History Of Developmental Regression Research Articles

Nutritional rickets presenting with developmental regression: a rare presentation of rickets

Rickets is a disorder of defective mineralisation of the growth plate. Vitamin D deficiency remains the leading cause of nutritional rickets worldwide.We present the case of a 3.5-year-old breastfed boy who presented with dental abscess when a history of developmental regression was noted. Clinical assessment revealed hypotonia, poor growth and stunting. Biochemistry identified hypocalcaemia (1.63mmol/L, [normal range (NR) 2.2-2.7mmol/L]), severe vitamin D deficiency (25hydroxyvitamin D 5.3nmol/L, [NR > 50nmol/L]) with secondary hyperparathyroidism (Parathormone 159pmol/L, [NR 1.6-7.5pmol/L]) and rickets on radiographs. Growth failure screening suggested hypopituitarism with central hypothyroidism and low IGF1 at baseline, however, dynamic tests confirmed normal axis. Management included nasogastric nutritional rehabilitation, cholecalciferol and calcium supplementation and physiotherapy. A good biochemical response in all parameters was observed within 3 weeks and reversal of developmental regression by 3 months from treatment. Developmental regression as a presentation of nutritional rickets is rare and requires a high index of suspicion.

Missed Opportunities and the Impact of the Pandemic.

Benjamin is a 9-month-old, former 36-week gestation infant who presented to the high-risk infant follow-up clinic with parental concern for developmental regression. His mother reported that Benjamin seemed to be developing typically, but over the past 2 months, he has lost the ability to visually track objects, is not as engaged with her as he once was, and now only rarely makes babbling sounds. His mother also reported episodes of intermittent "bursts" of stiffening of his extremities and brief staring spells. Benjamin's mother described him as a "good, quiet baby." She commented that he used to laugh and cry more frequently but has recently been "very peaceful and calm." Benjamin's mother recently relayed her concerns for developmental regression to his pediatrician during an audio-only telehealth visit. Benjamin was referred to a pediatric neurologist, and the consultation visit is pending.His mother is a 28-year-old single parent whose pregnancy was complicated by pre-eclampsia, gestational diabetes, and anxiety. Benjamin required admission to the neonatal intensive care unit because of initial feeding difficulties. After 1 week, Benjamin was discharged to home and was referred for early intervention services. Owing to the pandemic, there were delays with initiating intervention, but bimonthly virtual interaction with a representative from the infant development program was eventually provided.Benjamin's mother expressed significant concerns regarding the potential of exposing him to a pandemic-related illness because of bringing her son to in-person medical visits. In fact, because of her concerns, she attended only virtual well-child pediatric visits over the past 6 months. A thorough social history revealed that she is a former dance studio instructor. The studio closed and she lost her primary source of income because of the pandemic. As a result, she decided to not send Benjamin to child care and maintained isolation from extended family members.On physical examination, pertinent findings included poor truncal tone, lack of orientation toward sounds, and limited eye contact. The Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) was administered, and the results indicated severe delays across all developmental areas, consistent with a diagnosis of global developmental delay.Benjamin's clinical presentation to the HRIF clinic and a history of developmental regression and intermittent body movements raised concerns for infantile spasms. He was transferred to the emergency department for evaluation and consideration for admission to the neurology service. An electroencephalogram confirmed epileptiform abnormalities consistent with infantile spasms, and he was immediately started on treatment.Impacts of the pandemic on the medical care of vulnerable/at-risk pediatric patients have included delayed receipt of early intervention services, parental fear regarding potential exposure to pandemic-related illness while seeking preventative care, increased use of virtual visit platforms for medical care and developmental intervention services, etc. What factors should be considered when providing support for these vulnerable/at-risk patients?

IL1RAPL1 Gene Deletion in a Female Patient with Developmental Delay and Continuous Spike-Wave during Sleep

AbstractInterleukin-1 receptor accessory protein-like 1 (IL1RAPL1) encodes a protein that is highly expressed in neurons and has been shown to regulate neurite outgrowth as well as synapse formation and synaptic transmission. Clinically, mutations in or deletions of IL1RAPL1 have been associated with a spectrum of neurological dysfunction including autism spectrum disorder and nonsyndromic X-linked developmental delay/intellectual disability of varying severity. Nearly all reported cases are in males; in the few reported cases involving females, the clinical presentation was mild or the deletion was identified in phenotypically normal carriers in accordance with X-linked inheritance. Using genome-wide microarray analysis, we identified a novel de novo 373 kb interstitial deletion of the X chromosome (Xp21.1-p21.2) that includes exons 4 to 6 of the IL1RAPL1 gene in an 8-year-old girl with severe intellectual disability and behavioral disorder with a history of developmental regression. Overnight continuous video electroencephalography revealed electrical status epilepticus in sleep (ESES). This case expands the clinical genetic spectrum of IL1RAPL1-related neurodevelopmental disorders and highlights a new genetic association of ESES.

