Search

The tRNA methyltransferase 10 homologue A (TRMT10A) gene encodes a tRNA methyl transferase, and biallelic loss of function mutations cause a recessive syndrome of intellectual disability, microcephaly, short stature and diabetes. A case with intellectual disability and distinctive features including microcephaly was admitted. She was diagnosed with epilepsy at 2.5 years old. At 3.6 years of age, severe short stature related to growth hormone deficiency was detected. She had an incidental diagnosis of diabetes at age 11.4 years that was negative for diabetes antibodies with persistent C-peptide level and treated with metformin. Spontaneous puberty did not begin until 15.7 years of age and she was found to have primary ovarian failure. A homozygous p.Arg127* mutation in TRMT10A was detected. In addition to the typical clinical features that characterize TRMT10A syndrome we observed in our patient an unusual form of impaired glucose metabolism that was presented in early childhood with hypoglycemia followed by diabetes in late childhood. Growth hormone deficiency and primary ovarian failure may also be additional findings of this syndrome. Patients with slow onset diabetes that are negative for auto-antibodies and have extra-pancreatic features should be tested for all known subtypes monogenic diabetes.

A 20-year-old woman was referred to the diabetes clinic with type 2 diabetes diagnosed at the age of 19. Her body mass index was 31.4 kg/m2, HbA1C was 76 mmol/mol, GAD antibodies were negative with a detectable C-peptide. She had a characteristic facial appearance with widespread eyes, posterior hairline suggesting a facial gestalt and abnormal dentition. She also had hypothyroidism, mild intellectual disability, primary amenorrhoea and patent ductus arteriosus. Karyotyping reported normal 46XX karyotype. Genetic testing revealed a pathogenic variant in the gene encoding the HIST1H1E protein which confirmed her diagnosis of HIST1H1E syndrome. Type 2 diabetes has not been reported in previous cases of HIST1H1E and so this is the first reported case of type 2 diabetes with HIST1H1E syndrome.

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1–3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1–3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1–3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

For autism spectrum disorder (ASD) in adults there are several diagnostic instruments available with a need for consideration of the psychometric properties. This study aimed to conduct a first psychometric evaluation of a new diagnostic ASD instrument, the NIDA (Dutch Interview for Diagnostic assessment of ASD in adults) in 90 adult males without intellectual disability (age 18-65 years) in the Netherlands: 30 with ASD, 30 with a Personality Disorder and 30 nonpatient controls. The interrater agreement ranged from 0.79 to 1.00, the convergent validity including sensitivity and specificity ranged from 0.76 to 1.00, and we observed an adequate concurrent criterion-related validity. These promising findings can serve as foundation for future psychometric NIDA studies in a more diverse population. TRIAL REGISTRATION: The Netherlands National Trial Register NTR6391. Registered 04 May 2017.

BACKGROUND There is limited information about sexual knowledge and behaviours in adults with complex care needs, including those with 22q11.2 deletion syndrome (22q) which represents a group predisposed to intellectual disabilities. METHODS We conducted sexual health assessments with 67 adults with 22q, examining whether those with knowledge deficits and a history of engaging in sexual activities with others would be more likely to engage in high-risk behaviours. RESULTS The majority (65.7%) of adults with 22q were sexually active with others; most (70.1%) had sexual knowledge deficits. Those with intellectual disabilities were more likely (p = .0012) to have deficits in certain topics. In the sexually active subgroup, most (81.8%) engaged in high-risk sexual behaviours, regardless of intellectual disability or knowledge deficits. CONCLUSION The results suggest a need for increased dialogue, repeated education, genetic counselling and preventive healthcare measures related to sexuality in 22q and potentially in other complex care conditions.

BackgroundO’Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E. It was first described by O’Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility.MethodsAffected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible.ResultsWe report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E. We confirm and refine the phenotypic spectrum of the KMT2E-related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances.ConclusionOur study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome.

Emerging evidence on the disproportionate impact of COVID-19 on people with intellectual and developmental disabilities (IDD) points to the underlying risk and burden of infectious diseases (IDs) in this population. The objective of this study was to examine the risk of ID-related emergency department (ED) visits, subsequent hospitalizations, and hospital-based mortality during ID-related visits among adults with IDD compared to those without IDD. The authors conducted a retrospective study using data from the 2016 Nationwide Emergency Department Sample. The sample included 94,928 adults with IDD identified using ICD-10-CM codes, and age- and sex-matched 284,763 non-IDD adults in a 1:3 case-control ratio. A Poisson regression model was used to compare the risk of ID-related ED visits, subsequent hospitalizations, and hospital-based mortality during ID-related visits between adults with and without IDD. Covariates included sociodemographic and hospital characteristics. Results showed that adults with IDD are at a higher risk for ID-related ED visits, subsequent hospitalization, and mortality during ID-related ED visits compared to non-IDD adults. Adults with IDD continued to experience higher risks even after accounting for sociodemographic, hospital, and clinical characteristics. Septicemia and respiratory tract infections are the leading causes of ED visits, hospitalization, and mortality. This study found substantial disparities in ID-related ED visits, subsequent hospitalization, and mortality among the burdens for adults with IDD. These observations underscore the importance of integrated strategies to reduce ID-related morbidity among adults with IDD.

