Developmental Delay Syndrome Research Articles

Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations

We present a neurodegenerative disorder starting in early childhood of two brothers consisting of severe progressive polyneuropathy, severe progressive cerebellar atrophy, microcephaly, mild epilepsy, and intellectual disability. The cause of this rare syndrome was found to be a homozygous mutation (c.1250_1266dup, resulting in a frameshift p.Thr424GlyfsX48) in PNKP, identified by applying homozygosity mapping and whole-genome sequencing. Mutations in PNKP have previously been associated with a syndrome of microcephaly, seizures and developmental delay (MIM 613402), but not with a neurodegenerative disorder. PNKP is a dual-function enzyme with a key role in different pathways of DNA damage repair. DNA repair disorders can result in accelerated cell death, leading to underdevelopment and neurodegeneration. In skin fibroblasts from both affected individuals, we show increased susceptibility to apoptosis under stress conditions and reduced PNKP expression. PNKP is known to interact with DNA repair proteins involved in the onset of polyneuropathy and cerebellar degeneration; therefore, our findings explain this novel phenotype.

Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin

Low copper and ceruloplasmin in serum are the diagnostic hallmarks for Menkes disease, Wilson disease, and aceruloplasminemia. We report on five patients from four unrelated families with these biochemical findings who presented with a lethal autosomal-recessive syndrome of congenital cataracts, hearing loss, and severe developmental delay. Cerebral MRI showed pronounced cerebellar hypoplasia and hypomyelination. Homozygosity mapping was performed and displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous or compound heterozygous mutations for all affected subjects in SLC33A1 encoding a highly conserved acetylCoA transporter (AT-1) required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization of the protein. We also showed that AT-1 knockdown in HepG2 cells leads to reduced ceruloplasmin secretion, indicating that the low copper in serum is due to reduced ceruloplasmin levels and is not a sign of copper deficiency. The severity of the phenotype implies an essential role of AT-1 in proper posttranslational modification of numerous proteins, without which normal lens and brain development is interrupted. Furthermore, AT-1 defects are a new and important differential diagnosis in patients with low copper and ceruloplasmin in serum.

Concomitant vesicoureteral reflux and gastroesophageal reflux: an analytic cross-sectional study

Vesicoureteral reflux (VUR) and Gastroesophageal reflux (GER) are both common disorders in children and could be associated with significant morbidities. Although they appear to be separate entities, their natural history and underlying pathophysiology are the same and they both tend to resolve over time. We aimed to appraise their concurrent occurrence and prevalence of GER in VUR patients to understand whether they can be considered different manifestations of a syndrome mainly caused by developmental delay resulting in dysfunction of the sphincters. Totally, 174 children ≤ 2 years of age were enrolled and 87 of them with primary VUR constituted patients group. The rest of the cases with the same age and sex distribution entered control group. All the study population underwent ultrasonographic evaluation to detect GER. GER was more frequent in patients with primary VUR. GER was more prevalent in higher grades of VUR. We observed higher prevalence of GER and higher grades of VUR in younger infants demonstrating the tendency of both conditions to resolve overtime. Bilateral VUR was more prevalent among patients with higher grades of VUR. GER was more prevalent in patients with bilateral VUR and Prevalence of bilateral VUR decreased with increase in age. These findings show that the chance of concomitant GER and VUR is higher in children with more severe developmental defect of sphincters. Regarding the higher prevalence of GER among VUR patients and correlation of VUR severity with co-occurrence of GER, besides the natural tendency of both conditions to resolve overtime, they may be considered parts of developmental delay syndrome of sphincters.

Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11

With the clinical implementation of genomic microarrays, the detection of cryptic unbalanced rearrangements in patients with syndromic developmental delay has improved considerably. Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 to 10.6 Mb. The smallest region of overlap is 306 kb, which includes WAC gene, known to be associated with microtubule function and to have a role in cell division. Another patient has previously been described with a 10 Mb deletion, partially overlapping with our six patients. All seven patients have developmental delay and a majority of the patients have abnormal behaviour and dysmorphic features, including bulbous nasal tip, deep set eyes, synophrys/thick eyebrows and full cheeks, whereas other features varied. All patients also displayed various visual impairments and six out of seven patients had cardiac malformations. Taken together with the previously reported patient, our study suggests that the detected deletions may represent a new contiguous gene syndrome caused by dosage-sensitive genes that predispose to developmental delay.

