Phelan-McDermid Syndrome

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The Phelan-McDermid syndrome (also 22q13.3 deletion syndrome , microdeletion 22q13.3 or abbreviated PMS ) is a primary genetically related global developmental disorder is usually accompanied by severe mental retardation, lack of speech development and neuromuscular symptoms. The cause is a microdeletion on the long arm of chromosome 22 .

Phelan-McDermid syndrome was first described in 1985 by Watt and co-workers as partial monosomy 22q. Subsequently, further investigations dealt with the modes of inheritance and genetic changes in different individuals. K. Phelan and H. McDermid were among the first researchers to characterize the syndrome phenotypically in a larger group of patients. More recent studies see the loss of a copy of the ProSAP2 / Shank3 ( Shank3 ) gene , which codes for a synaptic protein in nerve cells, as the cause of the phenotypic abnormalities (→ cause ).

Epidemiology

There are currently around 1000 diagnosed cases worldwide. However, it is known from recent studies on large collectives of autistic patients that the proportion of patients with Phelan-McDermid syndrome in autism spectrum disorders alone is approx. 0.5%. This means that the syndrome is in all likelihood significantly underdiagnosed. Since not all PMS cases are associated with autism , the epidemiological estimates are still very vague. However, if you take the current prevalence figures for autism spectrum disorders as a basis, you come to a cautious estimate of a frequency of at least 1: 20,000 of all newborns with PMS or with Shank3 mutations.

Appearance

The syndrome is extraordinarily diverse and individually pronounced. A triad of symptoms can be found in varying degrees in most of those affected: Almost all patients have a global developmental disorder, which is usually associated with severe intellectual disability, poor speech development and pronounced muscle hypotonia . The psychiatric component is not uniform. However, the current data shows that the diagnosis of early childhood autism or, more broadly, autism spectrum disorder can be made in around 80% of children , often accompanied by pronounced motor hyperactivity . There are also people with microdeletion 22q13.3 or mutations in the Shank3 gene known that, especially in later adolescence and adulthood (→ cause), further psychiatric disorders such as B. develop bipolar disorder or schizophrenia .

The speech disorder usually shows up very early in the inadequate or very delayed sounding. It is often reported that the children are initially able to speak individual words, in some cases even two-word sentences. This ability usually wears off with age. The triad is completed by muscular hypotension , which is often the first symptom that is noticeable in newborns ( floppy infant ). Symptoms that also occur more frequently include increased pain tolerance and a tendency towards infection. In addition, slight facial and extremity malformations are regularly found. Internal malformations of the heart or kidneys and the lower urinary tract are also common and appropriate examinations should be carried out. More than 25% of the patients suffer from epilepsy , which can be accompanied by brain malformations such as arachnoid cysts . Disorders of endocrine or internal organs such as autoimmune hepatitis have also been observed rarely .

The behavior of children with PMS is characterized by severe intellectual disabilities and often by autistic abnormalities such as lack of eye contact, lack of social reciprocity and repetitive behavior. Many children fail to develop a two-phase sleep-wake rhythm , so that shorter sleep phases alternate with longer night wake phases and the children also sleep longer during the day. A cleanliness development succeeds in the rarest of cases.

Differential diagnoses

The following disorders can be similar to Phelan-McDermid syndrome (reason for misdiagnosis in brackets due to similarities):

genetics

The 22q13.3 deletion syndrome has one hundred percent penetrance , so far no cases are known that are phenotypically normal. In most cases, the de novo deletion was inherited from germline mutations. In rarer cases, one of the parents has a balanced translocation , which in the offspring can manifest itself unbalanced as a partial monosomy or trisomy 22. In some cases a ring chromosome 22 is present, and mosaics with microdeletion 22q13.3 have also been described.

root cause

As described under Genetics , the cause of the disorder is based on the loss of genetic material on chromosome 22 . Several candidate genes were discussed in terms of their relevance, complicated by the vastly different deletion sizes.

There are strong indications that the loss of an allele of Shank3 - gene is responsible for a variety of symptoms described. This assumption is based on several observations made over the past few years. In almost all cases described, a copy of the Shank3 gene is lost. In 2001, a patient with typical symptoms of Phelan-McDermid syndrome was described who showed a balanced translocation . This genetic situation is usually asymptomatic because no genetic material is lost. In this case, however, the breaking point was in Shank3 - gene and prevented thereby exhibit a regular feature of this allele. Smaller mutations such as base exchanges or stop mutations can also lead to an appearance similar to Phelan-McDermid syndrome with intellectual disabilities, autistic phenotype, epilepsy , muscle hypotonia, etc.

The gene product of Shank3 is a structural protein of the postsynaptic density of glutamatergic neurons . It forms together with other proteins a flat multimer , on the one hand glutamate receptors anchored on the other hand contact with the actin - cytoskeleton is prepared. Experiments in neuron cell cultures and knockout mouse models (artificially switching off the Shank3 homolog) show that the protein plays an important role in the formation of mature synapses and in the correct balance between excitatory and inhibitory impulses in the nervous system. On the behavioral level, Shank3 is probably essential for the development of normal social behavior and for unimpaired cognition . This enormous importance for regular synapse function was seen early on in connection with a potential role in neuropsychiatric diseases.

diagnosis

The combination of global developmental disorder , lack of language development and hypotonia , in connection with slight external malformations such as dysmorphism of the face, should make one think of Phelan-McDermid syndrome.

