The EHMT1 gene provides instructions for creating an enzyme called euchromatic histone methyltransferase 1 (GLP). This enzyme is involved in epigenetics, a process that influences gene activity without changing the underlying DNA sequence. EHMT1 adds methyl groups to histone H3, a protein around which DNA is wrapped. This modification, known as histone methylation, typically represses the activity of certain genes.
The regulation of gene activity by EHMT1 is important for normal development and brain function. It plays a role in neurodevelopmental processes, including neuronal differentiation, migration, and synaptic plasticity. When EHMT1 function is disrupted, it can lead to changes in gene expression that impact neural network development.
EHMT1 and Kleefstra Syndrome
Mutations or deletions within the EHMT1 gene are the primary cause of Kleefstra Syndrome, a neurodevelopmental disorder. Approximately 50% of diagnoses result from a deletion on chromosome 9q34.3 that includes EHMT1, with the other 50% involving an intragenic EHMT1 pathogenic variant. This genetic change disrupts the gene’s ability to produce a functional EHMT1 enzyme, leading to the syndrome’s varied characteristics.
Individuals with Kleefstra Syndrome often exhibit intellectual disability, ranging from moderate to severe, though some may have mild delays. Speech development is typically affected, with many experiencing severe expressive speech delays or limited verbal communication. Low muscle tone (hypotonia) is common in childhood.
The syndrome is also associated with distinctive facial features that can become more pronounced with age. These may include a small head size (microcephaly), a wide and short skull, widely spaced eyes, and eyebrows that grow together. Other features can involve a sunken appearance in the middle of the face, nostrils that open forward, a protruding jaw, rolled-out lips, and a large tongue.
Beyond developmental and physical traits, individuals with Kleefstra Syndrome can experience a range of medical issues. These may include heart defects, kidney or urologic abnormalities, and genital anomalies in males. Severe respiratory infections, epilepsy, and febrile seizures are also observed in some individuals. Behavioral challenges, such as autistic-like features, attention deficit, aggressive outbursts, and sleep disturbances, are also commonly reported. In adolescence or adulthood, some individuals may experience a loss of interest or even catatonic-like features.
Diagnosis of Kleefstra Syndrome is made through molecular genetic testing that identifies the specific deletion or mutation involving the EHMT1 gene. This can involve unbiased genetic testing methods like chromosomal microarray, gene panels, or whole exome/genome sequencing. Targeted genetic testing can also be used if the syndrome is suspected based on clinical features.
Living with Kleefstra Syndrome
Managing Kleefstra Syndrome involves comprehensive, ongoing support focused on improving the quality of life for affected individuals. Since the condition presents with a wide range of symptoms, care is highly individualized and often requires a multidisciplinary approach. Early intervention is important to address developmental delays and support skill acquisition.
Supportive therapies form a core part of management:
Physical therapy to address low muscle tone and motor delays.
Occupational therapy to help with daily living skills and sensory integration.
Speech therapy to improve communication abilities.
Educational support, such as individualized education plans, to meet specific learning needs.
Behavioral interventions, including applied behavior analysis (ABA) and positive behavioral supports, to manage behavioral challenges.
Medical follow-up is lifelong, with regular monitoring for potential cardiac, renal, and urologic issues. Specialists, including neurologists and geneticists, play a part in providing comprehensive care. The goal of these interventions is to support individuals in reaching their full potential and to help families navigate the complexities of the syndrome.
Advancements in EHMT1 Research
Research into the EHMT1 gene and Kleefstra Syndrome is ongoing, focusing on a deeper understanding of the gene’s mechanisms. Scientists are investigating how EHMT1 dysregulation impacts brain development and function at a molecular level. This research aims to identify specific pathways that are affected, which could reveal potential targets for therapeutic interventions.
Efforts are also directed towards developing new diagnostic tools, including epigenetic signature analysis, which can offer alternative methods for diagnosis. Collaborative research is important in rare diseases like Kleefstra Syndrome, as it allows for the pooling of data and expertise from multiple institutions worldwide. These collaborations accelerate the pace of discovery and the translation of research findings into improved care and treatment strategies.