History of Genetics in Rett Syndrome

• Early Theories:
  • X-linked dominant, male-lethal (XDML) inheritance model.
  • Differences in severity linked to X-chromosome inactivation (XCI).
• Key Genetic Discoveries:
  • MECP2 mutations identified as the usual cause of classic RTT.
  • Mutations arise predominantly during spermatogenesis.
• Rare Cases:
  • Male presentations: Mosaicism or Klinefelter syndrome (47,XXY).

Molecular Genetics

• MECP2 Gene:
  • Eight common mutations account for 85% of cases.
  • C-terminal deletions and other mutations also implicated.
• Variants and Modifiers:
  • XCI impacts clinical severity but peripheral blood patterns may not reflect brain XCI.
  • BDNF polymorphisms (e.g., val/met genotype) influence epilepsy risk.

• X-Chromosome Inactivation (XCI)

  • Definition: XCI is the process during blastogenesis where one of the X-chromosomes is randomly inactivated to balance gene expression between males (XY) and females (XX).
  • Skewing in XCI:
    • In Rett Syndrome (RTT) and X-linked dominant conditions, skewing often favors the expression of the normal allele.
    • The extent of skewing, especially in the brain, significantly impacts clinical presentation
  • Limitations of XCI Studies:
    • XCI patterns studied in lymphocytes may not reflect:
      • Brain-specific XCI patterns.
      • Regional variations within the brain
    • Peripheral blood leukocyte XCI explains only about 20% of the variance in clinical severity, highlighting limited correlation between leukocyte and brain XCI
  • Genotype-Phenotype Correlations:
    • Evaluating phenotypes in large patient groups with identical MECP2 mutations is essential 
    • Robust methods to determine both the extent and direction of XCI skewing are necessary for meaningful genotype–phenotype correlations.
  • Genetic and Environmental Influences:
    • The clinical severity in RTT may be influenced by other complex genetic factors beyond XCI patterns, warranting further research.

Rett Syndrome Variants

• Congenital Variant (FOXG1 Gene):
  • Features include movement disorders but no regression.
• Early Seizure Variant (CDKL5 Gene):
  • Severe epileptic encephalopathy rather than classic RTT.
• Other Genetic Factors:
  • Array CGH and whole exome sequencing identify deletions or duplications in RTT-like phenotypes.

Differential Diagnosis

• Conditions Resembling RTT:
  • Angelman syndrome: Unique facial features, cheerful disposition, and hand flapping.
  • Pitt-Hopkins syndrome: Dysmorphic features and lack of regression.
  • Joubert syndrome: Molar tooth sign on MRI; episodic panting.
  • Distinguishing RTT from Angelman and Angelman-like syndromes:
    • RTT often involves developmental regression, which is absent in some Angelman-like conditions like Pitt-Hopkins.
    • EEG patterns, family history, and physical dysmorphisms provide important diagnostic clues.
    • Genetic testing plays a critical role in confirming the diagnosis.

Genetic Counseling

• Core Principles:
  • Educate families about RTT and its implications.
  • Address emotional and practical concerns.
• Reproductive Counseling:
  • Low recurrence risk (<1%) unless maternal germline mosaicism or constitutional mutation is identified.
  • Options include prenatal testing or preimplantation genetic diagnosis (PGD).

Recurrence Risk

• Recurrence Risk:

  • Generally less than 1% if no mutation is detected in the maternal lymphocytes. This represents the germline mosaicism risk.
  • Germline mosaicism implies a mutation in a proportion of maternal oocytes or paternal spermatogonia.

• Parent of Origin:

  • Over 90% of MECP2 mutations are of paternal origin, arising during spermatogenesis.
  • Maternal origin is rare (<10%).
    • If the mutation is maternal, recurrence risk is higher, especially if the mother is a constitutional carrier.

• Maternal Carriers:

  • Healthy mothers carrying the MECP2 mutation are rare and often due to skewed X-chromosome inactivation (XCI), favoring the normal allele.
  • If a mother carries the mutation constitutionally, recurrence risk is 50% for each pregnancy:
    • Daughters: Likely to have RTT.
    • Sons: Likely to have severe neonatal-onset encephalopathy, often lethal.

• Reported Cases:

  • Familial recurrences due to paternal germline mosaicism are rare, with only one documented instance.
• CDKL5 Mutations
  • Condition: Another X-linked dominant disorder linked to RTT-like features.
  • Recurrence Risk:
    • Rare familial cases, with only one documented case of maternal germline mosaicism.
    • No healthy carrier mothers reported to date.
    • Limited data on the parent of origin of mutations.
• FOXG1 Mutations
  • Condition: Causes a severe autosomal dominant RTT-like disorder.
  • Recurrence Risk:
    • Likely confined to germline mosaicism.
    • Few familial cases have been reported, suggesting low recurrence risk.
• Clinical Implications

• Routine Assessment: Determining parental origin of the mutation is not standard but could influence counseling about recurrence risks.
• Risk Counseling:
  • Families with no detected mutation in the mother's blood should be reassured of the low recurrence risk (<1%).
  • Constitutional carrier mothers require detailed genetic counseling, as the recurrence risk increases significantly (50%).

Future Directions

• Technological Advances:
  • Whole exome and genome sequencing are increasingly replacing array CGH.
  • Research into RTT-like conditions continues.
• Therapeutic Implications:
  • Genetic findings will guide the development of targeted treatments.
• Unresolved Cases:
  • Ongoing monitoring is critical for individuals without identified mutations.

Key Takeaways

• RTT Diagnosis:
  • Involves clinical observation, genetic testing, and exclusion of differential diagnoses.
• Family Impacts:
  • Families often require genetic counseling to understand recurrence risks and make informed decisions.
• Research and Treatment:
  • Advances in genetic research hold promise for novel therapies and improved outcomes.

References

• Amir RE, van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) RTT is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein. Nat Genet 23: 185‒188.
  • Discovery of MECP2 mutations.
• Clarke A, Gardner-Medwin D, Richardson J et al. (1990) Abnormalities of carbohydrate metabolism and of OCT gene function in the RTT. Brain Dev 12: 119‒124.
  • Mitochondrial abnormalities in RTT.
• Neul JL, Kaufmann WE, Glaze DG et al. for the Rett Search Consortium (2010) Rett syndrome: Revised diagnostic criteria and nomenclature. Ann Neurol 68: 951‒955.
• Neul J (2012) The relationship of RTT and MECP2 disorders to autism. Dialogues Clin Neurosci 14: 253‒262.
  • Diagnostic criteria and genotype-phenotype correlations.
• Archer HL, Evans JE, Leonard H et al. (2007) Correlation between clinical severity in patients with RTT with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X chromosome inactivation. J Med Genet 44: 148‒152.
  • Role of XCI in clinical variability.