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The COVID-19 pandemic has impacted the education of children around the world, forcing a large proportion of teaching to be carried out remotely. The implications of this disruption have yet to be fully elucidated, but initial assessments suggest that COVID-19-related school closures and reliance on virtual learning may have a long-term negative impact on educational attainment and future earnings as well as life expectancy of children in the United States. Among children with neurodegenerative disorders, such as neuronopathic mucopolysaccharidoses (MPS disorders), the effects of the pandemic are likely to be even greater. We aim to shine a spotlight on the impact of COVID-19 on the education, treatment and general wellbeing of children and families affected by MPS disorders by highlighting the important role that educators and therapists play in supporting the neurocognitive function and quality of life of children with neuronopathic MPS disorders. This article will serve as a resource that caregivers, educators, clinicians and therapists can use when considering how best to advocate for children with neuronopathic MPS disorders in circumstances where in-school teaching or in-clinic treatment is compromised or not possible. Given that the current pandemic is likely to have a prolonged course and impact and that similar epidemics and pandemics are a near certainty in the future, it is essential that steps are taken to support the learning and care of children with neuronopathic MPS disorders. We must prioritize strategies to safely resume this fragile community's access to in-person education and supportive care, and to address gaps that have emerged during prolonged pauses in access, whenever possible.

ObjectiveTo quantify benchmark treatment outcomes that may be enabled by newborn screening surveillance for X-linked adrenoleukodystrophy (ALD), we report neurocognitive, neuropsychiatric, and MRI change for boys who underwent hematopoietic stem cell transplant (HSCT) at initial stages of demyelination, prior to neurocognitive signs of disease.MethodsRetrospective chart review identified 36 patients whose cerebral ALD was detected and treated early, with lesion severity less than 5 on the ALD-specific MRI scoring system. Median age at transplant was 7.3 years (range, 4.0–16.1). Progression of radiologic disease on MRI in the 2 years following HSCT was examined relative to the severity of the initial lesion for 33 patients, and longitudinal neurocognitive and neuropsychiatric outcomes were studied for 30 patients.ResultsPatients whose pretransplant lesion extended beyond the splenium of the corpus callosum and adjacent periventricular white matter (MRI severity score >2) demonstrated lower posttransplant neurocognitive scores, more neuropsychiatric symptoms, and more disease progression on MRI than patients with a less severe lesion. Changes from baseline neurocognitive functioning were greater at 2 years posttransplant as compared to 1 year. There was greater variance and risk of lesion progression as pretransplant MRI severity increased.ConclusionTo realize the full benefits of newborn screening, clinicians must detect very small demyelinating lesions during surveillance and intervene quickly. Novel interventions that reduce risks inherent in allogeneic transplantation are needed. Trial endpoints should include direct neurocognitive assessment and extend at least 2 years posttreatment to provide the greatest sensitivity to detect neurocognitive morbidity.

CASE Carter is a 12-year-old boy who has been seeing a developmental-behavioral pediatrician since the age of 7 years for problems with behavioral regulation. Around that time, he began to receive special education services after an educational assessment of autism. He has average intellectual abilities, with below-average semantic-pragmatic speech (e.g., conversations are one-sided). His medical diagnoses included attention-deficit hyperactivity disorder (ADHD), combined presentation, and generalized anxiety disorder. He has never met the DSM criteria for autistic spectrum disorder (ASD) because although he has atypical sensory behaviors (e.g., preoccupied with sniffing objects), he has otherwise lacked restricted, repetitive behaviors. Other medical problems include obesity.His functional impairments associated with impulsivity, inattention, and anxiety improved with combined pharmacotherapy (a long-acting stimulant and a selective serotonin reuptake inhibitor [SSRI], on which he remains) and cognitive-behavioral therapy (CBT). After starting sixth grade, his Individualized Educational Plan (IEP) was modified to address his social impairments, with a self-contained classroom without windows. Soon thereafter, he began to talk about "hating myself" and developed mild-to-moderate depression, which improved after several weeks of a higher dose of SSRI and more frequent visits with his therapist.Several weeks after starting seventh grade, the teacher sent an email to Carter's parents, which they forwarded to his developmental-behavioral pediatrician: "Carter drew a picture of himself shooting and stabbing a student he was mad at today (). He was very upset when I told him I was going to tell you. We haven't processed it through yet but I think a conversation at home about appropriate drawings and using other ways to calm down would help this not happen again."

