Long-term neurodevelopmental outcomes of hematopoietic stem cell transplantation for late-infantile Krabbe disease.

Krabbe disease is a rare neurodegenerative disorder caused by a deficiency in galactocerebrosidase. The only effective treatment is hematopoietic stem cell transplantation (HSCT). Approximately 85% of Krabbe disease cases are the infantile subtypes, among which ∼20% are late infantile. Prior studies have demonstrated that HSCT is effective for early-infantile patients (0-6 months of age) who undergo transplantation while asymptomatic, compared with those receiving transplants while symptomatic. However, no studies evaluated the efficacy of HSCT for late-infantile patients (6-36 months). In this prospective, longitudinal study, patients were evaluated at a single site according to a standardized protocol. Survival analysis was performed using the Kaplan-Meier method. Differences between groups were estimated using mixed regression models to account for within-person repeated measures. Nineteen late-infantile patients underwent HSCT (March 1997 to January 2020). Compared with untreated patients, transplant recipients had a longer survival probability and improved cognitive and language function. Gross and fine motor development were most affected, with variable results. Asymptomatic patients benefitted the most from transplantation, with normal to near-normal development in all domains and some gross motor delays. Among symptomatic patients, those with disease onset at >12 months of age had better cognitive outcomes than untreated patients. Those with disease onset at ≤12 months were comparable to untreated patients. We found that HSCT prolonged the lifespan and improved the functional abilities of late-infantile patients with Krabbe disease, particularly those who underwent transplantation before onset of symptoms. In addition, our findings support prior literature that reclassifies late-infantile Krabbe disease to be symptom onset at 12 to 36 months of age.

Development of a newborn screening tool based on bivariate normal limits: using psychosine and galactocerebrosidase determination on dried blood spots to predict Krabbe disease.

PURPOSE: Newborn screening for Krabbe disease (KD) originated in New York State in 2006 but has proven to have a high false positive rate and low positive predictive value. To improve accuracy of presymptomatic prediction, we propose a screening tool based on two biomarkers, psychosine and galactocerebrosidase enzyme activity (GalC). METHODS: We developed the tool using measures from dried blood spots of 166 normal newborns and tested it on dried blood spot measures from 15 newborns who later developed KD, 8 newborns identified as "high risk" by the New York screening protocol but were disease-free at follow-up, and 3 symptomatic children with onset before 4 years of age. The tool was developed from the (1-10-6)100% prediction region of the natural logarithms of psychosine and GalC measures, assuming bivariate normality, and their univariate normal limits. RESULTS: Krabbe disease was predicted correctly for every patient who developed symptoms in infancy or early childhood. None of the high-risk patients were incorrectly identified as having early KD. CONCLUSION: Bivariate analysis of psychosine and GalC in newborn blood spots can accurately predict early Krabbe symptoms, control false positive rates, and permit presymptomatic treatment.

General anesthesia safety in progressive leukodystrophies: A retrospective study of patients with Krabbe disease and metachromatic leukodystrophy.

BACKGROUND: Krabbe disease and metachromatic leukodystrophy are leukodystrophies characterized by neurologic degeneration and early death. Patients often require general anesthesia for diagnostic and therapeutic interventions. METHODS: A retrospective review of medical records was conducted for patients with Krabbe disease and metachromatic leukodystrophy receiving general anesthesia at a large children's hospital between 2012 and 2017. Patient complications and American Society of Anesthesiologists Physical Status were recorded for all procedures. The Neurodevelopment in Rare Disorders classification system was created to categorize the severity of the patient's disease progression based on clinical markers. Descriptive and inferential statistics were used to compare: (a) complication rate of affected patients vs the general hospital population; (b) the accuracy of the novel Neurodevelopment in Rare Disorders classification system vs American Society of Anesthesiologists Physical Status regarding the assessment of complication risk; (c) complication rate in patients with hematopoietic stem cell transplantation vs those without transplantation; (d) complication rate in immunosuppressed patients vs nonimmunosuppressed patients; and (e) complication rate of the three most commonly performed procedures. RESULTS: A total of 96 patients underwent 287 procedures. Of these, 11 cases had complications, yielding a rate of 3.8%. This is significantly higher than the overall complication rate at our institution of 0.246%. Statistical analysis showed better correlation between the Neurodevelopment in Rare Disorders classification system and complication rate than American Society of Anesthesiologists Physical Status and complication rate. The system also showed better accuracy in differentiating low-risk and high-risk patients. No statistically significant difference in complication rate was found for patients with transplantation vs those without transplantation or for immunosuppressed vs nonimmunosuppressed patients. Of the three most common procedures, central catheter placement/removal exhibited the highest complication rate. CONCLUSIONS: Although the complication rate for patients with Krabbe disease and metachromatic leukodystrophy is higher than the general population, most complications were mild and self-limiting. These results suggest that, in experienced hands, general anesthesia is well tolerated in most children. Findings show that the Neurodevelopment in Rare Disorders classification system is a better indicator for assessing complication risk in patients with Krabbe and metachromatic leukodystrophy than American Society of Anesthesiologists Physical Status.

