Management and Treatment of Kleefstra Syndrome Associated with EHMT1 Mutations
Kleefstra syndrome requires a multidisciplinary management approach focused on addressing the specific neurological, developmental, and medical manifestations of the condition, with early intervention being critical for improving outcomes.
Clinical Features and Diagnosis
Kleefstra syndrome is a rare genetic disorder caused by haploinsufficiency of the EHMT1 gene (Euchromatic Histone Lysine Methyltransferase 1) on chromosome 9q34.3, which can result from either microdeletions or intragenic mutations 1, 2. The clinical presentation includes:
- Intellectual disability/developmental delay
- Childhood-onset hypotonia
- Characteristic facial dysmorphisms
- Autism spectrum disorder features
- Severely delayed or absent speech
- Seizures
- Behavioral and sleep abnormalities
- Congenital heart defects
Multidisciplinary Management Approach
Neurological and Developmental Management
- Early intervention services: Speech therapy, occupational therapy, and physical therapy should be initiated as soon as possible after diagnosis
- Neurodevelopmental monitoring: Regular assessment of developmental milestones and cognitive function
- Seizure management:
- Anticonvulsant medications if seizures are present
- Regular EEG monitoring for patients with seizure history
Behavioral and Psychiatric Management
- Autism-specific interventions: Applied behavior analysis (ABA) and other evidence-based autism interventions 1
- Behavioral therapy: Particularly important for addressing regressive behaviors that may appear in young adulthood 1
- Psychiatric medication management:
Medical Management
- Cardiac evaluation: Echocardiogram to assess for congenital heart defects
- Pulmonary hypertension screening: Particularly important for patients with 9q34.3 microdeletions, as there is an association between Kleefstra syndrome and pulmonary hypertension 4
- Sleep studies: To identify and manage sleep disorders
- Regular monitoring of growth parameters
Genetic Counseling
- Genetic counseling for families regarding:
- Recurrence risk in future pregnancies
- Importance of genetic testing for family planning
- Inheritance patterns (autosomal dominant)
Special Considerations
Regressive Behaviors
Young adults with Kleefstra syndrome may experience regressive behaviors. Management should include:
- Intensive behavioral therapy
- Careful selection of psychotropic medications based on pharmacogenomic testing when available 1
- Regular psychiatric assessment
Pulmonary Hypertension
Patients with 9q34.3 microdeletions should be monitored for signs of pulmonary hypertension, especially those with congenital heart defects 4:
- Regular cardiac evaluations
- Echocardiography
- Prompt treatment of respiratory infections
Psychosis
Some patients may develop psychosis, particularly in adolescence or adulthood:
- Regular psychiatric assessment
- Antipsychotic medication may be effective (zuclopenthixol has shown efficacy in case reports) 3
- Monitor for medication side effects
Coordinated Care Approach
- Multidisciplinary team: Should include neurologists, developmental pediatricians, geneticists, cardiologists, psychiatrists, psychologists, and therapists
- Transition planning: Develop a transition plan from pediatric to adult care
- Family support: Connect families with support groups and resources for rare genetic disorders
Monitoring and Follow-up
- Regular developmental assessments
- Annual medical evaluations
- Periodic reassessment of therapeutic interventions
- Ongoing genetic counseling as needed
Research Considerations
Recent research has identified functional convergence between EHMT1 and other genes involved in intellectual disability and autism spectrum disorder, particularly KMT2C 5. This molecular convergence may inform future targeted therapeutic approaches.
By implementing this comprehensive management approach, clinicians can address the diverse manifestations of Kleefstra syndrome and potentially improve long-term outcomes for affected individuals.