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Six individuals of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of severe global developmental delay, positive pyramidal signs, unique dysmorphism, skeletal abnormalities, and severe failure to thrive with normal birth weights. Patients had a profound intellectual disability and cognitive impairment with almost no acquired developmental milestones by 12 months. Early-onset axial hypotonia evolved with progressive muscle weakness, reduced muscle tone, and hyporeflexia. Craniofacial dysmorphism consisted of a triangular face with a prominent forehead and midface hypoplasia. Magnetic resonance imaging (MRI) demonstrated thinning of the corpus callosum and paucity of white matter. Genome-wide linkage analysis identified a single ~4 Mbp disease-associated locus on chromosome 7q21.13-q21.3 (LOD score5). Whole-exome and genome sequencing identified no nonsynonymous pathogenic biallelic variants in any of the genes within this locus. Following the exclusion of partially resembling syndromes, we now describe a novel autosomal recessive syndrome mapped to a ~4Mbp locus on chromosome 7.

It is widely believed that early diagnosis and treatment of autism spectrum disorder is essential for better outcome. This is demonstrated by the American Academy of Pediatrics recommendation to screen all 1.5–2.5-year-old toddlers for autism spectrum disorder. However, multiple longitudinal studies of children diagnosed with autism spectrum disorder at 1.5–6 years of age and treated in community settings have not reported any associations between earlier diagnosis and improved outcome in core symptoms. Here, we quantified Longitudinal changes in core autism spectrum disorder symptoms of 131 children diagnosed at 1.2–5 years of age using the Autism Diagnostic Observation Schedule–Second Edition Calibrated Severity Scores over a 1-2 year period. We examined the prevalence and magnitude of Calibrated Severity Scores changes across children who were diagnosed at different ages. The results revealed that age of diagnosis was significantly correlated with poorer outcome ( r(129) = 0.41, p Lay abstract It is widely believed that early diagnosis and treatment of autism spectrum disorder is essential for better outcome. This is demonstrated by the American Academy of Pediatrics recommendation to screen all 1.5–2.5-year-old toddlers for autism spectrum disorder. However, multiple longitudinal studies of children diagnosed with autism spectrum disorder at 1.5–6 years of age and treated in community settings have not reported any associations between earlier diagnosis and improved outcome in core autism spectrum disorder symptoms. In this study, we measured changes in core autism spectrum disorder symptoms over a 1–2-year period in 131 children diagnosed with autism spectrum disorder at 1.2–5 years of age, and treated in the community. The results revealed that children who were diagnosed before 2.5 years of age were three times more likely to exhibit considerable improvements in social autism spectrum disorder symptoms in comparison to children diagnosed at later ages. These results highlight the importance of early diagnosis and treatment of autism spectrum disorder even in community settings with heterogeneous services. In addition, these results motivate further prioritization of universal screening for autism spectrum disorder before 2.5 years of age.

Whole-exome sequencing (WES) is an effective approach to identify the susceptibility of genetic variants of autism spectrum disorder (ASD). The Israel Ministry of Health supports WES as an adjunct tool for ASD diagnosis, despite its unclear diagnostic yield and cost effectiveness. To address this knowledge gap, we applied WES to a population-based sample of 182 Bedouin and Jewish children with ASD from southern Israel, and assessed its yield in a gene panel of 205 genes robustly associated with ASD. We then compared the incremental cost-effectiveness ratios (ICERs) for an ASD diagnosis by WES, chromosomal microarray analysis (CMA), and CMA + WES. Overall, 32 ASD candidate variants were detected in 28 children, corresponding to an overall WES diagnostic yield of 15.4%. Interestingly, the diagnostic yield was significantly higher for the Bedouin children than for the Jewish children, i.e., 27.6% vs. 11.1% (p = 0.036). The most cost-effective means for genetic testing was the CMA alone, followed closely by the CMA + WES strategy (ICER = USD 117 and USD 124.8 per child). Yet, WES alone could become more cost effective than the other two approaches if there was to be a 25% increase in its yield or a 50% decrease in its cost. These findings suggest that WES should be recommended to facilitate ASD diagnosis in Israel, especially for highly consanguineous populations, such as the Bedouin.

Previous research has demonstrated that sleep disturbances are positively correlated with sensory sensitivities in children with ASD. Most of these studies, however, were based on cross-sectional analyses, where the relationship across symptom domains was examined at a single time-point. Here, we examined the development of 103 pre-school children with ASD over a 1-3-year period. The results revealed that spontaneous longitudinal changes in sleep disturbances were specifically correlated with changes in sensory sensitivities and not with changes in other sensory processing domains nor with changes in core ASD symptoms. These finding demonstrate a consistent longitudinal relationship between sleep disturbances and sensory sensitivities, which suggests that these symptoms may be generated by common or interacting underlying physiological mechanisms.

There is broad consensus about the importance of post-diagnostic genetic testing for children with ASD. However, the extent of compliance with these tests and the factors affecting compliance have rarely been examined. We surveyed a sample of 114 families with a child with ASD in Israel, where such genetic testing is funded by the government. We found that only one-third of these families completed post-diagnosis genetic testing for their child. The main factor influencing compliance was the doctor's recommendation (OR 11.6; 95% CI 3.2-42.4; p 0.001). Furthermore, 50% of the non-compliant families reported that genetic testing was irrelevant to them. Our findings highlight the importance of providing clear recommendations and explanations regarding the benefits and relevance of post-diagnosis genetic testing for children with ASD.

Mutations in myotubularin-related protein 2 (MTMR2) were shown to underlie Charcot-Marie-Tooth type 4B1 (CMT4B1) disease, a rare autosomal recessive demyelinating neuropathy, characterized by severe early-onset motor and sensory neuropathy. We describe three siblings of consanguineous kindred presenting with hypotonia, reduced muscle tone, action tremor, dysmetria, areflexia, and skeletal deformities, consistent with a diagnosis of CMT. Whole-exome sequencing identified a novel homozygous c.336_337 insertion mutation in MTMR2, resulting in a frameshift and putative truncated protein. In this concise report, we discuss the clinical presentation of this rare disease and support the limited number of observations regarding the pathogenesis of MTMR2-related neuropathies.

COX15 mutations were shown to underlie Leigh syndrome (LS), a progressive subacute necrotizing encephalopathy caused by defects in the mitochondrial respiratory chain. Here, two siblings of consanguineous kindred presented in infancy with a syndrome of hypotonia, nystagmus, psychomotor retardation, and pyramidal signs. Toward the end of their second year, both patients developed progressive quadriparesis, convulsions, and pseudobulbar palsy. Similar to two previously reported cases, one of the two affected siblings had severe hypertrophic obstructive cardiomyopathy, hearing loss, and no visual response. Through linkage analysis and whole-exome sequencing, we identified a homozygous p.R217W mutation in Cytochrome C oxidase assembly protein COX15 homolog. Consistent with the known heterogeneity of mitochondrial diseases in general and that of LS in particular, several phenotypic features were markedly distinguished between the affected siblings and in relation to previous reports of COX15 mutations. Interestingly, of the previously reported five cases of COX15-mutated patients, all of different ethnic origins, three had a p.R217W mutation. We highlight p.R217W as a hotspot mutation in COX15 and delineate the phenotypic variability, both between the patients we describe and in all cases reported to date.

