Potential Treatment and Current Research in Phelan-McDermid Syndrome. 11/16/2016 Frambu Center for Rare Disorders

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1 Potential Treatment and Current Research in Phelan-McDermid Syndrome 11/16/2016 Frambu Center for Rare Disorders

2 Genetics is Complicated!

3 Deletion 22q13: Therapies Under Investigation Intranasal insulin (INIT). Schmidt et al [2009] reported improved motor skills, cognition, and behavior in five of six children with Phelan- McDermid syndrome given INIT. Risperidone. Pasini et al [2010] reported that low-dose risperidone treatment improved behavior, mood, and sleep in an 18-year-old female with Phelan-McDermid syndrome. Risperidone has been shown to exert a dosedependent effect on glutamate receptors in animal models.

4 Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports The two patients were diagnosed with autism spectrum disorders in childhood and presented regression with catatonia features and behavioural disorders after a stressful event during adolescence. Different pharmacological treatments (antipsychotics, benzodiazepines, mood stabilizer drugs, antidepressants, and methylphenidate) failed to improve clinical symptoms Lithium therapy reversed clinical regression, stabilized behavioural symptoms and allowed patients to recover their pre-catatonia level of functioning, without significant side effects.

5 Intellectual Disability ID is primarily due to deficiencies in neuronal network connectivity in the major cognitive centers in the brain, which secondarily results in impaired information processing. Intellectual Disability is a highly diverse disorder in terms of the severity of the cognitive disability, as well as the manifestation of additional (noncognitive) symptoms, which can be partly related to the heterogeneity in the underlying causes. Dierssen and Ramakers. Genes, Brain and Behavior 5:48 60, 2006

6 Intellectual Disability Syndromic ID - the cognitive disability is associated with a fixed constellation of other manifestations, such as body and brain malformations, neurological or psychiatric symptoms or metabolic defects. Non-syndromic ID - no additional abnormalities are observed (including alterations in brain anatomy), and a subnormal intelligence is thus the only detectable deficit. The division between syndromic and non-syndromic forms of ID has become blurred, as (different) mutations in the same gene can produce both syndromic and non-syndromic ID Dierssen and Ramakers. Genes, Brain and Behavior 5:48 60, 2006

7 Neuronal Circuitry Formation Three major processes are know to be required for the proper formation of the extremely complex neuronal circuitry during development: 1. Migration of immature nerve cells from their birthplace to their specific locations 2. Guidance of growing nerve processes to their target cells 3. Formation of specific synaptic connections with the target cells

8 Neuronal Migration Neuronal migration establishes the laminar pattern of cortical regions, moving young neurons from ventricular zones where they are generated to the layers where they establish synaptic relationships. The neocortex has a six-layered structure, which is formed by sequential invasion of migrating cortical plate neurons into the preplate. The preplate is composed of the earliestborn neurons in the cortex and is split by invading cortical plate neurons into a marginal zone and a subplate. Cortical neurons are generated within the proliferative layer and follow a strict inside-out gradient of migration and positioning, which determines the characteristic layering and pattern of neural connections in the adult cerebral cortex.

9 Neuronal Migration The cerebral cortex is constructed by contributions from two distinct neuronal populations. One population consists of radially migrating neurons that originate in the ventricular zone of the neocortex and give rise to the glutamatergic pyramidal neurons that act as excitatory neurons. J Child Neurol 20: , 2005

10 Neuronal Migration The second population consists of tangentially migrating neurons that originate in the ganglionic eminence and give rise to GABA-producing (GABAergic) local circuit neurons. GABA is the principal inhibitory neurotransmitter, and GABAergic interneurons inhibit the postsynaptic potential, thus reducing cell excitability. Deficits of GABA-mediated postsynaptic inhibition contribute to higher excitability of the brain which leads to an increased risk of seizures. J Child Neurol 20: , 2005

11 Neuronal Migration

12 Radial Neuronal Migration Clin. Gen. 58: 16-24, 2000

13 Brain Development and Function A complex array of signals...

14 The molecular biology of memory storage: A dialogue between genes and synapses Associated with short- and long-term changes that reflect simple forms of memory storage Kandel described the process of memory storage and learning as a dialogue between genes and synapses Proposed that short-term memory results from immediate synaptic biochemical changes (such as activation of CaMKII and increase in AMPA glutamate receptor activity) Long-term memory storage generally requires transcription and translation of new proteins that enhance the strength or number of active synapses Kandel ER. Science 294: , 2001

15 Synaptic Balance

16 Synaptic Balance Glutaminergic excitatory GABAergic inhibitory

17 CADM1 Autism and Intellectual Disability Etiology and Neural Communication Synaptic Differentiation NLGN3 NLGN4X CADM1 CNTNAP2 SHANK3 Activity-dep. remodeling MECP2 PTEN Protein synthesis PTEN RPL10 TSC FMR1 RPL10

18 Pharmacological enhancement of mglu5 receptors rescues behavioral deficits in SHANK3 knock-out mice Investigated the molecular mechanisms associated with the ASD-like behaviors observed in Shank3Δ11 / mice Results indicate that Shank3 is essential to mediating metabotropic glutamate receptor 5 (mglu5)-receptor signaling by recruiting Homer1b/c to the PSD Augmenting mglu5-receptor activity ameliorated the functional and behavioral defects that were observed in Shank3Δ11 / mice Treatments that increase mglu5 activity may represent a new approach for treating patients that are affected by PMS and SHANK3 mutations. Molecular Psychiatry (2016), 1 14