Inherited Metabolic Disorders Presenting with Ataxia.

Ataxia is a common clinical feature in inherited metabolic disorders. There are more than 150 inherited metabolic disorders in patients presenting with ataxia in addition to global developmental delay, encephalopathy episodes, a history of developmental regression, coarse facial features, seizures, and other types of movement disorders. Seizures and a history of developmental regression especially are important clinical denominators to consider an underlying inherited metabolic disorder in a patient with ataxia. Some of the inherited metabolic disorders have disease specific treatments to improve outcomes or prevent early death. Early diagnosis and treatment affect positive neurodevelopmental outcomes, so it is important to think of inherited metabolic disorders in the differential diagnosis of ataxia.

Effect of prednisolone on language function in children with autistic spectrum disorder: a randomized clinical trial

ObjectiveTo describe the effect of prednisolone on language in children with autism spectrum disorder. This study is based upon two hypotheses: autism etiology may be closely related to neuroinflammation; and, an effective treatment should restore the individual's language skills. MethodThis is a prospective, double-blinded, randomized, placebo-controlled clinical trial, carried out in a federal university hospital. The initial patient sample consisted of 40 subjects, which were randomized into two parallel groups. Inclusion criteria were: male gender, 3–7 years of age, and meeting the Diagnostic and Statistical Manual of Mental Disorders – 4th edition (DSM-IV) diagnostic criteria. The final sample consisted of 38 patients, of whom 20 were randomized to the placebo group and 18 to the active group. The latter received prednisolone for 24 weeks, at an initial dose of 1mg/kg/day and a tapering dose from the ninth week onward. Language was measured on four occasions over a 12-month period by applying two Brazilian tools: the Language Development Assessment (ADL) and the Child Language Test in Phonology, Vocabulary, Fluency, and Pragmatics (ABFW). ResultsThe side effects were mild: two patients had hypertension, five had hyperglycemia, and two had varicella. Prednisolone increased the global ADL score in children younger than 5 years of age who had developmental regression (p=0.0057). The ABFW's total of communicative acts also responded favorably in those participants with regression (p=0.054). The ABFW's total of vocal acts showed the most significant results, especially in children younger than 5 years (p=0.004, power=0.913). ConclusionsThe benefit of prednisolone for language scores was more evident in participants who were younger than five years, with a history of developmental regression, but the trial's low dose may have limited this benefit. The observed side effects do not contraindicate corticosteroid use in autism.

Annual Research Review: Understudied populations within the autism spectrum - current trends and future directions in neuroimaging research.

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental conditions that vary in both etiology and phenotypic expression. Expressions of ASD characterized by a more severe phenotype, including autism with intellectual disability (ASD+ID), autism with a history of developmental regression (ASD+R), and minimally verbal autism (ASD+MV) are understudied generally, and especially in the domain of neuroimaging. However, neuroimaging methods are a potentially powerful tool for understanding the etiology of these ASD subtypes. This review evaluates existing neuroimaging research on ASD+MV, ASD+ID, and ASD+R, identified by a search of the literature using the PubMed database, and discusses methodological, theoretical, and practical considerations for future research involving neuroimaging assessment of these populations. There is a paucity of neuroimaging research on ASD+ID, ASD+MV, and ASD+R, and what findings do exist are often contradictory, or so sparse as to be ungeneralizable. We suggest that while greater sample sizes and more studies are necessary, more important would be a paradigm shift toward multimodal (e.g. imaging genetics) approaches that allow for the characterization of heterogeneity within etiologically diverse samples.