Multiple pieces of evidence support the prenatal predisposition of autism spectrum disorder (ASD). Nevertheless, robust data about abnormalities in foetuses later developing into children diagnosed with ASD are lacking. Prenatal ultrasound is an excellent tool to study abnormal foetal development as it is frequently used to monitor foetal growth and identify foetal anomalies throughout pregnancy. We conducted a retrospective case-sibling-control study of children diagnosed with ASD (cases); their own typically developing, closest-in-age siblings (TDS); and typically developing children from the general population (TDP), matched by year of birth, sex and ethnicity to investigate the association between ultrasonography foetal anomalies and ASD. The case group was drawn from all children diagnosed with ASD enrolled at the National Autism Research Center of Israel. Foetal ultrasound data from the foetal anatomy survey were obtained from prenatal ultrasound clinics of Clalit Health Services in southern Israel. The study comprised 659 children: 229 ASD, 201 TDS and 229 TDP. Ultrasonography foetal anomalies were found in 29.3% of ASD cases versus only 15.9% and 9.6% in the TDS and TDP groups [adjusted odds ratio (aOR) = 2.23, 95% confidence interval (CI) = 1.32–3.78, and aOR = 3.50, 95%CI = 2.07–5.91, respectively]. Multiple co-occurring ultrasonography foetal anomalies were significantly more prevalent among ASD cases. Ultrasonography foetal anomalies in the urinary system, heart, and head and brain were the most significantly associated with ASD diagnosis (aORUrinary = 2.08, 95%CI = 0.96–4.50 and aORUrinary = 2.90, 95%CI = 1.41–5.95; aORHeart = 3.72, 95%CI = 1.50–9.24 and aORHeart = 8.67, 95%CI = 2.62–28.63; and aORHead&Brain = 1.96, 95%CI = 0.72–5.30 and aORHead&Brain = 4.67, 95%CI = 1.34–16.24; versus TDS and TDP, respectively). ASD females had significantly more ultrasonography foetal anomalies than ASD males (43.1% versus 25.3%, P = 0.013) and a higher prevalence of multiple co-occurring ultrasonography foetal anomalies (15.7% versus 4.5%, P = 0.011). No sex differences were seen among TDS and TDP controls. ASD foetuses were characterized by a narrower head and a relatively wider ocular-distance versus TDP foetuses (ORBPD = 0.81, 95%CI = 0.70–0.94, and aOROcular distance = 1.29, 95%CI = 1.06–1.57). Ultrasonography foetal anomalies were associated with more severe ASD symptoms. Our findings shed important light on the multiorgan foetal anomalies associated with ASD.

sBackgroundPrenatal ultrasound is frequently used to monitor fetal growth and identify fetal anomalies that may suggest genetic or developmental abnormalities which may develop into congenital anomalies and diseases. Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, associated with a wide range of congenital anomalies. Nevertheless, very little has been done to investigate organ development using prenatal ultrasound as a means to identify fetuses with ASD susceptibility.MethodsA retrospective matched case-sibling-control study. ASD cases were matched to two control groups: typically developing sibling (TDS) closest in age to ASD child; and typically developing population (TDP), matched for age, sex, and ethnicity. The study comprised 659 children: 229 ASD, 201 TDS, and 229 TDP; 471 (71.5%) males.ResultsUltrasonography fetal anomalies (UFAs) were found in 29.3% of ASD cases vs. only 15.9% and 9.6% in the TDS and TDP groups (aOR=2.23, 95%CI=1.32-3.78, and OR=3.50, 95%CI=2.07-5.91, respectively). Also, multiple co-occurring UFAs were significantly more prevalent among ASD cases. UFAs in the urinary system, heart, and head&brain were the most significantly associated with ASD diagnosis (aORUrinary =2.08, 95%CI=0.96-4.50 and aORUrinary=2.90, 95%CI=1.41-5.95; aORHeart=3.72, 95%CI=1.50-9.24 and aORHeart=8.67, 95%CI=2.62-28.63; and aORHead&Brain=1.96, 95%CI=0.72-5.30 and aORHead&Brain=4.67, 95%CI=1.34-16.24; vs. TDS and TDP, respectively). ASD females had significantly more UFAs than ASD males (43.1% vs. 25.3%, p=0.013) as well as higher prevalence of multiple co-occurring UFAs (15.7% vs. 4.5%, p=0.011), while no sex differences were seen among TDS and TDP controls. ASD fetuses were characterized by a narrower head and a relatively wider ocular-distance vs. TDP fetuses (aORBPD=0.81, 95%CI=0.70-0.94, and aOROcular-Distance=1.29, 95%CI=1.06-1.57). Finally, UFAs were associated with more severe ASD symptoms.ConclusionsOur findings shed important light on the abnormal multiorgan embryonic development of ASD and suggest fetal ultrasonography biomarkers for ASD.

Previous eye-tracking studies have reported that children with autism spectrum disorders (ASD) fixate less on faces in comparison to controls. To properly understand social interactions, however, children must gaze not only at faces but also at actions, gestures, body movements, contextual details, and objects, thereby creating specific gaze patterns when observing specific social interactions. We presented three different movies with social interactions to 111 children (71 with ASD) who watched each of the movies twice. Typically developing children viewed the movies in a remarkably predictable and reproducible manner, exhibiting gaze patterns that were similar to the mean gaze pattern of other controls, with strong correlations across individuals (intersubject correlations) and across movie presentations (intra-subject correlations). In contrast, children with ASD exhibited significantly more variable/idiosyncratic gaze patterns that differed from the mean gaze pattern of controls and were weakly correlated across individuals and presentations. Most importantly, quantification of gaze idiosyncrasy in individual children enabled separation of ASD and control children with higher sensitivity and specificity than traditional measures such as time gazing at faces. Individual magnitudes of gaze idiosyncrasy were also significantly correlated with ASD severity and cognitive scores and were significantly correlated across movies and movie presentations, demonstrating clinical sensitivity and reliability. These results suggest that gaze idiosyncrasy is a potent behavioral abnormality that characterizes a considerable number of children with ASD and may contribute to their impaired development. Quantification of gaze idiosyncrasy in individual children may aid in assessing symptom severity and their change in response to treatments. Autism Res 2020, 13: 935-946. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Typically, developing children watch movies of social interactions in a reliable and predictable manner, attending faces, gestures, actions, body movements, and objects that are relevant to the social interaction and its narrative. Here, we demonstrate that children with ASD watch such movies with significantly more variable/idiosyncratic gaze patterns that differ across individuals and across movie presentations. We demonstrate that quantifying this gaze variability may aid in identifying children with ASD and in determining the severity of their symptoms.

