SNAP25 Developmental and Epileptic Encephalopathy (SNAP25-DEE)

Disease Overview

SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE), also known as developmental and epileptic encephalopathy type 117 (DEE117) is a rare genetic disease. It is characterized by early-onset seizures, developmental delays, low muscle tone (hypotonia), walking and speech problems, movement issues and intellectual disability. Other symptoms may include mild facial differences, joint problems and loss of previously acquired skills (developmental regression).¹

SNAP25-DEE is caused by changes (variants) in the SNAP25 gene.

Treatment is symptomatic and includes anti-seizure medication and early intervention for developmental delay and intellectual disability.

SNAP25-DEE is a specific type of developmental and epileptic encephalopathy (DEE), a group of rare, severe epilepsies that cause developmental problems, intellectual disability and seizures of different types, often starting in infancy or early childhood.^1-2,3

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Synonyms

• SNAP25 syndrome
• developmental and epileptic encephalopathy type 117 (DEE117)
• SNAP25-DEE

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Signs & Symptoms

The onset, progression and severity of symptoms can differ from person to person and may depend, in part, on the age at onset and severity of epilepsy.^2-5

Not everyone with SNAP25-DEE will have all the symptoms described below. The signs and symptoms that have been reported include:

Seizures

The frequency of seizures varies significantly among affected people. Some may have numerous seizures each day, while others have infrequent, isolated seizures. There is a broad spectrum of seizure types including:

• Focal seizures that originate in a specific area of the brain and may or may not impair awareness
• Focal to bilateral tonic-clonic seizures that begin in a specific area of the brain and then spread to involve both sides of the brain, leading to generalized convulsions
• Generalized seizures involving both hemispheres of the brain from the onset
• Epileptic spasms that are brief, sudden movements that typically occur in clusters
• Myoclonic seizures that are sudden, shock-like muscle jerks that can affect part or all of the body
• Atonic seizures that are characterized by a sudden loss of muscle tone, often resulting in falls
• Absence-like seizures that are brief episodes of impaired awareness, resembling absence seizures but not necessarily meeting classic EEG criteria
• Status epilepticus that are prolonged seizures or series of seizures without full recovery between them, requiring emergency medical intervention

Challenges with movement and development:

• Developmental delays, meaning that there is slower progress than expected in skills like walking, talking, or learning
• Low muscle tone (hypotonia) where muscles may feel floppy or weak
• Walking difficulties:
  • Delayed walking
  • Unsteady walking (ataxia)
  • Inability to walk
• Movement issues:
  • Involuntary movements (dystonia or tremor)
  • Muscle stiffness (spasticity)
  • Weakness and getting tired easily
• Problems with nerve-muscle communication, similar to congenital myasthenic syndrome, specifically at the neuromuscular junction where nerves and muscles interact, and characterized by muscle weakness and fatigue

Learning and communication challenges:

• Intellectual disability which may range from moderate to severe
• Speech and language difficulties:
  • Delayed speech
  • Slurred or unclear speech due to weakness in the muscles used for speech (dysarthria)
  • Trouble planning speech movements due to an inability of the brain to coordinate these movements (speech dyspraxia)
  • Absent speech

Other features: ^2,3

• Developmental regression, meaning that there is a loss of skills that were previously learned
• Abnormal findings on an electroencephalogram (EEG), a test that measures and records the electrical activity of the brain
• Difficulty eating
• Difficulty breathing, especially in newborns (neonatal respiratory insufficiency)
• Epicanthal folds (skin fold extending from the nose to the eyebrow)
• Drooping eyelids (ptosis)
• High-arched palate (the roof of the mouth is higher than usual)
• Very flexible joints (joint hypermobility)
• Stiff joints (joint contractures)

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Causes

SNAP25-DEE is caused by changes (disease-causing variants) in the SNAP25 gene. The SNAP25 gene plays a significant role in how brain cells communicate with each other, especially at the point where they connect, called the synapse.

All reported cases are de novo, meaning that the person with SNAP25-DEE was the first person in their family to be affected.

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Affected populations

SNAP25-DEE is extremely rare. The exact number of affected people worldwide is unknown but is estimated to affect about 0.1-1:100,000 births.⁶ Increased genetic testing has led to more diagnoses in recent years.

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Disorders with Similar Symptoms

Other neurodevelopmental disorders and epileptic encephalopathies share similar symptoms to SNAP25-DEE.

