Loss Of Developmental Milestones Research Articles

Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy

ObjectiveMetachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease. MethodsThe specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years. ResultsAcross an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th–75th %ile: 1.0–1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years). InterpretationEarly developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions.

ETMR-31. A UNIQUE CASE OF CNS DIFFUSE, NON-SYSTEMIC ALK+ HISTIOCYTOSIS IN A PEDIATRIC PATIENT

Abstract BACKGROUND Histiocytic disorders are a group of rare diseases with accumulation of of macrophages, monocytes, or dendritic cells in various parts of the body. ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 that is very rarely described in pediatrics. METHODS A 20 month old male presented to an adult hospital after a prolonged period of headaches, vomiting, and loss of developmental milestones. Imaging demonstrated severe hydrocephalus and extensive thickened leptomeningeal enhacement with mass effect. He underwent VP shunt placement and revision, a T7-T10 laminectomy, and tumor debulking. Extensive molecular testing, including DNA and RNA analysis by NGS was performed and a CLTC::ALK fusion was identified, along with Tier III DNA variants, yielding a diagnosis consistent with ALK-Positive Histiocytosis, with diffusivity in the CNS system. Full evaluation demonstrated no involvement of the peripheral nervous system or other systemic involvement. He initially demonstrated signs of neuro-irritation, altered tone, and lower extremity clonus. RESULTS After review of very little literature published on similar patients, although none with a clinical picture matching his, he was started on a treatment course of high dose dexamethasone, vinblastine, and lorlatinib targeting the ALK+, likely driver, mutation of his disease. On evaluation scans two months into treatment, he showed no change in his disease burden. He was transitioned to clofarabine cycles with daily lorlatinib for continued targetted therapy. After six total cycles, he demonstrated a high partial to complete remission (allowing for evidence of scarred tissue) and tremendous neurologic and developmental milestone gains. CONCLUSIONS This case demonstrates a unique presentation in which there is little described in the literature in way of clinical features or treatment standards, and further none exactly similar to this patient. After undergoing extensive evaluation and therapy modication, he responded remarkably well and continues to have optimal quality of life.

West Syndrome: A Case Report

Infantile spasms (IS), formerly known as West syndrome, are a type of seizure associated with the epileptic disorder known as West syndrome. Infants and children are affected by West syndrome. Mental deficits are associated with infantile spasms. A particular kind of seizure that starts in the first year of life is known as infantile spasms. Loss of developmental milestones or developmental regression. However, an electroencephalogram is required to confirm the diagnosis of west syndrome (EEG). We describe the unusual West syndrome case.

Acquisition and Loss of Developmental Milestones and Time to Disease-Related Outcomes in Cerebral Alexander Disease.

Objective: To determine the ages at acquisition of developmental milestones, loss of motor function, and clinical symptoms in Alexander disease. Methods: Patients with confirmed cerebral Alexander disease were included. Data abstraction of developmental and disease-specific milestones was performed from medical records, physical exams, and questionnaires. Mixed effects logistic regression was used to determine if key clinical features were associated with milestone achievement, controlling for patient age. Results: 51 patients with cerebral/infantile Alexander disease were evaluated at a mean age of 10.96 years (range 2.29-31.08 years). Developmental milestones in Alexander disease were often achieved but delayed. Ambulation was achieved in 44 subjects (86%); 34 (67%) subjects walked independently (mean age 1.9 years, range 0.91-3.25 years) and an additional 10 (20%) subjects walked with assistance (mean age 3.9 years, range 1.8-8 years) but did not progress to independent ambulation. Developmental delay was the earliest and most prevalent symptom (N = 48 [94%], mean age 0.58 years), compared to an initial seizure (N = 41 [80%], mean age 2.80 years), and macrocephaly (N = 28 [55%], mean age 4.04 years), P < .0001 between these ages of onset. Loss of independent ambulation occurred in 11 of the 34 (32%) children who had acquired ambulation (range 3.41-15.10 years). Presence of seizures or macrocephaly did not predict the achievement or loss of ambulation. Conclusions: The clinical triad of developmental delay, seizures, and macrocephaly are not universally present in cerebral Alexander disease. Clinicians should have a high index of suspicion for Alexander disease in patients with mild delays and a first seizure.

