INTRODUCTION:

Rett Syndrome is a neurological disorder that is most commonly seen in females¹. Andreas Rett, a pediatric neurologist was the first to recognize its features in year 1966; but, was first introduced by Bengt Hagberg in 1983². The disorder affects brain development and the symptoms increases as patient grows up. It is usually first seen in children between 6 to 18 months as they start missing developmental milestones. These patients show wide range of neurological and developmental symptoms which require care throughout their life. Rett syndrome is a monogenetic disorder which is caused by mutation in X Chromosome of MeCP2 gene³.

INCIDENCE:

Rett syndrome occurs in 1:10,000 females worldwide; it is rarely witnessed in males⁴.

GENETIC MUTATION IN MECP2 GENE:

MeCP2 is expressed throughout all human tissue but is particularly abundant in neurons. MeCP2 critically maintains synaptic excitation and inhibitions which are necessary for the function of brain circuit; any disruption in the circuit causes disorders like Rett Syndrome³.

TYPES:

There are two types of Rett Syndrome:

1. Classic/Typical Rett Syndrome: It is caused by the mutation in a gene called MeCP2, which encodes protein that is essential for the brain development. It appears at around 6-18 months of age.

2. Atypical Rett Syndrome: Some people have Rett like disease, but their symptoms do not meet the diagnostic criteria for classic Rett Syndrome. They are said to have atypical Rett syndrome. The symptoms may be milder or severe than the typical Rett Syndrome⁵.

CLINICAL MANIFESTATION WITH STAGES:

Following a period of normal neurological and physical development during the first 6-8 months of life, the first features of Rett syndrome begin to manifest in early childhood and appears in 4 clinical stages.

1) Early onset(stage I) stagnation Period- It occurs between 6 months-18 months of age, the symptoms include

· Change in the coordinated behavior of the baby

· Irritable and restlessness

· Delayed postural development

· Hypotonia

· Microcephaly begins

· Babbling and new words present poorly

It may last from weeks to months

2) The rapid development Regression Period (Stage II)- The Transition to this stage happens between 1-4 years and is characterized by rapid and specific regression. The symptoms include

· Deprivation of acquired motor and communication skills

· Stereotypic, repetitive hand movements

· Diminished interest in people and objects

· Previously acquired babbling, words and fine motor skills are lost during this period and mental deficiency now become obvious

· Microcephaly worsens

· Peculiar posturing of wrists and twisting of finger

· Febrile seizures

· Breathing irregularities occur

This stage may last from months to 1 year

3) The pseudo stationary/Plateau Period (Stage III)- This Stage starts when the regression stage is over. Symptoms include

· Prominent hand apraxia

· May show interest in surrounding and may have typical eye pointing behavior to express needs and wishes

· Unexplained night laughing, frequent daytime sleeping and night time awakening, crying spells and sudden agitation

· Seizures are common

· Dystonic Asymmetrical postures may lead to neurogenic scoliosis, often rapidly progressive.

· The feet and lower limbs are cold.

· Motor regression slowly progresses

This stage may last from years to decades

4) Late Motor Deterioration (Stage IV)- The symptoms include

· Walking cessation and individual with Rett syndrome becomes severely physically disabled with wheelchair dependency in some.

· Hand stereotype becomes less intense and simpler with age

· Visual contact and eye pointing behavior remains present

This stage may last for decade².

DIAGNOSIS:

It can be done by periodic clinical evaluation of the symptoms and through genetic testing for the MeCP2 mutation on X chromosome.

Revised Criteria for Diagnosis:

Required for Atypical or Variant Rett Syndrome

1. A period of regression followed by recovery or stabilization

2. At least 2 out of the 4 main criteria

3. 5 out of 11 supportive criteria

Main Criteria:

1. Partial or complete loss of acquired purposeful hand skills

2. Partial or complete loss of acquired spoken language

3. Gait Abnormalities: impaired (dyspraxic) or absence of ability

4. Stereotypic hand movements such as hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms

Exclusion Criteria for typical RTT

1. Brain injury secondary to trauma(peri or postnatal), neurometabolic disease or severe infection that causes neurological problems

2. Grossly abnormal psychomotor development in first 6 months of life

Supportive criteria for atypical RTT

1. Breathing disturbances when awake

2. Bruxism when awake

3. Impaired sleep pattern

4. Abnormal muscle tone

5. Peripheral vasomotor disturbances

6. Scoliosis/Kyphosis

7. Growth Retardation

8. Small cold hands and feet

9. Inappropriate laughing/screaming spells

10. Diminished response to pain

11. Intense eye communication-“eye pointing”⁶

Other Rett diagnosis:

Male Rett Encephalopathy:

· Seen in males with MeCP2 Mutation who meet criteria for typical Rett Syndrome diagnosis

MeCP2 related Disorders:

· Seen in individuals with MeCP2 mutation who do not meet criteria for typical or atypical Rett Syndrome diagnosis

· Individual may have isolated intellectual disability, autism, spectrum disorder or behavioral disturbances

MeCP2 Duplication Disorder:

· Seen in individuals with an extra copy (or more) of the MeCP2 gene; there may also be extra copies of other genes nearby to the MeCP2 gene.

· Individuals may have similar challenges as in Rett Syndrome, but the timing and severity of symptoms are different⁷.

TREATMENT:

There is no cure for Rett Syndrome but Supportive and multidisciplinary approach like physical therapy, speech language therapy, and occupational therapy and behavior intervention can be done⁸.

Medication can be used to help symptoms like seizures and muscle stiffness. Some medications like

· Bromocriptine- it is used to improve communication skills and to provide relaxation⁹

· Dextromethorphan- It aims to improve EEG abnormalities, cognition, reduces seizure as well as improves breathing abnormalities, motor capabilities, bone density and GI Dysfunction¹⁰.

· L- Carnitine- which may help improve language skills, muscle mass, alertness, energy & quality of life while decreasing constipation and daytime sleepiness¹¹.

· L- Dopa- it is used for motor rigidity in later stages of diseases.

· Trofinetide- it is a new drug that has been accepted in treatment of rett syndrome, it is thought to stimulate synaptic maturation and is showing promising results in the treatment of the syndrome¹².

PROGNOSIS:

Rett Syndrome is rare, so very little is known about the prognosis but on average most individual survive to the adulthood with comprehensive and multidisciplinary team support

REFERENCES:

1. About Rett Syndrome; Available at - https://reverserett.org/about-rett-syndrome/

2. EEJ Smeets et al. Rett Syndrome. Molecular syndeomology .2011;2:113-127 doi: 10.1159/000337637 Available at -https://www.karger.com/Article/Pdf/337637

3. Shervin Pejhan, Mojgan Rastegar. Role of DNA Methyl –CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease.biomolecules.2021;11(1):75 doi: http://doi.org/10.3390/biom11010075 Available at https://www.mdpi.com/2218-273X/11/1/75

4. Rett Syndrome. Available at -https://www.rettsyndrome.org/about-rett-syndrome/what-is-rett-syndrome/

5. Types of Rett Syndrome. Available at - https://rettsyndromenews.com/types-of-rett-syndrome/

6. Neul JL. Et al. Revised Diagnostic Criteria for Rett Syndrome,Typical and variant forms.Ann Neurol.2010,68:944 Available at-https://www.orpha.net/data/patho/Pro/en/Rett_DiagnosticCriteria_En.pdf

7. Rett Syndrome Diagnosis. Available at- https://www.rettsyndrome.org/about-rett-syndrome/rett-syndrome-diagnosis/

8. Stephen B S. Rett Syndrome .Available at-https://www.msdmanuals.com/en-in/professional/pediatrics/learning-and-developmental-disorders/rett-syndrome

9. Michele Zapella MD et al.Bromocriptine in the Rett Syndrome. Brain and development.1990;12(2):221-5 doi: http://doi.org/10.1016/S0387-7604(12)80329-9 Available at- https://www.sciencedirect.com/science/article/abs/pii/S0387760412803299

10. Constance L S Hicks et al. Randomized open- label trial of dextromethorphan in Rett Syndrome.Neurology.2017;89(16) doi: http://doi.org/10.1212/WNL.0000000000004515 Available at-https://n.neurology.org/content/89/16/1684.long

11. Laura R S et al.Acetyl-L-Carnitine improves behavior and dendritic morphology in a mouse model of Rett Syndrome.PLOS one.2012;7(12):e51586 doi: 10.1371/journal.pone.0051586 Available at-https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0051586&type=printable

12. https://www.formularywatch.com/view/fda-accepts-nda-for-rett-syndrome-drug

Received on 23.02.2023 Modified on 08.03.2023

Int. J. Nur. Edu. and Research. 2023; 11(2):180-182.

DOI: 10.52711/2454-2660.2023.00041