Cesarean section (CS) has been consistently associated with susceptibility to autism spectrum disorder (ASD), however, the underlying mechanism for this association remains vague. Here, we studied various pre-peri-and-neonatal factors among 347 children with ASD, 117 children with other developmental delays (DD), and 2226 age, sex and ethnicity matched controls. We found that CS is significantly associated with an increased risk of ASD but not DD (p = 0.019 and p = 0.540 respectively). Furthermore, we show that only CS performed with general anesthesia (GA) elevated the risk of ASD with no significant difference between indicated and non-indicated surgeries (aOR = 1.537; 95% CI 1.026–2.302, and aOR = 1.692; 95% CI 1.057–2.709, pdiff = 0.865). We therefore suggest that exposure to GA during CS may explain the association between CS and ASD.

Background: Benign external hydrocephalus (BEH) is defined by rapid increase in head circumference in infancy, with neuroimaging evidence of enlarged cerebrospinal fluid (CSF) spaces. BEH was postulated to predispose to subdural hematoma, neurocognitive impairments, and autism. There is currently no consensus on BEH diagnostic criteria and no biomarkers to predict neurological sequalae.Methods: MRI-based quantitative approach was used for measurement of potential imaging markers related to external hydrocephalus and their association with neurological outcomes. We scanned 23 infants diagnosed with BEH and 11 age-similar controls. Using anatomical measurements from a large sample of healthy infants (n = 150), Z-scores were calculated to classify subject's CSF spaces as enlarged (≥1.96SD of mean values) or normal.Results: Subjects with abnormally enlarged CSF spaces had a significantly wider and longer ON (p = 0.017 and p = 0.020, respectively), and a significantly less tortuous ON (p = 0.006). ON deformity demonstrated a high diagnostic accuracy for abnormally enlarged frontal subarachnoid space (AUC = 0.826) and interhemispheric fissure (AUC = 0.833). No significant association found between enlarged CSF spaces and neurological complications (OR = 0.330, 95%CI 0.070–1.553, p = 0.161). However, cluster analysis identified a distinct subgroup of children (23/34, 67.6%) with enlarged CSF spaces and a wider, longer and less tortuous ON, to have an increased risk for neurological complications (RR = 7.28, 95%CI 1.07–49.40).Discussion: This is the first report on the association between external hydrocephalus, ON deformity and neurological complications. Our findings challenge the current view of external hydrocephalus as a benign condition. ON deformity is a potential auxiliary marker for risk stratification in patients with enlarged CSF spaces.

Ataxia-Telangiectasia (A-T) is a neurodegenerative disease caused by bi-allelic mutations in the Ataxia-Telangiectasia-Mutated (ATM) gene. Complete lack of ATM activity leads to severe A-T and mutations allowing for residual activity cause a milder phenotype, termed variant A-T. There are only sparse data on the variability in phenotypes of variant A-T patients carrying the same mutations. A retrospective study of 15 patients with variant A-T, all double homozygous for the same mutations was conducted. The age of first symptom ranged from 4-180 months, including: truncal ataxia at

Background: Despite evidence for the prenatal onset of abnormal head growth in ASD children, studies on fetal ultrasound data in ASD are limited and controversial. Methods: A longitudinal matched case-sibling-control study on prenatal ultrasound biometric measures of ASD children was conducted. Children with ASD were matched to two control groups: (1) typically developed sibling (TDS) and (2) typically developed population (TDP). The cohort comprised 528 children (72.7% males): 174 ASD, 178 TDS, and 176 TDP. Results: Second-trimester ASD and TDS fetuses had significantly smaller biparietal diameter (BPD) than TDP fetuses (aORzBPD=0.685, 95%CI=0.527-0.890 and aORzBPD=0.587, 95%CI=0.459-0.751, respectively). However, these differences became statistically indistinguishable in the third trimester. Head biometric measures were associated with the sex of the fetus, with males having larger heads than females within and across groups. A linear mixed-effect model assessing the effects of sex and group assignment on fetal longitudinal head growth indicated faster BPD growth in TDS vs both ASD and TDP in males ({beta}=0.084 and {beta}=0.100 respectively; p

In many countries, parents can place autism spectrum disorder (ASD) children in either mainstream or special education settings, which differ in their ability to provide structured early intervention programs. There are no clear guidelines for how to make initial placement decisions and ongoing debate about the benefits and drawbacks of each educational setting. Previous studies have mostly examined placement of school-age children and reported that those with poorer cognitive abilities and more severe ASD symptoms tend to be placed in special education. The placement of younger children has rarely been studied. Here, we utilized the database at the National Autism Research Center of Israel to examine whether ASD severity, cognitive abilities, and parent education influenced the placement of 242 children. We performed the analyses separately for 1-3-year-old children who were placed in daycare centers and 3-5-year-old children who were placed in pre-school kindergartens. Our analyses revealed surprisingly small differences across special and mainstream education settings, particularly in daycare centers. Cognitive scores and parent education were significantly higher in ASD children placed in mainstream education, but these differences were of moderate effect size and explained a relatively small percentage of the variability in placement choices (

Large controversy exists regarding the potential benefits and drawbacks of placing young children with ASD in mainstream versus special education settings. Currently, there are no clear clinical recommendations for making such placement decisions and remarkably little information regarding which educational option is better for ASD children with specific abilities and difficulties. Previous studies, mostly focusing on school-age children, have reported that those with poorer cognitive abilities, more severe ASD symptoms, and more challenging behaviors tend to be placed in special education. Here, we utilized the database at the National Autism Research Center of Israel to determine whether behavioral and socio-demographic characteristics influenced the initial placement of 242 young children, immediately after receiving their ASD diagnosis. We performed these comparisons separately for 1-3-year-old children who were placed in daycare centers and 3-5-year-old children who were placed in pre-school kindergartens. Our analyses revealed surprisingly small differences across the two educational settings. The two main factors that differed significantly across groups were cognitive scores and parent education, which were lower in ASD children placed in special education. However, these differences were of moderate effect size and explained a relatively small percentage of the variability in placement choices (up to 15%). Indeed, we found remarkable overlap in the characteristics of ASD children across educational settings, which suggests that initial placement decisions are mostly performed regardless of the children’s behavioral abilities. Large-scale longitudinal studies that compare outcome across educational settings for children with different behavioral characteristics are, therefore, highly warranted.