Making Decisions About Krabbe Disease Newborn Screening.

Making Decisions About Krabbe Disease Newborn Screening.

Gene therapy offers new hope for children with metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) is a rare, progressive lysosomal storage disease caused by mutations in the gene encoding arylsulfatase A (ARSA), causing disease in the central and peripheral nervous systems. MLD presents in toddlers (late infantile disease) or in children (juvenile disease) with gait disturbances, loss of developmental milestones, and cognitive decline, leading to death in childhood. It is frequently not diagnosed until the later symptomatic phase when it is too late to intervene. Haematopoietic stem-cell transplantation (HSCT) from allogeneic donors has been used with mixed results. Although HSCT can slow progression of disease in the central nervous system, it does not prevent progression in the peripheral nervous system. HSCT is also associated with risks of graft-versus-host disease and treatment-related toxicity. 1 Boucher AA Miller W Shanley R et al. Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report. Orphanet J Rare Dis. 2015; 10: 94 Crossref PubMed Scopus (66) Google Scholar , 2 Wolf NI Breur M Plug B et al. Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction. Ann Clin Transl Neurol. 2020; 7: 169-180 Crossref PubMed Scopus (11) Google Scholar , 3 Beschle J Döring M Kehrer C et al. Early clinical course after hematopoietic stem cell transplantation in children with juvenile metachromatic leukodystrophy. Mol Cell Pediatr. 2020; 7: 12 Crossref PubMed Google Scholar , 4 Vander Lugt MT Chen X Escolar ML et al. Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders. Blood Adv. 2020; 4: 3041-3052 Crossref PubMed Scopus (3) Google Scholar Additionally, small trials of intrathecal gene therapy in mice or humans did not result in improvement in symptoms of clinical disease. 5 Miyake N Miyake K Sakai A Yamamoto M Suzuki H Shimada T Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A. Sci Rep. 2021; 1120513 Crossref PubMed Scopus (1) Google Scholar Thus, new therapeutic approaches are desperately needed. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded accessTreatment with arsa-cel resulted in sustained, clinically relevant benefits in children with early-onset MLD by preserving cognitive function and motor development in most patients, and slowing demyelination and brain atrophy. Full-Text PDF Open Access

Less is More: Aversion of Excessive Workup in Failure to Thrive.

A 14-month-old term boy with no significant medical history presents with 2 days of fever, vomiting, and diarrhea and 1 month of weight loss and poor appetite. On further history, his mother reported a 5 lb weight loss over 1 month, change in eating, and loss of developmental milestones. He was previously eating some solid foods but started refusing to eat or drink anything but breast milk. He also had loss of gross motor (he could no longer sit unsupported, crawl, or pull to stand), language (no longer speaking, previously said ∼5 words), and social (no longer exhibiting social reciprocity) milestones. He was last seen by a pediatrician at 6 months of age because of the family moving cross country and changing insurances. On physical examination, he was cachectic (BMI less than third percentile), had decreased muscle bulk and tone, and was mildly hyperreflexic with 3+ patellar reflexes bilaterally. He also had dry mucous membranes and tachycardia. He underwent fluid resuscitation and workup for his acute symptoms of fever, vomiting, and diarrhea and his chronic issues of poor feeding, weight loss, and loss of developmental milestones. Initial differential diagnosis included inadequate caloric intake, metabolic disorders, gastroesophageal reflux, malrotation, volvulus, intracranial process, and nonaccidental trauma. Initial laboratory workup was significant for metabolic alkalosis, hypocalcemia, and mildly elevated C-reactive protein. His infectious workup was notable for a positive Clostridium difficile assay. He was treated with a course of Flagyl. Imaging obtained on admission included chest radiograph, abdominal ultrasound and radiograph, echocardiogram, and skeletal survey for nonaccidental trauma, all of which were normal, and brain MRI, which showed significant diffuse white matter loss. Given his presentation, MRI findings, and the broad differential, neurology, medical genetics, and ophthalmology were consulted. He …

Recovery of HIV encephalopathy in perinatally infected children on antiretroviral therapy.

