Evaluation of catatonia in autism and severe depression revealing Phelan-McDermid syndrome and tetrahydrobiopterin deficiency.

The authors describe a female in her late twenties, presenting with catatonia and diagnosed with epilepsy, autism spectrum disorder, mild intellectual disability, psychosis, dysthymia, anxiety and bipolar disorder, receiving weekly electroconvulsive therapy (ECT). After testing, findings indicated an interstitial deletion in the 22q13.33 region associated with Phelan-McDermid syndrome. In addition, the patient had low cerebral spinal fluid tetrahydrobiopterin (BH4) levels, suggesting dysfunction in the pterin biosynthetic pathway. As a result, the patient started on sapropterin, a BH4 replacement small molecule. After sapropterin treatment, catatonia improved, and the need for ECT decreased. There was an improvement in her cognitive ability, attention and independence. However, there has been no improvement in seizure frequency.

Gait Abnormalities in Children with Phelan-McDermid Syndrome.

Background: Phelan-McDermid syndrome is a genetic disorder caused by haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 and is characterized by autism spectrum disorder, intellectual disability, speech and language abnormalities, hypotonia, and mild dysmorphic features. Early literature in Phelan-McDermid syndrome did not include gait abnormalities as part of the syndrome although recent prospective studies report that the prevalence of gait abnormalities ranges from 55% to 94%. We compared gait abnormalities in individuals with Phelan-McDermid syndrome, idiopathic autism spectrum disorder, and typically developing controls, and explored associations between gait abnormalities, autism spectrum disorder, and intellectual functioning. Method: The study cohort consists of 67 participants between the ages of 3 and 18 years, divided into 3 groups: Phelan-McDermid syndrome (n = 46), idiopathic autism spectrum disorder (n = 11), and typically developing controls (n = 10). Gait was recorded using a video camera and scored across 26 gait features using a "Gait Clinical Observations scale" designed specifically for this study. Results: Gait abnormalities were significantly higher in the Phelan-McDermid syndrome group as compared to idiopathic autism spectrum disorder or typically developing controls. The number of gait abnormalities across groups was also significantly correlated with Intellectual Quotient/Developmental Quotient (IQ/DQ). In analysis of covariance including IQ/DQ, the effect of group was not significant, but the effect of IQ/DQ was significant. Conclusions: Overall differences in gait abnormalities were determined by the degree of intellectual disability, which was significantly higher in Phelan-McDermid syndrome.

Consensus recommendations on sleeping problems in Phelan-McDermid syndrome.

Early onset sleep problems and disorders are very common in individuals with Phelan-McDermid Syndrome (PMS) with rates of up to 90%. These sleep problems and disorders cannot be taken lightly. Not only do they have a major impact on the health, behaviour, functioning and learning opportunities of affected individuals, they can also have detrimental effects on the well-being and resilience of parents and caregivers, ultimately affecting the physical health, mental health and well-being of the whole social system. In this review we aim to understand the types and frequencies of sleeping problems in PMS as the basis for recommendations on their management and treatment and to provide general guidelines for clinicians and practitioners. We conducted an in-depth literature search, summarised findings, and participated in a series of consensus meetings with other consortium members - experts on PMS and stakeholders - to agree on guidelines and recommendations. In parallel, a world-wide survey was created and distributed amongst parents to include their perspective. Our literature search found only four articles specifically focused on sleeping problems in PMS, although some other articles mentioned prevalence and associated factors. Country-specific prevalence rates ranged between 24% and 46%, whereas our parental survey reported 59%. The main problems reported involved difficulty falling asleep and numerous night awakenings, with being restless in sleep, night-time incontinence, and tooth grinding also commonly reported. Only a small number of individuals had undergone a sleep study monitored by a specialist. Bedtime resistance normally decreases with age, but sleep-onset delay, sleep anxiety, parasomnias, problems falling and remaining asleep remain throughout lifespan, with total sleep time improving during adulthood. However, this improvement was also accompanied by a substantial increase in parasomnias. Ultimately, an increase in sleep disorders in children correlates with increased sleep disorders and daytime sleepiness in parents/caregivers. No study to date has focused on the underlying causes of sleeping problems in PMS, but comorbid mental health conditions, somatic causes, or (poly)pharmacy have been proposed as triggers for sleeping disturbances. Currently there is no PMS-specific treatment for sleeping problems, and current recommendations are mostly based on individuals with intellectual disability and/or neurodevelopmental conditions.