Mucopolysaccharidosis type I (MPS I) was added to the Recommended Uniform Screening Panel for newborn screening in 2016, highlighting recognition that early treatment of MPS I is critical to stem progressive, irreversible disease manifestations. Enzyme replacement therapy (ERT) is an approved treatment for all MPS I phenotypes, but because the severe form (MPS IH, Hurler syndrome) involves rapid neurocognitive decline, the impermeable blood-brain-barrier is considered an obstacle for ERT. Instead, hematopoietic cell transplantation (HCT) has long been recommended, as it is believed to be the only therapy that arrests neurocognitive decline. Yet ERT monotherapy has never been compared to HCT, because it is unethically unacceptable to evaluate a therapeutic alternative to one shown to treat Central Nervous System (CNS) disease. An unusual opportunity to address this question is presented with this clinical report of a 16-year-old female with MPS IH treated only with ERT since her diagnosis at age 2. Neurological functioning was stable until cervical spinal cord compression at age 8, hydrocephalus at age 11, and neurocognitive declines beginning at age 10. Somatic disease burden is significant for first degree AV block, restrictive lung disease, bilateral hearing loss, severe corneal clouding, joint pain/limitations requiring mobility assistance, and short stature. This patient's extended survival and prolonged intact neurocognitive functioning depart from the untreated natural history of MPS IH. Disease burden typically controlled by HCT emerged. Although not anticipated to provide benefit for CNS disease, ERT may have provided some amelioration or slowing of neurocognitive deterioration.

Pediatric clinical neuropsychological evaluations often compliment traditional psychoeducational evaluations and can facilitate the special education evaluation process in determining eligibility and providing recommendations to enhance a child’s progress. Many pediatric neuropsychologists have medical-legal experience along with knowledge of advanced assessment techniques. As a profession, pediatric neuropsychologists are in increasing demand to conduct independent educational evaluations. This article highlights the laws governing the Independent Educational Evaluation (IEE) and the basic procedures for providing IEEs.

Background Infantile gangliosidoses include GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease). To date, natural history studies in infantile GM2 (iGM2) have been retrospective and conducted through surveys. Compared to iGM2, there is even less natural history information available on infantile GM1 disease (iGM1). There are no approved treatments for infantile gangliosidoses. Substrate reduction therapy using miglustat has been tried, but is limited by gastrointestinal side effects. Development of effective treatments will require identification of meaningful outcomes in the setting of rapidly progressive and fatal diseases. Objectives This study aimed to establish a timeline of clinical changes occurring in infantile gangliosidoses, prospectively, to: 1) characterize the natural history of these diseases; 2) improve planning of clinical care; and 3) identify meaningful future treatment outcome measures. Methods Patients were evaluated prospectively through ongoing clinical care. Results Twenty-three patients were evaluated: 8 infantile GM1, 9 infantile Tay-Sachs disease, 6 infantile Sandhoff disease. Common patterns of clinical change included: hypotonia before 6 months of age; severe motor skill impairment within first year of life; seizures; dysphagia and feeding-tube placement before 18 months of age. Neurodevelopmental testing scores reached the floor of the testing scale by 20 to 28 months of age. Vertebral beaking, kyphosis, and scoliosis were unique to patients with infantile GM1. Chest physiotherapy was associated with increased survival in iGM1 (p = 0.0056). Miglustat combined with a low-carbohydrate ketogenic diet (the Syner-G regimen) in patients who received a feeding-tube was associated with increased survival in infantile GM1 (p = 0.025). Conclusions This is the first prospective study of the natural history of infantile gangliosidoses and the very first natural history of infantile GM1. The homogeneity of the infantile gangliosidoses phenotype as demonstrated by the clinical events timeline in this study provides promising secondary outcome measure candidates. This study indicates that overall survival is a meaningful primary outcome measure for future clinical trials due to reliable timing and early occurrence of this event. Combination therapy approaches, instead of monotherapy approaches, will likely be the best way to optimize clinical outcomes. Combination therapy approaches include palliative therapies (e.g., chest physiotherapy) along with treatments that address the underlying disease pathology (e.g. miglustat or future gene therapies).

Neuropsychological data are reviewed from two sets of dizygotic twins presenting with selective mutism characterized by situation specific anxiety, extreme passive behavior, lack of responsivity, lack of peer interaction, and a chronic course of selective mutism. Both sets of twins had a history of prematurity and delayed speech development. One set of twins presented with normal intelligence and normal receptive language skills but with expressive language and oral motor sequencing difficulties. The second set of twins presented with Verbal IQ deficits and significant receptive and expressive language deficits. A summary of current conceptualizations regarding etiology and treatment of selective mutism is provided.