Clinical management of Krabbe disease.

Krabbe disease (KD) is a rare neurodegenerative disorder caused by mutations in the gene encoding the galactocerebrosidase enzyme. The early- and late-infantile subtypes, which are the most common forms of the disease, are rapidly progressive and lead to early death, whereas the later-onset types are clinically heterogeneous. The only disease-modifying treatment currently available is hematopoietic stem cell transplantation, which is effective only when performed early in the course of the disease. Because most patients with KD are diagnosed too late for treatment, primary care physicians are faced with the challenge of caring for a child with severe neurologic impairment. This Review describes presenting symptoms, diagnosis, and disease manifestations of KD and provides basic guidelines for its management. Symptomatic treatment and supportive care that address the unique requirements of these patients can greatly improve the quality of life of patients and their families. © 2016 Wiley Periodicals, Inc.

Thickening of the cauda equina roots: a common finding in Krabbe disease.

OBJECTIVES: Evaluation of Krabbe disease burden and eligibility for hematopoietic stem cell transplantation are often based on neuroimaging findings using the modified Loes scoring system, which encompasses central but not peripheral nervous system changes. We show that quantitative evaluation of thickened cauda equina nerve roots may improve the evaluation of Krabbe disease and therapeutic guidance. METHODS: Lumbar spine MRI scans of patients obtained between March 2013 and September 2013 were retrospectively evaluated and compared to those of controls. Quantitative evaluation of cauda equina roots was performed on the axial plane obtained approximately 5 mm below the conus medullaris. The largest nerves in the right and left anterior quadrants of the spinal canal were acquired. RESULTS: Fifteen symptomatic patients with Krabbe disease (5-44 months old) and eleven age-matched controls were evaluated. The average areas (mm(2)) of anterior right and left nerves were 1.40 and 1.23, respectively, for patients and 0.61 and 0.60 for controls (differences: 0.79 and 0.63; p < 0.001). CONCLUSIONS: Cauda equina nerve root thickening is associated with Krabbe disease in both treated and untreated patients. Adding lumbar spine MRI to the current neurodiagnostic protocols, which fails to account for peripheral nerve abnormalities, will likely facilitate the diagnosis of Krabbe disease. KEY POINTS: • Neuroimaging is valuable for evaluating cauda equina nerve abnormality in Krabbe disease • MRI can be used to quantitatively evaluate cauda equina nerve thickening • Lumbar MRI could be useful for diagnosis and treatment monitoring of Krabbe disease.

Early treatment is associated with improved cognition in Hurler syndrome.

OBJECTIVE: Hurler syndrome is the most clinically severe form of an autosomal recessive lysosomal disorder characterized by the deficiency of α-L-iduronidase. The resulting accumulation of glycosaminoglycans causes progressive multisystem deterioration, resulting in death in childhood. Umbilical cord blood transplantation from unrelated donors has been previously shown to improve neurological outcomes of children <2 years of age and prolong life. The purpose of this article is to determine whether age at transplantation can predict cognitive outcomes. METHODS: Between June 1997 and February 2013, 31 patients with Hurler syndrome underwent umbilical cord blood transplantation and were evaluated at baseline and every 6 to 12 months thereafter. All 31 patients underwent complete neurodevelopmental evaluation (median follow-up = 7.3 years, range = 2-21.7) and a median of 7.0 evaluations (range = 3-18). RESULTS: Younger age at transplantation was associated with improved cognitive function (p = 0.001), receptive and expressive language (p = 0.004 and p = 0.01), and adaptive behavior (p = 0.03). INTERPRETATION: Early age at transplantation is a strong predictor of cognitive, language, and adaptive behavior outcomes. Children younger than 9 months at the time of transplant showed normal cognitive development. Our results demonstrate that early diagnosis is necessary for optimal outcomes and support the need for newborn screening, because most patients are not identified at this young age.

