SYNGAP syndrome

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Classification according to ICD-10
F79 Unspecified intellectual disability
ICD-10 online (WHO version 2019)

The SynGAP syndrome (also called SYNGAP1 syndrome) is a rare congenital disease with the main feature of a mental disability . In the past, the disease was also referred to as mental retardation  5 (MRD5) and counted as a non-syndromic, autosomal dominant mental retardation. However, the entirety of the symptoms is now referred to as a syndrome.

frequency

The Bridge the Gap Foundation to be about 1-2% should syndrome SynGAP be affected the mentally disabled from. With a number of 420,000 mentally handicapped people in Germany, the frequency is around 1: 10,000 to 1: 20,000.

root cause

It is based on a mutation in SYNGAP1 - Gen . It is located on the short arm (p-arm) of chromosome 6 and codes for a synapse protein that activates RasGTPase .

Clinical manifestations

The main symptoms of syngap syndrome are:

  • Global developmental delay or developmental disorder
    • Motor development
      Syngap patients usually reach the development milestones later than normally developed children. Parents and paediatricians often notice this as early as the first year of life due to hypotonia . This significantly slows motor development and the affected children learn to walk later. Later, the children stand out because of a wide-legged, lanky corridor. Fine motor skills are also severely impaired and manifest in many children as pronounced dyspraxia .
    • language development
      Already the newborn falls a poor oral motor skills on such. B. in the form of feeding problems and reduced vocalisation. Sounds and syllables that have already been acquired are often forgotten. Verbal developmental dyspraxia (VED) or apraxia is often diagnosed at an advanced age . Most Syngap patients are non-verbal or have a very limited vocabulary of just a few words or syllables that can be used to communicate. In order to express their needs, those affected use the body's own language (gestures and facial expressions) as well as means of assisted communication (such as gestures, symbol cards and complex communication aids, also called talkers)
    • Mental development
      Some children show slow cognitive development on early development tests. What is called mental retardation in medical reports . In later intelligence tests , the patients are in the range of moderate to severe intellectual disabilities.
  • Epilepsy
    Parents first consciously notice epileptic seizures at the age of 2–3 years. But mostly they only realize in retrospect that the first signs of seizures were seen much earlier (in the first year of life). These show up as (atypical) absenteeism ( staring or pausing), eyelid myoclonus ( eyelid flutter ), myoclonic-astatic seizures ( eye rolls with a brief loss of tone), falls ( sudden falling over ). The seizures are similar to those of Doose Syndrome .
    In the EEG , the seizures begin in the visual center ( occipital lobe ) and become generalized in a secondary manner. This is usually also expressed in the clinical picture by a conspicuous look with subsequent loss of tone.
    • Trigger: The epileptic seizures are mainly triggered by tiredness, stress and sensory stimuli. Epileptic seizures triggered by eating (reflex epilepsy) are particularly noticeable in Syngap patients. These short seizures, which usually only last a few seconds, are often perceived as epilepsy far too late and, especially in smaller children, misinterpreted as tiredness or enjoyable food. Therefore, parents of (possible) Syngap children should try to record the eating situation on video for the treating pediatrician or neurologist. In the EEG, especially if it is a sleep EEG, these patients can be completely normal or the EEG is described as abnormal but not pathogenic. However, if you give them something to eat in the awake EEG, many patients show a typical EEG pattern.
  • Autism and Behavior
    About 50% of Syngap patients have been diagnosed with an autism spectrum disorder . According to the classic classification, the autistic symptoms would most likely be assigned to atypical autism. The actual number of those affected by autism is probably much higher, however, since the diagnosis of autism in non-verbal, mentally disabled people with dyspraxia is not easy. In addition, behavior problems such as impulsiveness and aggressiveness can occur.
    However, obsessive behavior is particularly noticeable. Syngap children especially love water and music, but also things like fans, elevators, escalators, switches, glass roofs and spatial perspectives in motion (e.g. tunnels, driving a car). As soon as they feel the need to do so, they appear unusually motivated. However, if they are denied access to the object of desire, because of the lack of language they use all physical means to enforce their will.
  • Other characteristics
    Constipation , fecal incontinence , difficulty sleeping, flat feet

diagnosis

The diagnosis of SYNGAP syndrome can only be made through a genetic test. The SYNGAP1 gene is examined for changes in human genetics. This analysis is carried out on the one hand with a single gene test as Sanger sequencing . On the other hand, different laboratories offer different gene panels in which they analyze the SYNGAP1 gene using next-generation sequencing . Depending on the laboratory, this can be a gene panel for developmental disorders, mental retardation, epilepsy, epileptic encephalopathy or autism.

therapy

A causal therapy was successfully used worldwide for the first time by the working group of Prof. Dr. med. Gerhard Kluger tested statins at the Schön Klinik in Vogtareuth as part of an individual observation . The overactive RAS cascade in Syngap syndrome is inhibited by statins . Further clinical studies by the working group of Prof. Dr. med. Gerhard Kluger are in preparation.

