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atypical Rett syndrome - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

atypical Rett syndrome

MONDO:0017746

Also known as:Rett syndrome variantatypical RTTRett like syndrome

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Overview

A neurodevelopmental disorder that is diagnosed when a child presents with a Rett-like syndrome but does not fulfill all the diagnostic criteria for typical Rett syndrome (classic/typical RTT).

Clinical Trials2 registered · 2 recruiting

Patient Orgs1 organizations · Rett Syndrome Research Trust

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

No HPO annotations are available for this condition.

GeneReviews

Clinical Guidance

CDKL5 deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe early-onset epilepsy and motor, cognitive, visual, and autonomic disturbances [, , , , , , , ]. Movement disorders include chorea, dystonia, and stereotypical hand and leg movements . Cardiac involvement is nonspecific . Because the full spectrum of phenotypic severity is still emerging, especially given the possibility of mosaicism (in males and females) and the potential for skewed X-chromosome inactivation (in females), an individual with a de novo CDKL5 pathogenic variant may have a mild phenotype (for example, minimal epilepsy and global developmental delays). To date, approximately 500 individuals have been identified with CDD .

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

For the purposes of this GeneReview, the terms "male" and "female" are narrowly defined as the individual's biological sex at birth as it determines clinical care . Diagnostic criteria for CDKL5 deficiency disorder (CDD) have been proposed .

Suggestive Findings

CDD should be suspected in females and males with motor and cognitive developmental delays and epilepsy with onset in the first year of life (developmental delays and early-onset epilepsy constitute the minimal clinical diagnostic criteria proposed by ). Note: (1) Although females are more commonly affected than males with this X-linked disorder, the severity of manifestations in affected females and males can be equivalent.

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for atypical Rett syndrome. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

International consensus recommendations for the assessment and management of individuals with CDKL5 deficiency disorder (CDD) have been published (full text). The management of individuals with CDD is complex and requires multiple specialty appointments; referral to a CDKL5 Center of Excellence may allow families to more easily coordinate care for affected individuals (to date, ten CDKL5 Centers of Excellence have been established in the United States).

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. In general, annual assessments by a medical home/primary care physician and specialists are needed.

Table 7.

CDKL5 Deficiency Disorder: Recommended Surveillance

System/Concern | Evaluation | Frequency

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

2 clinical trials registered, 2 recruiting. Interventions under study include other interventions. Research is primarily sponsored by academic and government institutions.

12 publications have been identified in PubMed for atypical Rett syndrome. Research spans Epidemiology / Natural History (33%), Case Report / Case Series (25%), and Basic Science / Preclinical (25%).

Research Type	Count	% of Total
Disease patterns and progression	4	33%

Data assembled from 5 of 12 sources · Last updated Nov 4, 2026, 6:11 AM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Patient Support

Patient Advocacy Groups

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Rett Syndrome Research TrustPrimary Focus

USWebsite ↗

Patient Advocacy Groups (PAGs) provide support, resources, and community for patients and caregivers.

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Medical References

External Resources

Orphanet

European rare disease database

Orphanet:3095

GARD

Genetic and Rare Diseases Info Center

GARD:4694

Questions for Your Care Team

→Are any of the 2 active clinical trials a good fit for my situation?
→Are there specialists or centers of excellence for this condition in my area?
→How can I connect with Rett Syndrome Research Trust and other patient organizations for support?

← Back to All Diseases

GeneReviews

Differential Diagnosis

Table 3. Developmental and Epileptic Encephalopathies in the Differential Diagnosis of CDKL5 Deficiency Disorder

Gene(s)	Disorder	MOI
ARX	ARX-related DEE (OMIM 308350)	XL FOXG1
GABRA1	GABRA1-related DEE (OMIM 615744)	AD
GABRB3	GABRB3-related DEE (OMIM 617113)	AD
GABRG2	GABRG2-related DEE (OMIM 618396)	AD GRIN2A
KCNQ2	KCNQ2-related developmental epileptic encephalopathy (OMIM 613720)	AD KCNT1
MECP2	MECP2 classic Rett syndrome (See MECP2 Disorders.)	XL MECP2 duplication syndrome
PCDH19	PCDH19-related DEE (OMIM 300088)	XL SCN1A
SCN2A	SCN2A-related DEE (OMIM 613721)	AD SCN8A
SLC2A1	Classic glucose transporter type 1 deficiency syndrome (See Glucose Transporter Type 1 Deficiency Syndrome.)	AD(AR)1 STXBP1

Source: GeneReviews — "CDKL5 Deficiency Disorder"