Surgical History and Outcomes in Trisomy 13 and 18: A Thirty-year Review.

BACKGROUND: Patients with Trisomy 13(T13) and 18(T18) have many comorbidities that may require surgical intervention. However, surgical care and outcomes are not well described, making patient selection and family counseling difficult. Here the surgical history and outcomes of T13/ T18 patients are explored. METHODS: A retrospective review of patients with T13 or T18 born between 1990 and 2020 and cared for at a tertiary children's hospital (Riley Hospital for Children, Indianapolis IN) was conducted, excluding those with insufficient records. Primary outcomes of interest were rates of mortality overall and after surgery. Factors that could predict mortality outcomes were also assessed. RESULTS: One-hundred-seventeen patients were included, with 65% T18 and 35% T13. More than half of patients(65%) had four or more comorbidities. Most deaths occurred by three months at median 42.0 days. Variants of classic trisomies (mosaicism, translocation, partial duplication; p = 0.001), higher birth weight(p = 0.002), and higher gestational age(p = 0.01) were associated with lower overall mortality, while cardiac(p = 0.002) disease was associated with higher mortality. Over half(n = 64) underwent surgery at median age 65 days at time of first procedure. The most common surgical procedures were general surgical. Median survival times were longer in surgical rather than nonsurgical patients(p<0.001). Variant trisomy genetics(p = 0.002) was associated with lower mortality after surgery, while general surgical comorbidities(p = 0.02), particularly tracheoesophageal fistula/esophageal atresia(p = 0.02), were associated with increased mortality after surgery. CONCLUSIONS: Trisomy 13 and 18 patients have vast surgical needs. Variant trisomy was associated with lower mortality after surgery while general surgical comorbidities were associated with increased mortality after surgery. Those who survived to undergo surgery survived longer overall. LEVEL OF EVIDENCE: III.

Phelan-McDermid and general anesthesia with different hypnotics.

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disease, caused by an autosomal dominant mutation due to the terminal deletion of 22q13, leading to a defect in the SHANK3 protein. We present the clinical case of a 12-year-old patient with this syndrome, who underwent three interventions that required general anesthesia. In none of them did she present intraoperative or postoperative complications.

Sensory processing in 16p11.2 deletion and 16p11.2 duplication.

Deletions and duplications at the chromosomal region of 16p11.2 have a broad range of phenotypic effects including increased likelihood of intellectual disability, autism, attention deficit hyperactivity disorder (ADHD), epilepsy, and language and motor delays. However, whether and how sensory processing is affected has not yet been considered in detail. Parents/caregivers of 38 children with a 16p11.2 deletion and 31 children with a 16p11.2 duplication completed the Sensory Behavior Questionnaire (SBQ) and the Child Sensory Profile 2 (CSP-2) along with other standardized questionnaires assessing autistic traits (SRS-2), ADHD traits (Conners 3), anxiety (SCAS-P) and adaptive behavior (VABS-3). SBQ and CSP-2 responses found that sensory processing differences were clearly evident in both 16p11.2 deletion and 16p11.2 duplication, though there was significant variation in both cohorts. SBQ data indicated the frequency and impact of sensory behavior were more severe when compared to neurotypical children, with levels being similar to autistic children. CSP-2 data indicated over 70% of children displayed clear differences in sensory registration (missing sensory input). Seventy-one percent with 16p11.2 duplications were also unusually sensitive to sensory information and 57% with 16p11.2 duplications were unusually avoidant of sensory stimuli. This first detailed assessment of sensory processing, alongside other clinical features, in relatively large cohorts of children with a 16p11.2 deletion and 16p11.2 duplication demonstrates that sensory processing differences have a profound impact on their lives.

Sensory processing and adaptive behavior in Phelan-McDermid syndrome: a cross-sectional study.