Fluorescence in situ hybridization (FISH) , MLPA (multiplex ligation-dependent probe amplification) and array CGH (comparative genome hybridization) are reliable methods for the reliable detection of the suspected diagnosis . Classic karyograms can lead to false negative results in the case of very small deletions.

treatment

The current therapy is mainly symptomatic and aims through optimal early support in the motor, cognitive, linguistic and social areas to improve the quality of life, which can be limited by the numerous comorbidities ( see appearance ). The treatment of gastrointestinal disorders that are frequently observed, such as recurrent vomiting , reflux or difficulties in sucking and swallowing, which can occur at an early age due to muscular hypotension, may be necessary.

Experimental therapy attempts with intranasal insulin or risperidone have shown positive effects on cognitive functions and behavior. However, there is a lack of experience in controlled studies and long-term studies with larger patient collectives. Several potential drugs are currently being preclinical and z. Some of them have already been clinically tested, including modulators of the metabotropic glutamate receptor mGluR5 and the growth factor IGF-1 (insulin-derived growth factor 1). However, their effectiveness and safety in the treatment of Phelan-McDermid syndrome must first be adequately investigated.

forecast

There is currently no cure for Phelan-McDermid syndrome. The early childhood promotion of intellectual, motor and social development plays an important role. Treatment is mostly symptomatic. Neurological and psychiatric abnormalities are currently treated in accordance with the guidelines for these disorders. However, psychopharmacological therapy in particular is significantly less effective in PMS.

As far as is known, life expectancy is not restricted and is largely determined by the degree of disability and the corresponding care of those affected.

Web links

Individual evidence

  1. ↑ JL Watt et al .: A familial pericentric inversion of chromosome 22 with a recombinant subject illustrating a “pure” partial monosomy syndrome. In: Journal of medical genetics. 1985; 22 (4), pp. 283-287. PMC 1049449 (free full text)
  2. ↑ MC Phelan et al.: 22q13 deletion syndrome. In: American journal of medical genetics. 2001; 101 (2), pp. 91-99. PMID 11391650 .
  3. ↑ a b c d e K. Phelan, HE McDermid: The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome). In: Molecular Syndromology. 2011, pp. 186–201. doi: 10.1159 / 000334260
  4. ^ A b C. Betancur, JD Buxbaum: SHANK3 haploinsufficiency: a “common” but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders. In: Molecular autism. 2013; 4 (1), p. 17. PMC 3695795 (free full text)
  5. ↑ a b c L. Soorya et al .: Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. In: Molecular autism. 2013; 4 (1), p. 18. PMC 3707861 (free full text)
  6. ↑ A. Denayer et al.: Neuropsychopathology in 7 Patients with the 22q13 Deletion Syndrome: Presence of Bipolar Disorder and Progressive Loss of Skills. In: Molecular syndromology. 2012 3 (1), pp. 14-20. doi: 10.1159 / 000339119
  7. ↑ J. Gauthier et al .: De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. In: Proceedings of the National Academy of Sciences . 2010; 107 (17), pp. 7863-7868. PMC 2867875 (free full text)
  8. ↑ M. Riegel et al .: Prenatal diagnosis of mosaicism for a del (22) (q13). In: Prenatal diagnosis. 2000; 20 (1), pp. 76-79. PMID 10701858 .
  9. ↑ MC Bonaglia et al .: Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan / McDermid syndrome. In: PLoS genetics. 2011; 7 (7), p. E1002173. PMC 3136441 (free full text)
  10. ↑ MC Bonaglia et al .: Disruption of the ProSAP2 gene in at (12; 22) (q24.1; q13.3) is associated with the 22q13.3 deletion syndrome. In: American Journal of Human Genetics . 2001; 69 (2), pp. 261-268. PMC 1235301 (free full text)
  11. ↑ CM Durand et al .: Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. In: Nature genetics. 2007; 39 (1), pp. 25-27. PMC 2082049 (free full text)
  12. ↑ AM Grabrucker et al .: Postsynaptic ProSAP / Shank scaffolds in the cross-hair of synaptopathies. In: Trends in cell biology. 2011; 21 (10), pp. 594-603. PMID 21840719 .
  13. ↑ TM Boeckers: The postsynaptic density. In: Cell and tissue research. 2006; 326 (2), pp. 409-422. PMID 16865346 .
  14. ↑ G. Roussignol et al: Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. In: The Journal of neuroscience: the official journal of the Society for Neuroscience. 2005; 25 (14), pp. 3560-3570. PMID 15814786 .
  15. ↑ J. Peça et al .: Shank3 mutant mice display autistic-like behaviors and striatal dysfunction. In: Nature. 2011; 472 (7344), pp. 437-442. PMC 3090611 (free full text)
  16. ↑ TM Boeckers et al: ProSAP / Shank proteins - a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease. In: Journal of neurochemistry. 2002; 81 (5), pp. 903-910. PMID 12065602 .
  17. ↑ H. Schmidt et al .: Intranasal insulin to improve developmental delay in children with 22q13 deletion syndrome: an exploratory clinical trial. In: Journal of medical genetics. 2009; 46 (4), pp. 217-222. PMID 18948358 .
  18. ↑ A. Pasini et al .: Dose-dependent effect of risperidone treatment in a case of 22q13.3 deletion syndrome. In: Brain & development. 2010; 32 (5), pp. 425-427. PMID 19428206
  19. ↑ A. Shcheglovitov et al: SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. In: Nature. 2013; doi: 10.1038 / nature12618