To describe the trajectory of clinical signs in children who developed human immunodeficiency virus encephalopathy (HIVE) after starting early antiretroviral therapy (ART). This was a retrospective case-cohort description of HIVE among Cape Town participants from the Children with HIV Early AntiRetroviral treatment (CHER) trial. Criteria for HIVE diagnosis were at least two of: (1) acquired central motor deficit, (2) impaired brain growth, and (3) failure to attain or loss of developmental milestones in the absence of an alternative aetiology. Of 133 surviving participants who initiated ART at a median age of 9weeks and who were followed until a median age of 6years, 20 (12%) developed HIVE at a median age 31months (interquartile range 19-37). In these, the first neurological deterioration was noticed at a median age of 19months, when 16 were on ART and nine had undetectable HIV viral load for a median of 12months. Signs of upper motor neurons were present in 18, of whom 12 resolved and four had persistent spastic diplegia; 19 had motor delay, of whom 14 resolved; 12 had language delay, of whom 11 resolved; and 16 had impaired brain growth, of whom only five recovered. For the 16 participants already on ART at HIVE diagnosis, regimens were not altered in response to diagnosis. HIVE may occur despite early ART initiation and virological suppression and then resolve on unchanged ART, most likely as intrathecal inflammation subsides. Despite suppressive antiretroviral therapy, children can develop human immunodeficiency virus encephalopathy, The most common manifestations are motor deficits and impaired brain growth. Most experience improvement, with many resolving without additional intervention.

Leveraging the genetic basis of Rett syndrome to ascertain pathophysiology.

Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), a progressive X-linked neurological disorder characterized by loss of developmental milestones, intellectual disability and breathing abnormality. Despite being a monogenic disorder, the pathogenic mechanisms by which mutations in MeCP2 impair neuronal function and underlie the RTT symptoms have been challenging to elucidate. The seemingly simple genetic root and the availability of genetic data from RTT patients have led to the generation and characterization of a series of mouse models recapitulating RTT-associated genetic mutations. This review focuses on the studies of RTT mouse models and describe newly obtained pathogenic insights from these studies. We also highlight the potential of studying pathophysiology using genetics-based modeling approaches in rodents and suggest a future direction to tackle the pathophysiology of intellectual disability with known or complex genetic causes.

Infantile neurodegenerative disorder associated with mutations in TBCD, an essential gene in the tubulin heterodimer assembly pathway.

Mutation in a growing spectrum of genes is known to either cause or contribute to primary or secondary microcephaly. In primary microcephaly the genetic determinants frequently involve mutations that contribute to or modulate the microtubule cytoskeleton by causing perturbations of neuronal proliferation and migration. Here we describe four patients from two unrelated families each with an infantile neurodegenerative disorder characterized by loss of developmental milestones at 9–24 months of age followed by seizures, dystonia and acquired microcephaly. The patients harboured homozygous missense mutations (A475T and A586V) in TBCD, a gene encoding one of five tubulin-specific chaperones (termed TBCA-E) that function in concert as a nanomachine required for the de novo assembly of the α/β tubulin heterodimer. The latter is the subunit from which microtubule polymers are assembled. We found a reduced intracellular abundance of TBCD in patient fibroblasts to about 10% (in the case of A475T) or 40% (in the case of A586V) compared to age-matched wild type controls. Functional analyses of the mutant proteins revealed a partially compromised ability to participate in the heterodimer assembly pathway. We show via in utero shRNA-mediated suppression that a balanced supply of tbcd is critical for cortical cell proliferation and radial migration in the developing mouse brain. We conclude that TBCD is a novel functional contributor to the mammalian cerebral cortex development, and that the pathological mechanism resulting from the mutations we describe is likely to involve compromised interactions with one or more TBCD-interacting effectors that influence the dynamics and behaviour of the neuronal cytoskeleton.