Latest News & Developments

5 recent

View all

AI-curated news mentioning atypical Rett syndrome

Updated Oct 26, 2026

Gene & Cell Therapy•

Science & Discovery

•9 days ago(Oct 26)

Neurogene, Taysha near finish line in ‘two-horse race’ for first Rett syndrome gene therapy - BioSpace

As both Taysha Gene Therapies and Neurogene warm up for an important year of readouts, the Rett syndrome community is hopeful of seeing a therapy that can truly change the disease's path. Zolgensma was greenlit by the FDA in 2019 as the first gene therapy for SMA after infants in Novartis’ Phase 1 START trial achieved motor milestones never seen before in the natural history of the disease, according to Novartis’ approval announcement. Rett syndrome is a genetic neurodevelopmental disorder mainly affecting girls and women that causes a loss of motor and speech skills over time. Patients with Rett syndrome have historically had few treatment options—but 2027 could change that. Two gene therapies are at the FDA’s doorstep with strong data showing they can alter the trajectory of the rare neurodevelopmental disorder. Because of the challenges elicited by subjective outcomes, Coenraads is looking to gene therapies for a potential game-changing moment. For that, she takes cues from Zolgensma, with optimism that the data will speak for itself in a more objective manner. While Rett syndrome has been classified as a neurodevelopmental disorder, it is perhaps more accurately defined as a “neural network disorder” for the widespread effects of the central gene at its core, MECP2, Sukumar Nagendran, head of R&D at Taysha, told BioSpace. Taysha’s gene therapy is also delivered via AAV, but has avoided the fatal safety issue that compromised Neurogene’s trial. Despite the efficacy seen so far from these treatments, both McMinn and Nagendran are careful not to offer false hope. “For CNS diseases, we are not in a place where it is remotely responsible to use the word ‘cure,’ McMinn said, “even though what we’re seeing are very encouraging signs of improvements.

PubMed Rare Disease•

Science & Discovery

•13 days ago(Oct 22)

Release factor 3 degradation enhances aminoglycoside-mediated translational readthrough at MECP2 nonsense mutations.

Research indicates that degradation of release factor 3 can improve aminoglycoside-mediated translational readthrough at MECP2 nonsense mutations. This finding may have implications for therapeutic strategies targeting mutations associated with Rett syndrome.

PubMed Rare Disease•

Science & Discovery

•about 1 month ago(Sep 29)

Fenfluramine in Rett syndrome: A multidimensional clinical study.

A recent clinical study explores the effects of fenfluramine in patients with Rett syndrome, providing multidimensional insights into its potential benefits. This research adds to the growing body of evidence regarding treatment options for this rare neurological disorder.

PubMed Rare Disease•

Science & Discovery

•about 1 month ago(Sep 28)

A Heterozygous Variant in the GABBR2 Gene in a Girl With Clinical Classic Rett Syndrome.

A study identifies a heterozygous variant in the GABBR2 gene associated with classic Rett syndrome in a patient. This discovery adds to the understanding of genetic factors contributing to Rett syndrome.

Treatment & Clinical News•

Pipeline & Approvals

•8 months ago(Mar 4)

Neurogene’s Rett Syndrome Gene Therapy NGN-401 Demonstrates Efficacy in Low-Dose Cohort, But Serious Adverse Event in High-Dose Group Raises Concerns | CGTlive®

Neurogene's gene therapy NGN-401 shows efficacy in a low-dose cohort for Rett syndrome, with plans to enroll 8 patients by year-end. However, a serious adverse event in the high-dose group raises concerns, prompting the company to prepare for a registrational clinical trial in 2025.

View all news for atypical Rett syndrome

atypical Rett syndrome

Overview

Clinical Presentation

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Research Landscape

Patient Support

Patient Advocacy Groups

Medical References

External Resources

Orphanet

GARD

Subtypes

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

Differential Diagnosis

Constitutional

Neurologic

Vision

Therapies Under Investigation

Clinical Trials

Neurologic

Feeding

Development

Psychiatric

Gastrointestinal

Respiratory

Musculoskeletal

Family/Community

Recent Publications

Latest News & Developments

Neurogene, Taysha near finish line in ‘two-horse race’ for first Rett syndrome gene therapy - BioSpace

Release factor 3 degradation enhances aminoglycoside-mediated translational readthrough at MECP2 nonsense mutations.

Fenfluramine in Rett syndrome: A multidimensional clinical study.

A Heterozygous Variant in the GABBR2 Gene in a Girl With Clinical Classic Rett Syndrome.

Neurogene’s Rett Syndrome Gene Therapy NGN-401 Demonstrates Efficacy in Low-Dose Cohort, But Serious Adverse Event in High-Dose Group Raises Concerns | CGTlive®