Phelan-McDermid syndrome (PMS) is a genetic disorder caused by a mutation or deletion of the SHANK3 gene (chromosome 22q13.3), characterized by different sensory processing anomalies. The objective of this study is to expand and provide a detailed definition of the sensory profile of patients with PMS. The secondary objective was to examine the relationship between sensory patterns and adaptive behavior. A cross-sectional study was carried out among 51 Spanish patients with a confirmed genetic diagnosis of PMS. All the participants' parents completed the Short Sensory Profile-Spanish (SSP-S) and the Adaptive Behavior Assessment System II (ABAS-II). Correlational, multiple regression and hierarchical cluster analyses were performed. An atypical sensory profile was identified in almost 75% of PMS patients. Definite differences were found among scores; nonetheless, sub-threshold values were observed in tactile sensitivity, underresponsive/seeks sensation, auditory filtering, and low energy/weak sensory categories. Conceptual, social, and practical domains, as well as the General Adaptive Composite (GAC) of the ABAS-II showed extremely low scores (i.e., <70). Significant correlations were found (p<0.005) between SSP-S scores and the conceptual, social, practical, and GAC index of the ABAS-II, whereby higher SSP-S scores were associated with better skills and higher adaptive performance. The cluster analysis indicated that the group with the largest mutation size (7.23 Mb) showed the greatest sensory processing difficulties and very low adaptive skills. CONCLUSIONS: Patients with PMS show an atypical sensory profile, which correlates with limitations in general adaptive behaviors. WHAT IS KNOWN: • PMS sensory processing difficulties were associated with a pattern of underresponsive/seeks sensation, low energy/weak, and tactile hyporeactivity. • Sensory processing difficulties have been associated with limitations in the development of appropriate adaptive communication and interaction behaviors. WHAT IS NEW: • Sensory definite differences associated with tactile hyperreactivity, as well as significant effects of underresponsiveness/seeks sensation and auditory filtering categories on the adaptive abilities were found in SHANK3deletion patients. • Cluster analysis suggests that smaller mutation sizes were related to better sensory processing and higher adaptive skills, while patients with larger deletion sizes have greater adaptive difficulties and worse sensory processing skills.

A Case Report of Respiratory Syncytial Virus-Infected 8p Inverted Duplication Deletion Syndrome with Low Natural Killer Cell Activity.

The 8p inverted duplication deletion [inv dup del(8p)] is a complex structural rearrangement in chromosome 8. Patients with this chromosomal abnormality exhibit developmental delay, facial dysmorphism, central nervous abnormalities, hypotonia, orthopedic abnormalities, and congenital heart defects. However, cellular immune function in inv dup del(8p) syndrome has never been reported. We present the case of a 1-month-old boy with inv dup del(8p) syndrome who had severe respiratory syncytial (RS) virus bronchiolitis. Natural killer (NK) cells are recruited to airway epithelium in the early phase of RS viral infection. A cluster of defensin genes (DEFs), which are deleted in inv dup del(8p), are located in 8p23.1. Human defensins are involved in antiviral activity through the NK cell-mediated cytotoxic pathway and envelope disruption in the normal immune response. This patient showed lower NK cell activity and α-defensin level compared with healthy controls. These results suggest that decreased NK cell activity can result from DEF haploinsufficiency. In addition to a skeletal deformity with chromosomal abnormality, NK cell-mediated immune deficiency may account for the exacerbation of RS virus bronchiolitis.

Otodental syndrome: Case report and differential diagnosis with Treacher Collins syndrome.

BACKGROUND: Otodental syndrome and Treacher Collins syndrome are rare diseases that have similar clinical features, which can complicate the diagnostic process. These syndromes cause skeletal and dental abnormalities, the differential diagnosis can be based on clinical signs but only the genetic analysis can confirm it. The aim of this case report is to describe and compare clinical signs of these syndromes. CASE REPORT: A 7-year-old patient came to our department: he presented abnormal tooth shapes and sizes, delayed teeth replacement and micrognathia. After extra- and intra-oral examination and radiographic exams, a clinical diagnosis of otodental syndrome was made, and a genetic testing was requested to confirm the diagnosis. CONCLUSION: Dental management of patients with otodental syndrome is challenging due to agenesis, teeth malformation, lack of space for permanent dentition. Proper treatment decision is crucial to obtain the best result for the patient.