P83 – 2742: Clinical characteristics of MLD patients admitted to Hacettepe University in one-year period

Objective Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disorder caused by deficieny of arylsulfatase A (ARSA), leading to accumulation of sulfatide in myelinating cells and resulting progressive central and peripheral demyelination. Late-infantile, juvenile and adult forms have been distinguished. Clinical presentation shows great variations according to the age of onset. We report seven MLD cases with clinical and radiologic characteristics and we also share unusual presentations of two of them. Methods We collected clinical, radiological and laboratory findings of patients with MLD diagnosed in our center between 2014 and 2015, retrospectively. Results The age at onset of symptoms ranged between 18 months and 6 years. The median age at MLD diagnosis was 5 years (2–8.5 years). Four patients were late-infantile, three were juvenile form of MLD. Three patients had positive family history. Common symptoms in the late-infantile group were loss of developmental milestones, regression of motor skills, difficulty in swallowing. One patient suffered from seizures. Unusual presentation with peripheral neuropathy was observed in a patient. In the juvenile-onset group patients presented with cognitive decline, behavioral problems and gait disturbance. Gallbladder disease was detected in two patients. One of them was referred to our center due to gallbladder polyps without any neurological symptoms. Two patients were ambulatory in admission. All of the patients had low ARSA level and two of them had genetic evaluation for MLD. The brain magnetic resonance imaging results showed typical white matter alterations of MLD except the asymptomatic one. Conclusion Presenting symptoms and clinical course of MLD show remarkable variability among patients. In one-year period, we have seen a wide range of clinical presentations and, we have also experienced unusual clinical findings of MLD.

P87 – 2840: Establishment of rare diagnoses is possible in countries with limited resources

Objective Globoid cell leukodystrophy is a rare autosomal recessive lysosomal storage disorder caused by the deficiency of galactocerebrosidase. Methods This report describes a case in which clinical and MRI picture lead to the direct diagnosis. Results 12 months old girl presented with loss of developmental milestones. Her development was not concerning until 4 months. Starting from that age she started to have difficulties in head control, lost emotional contact, later she started to have difficulties with swallowing and myoclonias. Examination revealed absence of head control, short fixation and eye tracking movements, spastic quadriparesis, startle myoclonic reflex to auditory stimuli, absence of TDRs from legs. NCS showed distal symmetrical demyelinating polyneuropathy. Brain MRI showed supratentorial and vermian atrophy, abnormal signal from PLIC, increased T2 signal from periventricular white matter (with sparing of subcortical U-fibers), enlargement of optic nerves and chiasm, bilateral areas of T2 hyperintensity in the dentate hilum and cerebellar white matter, hypointensity in the peridentate area. Brain CT scan was done for possible calcifications in basal ganglia (to exclude Aicardi-Goutieres syndrome), which surprisingly revealed communicating obstructive hydrocephalus. We went through the literature and found that the latter was also described in some cases of globoid cell leukodystrophy. Decreased galactocerebrosidase activity in leukocytes confirmed the diagnosis of Krabbe disease. Conclusion In developed countries this patient would undergo full metabolic screening to exclude most relevant possible diagnoses, but physicians in developing world are forced to put together clinical picture and other findings to reach to the most likely diagnosis, which is a very important step to narrow the list of differential diagnosis and costs of needed investigations.