INTRODUCTION Children with severe motor and intellectual disabilities (SMID) are susceptible to severe lower respiratory tract infection (LTRI). As SMID patients are prone to develop recurrent wheezing and are often diagnosed with bronchial asthma, they frequently receive systemic corticosteroids as an adjunctive treatment for LRTIs. However, the efficacy of corticosteroid therapy for LTRIs in SMID children is unclear. We investigated whether or not corticosteroid therapy was associated with better clinical outcomes for SMID children with LRTIs. METHODS Our retrospective study enrolled 217 SMID children 1-15 years old hospitalized for LTRIs. We compared the clinical characteristics and outcomes between patients with and without corticosteroid therapy. RESULTS Of the 217 patients, 29 (13.3%) received corticosteroid therapy. The proportion of patients with a history of bronchial asthma was higher and LRTI was more severe in patients with corticosteroid therapy than in those without the therapy. The length of hospital stay (LOHS) was significantly longer in patients with corticosteroid therapy (median 13 days) than in those without corticosteroid therapy (median 9 days) (P = 0.02). The same tendency was shown for the LOHS in patients with severe or moderate LRTI, although not to a significant extent. CONCLUSION Systemic corticosteroid therapy was not associated with better clinical outcomes in SMID children with LRTIs, even if the patients suffer from severe LRTIs. Corticosteroids should be used cautiously for LRTIs in SMID children because bronchial asthma is likely to be overdiagnosed in these children.

Individuals with intellectual and developmental disabilities (IDD) are at high risk of co-occurring mental health conditions, including major depressive disorder, bipolar disorder, psychotic disorders, anxiety disorders, impulse control disorders, and others. Because of symptoms associated with these illnesses and with the disabilities themselves, these individuals are often served in a mental health service system framework. In this second of two articles on care for persons with IDD in the mental health system, the authors focus on policy and systems considerations to assist practitioners and administrators to provide high-quality mental health services for these individuals by recognizing existing infrastructures of support. The authors describe historical factors, including legislation and case law, that have led to greater inclusion of persons with IDD in mainstream settings; systemic barriers to integrating services for persons with IDD and Medicaid waivers and provisions of the Affordable Care Act designed to overcome such barriers; and considerations for treating persons with IDD in various settings, such as emergency departments and forensic settings. They propose approaches to developing the workforce, such as by training direct service professionals and utilizing the services of board-certified behavioral analysts. A robust continuum of care and service delivery system that is increasingly sophisticated in working with persons with IDD, with and without co-occurring mental illness, is critical to maximize the autonomy and community inclusion of these individuals.

2p25.3 deletion syndrome is a rare genetic disorder that accompanies various phenotypic features, including early‐onset obesity and intellectual disability. Here, we report the first Japanese case of this deletion associated with severe obesity and diabetes mellitus. Microarray‐based comparative genomic hybridization analysis identified a 3.1‐Mb deletion of distal chromosome band 2p25.3, which was suspected as de novo. The patient also presented bilateral cataracts and adolescent‐onset muscular weakness of the upper limbs, both of which were uncommon in previously reported cases. It is possible that these symptoms are also important clinical features suggestive of this syndrome.

This seminar in epileptology addresses Learning Objective 6.1.4 of the International League against Epilepsy Curriculum: Demonstrate the ability to recognize and manage the special needs of persons with epilepsy (and Neurodevelopmental Disorders [NDDs]). The review identifies the essential competencies for neurologists working with people with epilepsy and NDDs, and these competencies are discussed alongside clinical examples. Furthermore, the seminar explores the opportunities offered by integrated service provision between neurology and services for NDD. The epileptic encephalopathies are not a subject of this seminar paper as they are circumscribed by other ILAE learning objectives. This seminar frames the complexity of seizures in association with NDD with a focus on major NDDs; intellectual disability, autism spectrum disorder, and attention deficit hyperactivity disorder. The evidence presented considers epidemiology, co-morbidities, risk factors, mortality, and the diagnostic and treatment challenges. People with NDDs and epilepsy have higher rates of physical and psychiatric co-morbidity, polypharmacy, neuropsychiatric side effects of drugs, and premature mortality including sudden unexpected death in epilepsy. There is a limited Level 1 evidence base to guide assessment and treatment for seizures in adults with NDDs. Therefore, throughout this seminar, the evidence presented for associations and treatment should be observed in context along with its limitations. The evidence for pharmacological treatment of seizures in association with NDDs is presented alongside expert commentary and guidance. There is Level 2 evidence to support treatment with some of the newer anti-seizure medications including brivaracetam, lacosamide, eslicarbazepine acetate, and perampanel as second-line choices. Seizures with a co-morbid NDD should be considered as a collective complex clinical presentation and not discrete conditions. This seminar was co-designed, co-produced and co-authored by an expert by experience and includes case studies and a video to highlight what can go wrong and how it can be avoided.

Prader–Willi syndrome (PWS) is a rare genetic syndrome, caused by the loss of expression of the paternal chromosome 15q11-q13 region. Over the past years, many cases of patients with characteristics similar to PWS, but without a typical genetic aberration of the 15q11-q13 region, have been described. These patients are often labelled as Prader–Willi-like (PWL). PWL is an as-yet poorly defined syndrome, potentially affecting a significant number of children and adults. In the current clinical practice, patients labelled as PWL are mostly left without treatment options. Considering the similarities with PWS, children with PWL might benefit from the same care and treatment as children with PWS. This review gives more insight into the pheno- and genotype of PWL and includes 86 papers, containing 368 cases of patients with a PWL phenotype. We describe mutations and aberrations for consideration when suspicion of PWS remains after negative testing. The most common genetic diagnoses were Temple syndrome (formerly known as maternal uniparental disomy 14), Schaaf–Yang syndrome (truncating mutation in the MAGEL2 gene), 1p36 deletion, 2p deletion, 6q deletion, 6q duplication, 15q deletion, 15q duplication, 19p deletion, fragile X syndrome, and Xq duplication. We found that the most prevalent symptoms in the entire group were developmental delay/intellectual disability (76%), speech problems (64%), overweight/obesity (57%), hypotonia (56%), and psychobehavioral problems (53%). In addition, we propose a diagnostic approach to patients with a PWL phenotype for (pediatric) endocrinologists. PWL comprises a complex and diverse group of patients, which calls for multidisciplinary care with an individualized approach.