Morbidity and mortality following noncardiac surgical procedures among children with autosomal trisomy.

BACKGROUND: Trisomy 13 (T13), trisomy 18 (T18), and trisomy 21 (T21) are the most common autosomal trisomies. One unifying feature of all trisomies is their association with major congenital malformations, which often require life-prolonging surgical procedures. Few studies, mostly among cardiac surgery patients, have examined the outcome of those who undergo surgical procedures. We examined the differences in postsurgical outcomes between the trisomy groups. METHOD: Using the National Surgical Quality Improvement Program dataset, we identified children (<18 years of age) with T13, T18, or T21 who underwent noncardiac surgery (2012-2018). We estimated the incidence of mortality and indicator of resource utilization (unplanned reoperation, unplanned tracheal reintubation, and extended length of hospital stay). RESULTS: Of the 349 158 inpatient surgical cases during the study period, we identified 4202 children with one of the autosomal trisomies of interest (T13: 152; T18: 335; and T21: 3715). The rates of postoperative mortality were substantially higher for T18 and T13 than T21 and nontrisomy children (T18 vs. T21: 11.1% vs. 1.6%, adjusted odds ratio: 5.01, 95%CI: 2.89,8.70, p < .01), (T13 vs. T21: 8.1% vs. 1.6%, adjusted odds ratio: 2.86, 95%CI: 1.25,6.54, p = .01). Children with T18 had the highest rates of extended length of stay (62.7%) and prolonged mechanical ventilation (32.5%). T18 and T13 neonates had the highest surgical mortality burden (T13: 26.5%, T18: 31.8%, and T21: 2.8%). CONCLUSION: Approximately, one-third of T18 and T13 neonates, who had surgery, died, underscoring the lethality of these trisomies and the need for a comprehensive preoperative ethical discussion with families of these children.

Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series.

OBJECTIVE: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations. METHOD: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. RESULTS: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. CONCLUSION: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations.

Emanuel syndrome and congenital diaphragmatic hernia: A systematic review.

BACKGROUND: Emanuel Syndrome (ES), a rare chromosomal disorder caused by a supernumerary chromosome 22 derivative (der(22)t(11;22)), was identified in a fetus with congenital diaphragmatic hernia (CDH) at our fetal center. We aimed to identify a precedent for clinical care and patient outcomes to guide family decision-making. METHODS: This non-funded and non-registered study queried the entire CDH Registry (CDHR) including >10,000 patients since 1995 and conducted a systematic literature review for patients with concomitant ES and CDH. RESULTS: Literature review captured 12 citations and identified 9 patients with CDH+ES from over 400 known ES cases. Given the rarity of the disease and to reduce bias, there were no exclusion criteria aside from non-English language. Of these 9, two underwent surgical CDH repair with neither surviving. The CDHR identified 6 patients with ES, all reported after 2013 and prenatally diagnosed. Median estimated gestational age was 39 weeks (range 37-40) and median birth weight was 2.72 kg (range 2.4-3.4 kg). 3 patients died within the first few postnatal days; surgical repair was not offered due to "anomalies" and "pulmonary hypertension" in two and one family chose comfort measures. The other 3 patients underwent surgical repair, and 2 were supported with ECMO. Two patients survived to discharge, incurring surgical comorbidities associated with severe CDH including gastrostomy dependence, tracheostomy, and CDH recurrence. CONCLUSIONS: ES patients with CDH have potential to tolerate repair and survive to discharge, however with significant additional morbidity combined with severe challenges inherent to ES. This represents the largest series of patients with CDH and ES to date. LEVEL OF EVIDENCE: IV (Case series with no comparison group).

Social visual attentional engagement and memory in Phelan-McDermid syndrome and autism spectrum disorder: a pilot eye tracking study.

