A rare genetic mutation that affects development:
- Discovered at Sainte-Justine Hospital in Montreal, Canada, in 2009;
- Complex symptoms: intellectual disability (moderate to severe), epilepsy, autism spectrum, language delay, apraxia, difficulty perceiving sensory functions, sleep problems and hypotonia.
A little-known mutation, and currently poorly supported.
It is assumed that the majority of patients have not been diagnosed. However, an early diagnosis would allow appropriate management by health professionals (speech therapists, psychomotor therapists in particular) during key phases of intellectual development. This would increase the chances that patients will subsequently reach their potential.
Currently, no cure exists and researchers are still working to determine the biological causes of this genetic mutation.
Did you know?
- SynGAP1 is currently one of the 5 most important unique genetic mutations in autism researched in the world.
- Patients with SynGAP1 have the highest rate of combined epilepsy with intellectual disability in the world: 94% to 100% of patients treated with SynGAP1 have some form of epilepsy. Epilepsy, often resistant to treatment, is a major symptom of the mutation, and a big handicap for patients.
- Intellectual disability affects 0.5% of the world’s population. It is estimated that the intellectual disability linked to SynGAP1 represents 0.25% of intellectual disability cases, or about 96,250 patients worldwide! (only 600 have been diagnosed to date).
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The role of the gene SYNGAP1 as a cause of intellectual disability was first described in 2009 by a team from Sainte-Justine in Montreal. Since this discovery, the number of children with intellectual disabilities related to the SYNGAP1 gene increases rapidly. Mutations in SYNGAP1 could represent one of the most common genetic causes of intellectual disability.
Children with SYNGAP1-related NSID present with mild hypotonia and global developmental delay at the end of the first year or during the second year of life. They can start to walk at a normal age but more frequently later in life (range: 14 months to 30 months of age). Rarely, their gait is described as being ataxic (unstable). Language development is also variably impaired with some children speaking with isolated words, associations of two or three words or with simple short sentences, whereas others remain non-verbal. Some of the children show oral dyspraxia (oral motor dysfunction), which can result in some drooling or eating difficulties.
While the primary disorder with SYNGAP1-related NSID is moderate to severe cognitive impairment, a subset of children are also diagnosed with autism spectrum disorder (ASD). Other behavioral abnormalities include inattention, impulsivity, and physical aggression (hitting, biting). Mood swings, sullenness, and rigidity are also reported in many children.
Approximately 2/3 of SYNGAP1-related cases display epilepsy characterized by a variety of seizures including absences, myoclonia (brief, involuntary twitching of a group of muscles), generalized tonic-clonic seizures (Grand Mal seizures), and drop attacks. The seizures usually start during the first few years of life. Seizures are well controlled in most of the children with the administration of a single anti-epileptic drug but in some cases seizures are refractory (difficult to control even with multiple drugs).
The appearance and the growth of children with SYNGAP1-related NSID are not unusual. Some of the children will develop microcephaly (smaller head circumference). The presence of this feature does not correlate with the severity of the cognitive impairment.
Children (and presumably adults) with SYNGAP1-related NSID continue to develop, progressing at their own pace. Unless their epilepsy is not well controlled, they do not regress or deteriorate and can always continue to learn.
The human genome is composed of approximately 20,000 genes. A great majority of these genes, including the SYNGAP1 gene, are expressed as two copies (one copy inherited from each parent). Only a single abnormal copy of the SYNGAP1 gene is sufficient to cause NSID (haploinsufficiency). The abnormal gene is usually the result of spontaneous mutation(s) (not inherited from either parent, also called de novo mutation). These new mutations occur spontaneously in the sperm or egg cells of one of the parents, without the influence of an environmental risk factor.
Intellectual disability caused by mutations in SYNGAP1 appears to be equally prevalent in women and men. The disorder is recognizable early during childhood. No adult has yet been reported with a mutation in SYNGAP1. However, because affected children are generally healthy, we expect that this disorder is as prevalent in the adult population as it is in children. SYNGAP1-related NSID is found in all ethnic groups, with the same prevalence.
The SYNGAP1 gene encodes for the protein, SynGAP (brain-specific RAS GTPase-activating). Normal levels of SynGAP protein are essential for proper brain function and development. Within the brain, the protein is most often found at synapses where it regulates critical biochemical signaling pathways that support learning and memory capabilities.
Living with SYNGAP1
Children with moderate to severe non-syndromic global developmental delay (GDD) or ID should be genetically screened for potential involvement of genes. The presence of a generalized form of epilepsy (recognizable by physicians by the type of seizures and the EEG pattern) is consistent with the diagnosis. Microcephaly, when present, is not congenital but acquired. Brain imaging techniques such as MRI usually do not show any specific neural abnormalities.
Because such a clinical presentation is common and associated with numerous genes, specific genetic testing for mutations in SYNGAP1 results in a low yield. More recently, physicians are requesting genomic testing (the exploration of all genes at once) for the investigation of children with GDD/ID. By exploring the whole genome in this way, physicians aim to increase their chance of finding the gene causing their patient’s disorder. They usually start with a genome-wide search for deletions or duplications that encompass single or multiple genes using array hybridization. If this analysis does not yield answers, the next step could be the sequencing of all the genes (whole-exome or whole-genome sequencing).
Like other forms of intellectual disability, there are no known disease-altering treatments for SYNGAP1-related disorders. Current treatment for NSID in general is directed toward the specific symptoms that are apparent in each individual. Management may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, pediatric neurologists, gastroenterologists, psychiatrists, speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Treatment options that may be used to treat individuals with an ID are complex and varied. The specific treatment plan will need to be highly individualized.
There is a concerted, worldwide effort to develop personalized therapies for patients with genetic forms of NSID. With respect to SYNGAP1-related disorders, evidence indicates that pathogenic SYNGAP1 mutations disrupt biochemical signaling pathways in neurons that promote cognitive ability. Thus, repairing these disrupted signaling pathways is a promising pre-clinical therapeutic avenue.