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PubMed This is a summary of 20 peer-reviewed journal articles Updated
Pediatrics

Symptoms & Clinical Course

At a Glance

Atypical Rett syndrome variants, including CDKL5, FOXG1, and the Preserved Speech variant, follow unique developmental paths. While classic Rett typically involves a loss of skills (regression), atypical variants may present with delays from birth, early-onset seizures, or severe hypotonia.

Every child with an atypical Rett variant follows a unique path, but understanding the general “clinical course” can help you prepare for the road ahead. While classic Rett syndrome is famous for a period of regression (the loss of skills), many atypical variants follow different patterns [1][2].

Regression vs. Static Encephalopathy

One of the biggest differences between variants is how the condition progresses over time:

  • Regression (Classic and some Atypical Rett): This is a period where a child seems to develop normally for a few months but then loses skills they had already mastered, such as purposeful hand use or babbling [1][3].
  • Static Encephalopathy (FOXG1 Syndrome): This term sounds intimidating, but it essentially means the condition is “stable” rather than “degenerative.” Children with FOXG1 syndrome usually have significant delays from birth, but they do not typically experience a sudden loss of skills later on [4][5]. Their brain development follows a different track from the start [6][5].

Early Warning Signs and Common Symptoms

Regardless of the specific gene involved, several symptoms often appear early in infancy:

  • Early-Onset Seizures: In CDKL5 Deficiency Disorder (CDD), seizures often start within the first 3 months of life [7][8]. These can be intractable, meaning they are difficult to control with standard medications [9][10].
  • Severe Hypotonia: This is the medical term for “low muscle tone” or “floppiness.” It is a hallmark of both CDD and FOXG1 syndrome, making it harder for babies to hold their heads up or sit independently [11][5].
  • Postnatal Microcephaly: Many children are born with a typical head size, but growth slows down over time. This is called “postnatal” microcephaly and is often seen in FOXG1 and classic Rett [5][6].
  • Sleep Disturbances: Many families find that their children struggle to fall asleep or stay asleep throughout the night, which can be one of the most taxing parts of daily care [12].

Differences Between Major Variants

The “flavor” of symptoms depends heavily on the underlying genetic cause:

Feature CDKL5 (Early-Onset Seizure) FOXG1 (Congenital) Preserved Speech (Zappella)
Seizure Onset Very early (median 2 months) [1] Early, often with infantile spasms [5] Later, similar to classic Rett [13]
Regression Rare; delays usually present from birth [14] Rare; considered “static” from birth [4] Present, but often less severe [13]
Language Usually absent or very limited [1] Usually absent [4] Retain some words or phrases [13]
Motor Skills Severe impairment; walking is rare [15] Severe; may have hyperkinetic (busy) movements [16] Often better hand and walking skills [17]

The Preserved Speech Difference

The Preserved Speech Variant (PSV) is a unique category where children may regain the ability to say single words or short phrases after a period of regression [13]. Research has shown that between 9 and 12 months of age, children with PSV often show higher rates of social reciprocity (like responding to their name or making eye contact) compared to those with classic Rett syndrome [17]. While they still face significant challenges, their long-term functional outcomes in communication and hand use are often more advanced [17][13].

Variability is the Rule

It is important to remember that these are general patterns. Even children with the exact same genetic mutation can have very different daily lives [18]. Your child’s trajectory will be shaped by their specific genetics, their environment, and the intensive therapies and supports you provide [19][20].

Common questions in this guide

What is the difference between regression and static encephalopathy?
Regression is a period where a child loses skills they previously mastered, such as purposeful hand use or babbling. Static encephalopathy means the condition is stable; the child experiences significant developmental delays from birth but does not typically have a sudden loss of skills.
When do seizures usually start in CDKL5 Deficiency Disorder?
In CDKL5 Deficiency Disorder (CDD), seizures often begin very early, typically within the first three months of life. These seizures can sometimes be intractable, meaning they are difficult to control with standard anti-seizure medications.
What are the early warning signs of an atypical Rett syndrome variant?
Common early signs across different variants include early-onset seizures, severe hypotonia (floppiness or low muscle tone), postnatal microcephaly (a slowing of head growth after birth), and frequent sleep disturbances.
What makes the Preserved Speech variant different?
Children with the Preserved Speech variant, also known as the Zappella variant, may regain the ability to say single words or short phrases after a period of regression. They also tend to retain better hand function and exhibit higher rates of social interaction compared to classic Rett syndrome.
How does hypotonia affect my child's physical development?
Hypotonia, or low muscle tone, makes a baby feel 'floppy.' This lack of muscle strength makes it much harder for infants to achieve standard motor milestones, such as holding their head up, sitting independently, or crawling.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Based on my child's history, does their condition seem to follow a pattern of 'regression' or 'static encephalopathy'?
  2. 2.What type of seizures should I be looking for, and are they typically 'intractable' for children with this specific mutation?
  3. 3.How does my child's muscle tone (hypotonia) affect their ability to reach motor milestones like sitting or crawling?
  4. 4.Is the slowing of head growth (postnatal microcephaly) a common feature of this specific variant?
  5. 5.In the 'Preserved Speech' variant, what is the typical range of language or hand function that children might retain or regain?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (20)
  1. 1

    Comparison of Core Features in Four Developmental Encephalopathies in the Rett Natural History Study.

    Cutri-French C, Armstrong D, Saby J, et al.

    Annals of neurology 2020; (88(2)):396-406 doi:10.1002/ana.25797.

    PMID: 32472944
  2. 2

    Clinical and biological progress over 50 years in Rett syndrome.