The prevalence of autism spectrum disorder (ASD) is continuously rising worldwide, with remarkable differences in ASD rates being reported across ethnic and socioeconomic groups. We conducted a prospective cohort study to identify the reasons for differences in ASD rates between the Bedouin and Jewish populations in southern Israel. Screening, referral, and diagnosis of toddlers aged 16-36 months were compared between Bedouin and Jewish populations. ASD screening was conducted at 35 randomly selected mother and child health centers (MCHCs) by trained nurses using the Modified Checklist for Autism in Toddlers with follow-up (M-CHAT/F) instrument. Toddlers screened positive at the MCHCs were monitored throughout the referral and diagnosis process at a single medical center until a diagnosis was determined by a physician specialist using DSM-5 criteria. The study cohort comprised 3,343 toddlers (996 Jewish and 2,347 Bedouin). Bedouin toddlers, compared to Jewish toddlers, were less likely to screen positive with M-CHAT/F (3.0% vs. 3.9%; P = 0.165), were significantly less likely to begin the hospital diagnosis process (HR = 0.38, 95% CI: 0.14-1.08; P = 0.068), and had a higher rates of loss-to-follow-up during the hospital diagnosis process (42.9% vs. 15.6%, respectively; P = 0.001). The results suggest that ethnic-specific barriers in the diagnosis process of ASD contribute to under-diagnosis of ASD in the Bedouin population. Facilitating the diagnosis process for Bedouin families will help to identify more children with ASD at earlier ages and consequently close the ethnic gap in ASD rates. LAY SUMMARY: We followed Bedouin and Jewish toddlers aged 16-36 months from southern Israel through their autism spectrum disorder (ASD) screening referral and diagnosis to identify the reasons for the differences in ASD prevalence between these ethnic groups. Jewish and Bedouin toddlers were equally identified in the ASD screening. However, Bedouin toddlers were less likely to complete the diagnosis process due to higher rates of loss-to-follow-up and slower diagnosis process. Facilitating ASD diagnosis for the Bedouin population will help identifying more toddlers with ASD.

Aims Children with autism spectrum disorder (ASD) tend to suffer from various medical comorbidities. We studied the comorbidity burden and health services' utilisation of children with ASD to highlight potential aetiologies and to better understand the medical needs of these children. Methods In this nested case–control study, ASD cases and controls – matched by age, sex and ethnicity in a 1:5 ratio – were sampled from all children born between 2009 and 2016 at a tertiary medical centre. Data were obtained from the hospital's electronic database. Comorbid diagnoses were classified according to pathophysiological aetiology and anatomical/systemic classification of disease. Standard univariate and multivariate statistics were used to demonstrate comorbidities and health services' utilisation patterns that are significantly associated with ASD. Results ASD children had higher rates of comorbidities according to both pathophysiological and anatomical/systemic classifications (p < 0.001). The most marked significant differences were observed for: hearing impairments (OR = 4.728; 95% CI 2.207–10.127) and other auricular conditions (OR = 5.040; 95% CI 1.759–14.438); neurological (OR = 8.198; 95% CI 5.690–11.813) and ophthalmological (OR = 3.381; 95% CI 1.617–7.068) conditions; and ADD/ADHD (OR = 3.246; 95% CI 1.811–5.818). A subgroup analysis revealed a more profound case–control difference in anaemia rates among girls than in boys (OR = 3.25; 95% CI 1.04–10.19 v. OR = 0.74; 95% CI 0.33–1.64 respectively) and an opposite trend (larger differences in males than in females in cardiovascular diseases (OR = 1.99; 95% CI 1.23–3.23 v. OR = 0.76; 95% CI 0.17–3.45, respectively)). In addition, larger case–control differences were seen among Bedouin children than in Jewish children in a number of medical comorbidities (Breslow–Day test for homogeneity of odds ratio p-value 1 referrals and admissions per year, respectively). Conclusions The findings of this study contribute to the overall understanding of comorbid conditions and health services' utilisation for children with ASD. The higher prevalences of comorbidities and healthcare services' utilisation for children with ASD highlight the additional medical burden associated with this condition.

BackgroundConsanguineous kindred presented with an autosomal recessive syndrome of intrauterine growth retardation, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness and optic nerve atrophy with no eye fixation. Affected individuals died by the age of 4. Brain MRI demonstrated microcephaly, semilobar holoprosencephaly and agenesis of corpus callosum. We aimed at elucidating the molecular basis of this disease.MethodsGenome-wide linkage analysis combined with whole exome sequencing were performed to identify disease-causing variants. Functional consequences were investigated in fruit flies null mutant for the Drosophila SEC31A orthologue. SEC31A knockout SH-SY5Y and HEK293T cell-lines were generated using CRISPR/Cas9 and studied through qRT-PCR, immunoblotting and viability assays.ResultsThrough genetic studies, we identified a disease-associated homozygous nonsense mutation in SEC31A. We demonstrate that SEC31A is ubiquitously expressed, and that the mutation triggers nonsense-mediated decay of its transcript, comprising a practical null mutation. Similar to the human disease phenotype, knockdown SEC31A flies had defective brains and early lethality. Moreover, in line with SEC31A encoding one of the two coating layers comprising the Coat protein complex II (COP-II) complex, trafficking newly synthesised proteins from the endoplasmic reticulum (ER) to the Golgi, CRISPR/Cas9-mediated SEC31A null mutant cells demonstrated reduced viability through upregulation of ER-stress pathways.ConclusionWe demonstrate through human and Drosophila genetic and in vitro molecular studies, that a severe neurological syndrome is caused by a null mutation in SEC31A, reducing cell viability through enhanced ER-stress response, in line with SEC31A’s role in the COP-II complex.

Twelve individuals of consanguineous Bedouin kindred presented with autosomal recessive progressive spastic paraplegia evident as of age 0-24 months, with spasticity of lower limbs, hyperreflexia, toe walking and equinus deformity. Kyphoscolisois was evident in older patients. Most had atrophy of the lateral aspects of the tongue and few had intellectual disability. Nerve conduction velocity, electromyography and head and spinal cord magnetic resonance imaging were normal in tested subjects. Muscle biopsy showed occasional central nuclei and fiber size variability with small angular fibers. Genome-wide linkage analysis identified a 6.7Mbp disease-associated locus on chromosome 3q21.3-3q22.2 (LOD score 9.02; D3S1290). Whole-exome sequencing identified a single homozygous variant within this locus, c.51_52ins(28); p.(V18fs56*) in KY, segregating in the family as expected and not found in 190 Bedouin controls. High KY transcript levels were demonstrated in muscular organs with lower expression in the CNS. The phenotype is reminiscent of kyphoscoliosis seen in Ky null mice. Two recent studies done independently and parallel to ours describe somewhat similar phenotypes in one and two patients with KY mutations. KY encodes a tranglutaminase-like peptidase, which interacts with muscle cytoskeletal proteins and is part of a Z-band protein complex, suggesting the disease mechanism may resemble myofibrillar myopathy. However, the mixed myopathic-neurologic features caused by human and mouse Ky mutations are difficult to explain by loss of KY sarcomere stabilizing function alone. KY transcription in CNS tissues may imply that it also has a role in neuromotor function, in line with the irregularity of neuromuscular junction in Ky null mutant mice.