Midbrain morphology reflects extent of brain damage in Krabbe disease.

INTRODUCTION: To study the relationships between midbrain morphology, Loes score, gross motor function, and cognitive function in infantile Krabbe disease. METHODS: Magnetic resonance imaging (MRI) scans were evaluated by two neuroradiologists blinded to clinical status and neurodevelopmental function of children with early or late infantile Krabbe disease. A simplified qualitative 3-point scoring system based on midbrain morphology on midsagittal MRI was used. A score of 0 represented normal convex morphology of the midbrain, a score of 1 represented flattening of the midbrain, and a score of 3 represented concave morphology of the midbrain (hummingbird sign). Spearman correlations were estimated between this simplified MRI scoring system and the Loes score, gross motor score, and cognitive score. RESULTS: Forty-two MRIs of 27 subjects were reviewed. Analysis of the 42 scans showed normal midbrain morphology in 3 (7.1%) scans, midbrain flattening in 11 (26.2%) scans, and concave midbrain morphology (hummingbird sign) in 28 (66.7%) scans. Midbrain morphology scores were positively correlated with the Loes score (r = 0.81, p < 0.001) and negatively correlated with both gross motor and cognitive scores (r = -.84, p < 0.001; r = -0.87, p < 0.001, respectively). The inter-rater reliability for the midbrain morphology scale was κ = .95 (95% CI: 0.86-1.0), and the inter-rater reliability for the Loes scale was κ = .58 (95% CI: 0.42-0.73). CONCLUSIONS: Midbrain morphology scores of midsagittal MRI images correlates with cognition and gross motor function in children with Krabbe disease. This MRI scoring system represents a simple but reliable method to assess disease progression in patients with infantile Krabbe disease.

Neurodevelopmental outcomes of umbilical cord blood transplantation in metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an inherited demyelinating disease that causes progressive neurologic deterioration, leading to severe motor disability, developmental regression, seizures, blindness, deafness, and death. The disease presents as a late-infantile, juvenile, or adult form. Hematopoietic stem cell transplantation has been shown to slow disease progression. The purpose of this longitudinal study was to evaluate long-term treatment outcomes after unrelated donor umbilical cord blood (UCB) transplantation in pediatric patients according to disease burden and age at onset (ie, late-infantile versus juvenile). Engraftment, survival, treatment-related toxicity, graft-versus-host disease, neurophysiologic measures, and neurodevelopmental function were assessed. To evaluate whether signal intensity abnormalities on magnetic resonance imaging (ie, modified Loes scores) predict post-transplant cognitive and gross motor development, a general linear mixed model was fit to the data. Twenty-seven patients underwent transplantation after myeloablative chemotherapy; 24 patients engrafted after the initial transplantation. Seven patients died of infection, regimen-related toxicity, or disease progression. Twenty patients (6 with late-infantile onset and 14 with juvenile onset) were followed for a median of 5.1 years (range, 2.4 to 14.7). We found that patients with motor function symptoms at the time of transplant did not improve after transplantation. Brainstem auditory evoked responses, visual evoked potentials, electroencephalogram, and/or peripheral nerve conduction velocities stabilized or improved in juvenile patients but continued to worsen in most patients with the late-infantile presentation. Pretransplant modified Loes scores were highly correlated with developmental outcomes and predictive of cognitive and motor function. Children who were asymptomatic at the time of transplantation benefited most from the procedure. Children with juvenile onset and minimal symptoms showed stabilization or deterioration of motor skills but maintained cognitive skills. Overall, children with juvenile onset had better outcomes than those with late-infantile onset. As in other leukodystrophies, early intervention correlated with optimal outcomes. We conclude that UCB transplantation benefits children with presymptomatic late-infantile MLD or minimally symptomatic juvenile MLD.

Hyporesponsiveness to social and nonsocial sensory stimuli in children with autism, children with developmental delays, and typically developing children.