Received June 26, 2001; accepted August 21, 2001. Primary brain and other central nervous system (CNS) tumors are the most common solid tumors that occur during childhood, with an annual U.S. rate of approximately 3.0 cases per 100,000 persons aged 19 years or younger. Incidence rates of pediatric CNS malignancies were essentially unchanging during the 1990s; past concerns about trends that indicated increasing rates in the 1980s appears to be largely explainable by diagnostic and ascertainment improvements that occurred during that time period. The prevalence of persons alive with a previous diagnosis of a CNS malignancy is estimated by the National Cancer Institute to be 35 per 100,000 males and 29 per 100,000 females. Because nonmalignant CNS tumors (such as meningiomas) are not included in this statistic, the actual prevalence of CNS tumor survivors in the U.S. is substantially higher than the National Cancer Institute estimates. As treatment improves, more children are surviving cancer into adulthood. Survival rates for those with pediatric CNS tumors differ substantially by histology, site, and age at diagnosis. Overall, the 5-year survival probability for children with a CNS malignancy diagnosed between 1985 and 1994 was 67%. Pediatric patients generally have a better prognosis than adults with CNS tumors, although the morbidity from these tumors and their treatment can be substantial. As more children with CNS tumors survive and require treatment in primary care settings, it is increasingly important for health care providers to recognize long-term complications of these tumors and their treatments. The purpose of this article is to provide a concise review of the long-term effects of pediatric CNS tumors and their treatment. We hope this review will aid providers in managing CNS survivors’ existing problems and in anticipating problems that survivors may face.

Cerebral adrenoleukodystrophy (cALD) remains a devastating neurodegenerative disease; only allogeneic hematopoietic cell transplantation (HCT) has been shown to provide long-term disease stabilization and survival. Sixty boys undergoing HCT for cALD from 2000 to 2009 were analyzed. The median age at HCT was 8.7 years; conditioning regimens and allograft sources varied. At HCT, 50% demonstrated a Loes radiographic severity score ≥ 10, and 62% showed clinical evidence of neurologic dysfunction. A total of 78% (n = 47) are alive at a median 3.7 years after HCT. The estimate of 5-year survival for boys with Loes score < 10 at HCT was 89%, whereas that for boys with Loes score ≥ 10 was 60% (P = .03). The 5-year survival estimate for boys absent of clinical cerebral disease at HCT was 91%, whereas that for boys with neurologic dysfunction was 66% (P = .08). The cumulative incidence of transplantation-related mortality at day 100 was 8%. Post-transplantation progression of neurologic dysfunction depended significantly on the pre-HCT Loes score and clinical neurologic status. We describe the largest single-institution analysis of survival and neurologic function outcomes after HCT in cALD. These trials were registered at www.clinicaltrials.gov as #NCT00176904, #NCT00668564, and #NCT00383448.

Hematopoietic stem cell transplantation as a treatment for childhood cerebral adrenoleukodystrophy (ALD) has historically only been successful in early disease. As ALD is associated with oxidative damage, we reasoned that adjunctive therapy with an antioxidant agent, N-acetyl-L-cysteine (NAC), may provide protection from rapid neurologic decline in boys with advanced cerebral disease. We report three boys with advanced ALD, whose neurologic status and brain radiographic findings were stabilized by treatment including NAC 8-11 months after hematopoietic stem cell transplantation. These results contrast with previous survival data in cerebral ALD patients who had a similar degree of brain involvement, all of whom died within 1 year of stem cell infusion despite a full donor engraftment. Thus, NAC merits investigation as a therapeutic strategy for patients with advanced ALD as an intervention that could change this lethal disease to a condition amendable to treatment with hematopoietic stem cell transplantation.

We are writing this column as a first step in an effort to gain consensus from training programs and pediatric neuropsychologists about the future of the field and the best way to train students. The training of pediatric neuropsychologists is becoming an important issue for a number of reasons: The field is developing an identity of its own, and a critical mass has been achieved of those who call themselves pediatric neuropsychologists. There are individuals practicing who are poorly trained, and often convey misinformation to parents and schools. Having some criteria by which to judge the training and knowledge of pediatric neuropsychologists will enable parents, schools, and medical personnel to obtain higher quality services. Additionally, third-party payers are now seeking information regarding the training of pediatric neuropsychologists and often credentialing them as providers based on their training. Finally, research in this area is burgeoning. Functional imaging, new therapies, new dia...