Importance Sleep disturbances and insomnia are highly prevalent in children with Autism Spectrum Disorder (ASD). Sleep homeostasis, a fundamental mechanism of sleep regulation that generates pressure to sleep as a function of wakefulness, has not been studied in children with ASD. It is not clear whether abnormalities in sleep homeostasis contribute to sleep disturbances in children with ASD. Objective To determine whether slow wave activity (SWA), a potent measure of homeostatic sleep pressure, is impaired in children with ASD and associated with the severity of reported sleep disturbances. Design Case-control comparison of overnight electroencephalogram (EEG) recordings that were performed during Polysomnography (PSG) evaluations between 2015 and 2018. Setting Children with autism were deeply phenotyped at the National Autism Research Center of Israel. PSG was performed at a neighboring regional sleep disorders unit that accepts children with primary care referrals. Participants Final analyses were performed with PSGs from 29 children with ASD, 8 females, mean age 4.6 years old (range 1.9 – 7.8), and 23 typically developing children, 8 females, mean age 5.3 years old (range 3.5-8.9). Exposure A single overnight PSG evaluation. Main outcome measures SWA power, SWA slope, and sleep architecture. Results Children with ASD exhibited significantly weaker SWA power, shallower SWA slopes, and a decreased proportion of slow wave sleep in comparison to controls. This difference was largest during the first two hours following sleep onset and decreased gradually during sleep. Furthermore, SWA power of children with ASD was significantly correlated with the time of sleep onset and with parental report of latency to sleep at home. Conclusions and relevance These results reveal that children with ASD exhibit reduced sleep pressure, which is a dysregulation of sleep homeostasis. The extent of dysregulation in individual children is apparent in the amplitude of their SWA power, which is indicative of the severity of their sleep disturbances. These findings motivate clinical trials with specific interventions that increase homeostatic sleep pressure. Key points Question Are sleep disturbances in some children with autism due to disrupted sleep homeostasis? Findings In this case-control study, children with Autism Spectrum Disorder (ASD) exhibited significantly weaker slow-wave-activity power and less slow-wave-sleep, indicating a reduced pressure to sleep. The reduction in sleep pressure was significantly correlated with the severity of individual children’s sleep disturbances as observed in the sleep lab and as reported by parents at home. Meaning These findings demonstrate that disrupted sleep homeostasis manifested in reduced sleep pressure is common in children with ASD and likely to exacerbate sleep disturbances.

Language regression (LR) is a consistent and reproducible phenomenon that is reported by ~25% of parents who have children with autism spectrum disorder (ASD). However, there is controversy regarding the etiological and clinical significance of this phenomenon. Here, we examined data from a cohort of 218 children with ASD from the Negev Autism Center in Israel. We identified 36 children with ASD who were reported to exhibit clear LR by their parent on three independent occasions and compared them to 104 children whose parents did not report any concern of regression (NR). We compared a variety of key developmental characteristics across these two groups. We found that the age at which children with ASD in the LR group achieve key developmental milestones of crawling, walking, and use of first words is significantly younger than the age of children in the NR group, and comparable to the age of typically developing children. In contrast, no differences were observed in physical growth characteristics such as head circumference, weight, or height between the groups. Furthermore, almost all children with LR were born close to full term (>35 weeks) and none had a history of hypotonia. Notably, despite their apparently typical early development, children with LR were diagnosed with more severe symptoms of ASD than children with NR. These results strengthen the motivation to continue and study LR among children with ASD and suggest that early detection and intervention studies of ASD may benefit from stratifying children into LR and NR groups. Autism Res 2020, 13: 145-156. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The presence of language regression (LR) among children with autism is still a matter of scientific debate. Here, we show that children with autism and reported LR start to crawl, talk, and walk at the same age as other typically developing children and significantly earlier than other children with autism. These findings, along with other medical differences between these groups, suggest that children who experienced LR comprise a distinct subgroup within the autism spectrum.

Autism Spectrum Disorder (ASD) is a remarkably heterogeneous condition where individuals exhibit a variety of symptoms at different levels of severity. Quantifying the severity of specific symptoms is difficult, because it either requires long assessments or observations of the ASD individual, or reliance on care-giver questionnaires, which can be subjective. Here we present a new technique for objectively quantifying the severity of several core social ASD symptoms using a motion capture system installed in a clinical exam room. We present several measures of child-clinician interaction, which include the distance between them, the proportion of time that the child approached or avoided the clinician, and the direction that the child faced in relation to the clinician. Together, these measures explained ~30% of the variance in ADOS scores, when using only ~5 minute segments of “free play” from the recorded ADOS assessments. These results demonstrate the utility of motion capture for aiding researchers and clinicians in the assessment of ASD social symptoms. Further development of this technology and appropriate motion capture measures for use in kindergartens and at home is likely to yield valuable information that will aid in quantifying the initial severity of core ASD symptoms and their change over time.

Ataxia-telangiectasia (A-T), an autosomal recessive disorder characterized by progressive neurologic dysfunction, oculocutaneous telangiectasia, immunodeficiency, and cancer susceptibility, is caused by mutations in the ATM gene. A previous study of 4 A-T patients identified 2 rare homozygous missense mutations residing on the same allele of the ATM gene: c.1514T>C and c.1547T>C, which were shown to decrease ATM levels and increase T-cell acute lymphoblastic leukemia predisposition. We studied 5 patients from 2 consanguineous Bedouin families of the same tribe, presenting with A-T. Whole-exome sequencing data identified the 2 aforementioned mutations in ATM, which segregated within all family members as expected of autosomal recessive heredity. Interestingly, one individual was diagnosed with malignant peritoneal mesothelioma (MPM), an extremely rare neoplasm in pediatric patients. Here, we describe a case of a 4-month-old infant homozygous for the 2 ATM mutations, who developed MPM and died by the age of 2 years. To the best of our knowledge, this is the first case of peritoneal mesothelioma in an infant bearing ATM mutations, and one of the youngest pediatric mesotheliomas described. Thus, the risk of MPM might be considered in the follow-up of A-T patients, and ATM mutations sought in cases of early-onset MPM.

Microcephaly is a genetically heterogeneous disorder. Through molecular genetic studies, Perez et al. demonstrate that homozygous loss-of-function mutations in C7orf43 (now termed microtubule-associated protein 11, MAP11) cause microcephaly in humans and zebrafish. Functional analyses show that MAP11 associates with α-tubulin in mitotic spindles and influences cell proliferation., Microtubule associated protein 11 (MAP11, previously termed C7orf43) encodes a highly conserved protein whose function is unknown. Through genome-wide linkage analysis combined with whole exome sequencing, we demonstrate that human autosomal recessive primary microcephaly is caused by a truncating mutation in MAP11. Moreover, homozygous MAP11-orthologue CRISPR/Cas9 knock-out zebrafish presented with microcephaly and decreased neuronal proliferation, recapitulating the human phenotype. We demonstrate that MAP11 is ubiquitously transcribed with high levels in brain and cerebellum. Immunofluorescence and co-immunoprecipitation studies in SH-SY5Y cells showed that MAP11 associates with mitotic spindles, co-localizing and physically associating with α-tubulin during mitosis. MAP11 expression precedes α-tubulin in gap formation of cell abscission at the midbody and is co-localized with PLK1, a key regulator of cytokinesis, at the edges of microtubule extensions of daughter cells post cytokinesis abscission, implicating a role in mitotic spindle dynamics and in regulation of cell abscission during cytokinesis. Finally, lentiviral-mediated silencing of MAP11 diminished SH-SY5Y cell viability, reducing proliferation rather than affecting apoptosis. Thus, MAP11 encodes a microtubule-associated protein that plays a role in spindle dynamics and cell division, in which mutations cause microcephaly in humans and zebrafish.