Background Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized by biphasic seizures and white matter lesions with reduced diffusion, which are often accompanied by involuntary movements. The neurological outcomes of AESD vary from normal to mild or severe sequelae, including intellectual disability, paralysis, and epilepsy. The present study aimed to clarify the prognostic factors of AESD, including involuntary movements. Methods We enrolled 29 patients with AESD admitted to Tottori University Hospital from 1991 to 2020 and retrospectively analyzed their clinical data. Neurological outcomes were assessed by the Pediatric Cerebral Performance Category score and cerebral paralysis as neurological sequelae. Results Of the 29 patients, 12 had favorable outcomes and 17 had unfavorable outcomes. Univariate analysis revealed that the presence of underlying diseases, a decline in Glasgow Coma Scale (GCS) score 12–24 h after early seizures, and involuntary movements were associated with unfavorable outcomes. In multivariate analysis, a decline in GCS score and involuntary movements were associated with unfavorable outcomes. The sensitivities and specificities of underlying diseases, a decline of ≥ 3 points in GCS score 12–24 h after early seizures, and involuntary movements for unfavorable outcomes were 53% and 92%, 92% and 65%, and 59% and 92%, respectively. Conclusions The appearance of involuntary movements may be associated with unfavorable outcomes of AESD. The prognostic factors identified herein are comparable with previously known prognostic factors of consciousness disturbances after early seizures.

PURPOSE: Adducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes, and form ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their function in the human brain is unknown. METHODS: We used exome sequencing to uncover ADD1 variants associated with intellectual disability (ID) and brain malformations. We studied ADD1 splice isoforms in mouse and human neocortex development with RNA Sequencing, super resolution imaging and immunoblotting. We investigated four variant ADD1 proteins and heterozygous ADD1 cells for protein expression and ADD1-ADD2 dimerization. We studied Add1 functions in vivo using Add1 knockout mice. RESULTS: We uncovered loss-of-function (LoF) ADD1 variants in four unrelated individuals affected by ID and/or structural brain defects. Three additional de novo copy number variations covering the ADD1 locus were associated with ID and brain malformations. ADD1 is highly expressed in the neocortex and the corpus callosum, while ADD1 splice isoforms are dynamically expressed between cortical progenitors and postmitotic neurons. Human variants impair ADD1 protein expression and/or dimerization with ADD2. Add1 knockout mice recapitulate corpus callosum dysgenesis and ventriculomegaly phenotypes. CONCLUSION: Our human and mouse genetics results indicate that pathogenic ADD1 variants cause corpus callosum dysgenesis, ventriculomegaly, and/or intellectual disability.

We report the case of the third patient with Tsukahara-Azuno-Kaiji syndrome. It is characterized by brachydactyly A1, dwarfism, microcephaly, scoliosis, intellectual disability, ptosis, and hearing loss. The first patient was reported in 1989, and the second in 2010. The present patient had many features in common with the previous 2 patients, with a few minor differences. Although this combination of symptoms is very characteristic, the clinicians should know about this syndrome to diagnose it. The syndrome in this patient appeared sporadically, and chromosome G-banding revealed a normal female karyotype of 46XX. However, further genetic research could not be performed. Steady accumulation of information will enable us to discover the true clinical and genetic nature of the disease and to make the diagnosis more easily.

BackgroundGPs are increasingly confronted with patients with both intellectual disabilities (ID) and mental health disorders (MHD). Currently, the care provided to these patients is found to be insufficient, putting them at risk of developing more severe MHD. Improving the quality of GP care will improve the whole of mental health care for this patient group. Therefore, an overview of the content and quality of care provided to them by the GP may be helpful.AimTo provide an up-to-date literature overview of the care provided by GPs to patients with ID and MHD, identify knowledge gaps, and inform research, practice, and policy about opportunities to improve care.Design and settingScoping review.MethodPubMed, PsycINFO, EMBASE, and grey literature were searched for publications concerning primary care and patients with ID and MHD. Selected publications were analysed qualitatively.ResultsOne hundred publications met the inclusion criteria. Five overarching themes were identified: GP roles, knowledge and experience, caregiver roles, collaboration, and a standardised approach. The results show GPs’ vital, diverse, and demanding roles in caring for patients with both ID and MHD. GPs experience problems in fulfilling their roles, and gaps are identified regarding effective GP training programmes, applicable guidelines and tools, optimal collaborative mental health care, and corresponding payment models.ConclusionThe improvement required in the current quality of GP care to patients with ID and MHD can be achieved by bridging the identified gaps and initiating close collaborations between care professionals, policymakers, and organisational managers.

Background/purpose: The association between sex and diagnostic behavior of autism spectrum disorder (ASD), and the effects of comorbid mental retardation (MR) and attention-deficit hyperactivity disorder (ADHD), were explored. Methods: Based on the Taiwan Longitudinal Health Insurance Database (LHID)-2000 and data from 1996 through 2008, the cumulative incidence of ASD over time was compared between the sexes (both cohorts n = 38,117) using the log-rank test. The effects of comorbid MR and ADHD on the incidence of ASD were evaluated using Cox proportional hazard regression analysis. The age at first diagnosis of ASD in the two sexes was compared using the independent-sample t-test. Results: The incidence was higher in males than in females (0.0007 vs. 0.0002) across ages. Comorbid MR or ADHD increased the incidence of ASD in both sexes; comorbid MR or ADHD also decreased the male to female hazard ratio of ASD, with no significant differences in the incidence density of ASD between sexes. ADHD delayed diagnosis in both sexes (males: 6.61 vs 5.10, p

Background : Studies examining epilepsy as a COVID-related death risk have come to conflicting conclusions. Our aim was to assess the prevalence of epilepsy among COVID-related deaths in Hungary. Methods : Each COVID-19 infection case is required to be reported on a daily basis to the National Public Health Center of Hungary. This online report includes the beginning and end of the infection, as well as information on comorbidities. Death during infection is regarded as COVID-related. The anonymized data of each deceased patient are published on an information website ( www.koronavirus.gov.hu ) and provides up-to-date information on each patient with the date of death, the patient's sex, age, and chronic illness. Results : There were 11,968 patients who died of COVID-19 in Hungary between 13 March, 2020 and 23 January, 2021. Among 11,686 patients with no missing values for comorbidities, 255 patients had epilepsy (2.2%). Epilepsy was much more common among those who died at a young age: 9.3% of those who died under the age of 50 had epilepsy, compared with only 1.3% in those over the age of 80. The younger an age group was, the higher was the prevalence of epilepsy. Conclusion : Based on our data, a strong association is observed between COVID-19 related death and young adult patient with epilepsy. Patients who died of COVID-19 under the age of 50 were 10 to 20 times more likely to have epilepsy than what would have been expected from epidemiological data. Our results highlight the need for increased protection of young people with epilepsy from COVID-19 infection and the development of a vaccination strategy accordingly.