Cerebral X-linked adrenoleukodystrophy (X-ALD) is a disorder of very-long-chain fatty acid metabolism, adrenal insufficiency, and cerebral demyelination. Death occurs within 2 to 5 years of clinical onset without hematopoietic cell transplantation (HCT). One hundred twenty-six boys with X-ALD received HCT from 1982 to 1999. Survival, engraftment, and acute graft-versus-host disease were studied. Degree of disability associated with neurologic and neuropsychological function and cerebral demyelination were evaluated before and after HCT. Complete data were available and analyzed for 94 boys with cerebral X-ALD. The estimated 5- and 8-year survival was 56%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Demyelination involved parietal-occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. Overall 5-year survival of 92% in patients with 0 or 1 neurologic deficits and magnetic resonance imaging (MRI) severity score less than 9 before HCT was superior to survival for all others (45%; P < .01). Baseline neurologic and neuropsychological function, degree of disability, and neuroradiologic status predicted outcomes following HCT. In this first comprehensive report of the international HCT experience for X-ALD, we conclude that boys with early-stage disease benefit from HCT, whereas boys with advanced disease may be candidates for experimental therapies.

Objectives: A recent patient series reported the incidental findings of improved social and language skills in 3 children with autistic spectrum disorders after the administration of secretin, a peptide hormone. However, a subsequent study did not find evidence for a drug effect. Parents are seeking treatment with secretin despite the absence of empirical investigations demonstrating amelioration in autism symptomology. In order to more precisely measure the effects of secretin, this study investigated the effect of a single intravenous dose of porcine secretin on 12 autistic children through a randomized, double-blind, placebo-controlled, crossover study. Children were assessed on objective language and on social, neuropsychological, and gastrointestinal measures to evaluate drug effects. The study was conducted over a 16-week trial. The results indicated that significant differences were not observed on the majority of the dependent variables. Statistically significant differences were observed on measures of positive affect and activity level following secretin infusion. In general, the autistic children did not demonstrate the improvements described in the initial retrospective report.

Hurler syndrome (HS) is an autosomal recessive, inherited metabolic storage disorder due to deficiency of lysosomal alpha-L-iduronidase (IDU) enzyme activity. Untreated patients develop progressive mental retardation and multisystem morbidity with a median life expectancy of 5 years. Allogeneic hematopoietic cell transplantation (HCT) can achieve stabilization and even improvement of intellect, with long-term survival. However, children with HS have an increased incidence of graft failure, usually with concomitant autologous marrow reconstitution. Between 1983 and 2000, 71 Hurler children underwent HCT at the University of Minnesota. Of these 71, 19 (27%) experienced graft failure. We report HCT outcomes in all 11 Hurler patients receiving a second HCT at the University of Minnesota. Median age at second HCT was 25 months (range, 16 to 45 months); median time from first HCT was 8 months (range, 4 to 18.5 months). The conditioning regimen consisted of cyclophosphamide/TBI/ATG (n = 8) or busulfan/cyclophosphamide/ATG (n = 3). The source of bone marrow was an unrelated donor in six, matched sibling in four, and mismatched related in one. Five of the 11 grafts were T cell depleted prior to infusion. Overall, 10 of 11 patients showed donor-derived engraftment, of whom three developed grade 3 to 4 acute GVHD. Five of 11 patients are surviving a median of 25 months (range, 2 months to 12 years) with an overall actuarial survival of 50% (95% CI, 27% to 93%) at 4 years. All five show sustained donor engraftment with normalization of IDU activity levels. Three of five evaluable patients demonstrated stabilization of neuropsychological function after second HCT. Currently, allogeneic donor-derived hematopoiesis provides the only chance for long-term survival and improved quality of life in Hurler patients. While graft failure in Hurler patients requires further investigation, a timely second HCT can be well-tolerated and beneficial.

Summary Background The childhood-onset cerebral form of X-linked adrenoleukodystrophy, a demyelinating disorder of the central nervous system, leads to a vegetative state and death within 3–5 years once clinical symptoms are detectable. The hypothesis to be tested was whether bone-marrow transplantation can over an extended period of time halt the inexorable progressive demyelination and neurological deterioration. Methods 12 patients with childhood onset of cerebral X-linked adrenoleukodystrophy have been followed for 5–10 years after bone-marrow transplantation. Magnetic resonance imaging (MRI), neurological, neuropsychological, electrophysiological, and plasma very-long-chain fatty acid (VLCFA) measurements were used to evaluate the effect of this treatment. Findings MRI showed complete reversal of abnormalities in two patients and improvement in one. One patient showed no change from baseline to last follow-up. All eight patients who showed an initial period of continued demyelination stabilised and remained unchanged thereafter. Motor function remained normal or improved after bone-marrow transplantation in ten patients. Verbal intelligence remained within the normal range for 11 patients. Performance (non-verbal) abilities were improved or were stable in seven patients. Decline in performance abilities followed by stability occurred in five patients. Plasma VLCFA concentrations decreased by 55% and remained slightly above the upper limits of normal. Interpretation 5–10-year follow-up of 12 patients with childhood-onset cerebral X-linked adrenoleukodystrophy shows the long-term beneficial effect of bone marrow transplantation when the procedure is done at an early stage of the disease.