This cross-sectional study seeks to (a) describe developmental correlates of sensory hyporesponsiveness to social and nonsocial stimuli, (b) determine whether hyporesponsiveness is generalized across contexts in children with autism relative to controls, and (c) test the associations between hyporesponsiveness and social communication outcomes. Three groups of children ages 11-105 months (N = 178; autism = 63, developmental delay = 47, typical development = 68) are given developmental and sensory measures including a behavioral orienting task (the Sensory Processing Assessment). Lab measures are significantly correlated with parental reports of sensory hyporesponsiveness. Censored regression models show that hyporesponsiveness decreased across groups with increasing mental age (MA). Group differences are significant but depend upon two-way interactions with MA and context (social and nonsocial). At a very young MA (e.g., 6 months), the autism group demonstrates more hyporesponsiveness to social and nonsocial stimuli (with larger effects for social) than developmental delay and typically developing groups, but at an older MA (e.g., 60 months) there are no significant differences. Hyporesponsiveness to social and nonsocial stimuli predicts lower levels of joint attention and language in children with autism. Generalized processes in attention disengagement and behavioral orienting may have relevance for identifying early risk factors of autism and for facilitating learning across contexts to support the development of joint attention and language.

Prevalence and risk factor analysis for methicillin-resistant Staphylococcus aureus nasal colonization in children attending child care centers.

Children attending child care centers (CCCs) are at increased risk for infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). Nasal colonization often precedes infection, and MRSA colonization has been associated with increased infection risk. Community-associated MRSA (CA-MRSA) has caused increased MRSA infections in the general population, including children. Little is known about the frequency of MRSA nasal colonization in young children, particularly in those attending CCCs where disease transmission is common. We sampled the nares of 1,163 children in 200 classrooms from 24 CCCs in North Carolina and Virginia to assess S. aureus colonization. MRSA strains were molecularly analyzed for staphylococcal cassette chromosome mec (SCCmec) type, Panton-Valentine leukocidin status, and multilocus sequence type. A case-control study was performed to identify risk factors for MRSA colonization. We found that 18.1% children were colonized with S. aureus and 1.3% with MRSA. Molecular analysis of the MRSA strains identified 47% as CA-MRSA and 53% as health care-associated MRSA (HA-MRSA). Although two centers had multiple children colonized with MRSA, genotyping indicated that no transmission had occurred within classrooms. The case-control study did not detect statistically significant risk factors for MRSA colonization. However, MRSA-colonized children were more likely to be nonwhite and to have increased exposure to antibiotics and skin infections in the home. Both CA-MRSA and HA-MRSA strains were found colonizing the nares of children attending CCCs. The low frequency of colonization observed highlights the need for a large multicenter study to determine risk factors for MRSA colonization and subsequent infection in this highly susceptible population.

Early clinical markers of central nervous system involvement in mucopolysaccharidosis type II.

OBJECTIVE: To identify early clinical markers of neurologic involvement in mucopolysaccharidosis type II. STUDY DESIGN: A retrospective review of neurobehavioral standardized assessments of patients with mucopolysaccharidosis type II evaluated at the Program for Neurodevelopmental Function in Rare Disorders was completed. Patients were grouped based on the presence or absence of central nervous system (CNS) involvement at the most recent evaluation. Differences in early signs and symptoms between resulting cohorts were tested for significance, and an index severity score was developed. RESULTS: Between December 2002 and November 2010, clinical evaluations of 49 patients and 151 patient encounters were reviewed. Thirty-seven patients exhibited neurologic deterioration. Of the 25 signs evaluated, 7 early clinical markers were strongly correlated with subsequent cognitive dysfunction: sleep disturbance, increased activity, behavior difficulties, seizure-like behavior, perseverative chewing behavior, and inability to achieve bowel training and bladder training. A new severity score index was developed, with a score ≥3 indicating a high likelihood of developing CNS disease. CONCLUSION: Seven early clinical markers and a severity score index of CNS involvement can be used for initial screening of children who might benefit from CNS-directed therapies.

Brain volumes in psychotic youth with schizophrenia and mood disorders.