    Leonard H, Cobb S, Downs J

    Nature reviews. Neurology 2017; (13(1)):37-51 doi:10.1038/nrneurol.2016.186.

    PMID: 27934853
  3. 3

    Visual Recovery Reflects Cortical MeCP2 Sensitivity in Rett Syndrome.

    Simon AJ, Picard N, d'Andrea V, et al.

    Annals of clinical and translational neurology 2026; (13(4)):700-713 doi:10.1002/acn3.70197.

    PMID: 41261374
  4. 4

    Longitudinal characterization of clinical, developmental, and behavioral phenotypes in 101 children and adults with FOXG1 syndrome.

    Brimble E, Ventola P, Blomenberg E, et al.

    Journal of neurodevelopmental disorders 2025; (17(1)):64 doi:10.1186/s11689-025-09653-1.

    PMID: 41136907
  5. 5

    The hyperkinetic movement disorder of FOXG1-related epileptic-dyskinetic encephalopathy.

    Cellini E, Vignoli A, Pisano T, et al.

    Developmental medicine and child neurology 2016; (58(1)):93-7 doi:10.1111/dmcn.12894.

    PMID: 26344814
  6. 6

    Identification of FOXG1 mutations in infantile hypotonia and postnatal microcephaly.

    Jang HN, Kim T, Jung AY, et al.

    Medicine 2021; (100(47)):e27949 doi:10.1097/MD.0000000000027949.

    PMID: 34964776
  7. 7

    CDKL5-mediated developmental tuning of neuronal excitability and concomitant regulation of transcriptome.

    Liao W, Lee KZ

    Human molecular genetics 2023; (32(23)):3276-3298 doi:10.1093/hmg/ddad149.

    PMID: 37688574
  8. 8

    Sodium channel blockers for the treatment of epilepsy in CDKL5 deficiency disorder: Findings from a multicenter cohort.

    Aledo-Serrano Á, Gómez-Iglesias P, Toledano R, et al.

    Epilepsy & behavior : E&B 2021; (118()):107946 doi:10.1016/j.yebeh.2021.107946.

    PMID: 33848848
  9. 9

    Developmental and Epileptic Encephalopathy due to Cyclin-Dependent Kinase-Like 5 Deficiency: A Single-Center Experience Across Sex Differences.

    Fasaludeen A, Menon RN, Jose M, et al.

    Pediatric neurology 2026; (177()):4-18 doi:10.1016/j.pediatrneurol.2026.01.001.

    PMID: 41619470
  10. 10

    Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder.

    Olson HE, Daniels CI, Haviland I, et al.

    Journal of neurodevelopmental disorders 2021; (13(1)):40 doi:10.1186/s11689-021-09384-z.

    PMID: 34530725
  11. 11

    Clinical manifestation of CDKL5 deficiency disorder and identified mutations in a cohort of Slovak patients.

    Kluckova D, Kolnikova M, Medova V, et al.

    Epilepsy research 2021; (176()):106699 doi:10.1016/j.eplepsyres.2021.106699.

    PMID: 34229227
  12. 12

    The clinical and sleep manifestations in children with FOXG1 syndrome.

    Wong LC, Huang CH, Chou WY, et al.

    Autism research : official journal of the International Society for Autism Research 2023; (16(5)):953-966 doi:10.1002/aur.2916.

    PMID: 36942618
  13. 13

    Rett Syndrome Spectrum in Monogenic Developmental-Epileptic Encephalopathies and Epilepsies: A Review.

    Spagnoli C, Fusco C, Pisani F

    Genes 2021; (12(8)) doi:10.3390/genes12081157.

    PMID: 34440332
  14. 14

    Gut microbiota profile in CDKL5 deficiency disorder patients.

    Borghi E, Xynomilakis O, Ottaviano E, et al.

    Scientific reports 2024; (14(1)):7376 doi:10.1038/s41598-024-56989-0.

    PMID: 38548767
  15. 15

    The natural history of CDKL5 deficiency disorder into adulthood.

    Aledo-Serrano A, Lewis-Smith D, Leonard H, et al.

    medRxiv : the preprint server for health sciences 2025; doi:10.1101/2025.01.12.24318239.

    PMID: 39867409
  16. 16

    Cognition and Evolution of Movement Disorders of FOXG1-Related Syndrome.

    Wong LC, Wu YT, Hsu CJ, et al.

    Frontiers in neurology 2019; (10()):641 doi:10.3389/fneur.2019.00641.

    PMID: 31316448
  17. 17

    Comparing social reciprocity in preserved speech variant and typical Rett syndrome during the early years of life.

    Townend GS, Bartl-Pokorny KD, Sigafoos J, et al.

    Research in developmental disabilities 2015; (43-44()):80-6.

    PMID: 26159884
  18. 18

    Early differential impact of MeCP2 mutations on functional networks in Rett syndrome patient-derived human cerebral organoids.

    Osaki T, Delepine C, Osako Y, et al.

    bioRxiv : the preprint server for biology 2024; doi:10.1101/2024.08.10.607464.

    PMID: 39149328
  19. 19

    The Changing Face of Survival in Rett Syndrome and MECP2-Related Disorders.

    Tarquinio DC, Hou W, Neul JL, et al.

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    PMID: 26278631
  20. 20

    Evidence-Based Physical Therapy for Individuals with Rett Syndrome: A Systematic Review.

    Fonzo M, Sirico F, Corrado B

    Brain sciences 2020; (10(7)) doi:10.3390/brainsci10070410.

    PMID: 32630125

This page provides educational information about atypical Rett syndrome variants and their clinical course. It is for informational purposes only and does not replace professional medical advice from your child's neurologist or care team.

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