Differential diagnostics

The main distinction is Angelman Syndrome .

literature

  • FF Hamdan, J. Gauthier, D. Spiegelman, A. Noreau, Y. Yang, S. Pellerin, S. Dobrzeniecka, M. Côté, E. Perreau-Linck, E. Perreault-Linck, L. Carmant, G. D 'Anjou, E. Fombonne, AM Addington, JL Rapoport, LE Delisi, MO Krebs, F. Mouaffak, R. Joober, L. Mottron, P. Drapeau, C. Marineau, RG Lafrenière, JC Lacaille, GA Rouleau, JL Michaud : Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. In: The New England Journal of Medicine . Vol. 360, No. 6, February 2009, pp. 599-605, doi: 10.1056 / NEJMoa0805392 , PMID 19196676 , PMC 2925262 (free full text).
  • C. Mignot, C. von Stülpnagel, C. Nava, D. Ville, D. Sanlaville, G. Lesca, A. Rastetter, B. Gachet, Y. Marie, GC Korenke, I. Borggraefe, D. Hoffmann-Zacharska, E. Szczepanik, M. Rudzka-Dybała, U. Yiş, H. Çağlayan, A. Isapof, I. Marey, E. Panagiotakaki, C. Korff, E. Rossier, A. Riess, S. Beck-Woedl, A. Rauch, C. Zweier, J. Hoyer, A. Reis, M. Mironov, M. Bobylova, K. Mukhin, L. Hernandez-Hernandez, B. Maher, S. Sisodiya, M. Kuhn, D. Glaeser, S. Weckhuysen, CT Myers, HC Mefford, K. Hörtnagel, S. Biskup,., JR Lemke, D. Héron, G. Kluger, C. Depi: Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. In: Journal of medical genetics. Vol. 53, No. 8, 08 2016, pp. 511-522, doi: 10.1136 / jmedgenet-2015-103451 , PMID 26989088 .
  • MH Berryer, FF Hamdan, LL Klitten, RS Møller, L. Carmant, J. Schwartzentruber, L. Patry, S. Dobrzeniecka, D. Rochefort, M. Neugnot-Cerioli, JC Lacaille, Z. Niu, CM Eng, Y. Yang, S. Palardy, C. Belhumeur, GA Rouleau, N. Tommerup, L. Immken, MH Beauchamp, GS Patel, J. Majewski, MA Tarnopolsky, K. Scheffzek, H. Hjalgrim, JL Michaud, G. Di Cristo: Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. In: Human mutation. Vol. 34, No. 2, February 2013, pp. 385-394, doi: 10.1002 / humu.22248 , PMID 23161826 .
  • N. Jeyabalan, JP Clement: SYNGAP1: Mind the Gap. In: Frontiers in cellular neuroscience. Vol. 10, 2016, p. 32, doi: 10.3389 / fncel.2016.00032 , PMID 26912996 , PMC 4753466 (free full text) (review).

Web links

Individual evidence

  1. ↑ Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation . PMID 19196676
  2. ↑ Flyer (PDF) Lebenshilfe
  3. ^ Genetics of nonsyndromic intellectual disability
  4. ↑ a b Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy . PMID 26989088
  5. ↑ a b Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency . PMID 23161826
  6. ↑ UniqueUK, Disorder Guide SYNGAP1 ( Memento of the original from February 28, 2018 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF) @1@ 2Template: Webachiv / IABot / www.rarechromo.org
  7. ↑ List of the testing gene laboratories and the gene panels.
  8. ^ Gerhard Kluger, Celina von Stülpnagel-Steinbeis, Stephan Arnold, Kirsten Eschermann, Till Hartlieb: Positive Short-Term Effect of Low-Dose Rosuvastatin in a Patient with SYNGAP1-Associated Epilepsy . In: Neuropediatrics . March 15, 2019, ISSN  0174-304X , doi : 10.1055 / s-0039-1681066 ( thieme-connect.de [accessed on May 26, 2019]).
  9. ↑ Genpanel: Angelman Syndrome and Differential Diagnoses