoliosis can be prevented from worsening

• Increased risk of osteoporosis

• Ketogenic diet and VNS effective for seizure control

• Melatonin effective for sleep disturbances

• Hyperventilation under cortical control

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Useful Links

• www.rettsyndrome.org

• www.ichr.uwa.edu.au/rett/irsa

• www.ichr.uwa.edu.au