A 4-year-old boy presented with his mother to genetics in the 1980s, with a family history (FH) of macrocephaly and intellectual disability (ID). He remained undiagnosed until his mother developed multiple cancers and was diagnosed with Cowden syndrome (CS) in 2017, a rare, multisystem cancer predisposition syndrome. CS was then confirmed in multiple family members. Clinical examination revealed potentially novel features; gingival enlargement, dental abnormalities and joint hyperextensibility. These features could contribute to revised PTEN hamartoma tumour syndrome, National Comprehensive Cancer Network, minor diagnostic criteria. The paediatric CS phenotype is still emerging and features expressed in this family during childhood could potentially aid paediatric diagnosis. This case reminds clinicians to seek genetic input for PTEN testing when macrocephaly is identified alongside, a personal or FH of ID, early-onset tumours (especially breast, bowel or thyroid) or multiple tumours. Thus detailed FH is pivotal to earlier CS diagnosis and improved patient outcomes.

There is limited knowledge about young persons with intellectual disability who are Not in Employment, Education or Daily activity (NEED) in Sweden. The aim of the study was to explore the post-upper secondary school situation for persons with intellectual disability not involved in traditional occupations. A national database containing 2955 persons, representing 24.1% of the total (N=12,269) was used. The results revealed a heterogeneous group where financial support was common and few made use of disability services. Gender, municipality, programme type, financial support and disability services were significantly associated with not having an occupation as opposed to being in employment, education or daily activity. Time was a central factor, as the early years after upper secondary school appear to be an important period for changing NEED status. This is the first large scale study to describe these persons not involved in traditional occupations in Sweden and further research is required. The study received financial support from Halmstad University and MISA AB, Stockholm, Sweden.

BACKGROUND 22q11.2 deletion syndrome is one of the most prevalent microdeletion syndromes in humans. The syndrome is characterized by extensive phenotypic variability. OBJECTIVE to investigate the clinical characteristics, immunological features, and intellectual status of 22q11.2 deletion syndrome patients at Chiang Mai University Hospital, Thailand. METHODS Patients who had a confirmed diagnosis of 22q11.2 deletion syndrome by fluorescent in situ hybridization (FISH) were enrolled. Data collated and evaluated included that pertaining to history, physical examination, laboratory testing including T-cell, immunoglobulin, calcium, thyroid and parathyroid levels in the blood, cardiac and urological imaging, and intellectual status. RESULTS 34 patients diagnosed with 22q11.2 deletion syndrome; 18 (53%) were female. The median age of patients was 18.5 months (IQR; 1.5-35.8). Ninety-one percent of patients had characteristic facial features; 94% had a congenital heart defect with tetralogy of Fallot being the most frequent (72%); 88% had hypocalcemia, and 35% had genitourinary tract abnormalities. Recurrence of 22q11.2 deletion syndrome in the family was detected in 18% of cases. Twenty-eight patients (82%) were found to have a low number or percentage of T-cells. Five patients (15%) had low immunoglobulin levels. Intellectual disability (IQ/DQ scores < 70) were found in 20 out of 25 patients who were evaluated (80%), whereas the other five (20%) performed at a level of borderline intellectual function. CONCLUSIONS Tetralogy of Fallot, hypocalcemia, immunologic defect, and cognitive impairment were common in our 22q11.2 deletion syndrome study group. We recommend that all affected patients have a multi-system evaluation by a comprehensive care team.

Objective This long‐term retrospective follow‐up study aimed to address the knowledge gap between prenatal diagnosis of complete isolated Agenesis of Corpus Callosum (cACC) at fetal MRI and postnatal neurodevelopmental outcome to improve prenatal counseling for parents. Methods Data on fetuses with isolated cACC from a single‐center MRI database built up in two decades were considered. Detailed postnatal clinical, neuropsychological evaluations were performed and descriptions of available neuroradiological and genetic data were provided. Results Following a detailed neuropsychological evaluation and a long‐term follow‐up, the subsequent results emerged: 38 school‐aged children (older than 6 years) of 50 (aged 2.5‐15 years) showed normal intellectual functions (50%), intellectual disability (21%), and borderline intelligence quotient (29%). Deficits in motor functions (58%), executive functions (37%), language (61%), memory abilities (58%), and academic performances (53%) were found. Twenty‐one percent of participants showed behavioral difficulties. Almost half of the participants underwent rehabilitation. Additional findings (21%) were detected at postnatal brain MRI, and a significant association between additional findings at postnatal imaging and abnormal neurodevelopmental outcome was observed. Interpretations This study supports the view that children with prenatal diagnosis of isolated cACC may present with several degrees of neurologic and neuropsychological impairment which become more evident only in their second decade of life. Postnatal MRI and detailed genetic analysis may add crucial information to prenatal data and substantially influence final judgment on the outcome and orient clinical management and counseling.

