People born with developmental brain disorders will benefit from medical interventions only if treated during a narrow window in infancy

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Schematic of signaling pathways regulated by Syngap1 gene. SynGAP protein has been shown to inhibit the activation of various small GTPases. In dendritic spines, SynGAP suppresses Ras/Erk activity and limits growth-related processes including protein translation and AMPA receptor exocytosis. Reduced SynGAP protein levels causes elevated basal Ras/Erk signaling. This results in increased AMPAR surface incorporation thought to contribute to excessive excitation in neural circuits. Enhanced Ras/ERK signaling is also linked to impaired synaptic plasticity, such as altered hippocampal long-term potentiation. Although Rab5 and Rap GTPases are regulated by SynGAP, these mechanisms are poorly understood and it remains unknown how they contribute to Syngap1-related disorders

A new study challenges the presumption that people born with developmental brain disorders such as severe autism will benefit from medical interventions only if treated during a narrow window in infancy or early childhood.

Writing in the journal eLife, an open-access scientific journal, the Rumbaugh lab at Scripps Research in Florida reports improvement in measures of seizure and memory in adult mouse models of a genetic cause of autism, called SYNGAP1 disorder.

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Intellectual disability (ID) is a common disorder defined by the presence of significant limitations in both cognitive and adaptive behaviors with onset before the age of 18.

ID is subdivided into syndromic intellectual disability, in which intellectual deficits and distinguishing morphologic, radiologic or metabolic features are present, and non-syndromic intellectual disability (NSID), in which intellectual deficits appear without  these physical abnormalities.

Mutations in the SYNGAP1 gene are thought to be a relatively common cause of NSID.

NSID patients, including those associated with SYNGAP1 mutation, typically exhibit moderate to severe ID with varying degrees of epilepsy and/or autism spectrum disorders (ASD) and may also have attention deficits, impulsivity, and/or mood disorders. 

SYNGAP1-related NSID patients with epilepsy usually respond well to medications, yet some are refractory (difficult to control even with multiple drugs). SYNGAP1-related NSID is a sporadic condition that is caused by de novo(spontaneous, noninherited) mutations.

The use of genomic sequencing has dramatically increased the capacity of physicians to identify these mutations.

Signs & Symptoms

Children with SYNGAP1-related NSID present with mild hypotonia (low muscle tone) 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 children with SYNGAP1-related NSID 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.

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.

Causes

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 SYNGAP1gene 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.

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.

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Children born with only one working copy of the SYNGAP1 gene don’t make enough of the critical SynGAP protein.

Two broken copies is lethal.

Depending on the extent of their deficit, these children can develop a range of developmental challenges as they mature.

This may include intellectual disability, autism-like behaviors, disordered sensory processing, and epileptic seizures that don’t respond to medication.

The disorder likely affects one to four individuals per 10,000, similar to the frequency of Fragile X syndrome, says Gavin Rumbaugh, Ph.D., an associate professor in the Department of Neuroscience at Scripps Research in Florida.

However, patients can only be discovered through genetic tests. As a result, only a small fraction of patients with this disorder have been discovered.

To study whether treatment of SYNGAP1 disorder in adulthood could be beneficial, Rumbaugh’s team genetically restored levels of the mice’s SynGAP protein to normal.

The treated adult mice showed multiple improvements.

It suggests that having one broken copy of the gene not only harms the brain as it develops, but it also has effects in the adult brain, Rumbaugh says.

There may be reason to treat at any stage of life once options become available, Rumbaugh adds.

“Our findings in mice suggest that neurodevelopmental disorders’ disease course can be altered in adult patients,” Rumbaugh says.

“We can correct brain dysfunction related to seizure as well as memory impairments after restoring SynGAP protein levels in the adult animals.”

Significantly, the paper offers a path to measure the effectiveness of potential medications or other therapies for neurodevelopmental disorders going forward.

Electrographic spikes between seizures is an indicator of epilepsy.

In their paper, the scientists looked at human EEG data collected from a SYNGAP1 disorder patient registry and found that the appearance of these spikes were much more likely to occur during sleep.

Similar findings were observed from mouse models of SYNGAP1 disorder, offering a useful endpoint.

Establishment of biomarkers that predict generalized improvements in brain function will be a critical step in advancing treatments for people with severe neurodevelopmental disorders, Rumbaugh says.

, the scientists looked at human EEG data collected from a SYNGAP1 disorder patient registry and found that the appearance of these spikes were much more likely to occur during sleep.

Similar findings were observed from mouse models of SYNGAP1 disorder, offering a useful endpoint.

Establishment of biomarkers that predict generalized improvements in brain function will be a critical step in advancing treatments for people with severe neurodevelopmental disorders, Rumbaugh says.

The need for a treatment option is clear, Rumbaugh says. Seizures typically become more frequent as children with SYNGAP1 disorders mature, and for many patients, those seizures do not respond to anti-epilepsy drugs.

“Getting to know families affected by this severe disorder has been invaluable, and drives us to develop treatments that will improve the lives of both children and adults,” Rumbaugh says.

“It is encouraging that gene therapy techniques that increase pathologically low protein levels for other types of brain disorders are showing promise in the clinic now.”

More information: Thomas K Creson et al, Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior, eLife (2019). DOI: 10.7554/eLife.46752
Journal information: eLife
Provided by The Scripps Research Institute

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