Genes and biological processes commonly disrupted in rare and heterogeneous developmental delay syndromes

Rare copy number variations (CNVs) are a recognized cause of common human disease. Predicting the genetic element(s) within a small CNV whose copy number loss or gain underlies a specific phenotype might be achieved reasonably rapidly for single patients. Identifying the biological processes that are commonly disrupted within a large patient cohort which possess larger CNVs, however, requires a more objective approach that exploits genomic resources. In this study, we first identified 98 large, rare CNVs within patients exhibiting multiple congenital anomalies. All patients presented with global developmental delay (DD), while other secondary symptoms such as cardiac defects, craniofacial features and seizures were varyingly presented. By applying a robust statistical procedure that matches patients' clinical phenotypes to laboratory mouse gene knockouts, we were able to strongly implicate anomalies in brain morphology and, separately, in long-term potentiation as manifestations of these DD patients' disorders. These and other significantly enriched model phenotypes provide insights into the pathoetiology of human DD and behavioral and anatomical secondary symptoms that are specific to DD patients. These enrichments set apart 103 genes, from among thousands overlapped by these CNVs, as strong candidates whose copy number change causally underlies approximately 46% of the cohort's DD syndromes and between 59 and 80% of the cohort's secondary symptoms. We also identified significantly enriched model phenotypes among genes overlapped by CNVs in both DD and learning disability cohorts, indicating a congruent etiology. These results demonstrate the high predictive potential of model organism phenotypes when implicating candidate genes for rare genomic disorders.

A novel syndrome of paediatric cataract, dysmorphism, ectodermal features, and developmental delay in Australian Aboriginal family maps to 1p35.3-p36.32

BackgroundA novel phenotype consisting of cataract, mental retardation, erythematous skin rash and facial dysmorphism was recently described in an extended pedigree of Australian Aboriginal descent. Large scale chromosomal re-arrangements had previously been ruled out. We have conducted a genome-wide scan to map the linkage region in this family.MethodsGenome-wide linkage analysis using Single Nucleotide Polymorphism (SNP) markers on the Affymetrix 10K SNP array was conducted and analysed using MERLIN. Three positional candidate genes (ZBTB17, EPHA2 and EPHB2) were sequenced to screen for segregating mutations.ResultsUnder a fully penetrant, dominant model, the locus for this unique phenotype was mapped to chromosome 1p35.3-p36.32 with a maximum LOD score of 2.41. The critical region spans 48.7 cM between markers rs966321 and rs1441834 and encompasses 527 transcripts from 364 annotated genes. No coding mutations were identified in three positional candidate genes EPHA2, EPHB2 or ZBTB17. The region overlaps with a previously reported region for Volkmann cataract and the phenotype has similarity to that reported for 1p36 monosomy.ConclusionsThe gene for this syndrome is located in a 25.6 Mb region on 1p35.3-p36.32. The known cataract gene in this region (EPHA2) does not harbour mutations in this family, suggesting that at least one additional gene for cataract is present in this region.

Applied kinesiology methods for a 10-year-old child with headaches, neck pain, asthma, and reading disabilities

Objective The purpose of this case report is to describe the chiropractic care of a 10-year-old boy who presented with developmental delay syndromes, asthma, and chronic neck and head pain and to present an overview of his muscular imbalances during manual muscle testing evaluation that guided the interventions offered to this child. Clinical Features The child was a poor reader, suffered eye strain while reading, had poor memory for classroom material, and was unable to move easily from one line of text to another during reading. He was using 4 medications for the asthma but was still symptomatic during exercise. Intervention and Outcome Chiropractic care, using applied kinesiology, guided evaluation, and treatment. Following spinal and cranial treatment, the patient showed improvement in his reading ability, head and neck pain, and respiratory distress. His ability to read improved (in 3 weeks, after 5 treatments), performing at his own grade level. He has remained symptom free for 2 years. Conclusion The care provided to this patient seemed to help resolve his chronic musculoskeletal dysfunction and pain and improve his academic performance.