Teaching Neuro Images : Glutaric aciduria type 1 (glutaryl-CoA dehydrogenase deficiency)

A 14-month-old boy presented with loss of developmental milestones and tonic spasms following a diarrheal illness. He was born to nonconsanguineous parents and had mild motor delays. Examination was remarkable for macrocephaly, axial hypotonia, and asymmetric dystonic posturing of neck, trunk, and extremities. …

Paediatric neurology: advances on many fronts

Paediatric neurology: advances on many fronts

Cerebral symptoms in pre- or perinatally HIV-infected children

Eight of 13 children pre- or perinatally infected with the HIV virus subsequently developed neurological symptoms. Three children also had other nonspecific symptoms (fever, lymphadenopathy, diarrhoea, hepatosplenomegaly, failure to thrive and mucocutaneous thrush). Five children developed illnesses associated with AIDS (opportunistic infections, cachexia and lymphocytic interstitial pneumonia). The neurological abnormalities predominantly affected motor functions, only later also involving sensory ones. Motor, cognitive and language development was impaired in all eight children. A loss of developmental milestones occurred in three children with HIV encephalopathy: they have since died. In all the children the HIV infection caused symptoms within the first year, progressing more quickly in the three with encephalopathy. There were no discernible risk factors to account for the difference in the course of the disease.

A Seven-Month-Old Infant With Acute Onset of Neurologic Deterioration

A Seven-Month-Old Infant With Acute Onset of Neurologic Deterioration

Pediatrician Practices Regarding Referral to Early Intervention Services: Is an Established Diagnosis Important?

Early intervention (EI) programs provide services to children with developmental conditions, regardless of whether such children have an underlying medical diagnosis. We aim to (1) Determine the proportion of general pediatricians who believe an established diagnosis is important when considering EI referral; and (2) Determine whether this perception is associated with lower reported likelihood of referral. Mailed survey to random sample of pediatricians. We used multivariable logistic regression to study the association between the perception that a medical diagnosis is important when referring to EI, and the reported likelihood of EI referral for children with common developmental conditions. Response rate was 55% (894 of 1617). A total of 64% of respondents considered an established diagnosis important for EI referral. Likelihood of referral for delayed speech was lower among those who considered a diagnosis important than among those who did not (77% vs 87%; P = .02). Similar patterns held for global delay (91% vs 97%; P = .02), loss of developmental milestones (80% vs 88%; P = .03), and parental concern for inappropriate development (45% vs 60%; P = .002). In multivariable models, perception of the importance of an established diagnosis was associated with lower likelihood of referral for children with delayed speech (adjusted odds ratio [aOR] 0.48; 95% confidence interval [CI] 0.26-0.87) and for parental concern for inappropriate development (aOR 0.46; 95% CI 0.30-0.72). A majority of general pediatricians believe that an established diagnosis is important when considering EI referral. This perception is associated with decreased reported referral for children with speech delay and those whose parents express concern for inappropriate development.

Diagnosis and treatment of childhood mitochondrial diseases.

Mitochondrial cytopathies are caused by genetic alterations of nuclear- or mitochondrial-encoded genes involved in the synthesis of subunits of the electron transport chain. Mutations of mitochondrial DNA are associated with a wide range of clinical presentations [1-4]. The ubiquitous nature of mitochondria and the role of the mitochondria in cellular metabolism result in the potential for any tissue in the body to be affected [5-7,8..,9]. Although some children with mitochondrial disease present with life-threatening lactic acidosis in the newborn period, the majority of children come to clinical attention for nonspecific problems, including failure to thrive, developmental delay, seizures, hypotonia, and loss of developmental milestones. The diagnosis of these disorders is made through careful clinical evaluation, coupled with biochemical, morphologic, and molecular biologic techniques. Genetic counseling is difficult due to unique aspects of mitochondrial genetics. Despite advances in our understanding of mitochondrial biochemistry and genetics, treatment options remain limited.

Predicting shunt failure on the basis of clinical symptoms and signs in children.