PROBLEM/CONDITION Autism spectrum disorder (ASD). PERIOD COVERED 2018. DESCRIPTION OF SYSTEM The Autism and Developmental Disabilities Monitoring (ADDM) Network conducts active surveillance of ASD. This report focuses on the prevalence and characteristics of ASD among children aged 8 years in 2018 whose parents or guardians lived in 11 ADDM Network sites in the United States (Arizona, Arkansas, California, Georgia, Maryland, Minnesota, Missouri, New Jersey, Tennessee, Utah, and Wisconsin). To ascertain ASD among children aged 8 years, ADDM Network staff review and abstract developmental evaluations and records from community medical and educational service providers. In 2018, children met the case definition if their records documented 1) an ASD diagnostic statement in an evaluation (diagnosis), 2) a special education classification of ASD (eligibility), or 3) an ASD International Classification of Diseases (ICD) code. RESULTS For 2018, across all 11 ADDM sites, ASD prevalence per 1,000 children aged 8 years ranged from 16.5 in Missouri to 38.9 in California. The overall ASD prevalence was 23.0 per 1,000 (one in 44) children aged 8 years, and ASD was 4.2 times as prevalent among boys as among girls. Overall ASD prevalence was similar across racial and ethnic groups, except American Indian/Alaska Native children had higher ASD prevalence than non-Hispanic White (White) children (29.0 versus 21.2 per 1,000 children aged 8 years). At multiple sites, Hispanic children had lower ASD prevalence than White children (Arizona, Arkansas, Georgia, and Utah), and non-Hispanic Black (Black) children (Georgia and Minnesota). The associations between ASD prevalence and neighborhood-level median household income varied by site. Among the 5,058 children who met the ASD case definition, 75.8% had a diagnostic statement of ASD in an evaluation, 18.8% had an ASD special education classification or eligibility and no ASD diagnostic statement, and 5.4% had an ASD ICD code only. ASD prevalence per 1,000 children aged 8 years that was based exclusively on documented ASD diagnostic statements was 17.4 overall (range: 11.2 in Maryland to 29.9 in California). The median age of earliest known ASD diagnosis ranged from 36 months in California to 63 months in Minnesota. Among the 3,007 children with ASD and data on cognitive ability, 35.2% were classified as having an intelligence quotient (IQ) score ≤70. The percentages of children with ASD with IQ scores ≤70 were 49.8%, 33.1%, and 29.7% among Black, Hispanic, and White children, respectively. Overall, children with ASD and IQ scores ≤70 had earlier median ages of ASD diagnosis than children with ASD and IQ scores >70 (44 versus 53 months). INTERPRETATION In 2018, one in 44 children aged 8 years was estimated to have ASD, and prevalence and median age of identification varied widely across sites. Whereas overall ASD prevalence was similar by race and ethnicity, at certain sites Hispanic children were less likely to be identified as having ASD than White or Black children. The higher proportion of Black children compared with White and Hispanic children classified as having intellectual disability was consistent with previous findings. PUBLIC HEALTH ACTION The variability in ASD prevalence and community ASD identification practices among children with different racial, ethnic, and geographical characteristics highlights the importance of research into the causes of that variability and strategies to provide equitable access to developmental evaluations and services. These findings also underscore the need for enhanced infrastructure for diagnostic, treatment, and support services to meet the needs of all children.

22q11.2 duplication syndrome has a frequency of ~1/700 in the intellectual disability population. Despite this frequency, there is limited information on the variable clinical presentation. Although the phenotype and incidence of congenital anomalies are well described for 22q11.2 deletion syndrome, they are not as well understood for individuals with 22q11.2 duplication syndrome. This study is a single-center, retrospective review of patients diagnosed with 22q11.2 duplication syndrome designed to categorize the variable phenotype seen in these individuals. The data suggest that the incidence of congenital anomalies may be higher than previously reported for this syndrome. Affected individuals are at increased risk for a variety of problems including gastrointestinal complications, endocrine dysfunction, ophthalmologic abnormalities, palatal anomalies, congenital heart disease, musculoskeletal differences, and neurologic abnormalities. Individuals with 22q11.2 duplication syndrome would benefit from care coordinated by a multidisciplinary team and managed according to the 22q11.2 deletion syndrome guidelines.

Previous findings show executive functioning advantages associated with dual language learning (DLL) among neurotypical individuals, yet few studies have investigated these effects in youth with autism spectrum disorder (ASD). The present study investigated effects of DLL and socioeconomic status (SES) on parent-reported executive functioning, verbal ability, and social-emotional functioning using a sample of DLL (n = 53) and monolingual (n = 106) youth with ASD without intellectual disability, matched on gender and full-scale IQ scores. After controlling for the effects of SES, results showed that monolingual youth had better outcomes on verbal ability, while DLL youth had fewer parent-reported problems with executive functioning and unusual behaviors. These findings indicate that bilingualism may mitigate executive functioning deficits in youth with ASD.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental-related disorders with a high genetic risk. Recently, chromatin remodeling factors have been found to be related to ASDs. SMARCA4 is such a catalytic subunit of the chromatin-remodeling complex. In this report, we identified seven novel missense variants in the SMARCA4 gene from eight pediatric patients. All eight patients had moderate to severe intellectual disability, and seven showed autistic/likely autistic features. Compared with the patients reported in the literature, our patients were less likely to show craniofacial or finger/toe anomalies. Our findings further supported that SMARCA4 is associated with ASDs. We suggest that individuals with the abovementioned phenotypes should consider genetic testing.

This paper reviews the current state of knowledge on psychological interventions with empirical evidence of efficacy in treating common psychiatric and behavioral disorders in people with intellectual disability (ID) at all stages of their life. We begin with a brief presentation of what is meant by psychiatric and behavioral disorders in this population, along with an explanation of some of the factors that contribute to the increased psychosocial vulnerability of this group to present with these problems. We then conduct a review of empirically supported psychological therapies used to treat psychiatric and behavioral disorders in people with ID. The review is structured around the three generations of therapies: Applied behavior analysis (e.g., positive behavior support), cognitive behavioral therapies (e.g., mindfulness-based cognitive therapy), and contextual therapies (e.g., dialectical behavior therapy). We conclude with some recommendations for professional practice in the fields of ID and psychiatry.