BACKGROUND: The current study used eye tracking to investigate attention and recognition memory in Phelan-McDermid syndrome (PMS), a rare genetic disorder characterized by intellectual disability, motor delays, and a high likelihood of comorbid autism spectrum disorder (ASD). Social deficits represent a core feature of ASD, including decreased propensity to orient to or show preference for social stimuli. METHODS: We used a visual paired-comparison task with both social and non-social images, assessing looking behavior to a novel image versus a previously viewed familiar image to characterize social attention and recognition memory in PMS (n = 22), idiopathic ASD (iASD, n = 38), and typically developing (TD) controls (n = 26). The idiopathic ASD cohort was divided into subgroups with intellectual disabilities (ID; developmental quotient < 70) and without (developmental quotient > 70) and the PMS group into those with and without a co-morbid ASD diagnosis. RESULTS: On measures of attention, the PMS group with a comorbid ASD diagnosis spent less time viewing the social images compared to non-social images; the rate of looking back and forth between images was lowest in the iASD with ID group. Furthermore, while all groups demonstrated intact recognition memory when novel non-social stimuli were initially presented (pre-switch), participants with PMS showed no preference during the post-switch memory presentation. In iASD, the group without ID, but not the group with ID, showed a novelty preference for social stimuli. Across indices, individuals with PMS and ASD performed more similarly to PMS without ASD and less similarly to the iASD group. CONCLUSION: These findings demonstrate further evidence of differences in attention and memory for social stimuli in ASD and provide contrasts between iASD and PMS.

Clinical Characteristics and Long-Term Recombinant Human Growth Hormone Treatment of 18q- Syndrome: A Case Report and Literature Review.

Background: 18q- syndrome is a rare chromosomal disease caused by the deletion of the long arm of chromosome 18. Some cases with 18q- syndrome can be combined with growth hormone deficiency (GHD), but data on the efficacy of recombinant human growth hormone (rhGH) treatment in 18q- syndrome are limited. Methods: Here, we report one case of 18q- syndrome successfully treated with long-term rhGH supplement. Previously reported cases in the literature are also reviewed to investigate the karyotype-phenotype relationship and their therapeutic response to rhGH. Results: A 7.9-year-old girl was referred for evaluation for short stature. Physical exam revealed proportionally short stature with a height of 111.10 cm (-3.02 SD score (SDS)), low-set ears, a high-arched palate, a small jaw, webbed neck, widely spaced nipples, long and tapering fingers, and cubitus valgus. Thyroid function test indicated subclinical hypothyroidism. The peak value of growth hormone was 10.26 ng/ml in the levodopa provocation test. Insulin-like growth factor 1 (IGF-1) was 126 ng/ml (57-316 ng/ml). Other laboratory investigations, including complete blood cell count, liver and kidney function, gonadal function, serum adrenocorticotropin levels, and serum cortisol levels, were all within normal ranges. Karyotype analysis showed 46, XX, del (18) (q21). L-Thyroxine replacement and rhGH treatment were initiated and maintained in the following 7 years. At the age of 14.8, her height has reached 159.5 cm with a height SDS increase of 2.82 SDS (from -3.02 SDS to -0.20 SDS). No significant side effects were found during the treatment. The literature review indicated the average rhGH treatment duration of 16 patients was 5.9 ± 3.3 years, and the average height SDS significantly increased from -3.12 ± 0.94 SDS to -1.38 ± 1.29 SDS after the rhGH treatment (p < 0.0001). Conclusion: The main clinical manifestations of 18q- syndrome include characteristic appearance, intellectual disability, and abnormal genital development. The literature review suggested a significant height benefit for short stature with 18q- syndrome from long-term rhGH treatment.

Parent-reported measure of repetitive behavior in Phelan-McDermid syndrome.