Studies of ciliopathies have served in elucidating much of our knowledge of structure and function of primary cilia. We report humans with Bardet-Biedl syndrome who display intellectual disability, retinitis pigmentosa, obesity, short stature and brachydactyly, stemming from a homozyogous truncation mutation in SCAPER, a gene previously associated with mitotic progression. Our findings, based on linkage analysis and exome sequencing studies of two remotely related large consanguineous families, are in line with recent reports of SCAPER variants associated with intellectual disability and retinitis pigmentosa. Using immuno-fluorescence and live cell imaging in NIH/3T3 fibroblasts and SH-SY5Y neuroblastoma cell lines over-expressing SCAPER, we demonstrate that both wild type and mutant SCAPER are expressed in primary cilia and co-localize with tubulin, forming bundles of microtubules. While wild type SCAPER was rarely localized along the ciliary axoneme and basal body, the aberrant protein remained sequestered to the cilia, mostly at the ciliary tip. Notably, longer cilia were demonstrated both in human affected fibroblasts compared to controls, as well as in NIH/3T3 cells transfected with mutant versus wildtype SCAPER. As SCAPER expression is known to peak at late G1 and S phase, overlapping the timing of ciliary resorption, our data suggest a possible role of SCAPER in ciliary dynamics and disassembly, also affecting microtubule-related mitotic progression. Thus, we outline a human ciliopathy syndrome and demonstrate that it is caused by a mutation in SCAPER, affecting primary cilia.

Background Sensory abnormalities and sleep disturbances are highly prevalent in children with autism, but the potential relationship between these two domains has rarely been explored. Understanding such relationships is important for identifying children with autism who exhibit more homogeneous symptoms. Methods Here, we examined this relationship using the Caregiver Sensory Profile and the Children’s Sleep Habits Questionnaire, which were completed by parents of 69 children with autism and 62 age-matched controls. Results In line with previous studies, children with autism exhibited more severe sensory abnormalities and sleep disturbances than age-matched controls. The sleep disturbance scores were moderately associated with touch and oral sensitivities in the autism group and with touch and vestibular sensitivities in the control group. Hypersensitivity towards touch, in particular, exhibited the strongest relationship with sleep disturbances in the autism group and single-handedly explained 24% of the variance in total sleep disturbance scores. In contrast, sensitivity in other sensory domains such as vision and audition was not associated with sleep quality in either group. Conclusions While it is often assumed that sensitivities in all sensory domains are similarly associated with sleep problems, our results suggest that hypersensitivity towards touch exhibits the strongest relationship with sleep disturbances when examining children autism. We speculate that hypersensitivity towards touch interferes with sleep onset and maintenance in a considerable number of children with autism who exhibit severe sleep disturbances. This may indicate the existence of a specific sleep disturbance mechanism that is associated with sensitivity to touch, which may be important to consider in future scientific and clinical studies.

BackgroundSensory abnormalities and sleep disturbances are highly prevalent in children with autism, but the potential relationship between these two domains has rarely been explored. Understanding such relationships is important for identifying children with autism who exhibit more homogeneous symptoms.MethodsHere we examined this relationship using the Caregiver Sensory Profile and the children’s sleep habit questionnaires, which were completed by parents of 69 children with autism and 62 frequency age-matched controls.ResultsIn line with previous studies, children with autism exhibited more severe sensory abnormalities and sleep disturbances than age-matched controls. The sleep disturbance scores were strongly associated with touch and oral sensitivities in the autism group and with touch and vestibular sensitivities in the control group. Hyper sensitivity towards touch, in particular, exhibited the strongest relationship with sleep disturbances in the autism group and single-handedly explained 24% of the variance in sleep disturbance scores. In contrast, sensitivity in other sensory domains such as vision and audition was not associated with sleep quality in either group.ConclusionsWhile it is often assumed that sensitivities in all sensory domains are similarly associated with sleep problems, our results suggest that hyper sensitivity towards touch exhibits the strongest relationship to sleep disturbances when examining children autism. We speculate that hyper sensitivity towards touch interferes with sleep onset and maintenance in a considerable number of children with autism who exhibit severe sleep disturbances. Studies that examine the effects of tactile sensory therapies/aids on sleep quality and behavioral improvement in these children are, therefore, highly warranted.

Elucidating the heterogeneous etiologies of autism will require investment in comprehensive longitudinal data acquisition from large community based cohorts. With this in mind, we have established a hospital-university-based (HUB) database of autism which incorporates prospective and retrospective data from a large and ethnically diverse population. The collected data includes social-demographic characteristics, standardized behavioral testing, detailed clinical history from electronic patient records, genetic samples, and various neurological measures. We describe the initial cohort characteristics following the first 18 months of data collection (188 children with autism). We believe that the Negev HUB autism database offers a unique and valuable resource for studying the heterogeneity of autism etiologies across different ethnic populations.

PAX7 encodes a transcription factor essential in neural crest formation, myogenesis, and pituitary lineage specification. Pax7 null mice fail to thrive and exhibit muscle weakness, dying within 3 weeks. We describe a human autosomal-recessive syndrome, with failure to thrive, severe global developmental delay, microcephaly, axial hypotonia, pyramidal signs, dystonic postures, seizures, irritability, and self-mutilation. Aside from low blood carnitine levels, biochemical and metabolic screen was normal, with growth hormone deficiency in one patient. Electromyography was normal, with no specific findings in brain MRI/MRS yet nondemonstrable neuropituitary, a finding of unclear significance. Muscle biopsy showed unaffected overall organization of muscle fibers, yet positive fetal alpha myosin staining, suggesting regeneration. Homozygosity mapping with whole-exome sequencing identified a single disease-associated mutation in PAX7, segregating as expected in the kindred with no homozygosity in 200 ethnically matched controls. Transfection experiments showed that the PAX7 splice-site mutation putatively causes nonsense-mediated mRNA decay affecting onlyPAX7 isoform 3. This isoform, expressed specifically in brain, skeletal muscle and testes, is the sole Pax7 variant normally found in mice. The human muscle phenotype is in line with that in conditional Pax7 null mutant mice, where initial aberrant histological findings resolve postnatally through muscle regeneration.

Elucidating the heterogeneous etiologies of autism will require investment in comprehensive longitudinal data acquisition from large community based cohorts. With this in mind, we have established a hospital-university-based (HUB) database of autism which incorporates prospective and retrospective data from a large and ethnically diverse population. Here we present initial findings from 188 children who were diagnosed with autism during the first eighteen months of the study. The unique characteristics of this cohort included: significant differences between Bedouin and Jewish children in different risk factors and clinical characteristics; complete birth records for >90% of the children; and a high frequency of consanguineous marriages. Thus, the Negev HUB autism database comprises a remarkably unique resource to study different aspects of autism.