Age of autism spectrum disorder diagnosis is associated with child's variables and parental experience

Early diagnosis of autism spectrum disorder (ASD) is highly important as it enables an early start to intervention. The current study examined familial (parental ages; education; having an older sibling) and child (gender; reported and observed autism symptoms severity; adaptive skills) related variables that might predict the age of ASD diagnosis. The study included 551 participants, age range 15–72 months, diagnosed with ASD who underwent comprehensive medical and behavioral assessment using standardized tests. Of the child's examined variables, the severity of the social interaction impairment reported by the parents and having a history of developmental regression was associated with an earlier age of ASD diagnosis. In contrast, the severity of the restricted and repetitive behaviors was associated with delayed age of ASD diagnosis. Vineland Adaptive Behavior Scales scores lower or higher than the group's mean (70 points) were associated with a relatively delayed age of ASD diagnosis. Of the familial variables, only having an older sibling was associated with an earlier diagnosis. Professionals should be aware that subtle signs of ASD, developmental delay and close to normal adaptive functioning might delay age of ASD diagnosis. Educating parents on “red flags” for ASD and periodic surveillance in early childhood are important.

Clinical Characteristics of Children with Autism Spectrum Disorder and Co-Occurring Epilepsy

ObjectivesTo estimate the prevalence of epilepsy in children with Autism Spectrum Disorder (ASD) and to determine the demographic and clinical characteristics of children with ASD and epilepsy in a large patient population.MethodsCross-sectional study using four samples of children with ASD for a total of 5,815 participants with ASD. The prevalence of epilepsy was estimated from a population-based sample. Children with and without epilepsy were compared on demographic and clinical characteristics. Multivariate logistic regression was used to examine the association between demographic and clinical characteristics and epilepsy.ResultsThe average prevalence of epilepsy in children with ASD 2–17 years was 12.5%; among children aged 13 years and older, 26% had epilepsy. Epilepsy was associated with older age, lower cognitive ability, poorer adaptive and language functioning, a history of developmental regression and more severe ASD symptoms. The association between epilepsy and the majority of these characteristics appears to be driven by the lower IQ of participants with epilepsy. In a multivariate regression model, only age and cognitive ability were independently associated with epilepsy. Children age 10 or older had 2.35 times the odds of being diagnosed with epilepsy (p<.001) and for a one standard deviation increase in IQ, the odds of having epilepsy decreased by 47% (p<.001).ConclusionThis is among the largest studies to date of patients with ASD and co-occurring epilepsy. Based on a representative sample of children with ASD, the average prevalence of epilepsy is approximately 12% and reaches 26% by adolescence. Independent associations were found between epilepsy and older age and lower cognitive ability. Other risk factors, such as poor language and developmental regression, are not associated with epilepsy after controlling for IQ. These findings can help guide prognosis and alert clinicians to patients with ASD who are at increased risk for epilepsy.

Evaluation of two year treatment outcome and limited impact of arginine restriction in a patient with GAMT deficiency

A 4-year-old female with history of developmental regression and autistic features was diagnosed with guanidinoacetate methyltransferase deficiency at age 21months. Upon treatment, she showed improvements in her developmental milestones, sensorial-neural hearing loss and brain atrophy on cranial-MRI. The creatine/choline ratio increased 82% in basal ganglia and 88% in white matter on cranial MR-spectroscopy. The CSF guanidinoacetate decreased 80% after six months of ornithine and creatine supplementation and an additional 8% after 18months of additional arginine restricted diet. We report the most favorable clinical and biochemical outcome on treatment in our patient.

The burden of inherited leukodystrophies in children

Leukodystrophies are diseases of the white matter for which data concerning clinical characteristics, incidence, disease burden, and description of outcomes are sparse. The purpose of our study was to determine the incidence and most common types of inherited leukodystrophies in a population, the mortality and time course of deaths, common neurologic features in patients, and health care costs associated with leukodystrophies. We conducted a retrospective, hospital- and clinic-based surveillance of inherited leukodystrophies among children younger than 18 years presenting to a regional children's hospital. We enrolled children evaluated from January 1, 1999, through December 31, 2007; clinical information was obtained from medical records. We calculated incidence based on state birth rates. A total of 122 children with an inherited leukodystrophy were identified; 542 patients were excluded. A total of 49% had epilepsy, 43% required a gastrostomy tube, and 32% had a history of developmental regression. Mortality was 34%; average age at death was 8.2 years. No final diagnosis was reported in 51% of patients. The most common diagnoses were metachromatic leukodystrophy (8.2%), Pelizaeus-Merzbacher disease (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (4.1%). Endocrine abnormalities and hypoplastic cerebellum were noted in significant portions of patients (15% and 14%). Average yearly per-patient medical costs were $22,579. Population incidence was 1 in 7,663 live births. Inherited leukodystrophies are associated with substantial morbidity and mortality in children. Overall population incidence is higher than generally appreciated (1 in 7,663 live births). Most leukodystrophies remain undiagnosed, but a logical algorithm based on prevalence could aid testing.