Effects of Symptoms of Comorbid Psychopathology on Challenging Behaviors Among Atypically Developing Infants and Toddlers as Assessed With the Baby and Infant Screen for Children With Autism Traits (BISCUIT)

Comorbid psychopathology and challenging behaviors often occur among persons with developmental disabilities. However, little attention to this issue has been reported in young children. In this study, individuals 17 through 36 months of age with varying diagnoses, such as intellectual disability, developmental delay, and Down syndrome, among others, were evaluated. Greater levels of symptoms of comorbid psychopathology were related to higher rates of challenging behaviors. Additionally, Inattention/Impulsivity, Avoidant Behavior, Anxiety/Repetitive Behaviors, and Tantrum/Conduct Problems were significantly related to high rates of Aggressive and Destructive Behaviors, Stereotypies, and Self-Injurious Behavior. Also, those who displayed greater levels of Eating/Sleep Problems engaged in more Aggressive and Destructive Behaviors and Stereotypies but not Self-Injurious Behavior. Thus, even at young ages, children with atypical development without an autism spectrum disorder diagnosis are at high risk for a variety of problem behaviors and disorders that may be related to one another.

Reevaluation of a case of type 1 diabetes mellitus diagnosed before 6 months of age

A 17-year-old female was referred for the reassessment of her type 1 diabetes mellitus, with which she had been diagnosed at the age of 15 weeks owing to symptoms of ketoacidosis. The patient had mild learning difficulties, which resulted in her requiring additional support at school. There was no family history of diabetes. Measurements of plasma C-peptide and glutamate decarboxylase autoantibodies. Molecular genetic testing was performed. Intermediate developmental delay, epilepsy and neonatal diabetes mellitus (DEND) syndrome as a result of a 59V>M Kir6.2 mutation. Treatment with high-dose oral glibenclamide replaced insulin treatment. Good glycemic control was achieved with levels of HbA(1c) consistently below 6.5% and no hypoglycemia.

Successful transfer from insulin to oral sulfonylurea in a 3-year-old girl with a mutation in the KCNJ11 gene

Neonatal diabetes mellitus is considered a rare disease that is diagnosed in the first six months of life, and can be either transient or permanent. Recent advances in molecular genetics have shown that activating mutations in KCNJ11 (the gene that encodes for the Kir6.2 subunit of the KATP potassium channel of the pancreatic β-cell) is a common cause of permanent neonatal diabetes mellitus. Patients with mutations in this gene may respond to oral sulfonyureas. We describe a 3-year-old girl with permanent neonatal diabetes mellitus with a mutation in the KCNJ11 gene (R201H), who was successfully transferred from subcutaneous insulin to oral glibenclamide, with a marked improvement in glycemic control. This is the first successful switch from insulin to oral sulfonylurea in a patient with R201H mutation, in the Arabian Gulf.

Developmental Delay Syndromes: Psychometric Testing Before and After Chiropractic Treatment of 157 Children

Objective This study presents a case series of 157 children with developmental delay syndromes, including the conditions such as dyspraxia, dyslexia, attention-deficit hyperactivity disorder, and learning disabilities who received chiropractic care. Clinical Features A consecutive sample of 157 children aged 6 to 13 years (86 boys and 71 girls) with difficulties in reading, learning, social interaction, and school performance who met these inclusion criteria were included. Intervention and Outcomes Each patient received a multimodal chiropractic treatment protocol, applied kinesiology chiropractic technique. The outcome measures were a series of 8 standardized psychometric tests given to the children by a certified speech therapist pre- and posttreatment, which evaluate 20 separate areas of cognitive function, including patient- or parent-reported improvements in school performance, social interaction, and sporting activities. Individual and group data showed that at the end of treatment, the 157 children showed improvements in the 8 psychometric tests and 20 areas of cognitive function compared with their values before treatment. Their ability to concentrate, maintain focus and attention, and control impulsivity and their performance at home and school improved. Conclusions This report suggests that a multimodal chiropractic method that assesses and treats motor dysfunction reduced symptoms and enhanced the cognitive performance in this group of children.

Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival

Autosomal recessive cutis laxa type 2 (ARCL2), a syndrome of growth and developmental delay and redundant, inelastic skin, is caused by mutations in the a2 subunit of the vesicular ATPase H+-pump (ATP6V0A2). The goal of this study was to define the disease mechanisms that lead to connective tissue lesions in ARCL2. In a new cohort of 17 patients, DNA sequencing of ATP6V0A2 detected either homozygous or compound heterozygous mutations. Considerable allelic and phenotypic heterogeneity was observed, with a missense mutation of a moderately conserved residue p.P87L leading to unusually mild disease. Abnormal N- and/or mucin type O-glycosylation was observed in all patients tested. Premature stop codon mutations led to decreased ATP6V0A2 mRNA levels by destabilizing the mutant mRNA via the nonsense-mediated decay pathway. Loss of ATP6V0A2 either by siRNA knockdown or in ARCL2 cells resulted in distended Golgi cisternae, accumulation of abnormal lysosomes and multivesicular bodies. Immunostaining of ARCL2 cells showed the accumulation of tropoelastin (TE) in the Golgi and in large, abnormal intracellular and extracellular aggregates. Pulse-chase studies confirmed impaired secretion and increased intracellular retention of TE, and insoluble elastin assays showed significantly reduced extracellular deposition of mature elastin. Fibrillin-1 microfibril assembly and secreted lysyl oxidase activity were normal in ARCL2 cells. TUNEL staining demonstrated increased rates of apoptosis in ARCL2 cell cultures. We conclude that loss-of-function mutations in ATP6V0A2 lead to TE aggregation in the Golgi, impaired clearance of TE aggregates and increased apoptosis of elastogenic cells.

A novel genetic syndrome characterized by pediatric cataract, dysmorphism, ectodermal features, and developmental delay in an indigenous Australian family

A novel syndrome initially presenting with cataract and developmental delay within an Indigenous Australian family is described. We present the extended four generation pedigree and describe in detail the phenotypic appearance of five clearly affected male second cousins in this family. The common features of these children include developmental delay, short stature, cortical cataract, facial dysmorphism, clinodactyly, thin hair and an erythematous skin rash. Initial inspection of the pedigree suggested an inherited disorder with possible X-linked inheritance. However, a thorough scan of the X chromosome failed to reveal linkage. This family represents a new syndrome of familial cataract, dysmorphic features, short stature and developmental delay with probable autosomal inheritance and variable expressivity.

Foetal distress and birth interventions in children with developmental delay syndromes: A prospective controlled trial

To investigate the incidence of birth intervention/foetal distress in children with developmental delay syndromes (attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, dyspraxia, obsessive compulsive disorder, Tourette's syndrome of childhood, autistic spectrum disorders). A population of 100 children aged 4–15 years and diagnosed with developmental delay syndrome(s) were investigated using a parental questionnaire to determine whether they had suffered any birth interventions or distress. These results were compared with an age- and gender-matched control group. On the basis of this relatively small study, significant risk of development delay syndrome(s) occurred with both foetal distress ( p < 0.001) and Ventouse assisted delivery ( p < 0.01).

Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene

Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the K(ATP) channels in pancreatic beta cells are a common cause of neonatal diabetes. One-third of patients also have developmental delay, which probably results from mutated K(ATP) channels in muscle, nerve and brain. Sulfonylureas, which bind to the sulfonylurea receptor 1 subunit of the K(ATP) channel, can replace insulin injections in patients with KCNJ11 mutations. The aim of this study was to investigate the long-term outcome and impact on neurological features of sulfonylurea treatment. We report the response to sulfonylurea treatment in a boy with neonatal diabetes and marked developmental delay resulting from the KCNJ11 mutation V59M. Glibenclamide (glyburide) treatment was started at 23 months and resulted in insulin being discontinued, lower overall glycaemia, reduced glucose fluctuations and reduced hypoglycaemia. Good control (HbA(1c) 6.5%) was maintained 2 years after discontinuing insulin, despite a reduction in the glibenclamide dose (from 0.41 to 0.11 mg.kg(-1).day(-1)). Within 1 month of starting glibenclamide there was marked improvement in motor function, resulting in the patient progressing from being unable to stand unaided to walking independently, but there was no improvement in mental function. This 2-year follow-up of a patient highlights that sulfonylurea treatment can result in prolonged, excellent glycaemic control and may improve motor features, but not mental features, associated with KCNJ11 mutations. This suggests that the neurological actions of sulfonylurea are initially principally on peripheral (nerve or muscle) rather than on central (brain) K(ATP) channels. Early molecular diagnosis is important in patients with neonatal diabetes and neurological features.