DeSanto-Shinawi syndrome (DESSH, OMIM #616708) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function variants in the WAC gene. Affected individuals are characterized by neonatal hypotonia, developmental delay, intellectual disability, behavioral problems, and dysmorphism. Epilepsy is present in some of the patients with DESSH. By far, less than 30 affected individuals have been reported worldwide. Herein, we report a 9-year-old Chinese girl with molecularly substantiated DESSH with a de novo nonsense c. 1648C>T p.(Arg550*) variant identified in the WAC gene. Aside from developmental delay and the characteristic facial gestalt, our proband also exhibited tethered cord syndrome due to filar lipoma and left duplex kidney complicated with hydronephrosis, features not observed in any of the previously reported individuals with DESSH.

Aims This study aimed to assess the longevity of a fixed prosthesis in patients with intellectual disability (ID) and to investigate the risk factors associated with the failure of a prosthesis due to abutment tooth extraction or prosthesis dislodgement or removal. Methods We studied past medical records to evaluate the longevity of 315 prostheses that were luted in 76 patients with ID. We calculated the survival rates and assessed 15 variables potentially associated with prosthetic failure using multivariate Cox regression analyses with shared frailty for patients. Results Three-quarters of our sample population had severe or profound ID. The maximum observation period was 31.0 years, and the corresponding survival ratio was 32.5%; the survival ratio at 10 years was 59.4%. The use of intravenous sedation significantly influenced the success of the prosthesis, with the hazard ratio (HR) being 0.49 times that of conventional treatment without behavior-altering drug therapy. The most significant risk factor for prosthetic failure was age at placement; the HR for patients aged ≥31 years was 2.82 times that for patients aged ≤ 20 years. Conclusions In patients with severe ID, appropriate intravenous sedation was effective in prolonging the longevity of a fixed prosthesis.

Spastic ataxia is characterized by the combination of cerebellar ataxia with spasticity and other pyramidal features. It is the hallmark of some hereditary ataxias, but it can also occur in some spastic paraplegias and acquired conditions. It often presents with heterogenous clinical features with other neurologic and non-neurological symptoms, resulting in complex phenotypes. In this review, the differential diagnosis of spastic ataxias are discussed and classified in accordance with inheritance. Establishing an organized classification method based on mode inheritance is fundamental for the approach to patients with these syndromes. For each differential, the clinical features, neuroimaging and genetic aspects are reviewed. A diagnostic approach for spastic ataxias is then proposed.

INTRODUCTION Kohlschutter-Tonz syndrome (KTS) is a rare, genetic condition, which typically manifests as a triad of symptoms: 1) amelogenesis imperfecta, 2) infantile onset epilepsy, and 3) intellectual disability. The condition poses dental treatment challenges given the manifestation of amelogenesis imperfecta. Additional considerations are needed to medically manage these patients who present with epilepsy and intellectual disability. CASE REPORT Our patient presented with multiple restorative needs, was treated under general anesthesia, and maintained good oral outcomes with close follow-up. DISCUSSION To the best of our knowledge, this is the first case report which documents comprehensive dental management of a pediatric patient with KTS.

The 22q11.2 deletion syndrome (22q11.2DS) is a multisystem disorder with an estimated prevalence of 1:3000 live births. Manifestations show a marked variability in expression and include speech- and language delay, intellectual disability, and neuropsychiatric disorders. We aim to provide an overview of ocular findings in 22q11.2DS in order to optimize recommendations for ophthalmic screening. We combined results from a systematic literature review with results from a multicenter cross-sectional study of patients with 22q11.2DS who were assessed by an ophthalmologist. Our systematic literature search yielded four articles, describing 270 patients. We included 132 patients in our cross-sectional study (median age 8.9 [range 0–56] years). Most reported ocular findings were retinal vascular tortuosity (32%–78%), posterior embryotoxon (22%–50%), eye lid hooding (20%–67%), strabismus (12%–36%), amblyopia (2%–11%), ptosis (4%–6%), and refractive errors, of which hyperopia (6%–48%) and astigmatism (3%–23%) were most common. Visual acuity was (near) normal in most patients (91%–94%). Refractive errors, strabismus, and amblyopia are treatable conditions that are frequently present in patients with 22q11.2DS and should be corrected at an early stage. Therefore, in 22q11.2DS, we recommend ophthalmic and orthoptic screening at the age of 3 years or at diagnosis, and a low-threshold referral in adults.

BACKGROUND Gabriele-de Vries syndrome is a rare autosomal dominant genetic disease caused by de novo pathogenic variants in YY1. In this study, we report a 10-year-old boy with a de novo novel pathogenic variant in YY1, the first Iranian patient with Gabriele-de Vries Syndrome. METHODS The novel de novo pathogenic variant detected in this study (NM_003403:c.690delA, p.Glu231Ilefs*25) was identified by whole-exome sequencing and confirmed by Sanger sequencing. RESULTS The proband presented with delayed motor and speech development, ataxia, abnormal gait, autistic behavior, brain atrophy, and severe learning disability. Finally, we provide a case-based review of the clinical features associated with Gabriele-de Vries Syndrome. Thus far, merely 13 Gabriele-de Vries Syndrome patients have been reported in the literature. CONCLUSION The investigations for a suspected case of Gabriele-de Vries Syndrome must involve molecular diagnosis of the disease and its underlying genetic defect because the clinical investigations are generally variable and nonspecific.

Muscular dystrophies encompass a wide and heterogeneous subset of hereditary myopathies that manifest by the structural or functional abnormalities in the skeletal muscle. Some pathogenic mutations induce a dysfunction or loss of proteins that are critical for the stability of muscle cells, leading to progressive muscle degradation and weakening. Several studies have well-established cognitive deficits in muscular dystrophies which are mainly due to the disruption of brain-specific expression of affected muscle proteins. We provide a comprehensive overview of the types of muscular dystrophies that are accompanied by intellectual disability by detailed consulting of the main libraries. The current paper focuses on the clinical and molecular evidence about Duchenne, congenital, limb-girdle, and facioscapulohumeral muscular dystrophies as well as myotonic dystrophies. Because these syndromes impose a heavy burden of psychological and financial problems on patients, their families, and the health care community, a thorough examination is necessary to perform timely psychological and medical interventions and thus improve the quality of life.