An Investigation of Sleep Characteristics, EEG Abnormalities and Epilepsy in Developmentally Regressed and Non-regressed Children with Autism

This study investigated sleep of children with autism and developmental regression and the possible relationship with epilepsy and epileptiform abnormalities. Participants were 104 children with autism (70 non-regressed, 34 regressed) and 162 typically developing children (TD). Results suggested that the regressed group had higher incidence of circadian rhythm disorders than non-regressed children. The regressed group showed higher Children's Sleep Habits Questionnaire Bedtime Resistance, Sleep Onset Delay, Sleep Duration and Night-Wakings scores. Epilepsy and frequent epileptiform EEG abnormalities were more frequent in regressed children. Past sleep disorders and a history of developmental regression were significantly associated with sleep disorders. This study is an initial step in better understanding sleep problems in regressed children with autism, further studies are necessary to better investigate these aspects.

Difference in Age at Regression in Children with Autism with and without Down Syndrome

Autism occurs more frequently in individuals with Down syndrome than it does in the general population. Among children with autism and Down syndrome, regression is reported to occur in up to 50%. The aim of this study was to characterize and compare regression in children with autism with and without Down syndrome. In this case-control study, children with Down syndrome and autism characterized by a history of developmental regression (n = 12) were compared to children with autism with regression who did not have Down syndrome, matched for chronologic age and gender. Comparisons were made on age at acquisition of language and age at loss of language and other skills as measured by the Autism Diagnostic Interview-Revised (ADI-R). The mean age at acquisition of meaningful use of single words was 40.6 months (SD = 38.0) in children with Down syndrome and autism compared to 14.9 months (SD = 8.5) in children with autism without Down syndrome (p = .005). The mean age at language loss in children with autism with Down syndrome was 61.8 months (SD = 22.9) compared to 19.7 months (SD = 5.8) for those with autism without Down syndrome (p = .01). The mean age at other skill loss was 46.2 months (SD = 19.1) and 19.5 months (SD = 5.6), respectively (p = .006). When regression occurs in children with autism and Down syndrome it is, on average, much later than is typically seen in children with autism without Down syndrome.

Gene expression changes in children with autism

The objective of this study was to identify gene expression differences in blood differences in children with autism (AU) and autism spectrum disorder (ASD) compared to general population controls. Transcriptional profiles were compared with age- and gender-matched, typically developing children from the general population (GP). The AU group was subdivided based on a history of developmental regression (A–R) or a history of early onset (A–E without regression). Total RNA from blood was processed on human Affymetrix microarrays. Thirty-five children with AU (17 with early onset autism and 18 with autism with regression) and 14 ASD children (who did not meet criteria for AU) were compared to 12 GP children. Unpaired t tests (corrected for multiple comparisons with a false discovery rate of 0.05) detected a number of genes that were regulated more than 1.5-fold for AU versus GP ( n = 55 genes), for A–E versus GP ( n = 140 genes), for A–R versus GP ( n = 20 genes), and for A–R versus A–E ( n = 494 genes). No genes were significantly regulated for ASD versus GP. There were 11 genes shared between the comparisons of all autism subgroups to GP (AU, A–E, and A–R versus GP) and these genes were all expressed in natural killer cells and many belonged to the KEGG natural killer cytotoxicity pathway ( p = 0.02). A subset of these genes ( n = 7) was tested with qRT-PCR and all genes were found to be differentially expressed ( p < 0.05). We conclude that the gene expression data support emerging evidence for abnormalities in peripheral blood leukocytes in autism that could represent a genetic and/or environmental predisposition to the disorder.

In children with autism, is intravenous secretin more effective than placebo in improving social skills, communication, behaviour or global functioning?

In children with autism, is intravenous secretin more effective than placebo in improving social skills, communication, behaviour or global functioning?

Prevalence of chronic gastrointestinal symptoms in children with autism and autistic spectrum disorders.

The purpose of this study was to estimate the prevalence of chronic gastrointestinal symptoms in a general population of children with autism or autistic spectrum disorder (ASD). The study site was a clinic specializing in ASD in a large pediatric medical center serving a 10 county area in the midwestern USA. In a sample of 137 children, age 24-96 months, classified as having autism or ASD by the Autism Diagnostic Observation Schedule-Generic, 24 percent had a history of at least one chronic gastrointestinal symptom. The most common symptom was diarrhea, which occurred in 17 percent. There was no association between chronic gastrointestinal symptoms and a history of developmental regression. The potential phenotypic association between autism and gastrointestinal symptoms is discussed.