In evaluating pediatric patients for shunt malfunction, predictive values for symptoms and signs are important in deciding which patients should undergo an imaging study, whereas determining clinical findings that correlate with a low probability of shunt failure could simplify management. Data obtained during the recently completed Pediatric Shunt Design Trial (PSDT) were analyzed. Predictive values were calculated for symptoms and signs of shunt failure. To refine predictive capability, a shunt score based on a cluster of signs and symptoms was derived and validated using multivariate methods. Four hundred thirty-one patient encounters after recent shunt insertions were analyzed. For encounters that took place within 5 months after shunt insertion (early encounters), predictive values for symptoms and signs included the following: nausea and vomiting (positive predictive value [PPV] 79%, likelihood ratio [LR] 10.4), irritability (PPV 78%, LR 9.8), decreased level of consciousness (LOC) (PPV 100%), erythema (PPV 100%), and bulging fontanelle (PPV 92%, LR 33.1). Between 9 months and 2 years after shunt insertion (late encounters), only loss of developmental milestones (PPV 83%, LR 36.7) and decreased LOC (PPV 100%) were strongly associated with shunt failure. However, the absence of a symptom or sign still left a 15 to 29% (early encounter group) or 9 to 13% (late encounter group) chance of shunt failure. Using the shunt score developed for early encounters, which sums from 1 to 3 points according to the specific symptoms or signs present, patients with scores of 0, 1, 2, and 3 or greater had shunt failure rates of 4%, 50%, 75%, and 100%, respectively. Using the shunt score derived from late encounters, patients with scores of 0, 1, and 2 or greater had shunt failure rates of 8%, 38%, and 100%, respectively. In children, certain symptoms and signs that occur during the first several months following shunt insertion are strongly associated with shunt failure; however, the individual absence of these symptoms and signs offers the clinician only a limited ability to rule out a shunt malfunction. Combining them in a weighted scoring system improves the ability to predict shunt failure based on clinical findings.

Hepatomegaly in neonates and children.

1. Ann D. Wolf, MD* 2. Joel E. Lavine, MD, PhD† 1. 2. *Chief Resident. 3. 4. †Associate Professor of Pediatrics and Chief, Joint Program in Gastroenterology and Nutrition, Department of Pediatrics, UCSD School of Medicine, San Diego, CA. After completing this article, readers should be able to: 1. Identify the possible causes of simultaneous hepatomegaly and splenomegaly. 2. List the important diagnostic considerations in patients who have hepatomegaly. 3. Delineate the most helpful initial radiographic test. 4. Describe what clinical findings occurring concomitantly in a patient who has hepatomegaly suggest metabolic or storage disease. 5. List the risk factors for infectious hepatitis. Hepatomegaly can represent intrinsic liver disease or may be the presenting physical finding of a generalized disorder. Early diagnosis and treatment of children who have liver disease is important because specific treatments are available for some diseases that can prevent disease progression or hepatic failure. The presence of a palpable liver does not always indicate hepatomegaly. Normal liver size is based on normative values of liver span by percussion, degree of extension below the right costal margin, or length of the vertical axis estimated from imaging techniques. In general, a liver edge greater than 3.5 cm in newborns and greater than 2 cm in children below the right costal margin suggests enlargement. Liver span is determined by measuring the distance between the upper edge, determined by percussion, and the lower edge, determined by palpation, in the midclavicular line. The lower border also may be determined by auscultation. With the stethoscope placed below the xiphoid, the examiner should gently scratch superiorly, starting in from the right lower quadrant, and listen for sound enhancement as the finger passes over the liver edge. Liver span increases linearly with body weight and age in both genders and correlates more with weight than with height. The normal range for liver span by percussion at 1 week of age is 4.5 to 5 cm. At 12 years, the normal value for boys is 7 to 8 cm and for girls is 6 to 6.5 cm. The liver …