Objective To investigate whether intravenous enzyme replacement therapy (ERT) benefits cognitive function in patients with mucopolysaccharidosis type IH (Hurler syndrome) undergoing hematopoietic cell transplantation (HCT). Study design Data were obtained for 9 children treated with HCT + ERT (ERT group) and 10 children treated with HCT only (no-ERT group) from neuropsychologic evaluations before HCT and at 1-year and 2-year post-HCT follow-up. Results At 2 years after HCT, children in the ERT group lost 9.19 fewer IQ points per year compared with children in the no-ERT group ( P = .031). Furthermore, the ERT group improved in nonverbal problem solving and processing, whereas the no-ERT group declined, resulting in a difference of 9.44 points per year between the 2 groups ( P Conclusion ERT in association with HCT enhances cognitive outcomes, providing new evidence that ERT is a valuable addition to the standard transplantation protocol. Although the mechanism responsible for this improved outcome is unknown, both direct benefits and indirect effects must be considered.

The International Storage Disease Collaborative Study Group has evaluated the effectiveness of hematopoietic cell transplant (HCT) to halt the progressive neurologic deterioration, dementia, and early death of cerebral X-adrenoleukodystrophy (CXALD) in 126 patients (? donor: 3) from July 1982 to January 1999. HCT can achieve neurologic and neuropsychologic stabilization as well as preservation of life in boys with CXALD especially when performed early in the disease course. A centralized HCT CXALD database is needed so that clinical trials can be performed.

Treatment of High Risk Childhood Onset Cerebral Adrenoleukodystrophy (COCALD) with Modified Hematopoietic Stem Cell Transplantation (HSCT) • 1893

Evidence for a presynaptic neuromodulatory effect of atrial natriuretic factor (ANF) has been obtained in rat adrenal pheochromocytoma cells (PC12), a clonal line that differentiates into adrenergic neuron-like cells when treated with nerve growth factor. ANF had no effect on basal norepinephrine (NE) release. In contrast, ANF markedly and significantly inhibited carbachol-induced NE release in a concentration-dependent manner. This result is consistent with the hypothesis that ANF may be an inhibitory neuromodulator.

Background Metachromatic Leukodystrophy (MLD) is a rare, fatal demyelinating disorder with limited treatment options. Published outcomes after hematopoietic stem cell transplantation (HSCT) are scant and mixed. We report survival and function following HSCT for a large, single-center MLD cohort. Methods Transplant-related data, survival and serial measures (brain MRI, nerve conduction velocity (NCV), neurologic and neuropsychology evaluations) were reviewed. When possible, parental interviews informed current neurologic status, quality-of-life, and adaptive functioning. Gross motor and expressive functions for late-infantile (LI-MLD) and juvenile (J-MLD) patients were described using previously reported, MLD-specific scales. Results Forty patients with confirmed MLD have undergone HSCT at our center. Twenty-one (53 %) survive at a median 12 years post-HSCT. Most deaths (n = 17) were treatment-related; two died from disease progression. Survival did not depend upon MLD subtype or symptom status at transplant. LI-MLD patients survive beyond reported life expectancy in untreated disease. Abnormal brain MRI and peripheral nerve conduction velocities (NCV) were common before HSCT. Following transplant, fewer patients experienced MRI progression compared to NCV deterioration. Sixteen LI-MLD and J-MLD survivors were evaluable for long-term gross motor and/or expressive language functioning using existing MLD clinical scoring systems. While most J-MLD patients regressed, the aggregate cohort demonstrated superior retention of function compared to published natural history. Seventeen LI-MLD, J-MLD and adult subtype (A-MLD) survivors were evaluable for long-term adaptive functioning, activities of daily living, and/or cognition. Relative cognitive sparing was observed despite overall global decline. Five sibling pairs (one LI-MLD and four J-MLD), in which at least one underwent transplant in our cohort, were evaluable. Within each familial dyad, survival or function was superior for the treated sibling, or if both siblings were transplanted, for the pre-symptomatic sibling. Conclusions HSCT is a viable treatment option for MLD, but has significant limitations. Later-onset phenotypes may benefit most from early, pre-symptomatic transplant. Until superior, novel treatment strategies are demonstrated, MLD patients should be carefully considered for HSCT.