Background Progressive cerebello-cerebral atrophy (PCCA) leading to profound mental retardation, progressive microcephaly, spasticity and early onset epilepsy, was diagnosed in four non-consanguineous apparently unrelated families of Jewish Moroccan ancestry. Common founder mutation(s) were assumed. Methods Genome-wide linkage analysis and whole exome sequencing were done, followed by realtime PCR and immunofluorescent microscopy. Results Genome-wide linkage analysis mapped the disease-associated gene to 0.5 Mb on chromosome 17p13.3. Whole exome sequencing identified only two mutations within this locus, which were common to the affected individuals: compound heterozygous mutations in VPS53 , segregating as expected for autosomal recessive heredity within all four families, and common in Moroccan Jews (∼1:37 carrier rate). The Golgi-associated retrograde protein (GARP) complex is involved in the retrograde pathway recycling endocytic vesicles to Golgi; c.2084A>G and c.1556+5G>A VPS53 founder mutations are predicted to affect the C-terminal domain of VPS53, known to be critical to its role as part of this complex. Immunofluorescent microscopy demonstrated swollen and abnormally numerous CD63 positive vesicular bodies, likely intermediate recycling/late endosomes, in fibroblasts of affected individuals. Conclusions Autosomal recessive PCCA type 2 is caused by VPS53 mutations.

The essential micronutrient selenium is found in proteins as selenocysteine (Sec), the only genetically encoded amino acid whose biosynthesis occurs on its cognate tRNA in humans. In the final step of selenocysteine formation, the essential enzyme SepSecS catalyzes the conversion of Sep-tRNA to Sec-tRNA. We demonstrate that SepSecS mutations cause autosomal-recessive progressive cerebellocerebral atrophy (PCCA) in Jews of Iraqi and Moroccan ancestry. Both founder mutations, common in these two populations, disrupt the sole route to the biosynthesis of the 21st amino acid, Sec, and thus to the generation of selenoproteins in humans.

Background A syndrome of profound hypotonia, intellectual disability, intrauterine growth retardation with subsequent failure to thrive, dyskinesia and epilepsy was diagnosed in Bedouin Israeli families. Mild dysmorphism was evident: plagiocephaly, broad forehead with prominent nose, smooth philtrum and congenital esotropia. We set out to decipher the molecular basis of this syndrome. Methods Genome-wide linkage analysis and fine mapping were done. Whole exome sequencing data were filtered for candidate variants within locus. Validation and segregation of the mutation was assayed via Sanger sequencing. UNC80 expression pattern was analysed through reverse transcription PCR. Results Homozygosity mapping followed by fine mapping identified a 7.5 Mb disease-associated locus (logarithm of odds score 3.5) on chromosome 2. Whole exome and Sanger sequencing identified a single homozygous nonsense mutation within this locus, segregating within the families as expected for recessive heredity and not found in a homozygous state in 150 Bedouin controls: c.151C>T, p.(R51*) in UNC80 . Conclusions The syndrome described is caused by a mutation in UNC80 , truncating most of the 3258 amino acids highly conserved encoded protein, that has no known motifs. UNC80 bridges between UNC79 and the cation channel NALCN, enabling NALCN's role in basal Na+ leak conductance in neurons, essential for neuronal function. The phenotype caused by the UNC80 mutation resembles that previously described for homozygous NALCN mutations.

A consanguineous Bedouin Israeli kindred presented with a novel autosomal recessive intellectual disability syndrome of congenital microcephaly, low anterior hairline, bitemporal narrowing, low-set protruding ears, strabismus and tented thick eyebrows with sparse hair in their medial segment. Brain imaging demonstrated various degrees of agenesis of corpus callosum and hypoplasia of the vermis and cerebellum. Genome-wide linkage analysis followed by fine mapping defined a 7.67 Mb disease-associated locus (LOD score 4.99 at θ=0 for marker D10S1653). Sequencing of the 48 genes within the locus identified a single non-synonymous homozygous duplication frameshift mutation of 13 nucleotides (c.2134_2146dup13) within the coding region of FRMD4A, that was common to all affected individuals and not found in 180 non-related Bedouin controls. Three of 50 remotely related healthy controls of the same tribe were heterozygous for the mutation. FRMD4A, member of the FERM superfamily, is involved in cell structure, transport and signaling. It regulates cell polarity by playing an important role in the activation of ARF6, mediating the interaction between Par3 and the ARF6 guanine nucleotide exchange factor. ARF6 is known to modulate cell polarity in neurons, and regulates dendritic branching in hippocampal neurons and neurite outgrowth. The FRMD4 domain that is essential for determining cell polarity through interaction with Par3 is truncated by the c.2134_2146dup13 mutation. FRMD4A polymorphisms were recently suggested to be a risk factor for Alzheimer's disease. We now show a homozygous frameshift mutation of the same gene in a severe neurologic syndrome with unique dysmorphism.

Autosomal recessive Weissenbacher-Zweymuller syndrome (WZS) is a skeletal dysplasia characterized by rhizomelic dwarfism and severe hearing loss. Mutations in the COL11A2 gene have been implicated in causing the autosomal dominant form of this syndrome as well as non-ocular Stickler syndrome and the autosomal recessive syndrome otospondylomegaepiphyseal dysplasia (OSMED). In a consanguineous Bedouin tribe living in Southern Israel, five individuals affected by autosomal recessive WZS were available for genetic analysis. Homozygosity of a mutation in the COL11A2 gene was found in all affected individuals. This finding lends molecular support to the clinical notion that autosomal recessive WZS and OSMED are a single entity.

Foveal hypoplasia, always accompanied by nystagmus, is found as part of the clinical spectrum of various eye disorders such as aniridia, albinism and achromatopsia. However, the molecular basis of isolated autosomal recessive foveal hypoplasia is yet unknown. Individuals of apparently unrelated non consanguineous Israeli families of Jewish Indian (Mumbai) ancestry presented with isolated foveal hypoplasia associated with congenital nystagmus and reduced visual acuity. Genome-wide homozygosity mapping followed by fine mapping defined a 830 Kb disease-associated locus (LOD score 3.5). Whole-exome sequencing identified a single missense mutation in the homozygosity region: c.95T>G, p.(Ile32Ser), in a conserved amino acid within the first predicted transmembrane domain of SLC38A8. The mutation fully segregated with the disease-associated phenotype, demonstrating an ∼10% carrier rate in Mumbai Jews. SLC38A8 encodes a putative sodium-dependent amino-acid/proton antiporter, which we showed to be expressed solely in the eye. Thus, a homozygous SLC38A8 mutation likely underlies isolated foveal hypoplasia.