BACKGROUND: Phelan McDermid syndrome (PMS) is a neurogenetic condition associated with a high prevalence of intellectual disability (ID) and autism spectrum disorder (ASD). This study provides a more comprehensive and quantitative profile of repetitive behaviors within the context of ID seen with the condition. METHODS: Individuals age 3-21 years with a confirmed PMS diagnosis participated in a multicenter observational study evaluating the phenotype and natural history of the disorder. We evaluated data collected from this study pertaining to repetitive behaviors from the Repetitive Behavior Scales-Revised (RBS-R). RESULTS: There were n = 90 participants who were part of this analysis. Forty-seven percent (n = 42/90) were female, and the average age at baseline evaluation was 8.88 ± 4.72 years. The mean best estimate IQ of the cohort was 26.08 ± 17.67 (range = 3.4-88), with n = 8 with mild ID (or no ID), n = 20 with moderate ID, and n = 62 with severe-profound ID. The RBS-R total overall score was 16.46 ± 13.9 (compared to 33.14 ± 20.60 reported in previous studies of ASD) (Lam and Aman, 2007), and the total number of items endorsed was 10.40 ± 6.81 (range = 0-29). After statistical correction for multiple comparisons, IQ correlated with the RBS-R stereotypic behavior subscale score (rs = - 0.33, unadjusted p = 0.0014, adjusted p = 0.01) and RBS-R stereotypic behavior total number of endorsed items (rs = - 0.32, unadjusted p = 0.0019, adjusted p = 0.01). IQ did not correlate with any other RBS-R subscale scores. CONCLUSIONS: The RBS-R total overall score in a PMS cohort appears milder compared to individuals with ASD characterized in previous studies. Stereotypic behavior in PMS may reflect cognitive functioning.

Case report: Spinal anesthesia for cesarean section in a parturient with Potocki-Lupski syndrome.

BACKGROUND: Potocki -Lupski syndrome is an uncommon disorder caused by a micro-duplication in chromosome 17p11.2. Variable clinical manifestations bring troubles to the general and neuraxial anesthesia, including mental retardation, facial dysmorphisms, structural cardiovascular anomalies, scoliosis, and malignant hyperthermia. Until now, the anesthesia management for cesarean section in these patients has not been reported yet. CASE PRESENTATION: Here we present a 23-year-old Chinese parturient with Potocki -Lupski syndrome who underwent elective cesarean section under spinal anesthesia. She was transferred to our hospital in her 40th week of gestation. She had a history of IgA nephropathy for more than three years and was diagnosed with Potocki -Lupski syndrome (17p12p11.2 segment 3.1 Mb repeat) in the 29th week of pregnancy. Amniocentesis showed the fetus had no abnormal autosomes. Preoperative multidisciplinary consultation suggested that she should terminate the pregnancy as soon as possible. She was ASA II. Her BMI was 26.43 kg/m2. Her airway evaluation was normal. Her spine could bend well and her spinal interspace could be touched clearly. We did the single spinal anesthesia at L2-3 interspace and gave 0.5% bupivacaine 1.7 ml. The absolute anesthesia level reached T8. The Apgar score for the newborn infant was 10 for 1st minute, 5th minute, and 10th minute. The vital signs were steady without using any vasoactive drugs. The patient had a good prognosis, and was subsequently discharged from hospital. CONCLUSION: To date, the case may be the first reported spinal anesthesia for the parturient with Potocki -Lupski syndrome. Although its manifestations are variable, the spinal anesthesia is feasible under careful and comprehensive preoperative evaluation.

Characterisation of the clinical phenotype in Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder compromising the 22q13 terminal region and affecting SHANK3, a gene crucial to the neurobehavioural phenotype and strongly linked to autism (ASD) and intellectual disability (ID). The condition is characterised by global developmental delay, ID, speech impairments, hypotonia and autistic behaviours, although its presentation and symptom severity vary widely. In this study, we provide a thorough description of the behavioural profile in PMS and explore differences related to deletion size and language ability. METHODS: We used standard clinical assessment instruments to measure altered behaviour, adaptive skills and autistic symptomatology in sixty participants with PMS (30 females, median age 8.5 years, SD=7.1). We recorded background information and other clinical manifestations and explored associations with deletion size. We performed descriptive and inferential analyses for group comparison. RESULTS: We found delayed gross and fine motor development, delayed and impaired language (~70% of participants non or minimally verbal), ID of different degrees and adaptive functioning ranging from severe to borderline impairment. Approximately 40% of participants experienced developmental regression, and half of those regained skills. Autistic symptoms were frequent and variable in severity, with a median ADOS-2 CSS score of 6 for every domain. Sensory processing anomalies, hyperactivity, attentional problems and medical comorbidities were commonplace. The degree of language and motor development appeared to be associated with deletion size. CONCLUSIONS: This study adds to previous research on the clinical descriptions of PMS and supports results suggesting wide variability of symptom severity and its association with deletion size. It makes the case for suitable psychotherapeutic and pharmacological approaches, for longitudinal studies to strengthen our understanding of possible clinical courses and for more precise genomic analysis.