19 Intellectual Disability in South Carolina Causation Other environmental insults (<1%) Chromosome (11%) Single Gene (8%) Multifactorial (2%) Culturofamilial (6%) Unknown (56%) Known syndromes (1%) Other genetic disorders (1%) Injury (5%) Infection (5%) Chemical (2%) Prematurity (5%)

20 Intellectual Disability in South Carolina Genetic Causes (28%) Single Gene (28.2%) Culturofamilial (20%) Multifactorial (6.3%) Other genetic syndromes (2.7%) Chromosome (40.4%) Syndromes presumed to be genetic (2.2%)

21 Etiology of Autism Buxbaum J. Dialogues in Clin Neurosci, 2009

22 Autosomal Genes Implicated in SHANK3 Chromosome 22q13 Autism Mutations in 1.1% of persons with ASDs Potential association with severe language and social impairments PTEN Chromosome 10q23 Causes several recognizable syndromes associated with macrocephaly and tumors Mutations found in 4.7% of persons with ASDs and macrocephaly +/- large body size

23 22q13 Deletion syndrome

24 Correcting the SHANK3 Deficit Increased expression of SHANK3 is an obvious route to therapy and could be accomplished by: A) gene therapy to add an extra copy of SHANK3 B) increasing expression from the unaffected copy of SHANK3 C) increasing Shank3 translation, assembly, synaptic targeting, or recycling D) reducing Shank3 degradation

25 Shank Proteins Shank proteins are abundant in growth cones and enrich at postsynaptic densities where they link PSD95 and ionotropic glutamate receptors as well as Homer and mglur complexes through their multiple protein protein interaction domains. Shank3 modulates dendritic spine morphology and synaptic signaling.

26 Induced Pluripotent Stem Cells (ipscs) Induced pluripotent stem cell lines were generated from PMS patients. Reduced amplitudes and frequency of excitatory postsynaptic currents and decreased numbers of excitatory synapses Treatment with insulin-like growth factor 1 (IGF-1) reversed these synaptic deficits IGF-1 supports a switch to developmentally more mature glutamatergic synapses

27 A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome IGF-1 is a commercially available compound that crosses the blood-brain barrier (BBB) and has beneficial effects on synaptic development by promoting neuronal cell survival, synaptic maturation, and synaptic plasticity. Increlex, dose titration was initiated at 0.04 mg/kg twice daily by subcutaneous injection, and increased, as tolerated, every week by 0.04 mg/kg per dose to a maximum of 0.12 mg/kg twice daily. Kolevzon et al. Molecular Autism 2014, 5:54

28 A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome Nine children with PMS aged 5 to 15 were enrolled in a placebo-controlled, double-blind, crossover design study, with 3 months of treatment with IGF-1 and 3 months of placebo in random order, separated by a4- week wash-out period. The IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale. Kolevzon et al. Molecular Autism 2014, 5:54

29 New approaches in the characterization of genotype/phenotype correlation in Phelan- McDermid syndrome The new results highlighted the contribution of other genes in the SHANK3 region (ALG12, ARHGAP8), rather than more interstitial loci (SULT4A1). If we consider the three patients with the most severe Vineland scores, one has the SHANK3 c c>t change, which has been proven to affect the gene regulation.

30 New approaches in the characterization of genotype/phenotype correlation in Phelan- METABOLOMICS McDermid syndrome 1) identify common metabolic patterns that distinguish patients with PMS from controls 2) delineate characteristic metabolic profiles correlating with the severity of the neurobehavioral phenotype 3) consider new pathogenic mechanisms based on the metabolic abnormalities, such as an impaired immune system, increased utilization of Krebs cycle intermediates, and abnormal response to growth factors 4) select new candidate genes, like ALG12.

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32 New approaches in the characterization of genotype/phenotype correlation in Phelan- McDermid syndrome The genetic screening of the preserved copies of seven 22q13 genes detected significant second hits in 11/15 (73.3%) patients with PMS. Variants in SHANK3, ALG12, and ARHGAP8 seem to affect neurobehavioral presentation.

33 New approaches in the characterization of genotype/phenotype correlation in Phelan- Biolog arrays: McDermid syndrome Common metabolic profile for 12 PMS cases Biomarkers for sub-groups characterized by deletion size and severity of phenotype New candidate genes (mannose α-6- mannosyltransferase ALG12) Potential tool for identification of new treatments, pre-treatment selection of patients (IGF-1), and follow-up.

34 Behavioral and Cerebellar Transmission Deficits in Mice Lacking the Autism-Linked Gene Islet Brain-2 Nearly all PMS deletions also span the tightly linked IB2 gene. IB2 protein is broadly expressed in the brain and is highly enriched within postsynaptic densities. Disruption of the IB2 gene in (-/-) mice alters synaptic function Support a role for human IB2 mutation as a contributing genetic factor in Chr22qter-associated cognitive disorders. The Journal of Neuroscience, 30(44): , 2010

35 Mitochondrial Dysfunction may explain symptom variation in PMS. Complex I, II, II + III and IV activity was measured in 51 PMS participants. Caretakers completed questionnaires and provided genetic information through the PMS foundation registry. Complex activity was abnormal in 59% of PMS participants. Abnormalities were found in complex I and IV but not complex II + III and II activity, consistent with disruption of genes within the 22q13 region. Complex activity abnormalities were not related to specific gene deletions suggesting a neighboring effect of regional deletions on adjacent gene expression. Scientific Reports 6:19544