MSY331270.indd Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Mol Syndromol 2011;2:181–185 DOI: 10.1159/000331270 Severe Intellectual Disability Associated with Recessive Defects in CNTNAP2 and NRXN1 C. Zweier Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen , Germany Bakkaloglu et al., 2008; Friedman et al., 2008; Kim et al., 2008; Kirov et al., 2008; Marshall et al., 2008; Vrijenhoek et al., 2008; Zahir et al., 2008; Bucan et al., 2009; Rujescu et al., 2009; Awadalla et al., 2010; Bradley et al., 2010; Ching et al., 2010; Magri et al., 2010; Mefford et al., 2010; Wiśniowiecka-Kowalnik et al., 2010]. A homozygous stop mutation in CNTNAP2 in 10 Old Order Amish children was reported to cause a distinct disorder, cortical dysplasia-focal epilepsy syndrome (MIM 610042), characterized by cortical dysplasia and early onset, intractable focal epilepsy leading to language regression, and behavioral and mental deterioration [Strauss et al., 2006; Jackman et al., 2009]. Recently, homozygous or compound heterozygous defects in CNTNAP2 or NRXN1 were reported to cause a severe in- tellectual disability disorder resembling Pitt-Hopkins syndrome (MIM 610954) [Zweier et al., 2009]. These 4 patients had an initially negative TCF4-testing and showed severe intellectual disability and additional vari- able symptoms such as epilepsy, breathing anomalies and stereotypies. In total, 13 patients with homozygous or compound heterozygous defects in CNTNAP2 and 1 patient with a compound heterozygous defect in NRXN1 are reported to date. Key Words CNTNAP2 � Epilepsy � Intellectual disability � Mental retardation � NRXN1 Abstract While heterozygous variants in CNTNAP2 and NRXN1 are re- ported as susceptibility factors for neuropsychiatric disor- ders, homozygous or compound heterozygous defects in either gene were reported as causative for severe neurode- velopmental disorders. This review provides an overview of the clinical aspects in patients with recessive defects in CNTNAP2 and NRXN1 . Copyright © 2011 S. Karger AG, Basel History of the Syndrome During recent years, heterozygous copy-number and missense variants in CNTNAP2 and NRXN1 have repeat- edly been reported as susceptibility factors for a wide spectrum of neuropsychiatric disorders such as develop- mental language delay and autism spectrum disorders, epilepsy and schizophrenia [Verkerk et al., 2003; Feng et al., 2006; Autism Genome Project Consortium, 2007; Bel- loso et al., 2007; Alarcón et al., 2008; Arking et al., 2008; Published online: September 8, 2011 Christiane Zweier Institute of Human Genetics, University Erlangen-Nuremberg Schwabachanlage 10 DE–91054 Erlangen (Germany) Tel. +49 9131 8529 113, E-Mail christiane.zweier   @   uk-erlangen.de © 2011 S. Karger AG, Basel 1661–8769/11/0025–0181$38.00/0 Accessible online at: www.karger.com/msy Zweier Mol Syndromol 2011;2:181–185 182 Clinical Features ( table 1 ) Facial Gestalt In contrast to patients with Pitt-Hopkins syndrome, the facial phenotype in patients with recessive CNTNAP2 and NRXN1 defects is rather unsuspicious. Two patients with a homozygous deletion within CNTNAP2 [Zweier et al., 2009] had previously been published as possible Pitt- Hopkins syndrome patients due to a wide mouth and thick lips [Orrico et al., 2001], but as indicated by Peippo et al. [2006] and supported by the present knowledge and perspective, they do not have the distinct Pitt-Hopkins syndrome facial phenotype. The remaining patients do not show specific facial dysmorphisms [Zweier et al., 2009] ( fig. 1 ), neither are any reported for the Amish pa- tients [Strauss et al., 2006; Jackman et al., 2009]. Intellectual Disability Intellectual disability is reported to be severe in all pa- tients. Developmental testing of 3 patients with cortical dysplasia-focal epilepsy syndrome at the ages of 32, 40 and 73 months revealed global mental ages of 21, 17 and 13 months, respectively [Strauss et al., 2006]. Particularly speech impairment is severe with either no or very lim- ited speech development or regression of speech abilities. Both receptive and expressive language was reported to be maintained at the 1-year level in a 7-year-old patient [Jackman et al., 2009]. In comparison, motor delay is rather mild with a normal or mildly delayed walking age. Developmental regression was not noted in 2 patients Table 1. Clinical findings in patients with