Desmosterolosis is a rare autosomal recessive disorder of elevated levels of the cholesterol precursor desmosterol in plasma, tissue and cultured cells. With only two sporadic cases described to date with two very different phenotypes, the clinical entity arising from mutations in 24-dehydrocholesterol reductase (DHCR24) has yet to be defined. We now describe consanguineous Bedouin kindred with four surviving affected individuals, all presenting with severe failure to thrive, psychomotor retardation, microcephaly, micrognathia and spasticity with variable degree of hand contractures. Convulsions near birth, nystagmus and strabismus were found in most. Brain MRI demonstrated significant reduction in white matter and near agenesis of corpus callosum in all. Genome-wide linkage analysis and fine mapping defined a 6.75 cM disease-associated locus in chromosome 1 (maximum multipoint LOD score of six), and sequencing of candidate genes within this locus identified in the affected individuals a homozygous missense mutation in DHCR24 leading to dramatically augmented plasma desmosterol levels. We thus establish a clear consistent phenotype of desmosterolosis (MIM 602398).

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by PLP1 mutations. A similar autosomal-recessive phenotype, Pelizaeus-Merzbacher-like disease (PMLD), has been shown to be caused by homozygous mutations in GJC2 or HSPD1. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD in which linkage to PLP1, GJC2, and HSPD1 was excluded. Through genome-wide homozygosity mapping and mutation analysis, we demonstrated in all affected individuals a homozygous frameshift mutation that fully abrogates the main active domain of AIMP1, encoding ARS-interacting multifunctional protein 1. The mutation fully segregates with the disease-associated phenotype and was not found in 250 Bedouin controls. Our findings are in line with the previously demonstrated inability of mutant mice lacking the AIMP1/p43 ortholog to maintain axon integrity in the central and peripheral neural system.

Objectives: There is a paucity of empirical studies of trust among parents of children with devel- opmental disabilities. Trust is an important element in the patient-physician relationship, especially in medical rehabilitation, where continuous cooperation is essential for positive therapeutic outcomes. Trust is dependent on a variety of psychosocial factors, one of which is the physician's communication style. The current study had three goals: (1) to compare two groups of Israeli parents, Jews and Bedouins, in terms of the levels of global trust in the pediatricians in a regional child development center; (2) to compare their perceptions of the pediatricians' communication styles; and (3) to assess the association between three communication styles (caring, interest, and collaboration) and the parents' trust in the pediatricians. Methods: The sample included 193 parents of disabled children ranging from 6 months to 6 years of age. Global trust and parents' perceptions concerning their communication with the center's pediatricians were measured by scales developed for this research. Results: Despite the large cultural differences that exist between the Jewish and Bedouin groups, the only significant difference between them was that Jewish parents' reported a significantly higher level of collaboration compared with the Bedouins. Global trust in the pediatrician was significantly predicted by the interest and collaboration communication styles, but ethnicity was not a significant predictor. Conclusion: These findings underscore the importance of physicians' interpersonal competence and skills in the therapeutic relationship and support the increasing trend of including doctor-patient communication training in undergrad- uate and continuing medical education. (J Dev Behav Pediatr 29:18-25, 2008) Index Terms: communication styles, trust, disabled children, rehabilitation services For children with developmental disabilities and special needs, rehabilitation is a long-term process that may last their entire life. The medical care of these children often involves the whole family system, especially the parents, in repeated interactions with health caregivers. The med- ical care usually demands special attention, including follow-up evaluations and exercising at rehabilitative ser- vices and at home. The effectiveness of this process depends on continuing care, leadership, and guidance of the parents and their willingness to cooperate with the medical staff. During this ongoing process, the parents must repeatedly interact and cooperate with a variety of medical and paramedical staff. Therefore, building and maintaining positive relationships with the medical staff are essential for the parents, especially in the face of frustrations and disappointments that are entailed in the treatment of children with developmental disabilities. It has been suggested by many researchers that trust is one of the key components in the patient-medical care- giver relationship. 1-3 In fact, a relationship of trust and partnership is a necessary condition for medical practice 4 and the prerequisite of any therapeutic success.5

Infantile neuroaxonal dystrophy (INAD) is an autosomal recessive progressive neurodegenerative disease that presents within the first 2 years of life and culminates in death by age 10 years. Affected individuals from two unrelated Bedouin Israeli kindreds were studied. Brain imaging demonstrated diffuse cerebellar atrophy and abnormal iron deposition in the medial and lateral globus pallidum. Progressive white-matter disease and reduction of the N-acetyl aspartate : chromium ratio were evident on magnetic resonance spectroscopy, suggesting loss of myelination. The clinical and radiological diagnosis of INAD was verified by sural nerve biopsy. The disease gene was mapped to a 1.17-Mb locus on chromosome 22q13.1 (LOD score 4.7 at recombination fraction 0 for SNP rs139897), and an underlying mutation common to both affected families was identified in PLA2G6, the gene encoding phospholipase A2 group VI (cytosolic, calcium-independent). These findings highlight a role of phospholipase in neurodegenerative disorders.

The purpose of this study was to assess the level of parental satisfaction with services of a child development center and to evaluate the physician-parent dimensions of communication. A total of 90 parents to children with disability ranging in age from 6 months to 6 years participated in the study (84% response rate). Attitudes regarding parental communication with physicians were evaluated by 15 items clustered into three factors, which expressed different dimensions of communication: caring, collaboration and interest. Parents ranked their general satisfaction with the center's services relatively high as well as their evaluations of physician behavior of caring, collaboration and interest. Positive and statistically significant correlations were found between the studied communication dimensions and general satisfaction. However, collaboration was the only dimension that explained the variability on general satisfaction in a multivariate analysis. The collaboration of the physician with the parents was a key factor to explain parental general satisfaction with child rehabilitative services. Collaboration, which is associated with processes such as mutual decision making and sharing of responsibility, should be nurtured, in order to increase parents' general satisfaction with the services given.

A consanguineous Israeli Bedouin kindred presented with an autosomal-recessive nonlethal phenotype of severe psychomotor retardation and extrapyramidal signs, dystonia, athetosis and ataxia, mild axial hypotonia, and marked global dementia with defects in verbal and expressive communication skills. Metabolic workup was normal except for mildly elevated blood lactate levels. Brain magnetic resonance imaging (MRI) showed increased density in the putamen, with decreased density and size of the caudate and lentiform nuclei. Reduced activity specifically of mitochondrial complex III and variable decrease in complex I activity were evident in muscle biopsies. Homozygosity of affected individuals to UQCRB and to BCSIL, previously associated with isolated complex III deficiency, was ruled out. Genome-wide linkage analysis identified a homozygosity locus of approximately 9 cM on chromosome 5q31 that was further narrowed down to 2.14 cM, harboring 30 genes (logarithm of the odds [LOD] score 8.82 at theta = 0). All 30 genes were sequenced, revealing a single missense (p.Ser45Phe) mutation in UQCRQ (encoding ubiquinol-cytochrome c reductase, complex III subunit VII, 9.5 kDa), one of the ten nuclear genes encoding proteins of mitochondrial complex III.