The aim of this study was to describe the social care provided for different age groups of people with intellectual disability, 55 years or above, and to investigate the association between such care and frailty factors for those with diagnosed level of intellectual disabilities. Descriptive and logistic regression analyses were used. Commonest forms of social care among the 7936 people were Residential care, Daily activities and Contact person. Home help and Security alarm increased with age. The frailty factors significantly associated with increased social care were age, polypharmacy and severe levels of intellectual disabilities. Persons most likely to be in residential care were in the age group 65–79 with polypharmacy and severe disability. The results indicate a need for further research of how frailty factors are considered in social care and longstanding medication, especially then severe intellectual disability hinders communication. A national strategic plan for preventive interventions should be developed to ensure the best possible healthy ageing.

Summary Adults with Down syndrome develop the neuropathological hallmarks of Alzheimer's disease and are at very high risk of developing early-onset dementia, which is now the leading cause of death in this population. Diagnosis of dementia remains a clinical challenge because of the lack of validated diagnostic criteria in this population, and because symptoms are overshadowed by the intellectual disability associated with Down syndrome. In people with Down syndrome, fluid and imaging biomarkers have shown good diagnostic performances and a strikingly similar temporality of changes with respect to sporadic and autosomal dominant Alzheimer's disease. Most importantly, there are no treatments to prevent Alzheimer's disease, even though adults with Down syndrome could be an optimal population in whom to conduct Alzheimer's disease prevention trials. Unprecedented research activity in Down syndrome is rapidly changing this bleak scenario that will translate into disease-modifying therapies that could benefit other populations.

To further define the epilepsy phenotype in a cohort of children with 15q13.3 microdeletion syndrome.We retrospectively reviewed the phenotypic spectrum of all children aged18 years with epilepsy and 15q13.3 microdeletion syndrome.Thirteen children were included, 69% were female. The median age of children in the cohort was 12 years (age range: 3 years-15 years). Median age at seizure onset was 4 years. Eleven children (85%) had intellectual disability. Nine of 13 children (69%) had a history of typical absence seizures with median age of onset at 5 years (2 had absence status epilepticus). Thirty-one percent (4/13) had focal with impaired awareness non-motor onset seizures. ILAE recognized absence epilepsy syndromes were diagnosed in 6/13 (46%). The remainder were classified as having genetic generalized epilepsies with overlap clinical features, combined or focal epilepsies. Electroencephalogram in the cohort showed generalized (85%) and focal epileptiform discharges (62%) and posterior dominant rhythm slowing (33%). One child had electrical status epilepticus of sleep. Neuroimaging was performed in 5 children (38%) and revealed abnormal findings in 3. Seizures were drug resistant in a third of the cohort. Valproate resulted in seizure freedom in 5 (42%). Oxcarbazepine caused clinical worsening in one child with combined seizure types. Two children tried cannabidiol and one tried the ketogenic diet; neither was effective.The epilepsy phenotype in children with 15q13.3 microdeletion syndrome is defined by childhood onset absence seizures, and may have atypical features such as, early onset absences, persistence into adolescence, status epilepticus, intellectual disability and treatment resistance. Focal seizures and focal EEG findings may be observed and should be treated cautiously, given the possibility of combined seizure types. Valproate appeared effective, although other treatments must be explored further.

The data on the congenital hyperinsulinism (CHI) in Asian Indian patients is limited. Diazoxide is often unavailable in India, which poses challenge in managing CHI. The study was aimed to present our experience with CHI with a special focus on the effectiveness and cost-effectiveness of octreotide long-acting release (OCT-LAR) among diazoxide-responsive CHI. The data of 14 index cases with CHI registered at our center were retrospectively analyzed. The diagnosis of CHI was based on elevated serum insulin (3.4–32.5 μIU/ml) and C-peptide (0.58–1.98 ng/ml) at the time of symptomatic hypoglycemia (BG≤41 mg/dl). Fourteen patients (13 males) presented at a median (range) age of 3 (1–270) days, seizures being the most common mode of presentation (78.6%). Ten patients were diazoxide-responsive, two were partially responsive, while two were unresponsive. Genetics was available for eight patients; ABCC8 (n=3, 1 novel) and HADH (n=2, both novel) were the most commonly mutated genes. OCT-LAR was offered to eight patients including four with diazoxide-responsive disease and was universally effective. We propose a cost-effective approach to use OCT-LAR in the management of CHI, which may also make it more cost-effective than diazoxide for diazoxide-responsive disease. Five of the 11 (45.5%) patients had evidence of neurological impairment; notably, two patients with HADH mutations had intellectual disability despite diazoxide-responsiveness. We report three novel mutations in CHI-associated genes. We demonstrate the effectiveness of and propose a cost-effective approach to use OCT-LAR in diazoxide-responsive CHI. Mutations in HADH may be associated with abnormal neurodevelopmental outcomes despite diazoxide-responsiveness.

To develop an evidence-based clinical practice guideline for the use of exome and genome sequencing (ES/GS) in the care of pediatric patients with one or more congenital anomalies (CA) with onset prior to age 1 year or developmental delay (DD) or intellectual disability (ID) with onset prior to age 18 years. The Pediatric Exome/Genome Sequencing Evidence-Based Guideline Work Group (n = 10) used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence to decision (EtD) framework based on the recent American College of Medical Genetics and Genomics (ACMG) systematic review, and an Ontario Health Technology Assessment to develop and present evidence summaries and health-care recommendations. The document underwent extensive internal and external peer review, and public comment, before approval by the ACMG Board of Directors. The literature supports the clinical utility and desirable effects of ES/GS on active and long-term clinical management of patients with CA/DD/ID, and on family-focused and reproductive outcomes with relatively few harms. Compared with standard genetic testing, ES/GS has a higher diagnostic yield and may be more cost-effective when ordered early in the diagnostic evaluation. We strongly recommend that ES/GS be considered as a first- or second-tier test for patients with CA/DD/ID.