recessive CNTNAP2 or NRXN1 defects CNTNAP2 (n = 13) NRXN1 (n = 1) Age at clinical assessment 2–20 years 18 years Normal body height 11/13 1/1 Head circumference 1 P75 P50–P75 Severe intellectual disability 13/13 1/1 Age of walking normal–30 months 2 years Speech none or single words none Developmental regression 11/13 1/1 Seizures with age of onset 13/13, 4–30 months 0/1 MRI anomalies CD 3/10, CH 1/10, PL 1/10 0/1 Behavioral anomalies 9/13 1/1 Decreased deep tendon reflexes 9/10 1/1 Breathing anomalies 3/3 1/1 P = Centile; CD = cortical dysplasia; CH = cerebellar hypoplasia; PL = periventricular leukomalacia. Data for CNTNAP2: Jackman et al., 2009; Strauss et al., 2006; Zweier et al., 2009. Data for NRXN1: Zweier et al., 2009. A B Fig. 1. Facial appearance of patients with compound heterozygous defects in CNTNAP2 ( A ) or NRXN1 ( B ). Note a wide mouth in the patient with NRXN1 defects but otherwise unsuspicious facial ge- stalts in both patients. Reprinted from Zweier et al. [2009], with permission from Elsevier. Recessive Defects in CNTNAP2 and NRXN1 Mol Syndromol 2011;2:181–185 183 [Orrico et al., 2001], but was reported in the other patients with CNTNAP2 defects, starting at the same age as onset of epilepsy between 4 and 30 months [Strauss et al., 2006; Zweier et al., 2009]. Later on, the degree of mental impair- ment seems to be stable. The early onset mandatory epi- lepsy with concurrent developmental regression in pa- tients with CNTNAP2 defects might be a discriminating aspect regarding other disorders with regression pheno- types such as Rett syndrome. Furthermore, the discrep- ancy between severe speech impairment and rather mild motor delay seems to be quite specific for recessive CNTNAP2 defects. Similarly, in the patient with the NRXN1 defect, only mild motor delay with a walking age of 2 years but no speech development was reported [Zwei- er et al., 2009]. Seizures The single patient with biallelic NRXN1 defects does not have epilepsy [Zweier et al., 2009]. Due to the limited number of patients, no conclusion about frequency of seizures in NRXN1 related intellectual disability can be made. All patients with recessive defects in CNTNAP2 do show epilepsy with an early onset between 4 and 30 months of age [Strauss et al., 2006; Jackman et al., 2009; Zweier et al., 2009]. Concurrent with the onset of epi- lepsy, language regression and deterioration of social behavior occur in most of the patients [Strauss et al., 2006]. Regarding available data reported by Strauss et al. [2006], the average peak seizure frequency (number of events per week) is 50 with complex partial, simple par- tial, secondarily generalized, and status epilepticus types of seizures. Growth Parameters As far as data is available, birth measurements are nor- mal. Apart from 2 siblings with short stature [Orrico et al., 2001; Zweier et al., 2009], later body measurements are reported to be normal as well. Interestingly, many pa- tients show a tendency to rather large head circumfer- ences in relation to body height [Strauss et al., 2006]. This might be a suitable discriminating factor in differential diagnosis to other severe intellectual disability disorders where microcephaly is common. Behavioral Observations Behavioral anomalies with autistic traits or pervasive developmental delay, stereotypic movements and atten- tion deficit-hyperactivity disorder are common [Strauss et al., 2006; Jackman et al., 2009; Zweier et al., 2009]. Magnetic Resonance Imaging MRI examination of the brain showed focal malfor- mations in 3 patients. Two of them had unilateral dyspla- sia of the anterior temporal lobe, and 1 had a malforma- tion of the left striatum [Strauss et al., 2006]. In 2 other patients, periventricular leukomalacia [Jackman et al., 2009] and cerebellar hypoplasia were observed, respec- tively [Orrico et al., 2001; Zweier et al., 2009]. Other Findings Breathing anomalies [Zweier et al., 2009] and de- creased deep tendon ref lexes [Strauss et al., 2006; Jack- man et al., 2009] were reported in some patients; hepato- megaly was observed in 1 girl [Jackman et al., 2009]. Natural History CNTNAP2 Early infant development appears to be normal or with only mild motor delay and is followed by onset of sei- zures, language regression or no speech development, with social and behavioral disturbances, and moderate to severe intellectual disability by late