The Neurological Manifestations of Phelan-McDermid Syndrome.

Phelan-McDermid syndrome (PMS) is a genetic disorder, caused by haploinsufficiency of the SHANK3 gene on chromosome 22q13.3. PMS is characterized by neurobehavioral symptoms and signs including intellectual disability, speech and language impairment, autism spectrum disorder (ASD), hypotonia, and other motor abnormalities. In the brain, SHANK3 is expressed in neurons, especially in the synapse, and encodes a master scaffolding protein that forms a key framework in the postsynaptic density of glutamatergic synapses. Mutations in SHANK3 have also been identified in individuals with ASD, intellectual deficiency (ID), and schizophrenia. Shank3 deficient mice have defects in basal glutamatergic synaptic transmission in the hippocampus, and in synaptic transmission plasticity, including deficits in long-term potentiation, and show behavioral deficits compatible with the clinical manifestations of PMS. The PMS phenotype varies between affected individuals, but ID and speech and language impairment are present in all cases. ASD is present in a great majority of these individuals. Neurological examination demonstrates hypotonia and abnormalities of motor coordination, visual motor coordination, and gait in the majority of affected individuals. Sleep disturbances and increased pain tolerance are frequent parental complaints. Seizures and epilepsy are common, affecting more than 40% of individuals. Brain magnetic resonance imaging abnormalities include corpus callosum hypoplasia, delayed myelination and white matter abnormalities, dilated ventricles, and arachnoid cysts. Recent advanced imaging anatomic studies including diffusion tensor imaging, point to abnormal brain connectivity. The natural history of the syndrome is not yet fully known, but some individuals with PMS have a later onset of psychiatric illnesses including bipolar disease, accompanied by functional and neurological regression. Individuals with the syndrome are treated symptomatically. Advances in understanding the pathophysiology of this syndrome and the generation of animal models have raised opportunities for a biological cure for PMS. A pilot clinical trial with insulin-like growth factor-1 (IGF-1) showed positive effects on some behavioral core symptoms.

Loss of cGMP-dependent protein kinase II alters ultrasonic vocalizations in mice, a model for speech impairment in human microdeletion 4q21 syndrome.

Chromosome 4q21 microdeletion leads to a human syndrome that exhibits restricted growth, facial dysmorphisms, mental retardation, and absent or delayed speech. One of the key genes in the affected region of the chromosome is PRKG2, which encodes cGMP-dependent protein kinase II (cGKII). Mice lacking cGKII exhibit restricted growth and deficits in learning and memory, as seen in the human syndrome. However, vocalization impairments in these mice have not been determined. The molecular pathway underlying vocalization impairment in humans is not fully understood. Here, we employed cGKII knockout (KO) mice as a model for the human microdeletion syndrome to test whether vocalizations are affected by loss of the PRKG2 gene. Mice emit ultrasonic vocalizations (USVs) to communicate in social situations, stress, and isolation. We thus recorded ultrasonic vocalizations as a model for human speech. We isolated postnatal day 5-7 pups from the nest to record and analyze USVs and found significant differences in vocalizations of KO mice relative to wild-type and heterozygous mutant mice. KO mice produced fewer calls that were shorter duration and higher frequency. Because neuronal activation in the arcuate nucleus in the hypothalamus is important for the production of animal USVs following isolation from the nest, we assessed neuronal activity in the arcuate nucleus of KO pups following isolation. We found significant reduction of neuronal activation in cGKII KO pups after isolation. Taken together, our studies indicate that cGKII is important for neuronal activation in the arcuate nucleus, which significantly contributes to the production of USVs in neonatal mice. We further suggest cGKII KO mice can be a valuable animal model to investigate pathophysiology of human microdeletion 4q21 syndrome.