• Other “SNAREopathies”: SNAP25-DEE is considered part of a group of disorders known as “SNAREopathies,” which involve variants in genes encoding components of the SNARE complex. Other conditions caused by variants in genes like STX1B, STXBP1, or VAMP2 share overlap with SNAP25-DEE, including intellectual disability, epilepsy, movement disorders and cerebral visual impairment.⁷
• Other genetic epileptic encephalopathies: Since SNAP25-DEE is characterized by early-onset epilepsy and intellectual disability, other genetic disorders that cause these symptoms should be considered. Examples include DEE caused by variants in genes like ALDH7A1, ATP6AP2, PCDH19, POLG, SLC2A1, SLC25A22, SPTAN1 and STXBP1.¹
• Other neurodevelopmental disorders: SNAP25-DEE can also involve developmental delays, variable cognitive impairment, movement disorders and features of autism spectrum disorder. Thus, other neurodevelopmental disorders presenting with similar symptoms should be considered such as tuberous sclerosis (TSC1 and TSC2 gene variants) or Rett syndrome (CDKL5, FOXG1, and MECP2 gene variants).⁸
• Metabolic disorders: Some metabolic disorders have been linked to neuropsychiatric diseases, and SNAP-25 has been implicated in metabolic homeostasis, the body’s ability to maintain a stable internal environment regarding metabolism, essentially keeping all the chemical processes within cells in balance. Therefore, certain metabolic conditions could be included in the differential diagnosis.⁹

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Diagnosis

A diagnosis of SNAP25-DEE may be suspected based on a thorough clinical evaluation including physical exam, detailed family and medical history and neurological exam. Genetic testing that identifies a disease-causing variant in the SNAP25 gene confirms the diagnosis.

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Standard Therapies

There is currently no cure or specific treatment for SNAP25-DEE. Treatment is directed at improving the symptoms that the affected person has, including seizure control.

After the diagnosis, the recommended evaluations include:

• Neurologic evaluation including brain images and electroencephalogram (EEG) to measure brain activity
• Developmental evaluation including cognitive and speech evaluation, behavioral and psychiatric evaluation
• Other evaluations as needed such as gastrointestinal evaluation for feeding difficulties and/or ophthalmologic evaluation for vision problems
• Genetic counseling for the family

Symptoms are treated the same way as in the general population. For example, seizures are treated with anti-seizure medication as needed. Treatment for movement disorders may include physical medicine and rehabilitation and treatment for feeding difficulties may require the placement of a feeding tube.

Early intervention is recommended for children with intellectual disability and developmental delay.

It is important for parents and caregivers to learn about common seizure presentations. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy see Epilepsy Foundation Toolbox.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

1. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512-521. doi:10.1111/epi.13709
2. Rohena L, Neidich J, Truitt Cho M, et al. Mutation in SNAP25 as a novel genetic cause of epilepsy and intellectual disability [published correction appears in Rare Dis. 2015 Apr 16;3(1):e1037119. doi: 10.1080/21675511.2015.1037119.]. Rare Dis. 2013;1:e26314. Published 2013 Sep 5. doi:10.4161/rdis.26314
3. Klöckner C, Sticht H, Zacher P, et al. De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy [published correction appears in Genet Med. 2021 Apr;23(4):796. doi: 10.1038/s41436-020-01090-w.]. Genet Med. 2021;23(4):653-660. doi:10.1038/s41436-020-01020-w
4. Hamdan FF, Myers CT, Cossette P, et al. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Am J Hum Genet. 2017;101(5):664-685. doi:10.1016/j.ajhg.2017.09.008
5. Shen XM, Selcen D, Brengman J, Engel AG. Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology. 2014 ;83(24):2247-2255. doi:10.1212/WNL.0000000000001079
6. López-Rivera JA, Pérez-Palma E, Symonds J, et al. A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants. Brain. 2020;143(4):1099-1105. doi:10.1093/brain/awaa051 3(24):2247-2255. doi:10.1212/WNL.0000000000001079
7. Matthijs Verhage, Jakob B. Sørensen, SNAREopathies: Diversity in Mechanisms and Symptoms, Neuron, Volume 107, Issue 1,2020, Pages 22-37, ISSN 0896-6273, https://doi.org/10.1016/j.neuron.2020.05.036.
8. Savatt JM, Myers SM. Genetic Testing in Neurodevelopmental Disorders. Front Pediatr. 2021;9:526779. Published 2021 Feb 19. doi:10.3389/fped.2021.526779
9. Barroso I, McCarthy MI. The Genetic Basis of Metabolic Disease. Cell. 2019;177(1):146-161. doi:10.1016/j.cell.2019.02.024

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Programs & Resources

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