childhood [Orrico et al., 2001; Strauss et al., 2006; Jackman et al., 2009; Zweier et al., 2009]. NRXN1 The development of the patient was reported to be nor- mal for the first year before severe intellectual disability with a walking age of 2 years and no speech development was noted [Zweier et al., 2009]. Recommendations for Management Not much information about treatment is available. In 1 patient, zonisamide was used for treatment of seizures [Jackman et al., 2009]. Electrocorticography-guided epi- lepsy surgery for disabling complex partial seizures in 3 patients resulted in a temporarily seizure-free period of 6–15 months but with recurrence after this time [Strauss et al., 2006]. Genetics Information about the Genes and Protein Function CNTNAP2 is one of the largest genes in the human genome spanning 2.3 Mb on chromosome 7q35–36.1 and Zweier Mol Syndromol 2011;2:181–185 184 consisting of 24 coding exons (NM_014141). NRXN1 also belongs to the largest known genes in humans with span- ning 1.1 Mb on chromosome 2p16.3. The classical neurex- in genes in mammals have 2 promoters, generating longer � - and shorter � - neurexins, and are subject to addition- al extensive alternative splicing, generating a large num- ber of variants [Missler and Südhof, 1998]. The represen- tative NRXN1 isoform � 1 (NM_004801) consists of 21 coding exons. CNTNAP2 encodes for CASPR2, a protein distantly related to the neurexins and regulating neuron-glia con- tact in vertebrates and glia-glia contact in insects [Bellen et al., 1998]. Vertebrate Caspr2 has been shown to colo- calize with Shaker-like K+ channels in the juxtaparanod- al areas of Ranvier nodes in myelinated axons of both the CNS and PNS [Arroyo et al., 2001; Poliak et al., 2003]. Furthermore, it seems to play a role in human cortical histogenesis as signs of neuronal migration anomalies were observed in brain samples of patients with a homo- zygous CNTNAP2 mutation [Strauss et al., 2006]. The presynaptic neurexins like NRXN1 and their postsynaptic binding partners, the neuroligins, are cru- cial synapse molecules [Li et al., 2007], with � -neurexins playing a role in normal neurotransmitter release and the function of synaptic calcium channels [Missler et al., 2003]. Recently, findings in Drosophila indicated that not only NrxI (NRXN1), but also NrxIV (CNTNAP2) might be involved in synaptic organization and that both pro- teins might be linked by a common target, presynaptic protein bruchpilot [Zweier et al., 2009]. Mode of Inheritance The mutations and deletions in the published patients were inherited in an autosomal recessive manner with homozygous or compound heterozygous defects in the patients and heterozygosity for 1 of the defects in each parent [Strauss et al., 2006; Jackman et al., 2009; Zweier et al., 2009]. The carrier parents were reported to be healthy; therefore, penetrance of clinical symptoms as- sociated with heterozygous defects in either gene might be lower than possibly appreciated from previous reports on neuropsychiatric disorders [Verkerk et al., 2003; Feng et al., 2006; Autism Genome Project Consortium, 2007; Belloso et al., 2007; Alarcón et al., 2008; Arking et al., 2008; Bakkaloglu et al., 2008; Friedman et al., 2008; Kim et al., 2008; Kirov et al., 2008; Marshall et al., 2008; Vri- jenhoek et al., 2008; Zahir et al., 2008; Bucan et al., 2009; Rujescu et al., 2009; Awadalla et al., 2010; Bradley et al., 2010; Ching et al., 2010; Magri et al., 2010; Mefford et al., 2010; Wiśniowiecka-Kowalnik et al., 2010]. However, an increased risk for variable neuropsychiatric disorders has to be considered in carrier individuals. Frequency of Certain Mutations/Copy Number Variations in Certain Patient Cohorts The number of patients carrying recessive defects in CNTNAP2 or NRXN1 is too small to give frequencies of certain mutations/copy number variations. In the Amish population, 1 specific stop mutation c.3709delG in the C- terminal region of CNTNAP2 is reported [Strauss et al., 2006]. The other published patients either harbor a ho- mozygous deletion of exons 2–9 or a compound hetero- zygous intragenic deletion of exons 5–8 and a splice site mutation in exon 10 of CNTNAP2 [Zweier et al., 2009]. For NRXN1 , to date only a deletion of exons 1–4 in com- pound heterozygosity with a stop mutation in exon 15 is known. 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