Kabuki syndrome is a rare congenital anomaly/mental retardation syndrome characterized by intellectual disability, developmental delay, short stature, facial dysmorphic features including ectropion of the lateral third of the lower eyelids and long palpebral fissures, and prominent finger pads. Pathogenic variants of KMT2D (MLL2) and KDM6A are found to be the major causes of Kabuki syndrome. Here, we report the first Iranian case with Kabuki syndrome with an IQ of 79, two episodes of viral pneumonia and distinctive facial features, prominent ears and persistent fetal fingertip pads. These characteristics raised our suspicion for performing whole-exome sequencing (WES), which revealed 2 heterozygous pathogenic missense variants in the KMT2D gene: c.C10024T in exon 34 leading to p.R3342C and c.G15005A in exon 48 leading to p.R5002Q. Hence, the definitive diagnosis of Kabuki syndrome was made based on molecular findings along with the intellectual disability and characteristic facial features.

Participation in research can provide direct and indirect benefit to individuals with autism spectrum disorder (ASD), their caregivers, families, and society at large. Unfortunately, individuals with high support needs, including those with intellectual disability, cognitive disability or minimal verbal ability, are often systematically excluded from research on ASD. This limits the ability to generalize discoveries to all people with ASD, and results in a disparity in who benefits from research. This piece outlines the importance and extent of the problem, which is part of a broader lack of inclusivity in ASD research. It also provides examples of studies that have directly addressed issues that arise when conducting inclusive research and makes recommendations for researchers to reduce disparities in research participation.

BACKGROUND Genetic variants involving the MED13L gene can lead to an autosomal dominant syndrome characterised by intellectual disability/developmental delay and facial dysmorphism. METHODS We investigated two cases (one familial and one isolated) of intellectual disability with speech delay and dysmorphic facial features by whole-exome sequencing analyses. Further, we performed a literature review about clinical and molecular aspects of MED13L gene and syndrome. RESULTS Two MED13L variants have been identified [MED13L(NM_015335.5):c.4417C>T and MED13L(NM_015335.5):c.2318delC] and were classified as pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines. One of the variants was present in sibs. CONCLUSIONS The two pathogenic variants identified have not been previously reported. Importantly, this is the first report of a familial case of MED13L nonsense mutation. Although the parents of the affected children were no longer available for analysis, their apparently normal phenotypes were surmised from familial verbal descriptions corresponding to normal mental behaviour and phenotype. In this situation, the familial component of mutation transmission might be caused by gonadal mosaicism of a MED13L mutation in a gonad from either the father or the mother. The case reports and the literature review presented in this manuscript can be useful for genetic counselling.

Objective Children and adolescents, who have less developed coping skills, are affected by natural disasters and other traumatic events differently than adults. Emotional and behavioral effects are particularly pronounced during a pandemic-related disaster, when support networks that typically promote healthy coping, such as friends, teachers, and family members, may be less available. Children and adolescents with fragile X syndrome (FXS), who are at increased risk for developing anxiety and depression, may be particularly vulnerable to behavioral or emotional difficulties during a pandemic. This study examined the mental health outcomes of school-aged girls with FXS during the COVID-19 pandemic and associated stay-at-home orders. Methods Participants included 47 school-aged girls with FXS and 33 age- and developmentally matched comparison girls. Associations between COVID-19 behavioral and emotional outcomes and prior academic, adaptive, behavioral, and emotional functioning as well as prior maternal mental health and characteristics of the mother–child relationship were examined. Qualitative data from the parental report of emotional and behavioral responses to the pandemic were also obtained. Results Results indicate that school-aged girls with FXS demonstrate a distinct profile of COVID-19 related associations compared to the comparison group, such that pandemic-related worries and emotional impact of pandemic restrictions were predicted by prior mental health factors for the comparison group but by prior social, behavioral, and relational factors for the FXS group. Conclusions Findings provide insight into factors that may confer risk or resilience for youth with special needs, suggesting potential therapeutic targets and informing public health initiatives in response to the pandemic.

BACKGROUND This pilot study aimed to explore the impact of visual, auditory and vestibular dysfunctions on the postural balance performance in adults with intellectual disabilities. Additionally, a comparison was made between the subjects with intellectual disabilities and a control group concerning static and dynamic balance tasks. METHOD Thirty adults with intellectual disabilities and 25 control subjects received a postural balance assessment. Additionally, the experimental group was subjected to a visual, auditory and vestibular screening. RESULTS The experimental group performed significantly worse and/or showed more sway compared to the control group for all balance tasks (p

Primary autosomal recessive microcephaly 5 (MCPH5) is a rare neurodevelopmental disorder with a relatively high incidence in regions where consanguineous marriage is widely practiced; So far, only a few MCPH5 cases have been reported from China. Here, we report clinical and molecular characteristics of two Chinese MCPH5 patients, a 24-year-old woman proband and her brother, a 19-year-old man, from a nonconsanguineous family. Main manifestations in the proband were small head circumference, premature closure of fontanelles, impaired concentration and moderate intellectual disability. The proband's brother had similar symptoms, but he was hyperactive and had a more severe sloping forehead. Brain imaging revealed global reduction in brain size, especially in the frontal lobes bilaterally and anterior horns of lateral ventricles. Sequencing results revealed that both patients carried a novel nonsense variant p.Tyr2004* (c.6012_6013delTA) and a novel frameshift variant p.Arg2005Serfs*48 (c.6015_6016delGG) in the ASPM gene. These variants were interpreted to be pathogenic in the in-silico analysis. Our findings help to expand the mutation spectrum of ASPM and provide new opportunities for assisting the traditional clinical diagnosis on the cases with atypical characteristics.