Molecular characterization of an 11q interstitial deletion in a patient with the clinical features of Jacobsen syndrome

The 11q terminal deletion disorder or Jacobsen syndrome is a contiguous gene disorder. It is characterized by psychomotor retardation, cardiac defects, blood dyscrasias (Paris-Trousseau syndrome) and craniofacial anomalies. We report on a female patient with an approximately 10 Mb interstitial deletion with many of the features of Jacobsen syndrome: A congenital heart defect, dysmorphic features, developmental delay, and Paris-Trousseau syndrome. The karyotype of the patient is 46,XX,del(11)(q24.1q24.3). The interstitial deletion was confirmed using FISH probes for distal 11q, and the breakpoints were characterized by microarray analysis. This is the first molecularly characterized interstitial deletion in a patient with the clinical features of Jacobsen syndrome. The deletion includes FLI-1, but not JAM-3, which will help to determine the critical genes involved in this syndrome.

Comorbidity of dyslexia, dyspraxia, attention deficit disorder (ADD), attention deficit hyperactive disorder (ADHD), obsessive compulsive disorder (OCD) and Tourette's syndrome in children: A prospective epidemiological study

Currently dyslexia, dyspraxia, attention deficit disorder, attention deficit hyperactive disorder, obsessive compulsive disorder and Tourette's syndrome of childhood are considered as being separate disorders. There is now evidence to suggest that, on the basis of comorbidity, they should be downgraded to symptoms that will appear in syndromes of developmental delay. To establish that a child diagnosed by a health practitioner or educational professional as having a single disorder in fact presents symptoms of other disorders in a pattern of comorbidity. A prospective epidemiological study of 100 children attending a specialist clinic. A clear pattern of comorbidity was demonstrated. Whilst not always quantifiable, no patient was found to have one condition in isolation and comorbidity rates were found at incidences of up to 95%, representing an increase on the expected prevalence in a general population of 160–2300%. The patterns of comorbidity occurred with such frequency that it would suggest that there could be an argument for the downgrading of these conditions from disorders per se to symptoms and that further investigation might suggest that the patterns of comorbidity may fit the criteria for a developmental delay syndrome.

Nephrotic syndrome, microcephaly, and developmental delay: Three separate syndromes

We describe a patient with microcephaly, developmental delay, and nephrotic syndrome who had normal renal function and normal brain imaging studies. She does not have the Galloway-Mowat syndrome. The concurrence of nephrotic syndrome with microcephaly and developmental delay may be coincidental, or may reflect one of at least three syndromes: Galloway-Mowat, a second syndrome of microcephaly, nephrotic syndrome and developmental delay (MNSDD), and a third syndrome of microcephaly, developmental delay, and spondylorhizomelic short stature. Am. J. Med. Genet. 82:257–260, 1999. © 1999 Wiley-Liss, Inc.

Nephrotic syndrome, microcephaly, and developmental delay: Three separate syndromes

We describe a patient with microcephaly, developmental delay, and nephrotic syndrome who had normal renal function and normal brain imaging studies. She does not have the Galloway-Mowat syndrome. The concurrence of nephrotic syndrome with microcephaly and developmental delay may be coincidental, or may reflect one of at least three syndromes: Galloway-Mowat, a second syndrome of microcephaly, nephrotic syndrome and developmental delay (MNSDD), and a third syndrome of microcephaly, developmental delay, and spondylorhizomelic short stature.

A syndrome of seizures and pervasive developmental delay associated with excessive cellular nucleotidase activity

A syndrome of seizures and pervasive developmental delay associated with excessive cellular nucleotidase activity