BACKGROUND: We sought to test the hypothesis that deficits in grey matter volume are characteristic of psychotic youth with early-onset schizophrenia-spectrum disorders (EOSS) but not of psychotic youth with early-onset mood disorders (EOMD). METHODS: We used magnetic resonance imaging to examine brain volume in 24 psychotic youth (13 male, 11 female) with EOSS (n = 12) or EOMD (n = 12) and 17 healthy controls (10 male, 7 female). We measured the volume of grey and white matter using an automated segmentation program. RESULTS: After adjustment for age and intracranial volume, whole brain volume was lower in the EOSS patients than in the healthy controls (p = 0.001) and EOMD patients (p = 0.002). The EOSS patients had a deficit in grey matter volume (p = 0.005), especially in the frontal (p = 0.003) and parietal (p = 0.006) lobes, with no significant differences in white matter volume. LIMITATIONS: The main limitations of our study were its small sample size and the inclusion of patients with depression and mania in the affective group. CONCLUSION: Adolescents with EOSS have grey matter deficits compared with healthy controls and psychotic adolescents with EOMD. Our results suggest that grey matter deficits are not generally associated with psychosis but may be specifically associated with schizophrenia. Larger studies with consistent methods are needed to reconcile the contradictory findings among imaging studies involving psychotic youth.

Correlation of neurodevelopmental features and MRI findings in infantile Krabbe's disease.

OBJECTIVE: The purpose of our study was to compare MRI findings with neurobehavioral development in infants with Krabbe's disease. MATERIALS AND METHODS: Nine infants with Krabbe's disease underwent a total of 19 MR studies during the first year of life as well as tests of mental development, gross motor skills, and fine motor skills (score range: 0-100) within 1 month of imaging. MR scans were scored using the Loes severity scale based on signal abnormality and atrophy, ranging from 0 (best) to 32. We performed three comparisons (Student's t test): each test versus total brain Loes score, fine motor and gross motor tests versus Loes score for the pyramidal tract, and fine motor and gross motor tests versus Loes score for the internal capsule. RESULTS: Mean test results were 65+/-31 for mental development, 48+/-39 for gross motor score, 57+/-35 for fine motor score, and mean total brain score was 7.79+/-6.20. Correlations for total Loes score were -0.78 (p=0.003) for mental development, -0.74 (p=0.003) for gross motor function, and -0.80 (p<0.001) for fine motor function. Correlations for pyramidal system Loes scores were -0.73 (p=0.003) for fine motor function and -0.58 (p=0.028) for gross motor function. Correlation between Loes scores for internal capsule and fine motor function was -0.38 (p>0.05) and between Loes scores for internal capsule and gross motor function was -0.35 (p>0.05). CONCLUSION: The very good correlation between testing results and Loes scores for the entire brain and moderately good correlation between test results and scores for specific brain regions indicate the Loes scoring system likely provides a reasonable means for assessing prognosis and therapeutic response for infants with Krabbe's disease.

A pilot study: coordination of precision grip in children and adolescents with high functioning autism.

PURPOSE: This pilot study compared temporal coordination during a precision grip task between 13 children and adolescents with autism spectrum disorders (ASD) who were high functioning and 13 peers with typical development. METHODS: Temporal coordination between grip and load forces was measured using latency between onset of grip and load forces, grip force at onset of load force, peak grip force (PGF), and time to PGF. RESULTS: Compared with peers with typical development, participants with ASD demonstrated prolonged latency between grip and load forces, elevated grip force at onset of load force, and increased movement variability. PGF and time to PGF were not significantly different between the 2 groups. CONCLUSIONS: These findings indicate temporal dyscoordination in participants with ASD. The findings also enhance our understanding of motor coordination deficits in persons with ASD and have theoretical as well as clinical implications.

Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months.

BACKGROUND: Krabbe disease is a rare neurological disorder caused by a deficiency in the lysosomal enzyme, ß-galactocerebrosidase, resulting in demyelination of the central and peripheral nervous systems. If left without treatment, Krabbe disease results in progressive neurodegeneration with reduced quality of life and early death. The purpose of this prospective study was to describe the natural progression of early onset Krabbe disease in a large cohort of patients. METHODS: Patients with early onset Krabbe disease were prospectively evaluated between 1999 and 2018. Data sources included diagnostic testing, parent questionnaires, standardized multidisciplinary neurodevelopmental assessments, and neuroradiological and neurophysiological tests. RESULTS: We evaluated 88 children with onset between 0 and 5 months. Median age of symptom onset was 4 months; median time to diagnosis after onset was 3 months. The most common initial symptoms were irritability, feeding difficulties, appendicular spasticity, and developmental delay. Other prevalent symptoms included axial hypotonia, abnormal deep tendon reflexes, constipation, abnormal pupillary response, scoliosis, loss of head control, and dysautonomia. Results of nerve conduction studies showed that 100% of patients developed peripheral neuropathy by 6 months of age. Median galactocerebrosidase enzyme activity was 0.05 nmol/h/mg protein. The median survival was 2 years. CONCLUSIONS: This is the largest prospective natural history study of Krabbe disease. It provides a comprehensive description of the disease during the first 2 years of life. With recent inclusion of state mandated newborn screening programs and promising therapeutic interventions, enhancing our understanding of disease progression in early onset Krabbe disease will be critical for developing treatments, designing clinical trials, and evaluating outcomes.

Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease.

BACKGROUND: Infantile Krabbe's disease produces progressive neurologic deterioration and death in early childhood. We hypothesized that transplantation of umbilical-cord blood from unrelated donors before the development of symptoms would favorably alter the natural history of the disease among newborns in whom the disease was diagnosed because of a family history. We compared the outcomes among these newborns with the outcomes among infants who underwent transplantation after the development of symptoms and with the outcomes in an untreated cohort of affected children. METHODS: Eleven asymptomatic newborns (age range, 12 to 44 days) and 14 symptomatic infants (age range, 142 to 352 days) with infantile Krabbe's disease underwent transplantation of umbilical-cord blood from unrelated donors after myeloablative chemotherapy. Engraftment, survival, and neurodevelopmental function were evaluated longitudinally for four months to six years. RESULTS: The rates of donor-cell engraftment and survival were 100 percent and 100 percent, respectively, among the asymptomatic newborns (median follow-up, 3.0 years) and 100 percent and 43 percent, respectively, among the symptomatic infants (median follow-up, 3.4 years). Surviving patients showed durable engraftment of donor-derived hematopoietic cells with restoration of normal blood galactocerebrosidase levels. Infants who underwent transplantation before the development of symptoms showed progressive central myelination and continued gains in developmental skills, and most had age-appropriate cognitive function and receptive language skills, but a few had mild-to-moderate delays in expressive language and mild-to-severe delays in gross motor function. Children who underwent transplantation after the onset of symptoms had minimal neurologic improvement. CONCLUSIONS: Transplantation of umbilical-cord blood from unrelated donors in newborns with infantile Krabbe's disease favorably altered the natural history of the disease. Transplantation in babies after symptoms had developed did not result in substantive neurologic improvement.

Development of a mouse test for repetitive, restricted behaviors: relevance to autism.

Repetitive behavior, a core symptom of autism, encompasses stereotyped responses, restricted interests, and resistance to change. These studies investigated whether different components of the repetitive behavior domain could be modeled in the exploratory hole-board task in mice. Four inbred mouse strains, C57BL/6J, BALB/cByJ, BTBR T+tf/J, and FVB/NJ, and mice with reduced expression of Grin1, leading to NMDA receptor hypofunction (NR1neo/neo mice), were tested for exploration and preference for olfactory stimuli in an activity chamber with a 16-hole floor-board. Reduced exploration and high preference for holes located in the corners of the chamber were observed in BALB/cByJ and BTBR T+tf/J mice. All inbred strains had initial high preference for a familiar olfactory stimulus (clean cage bedding). BTBR T+tf/J was the only strain that did not demonstrate a shift in hole preference towards an appetitive olfactory stimulus (cereal or a chocolate chip), following home cage exposure to the food. The NR1neo/neo mice showed lower hole selectivity and aberrant olfactory stimulus preference, in comparison to wildtype controls. The results indicate that NR1neo/neo mice have repetitive nose poke responses that are less modified by environmental contingencies than responses in wildtype mice. 25-30% of NMDA receptor hypomorphic mice also show self-injurious responses. Findings from the olfactory studies suggest that resistance to change and restricted interests might be modeled in mice by a failure to alter patterns of hole preference following familiarization with an appetitive stimulus, and by high preference persistently demonstrated for one particular olfactory stimulus. Further work is required to determine the characteristics of optimal mouse social stimuli in the olfactory hole-board test.

Methods for assessing neurodevelopment in lysosomal storage diseases and related disorders: a multidisciplinary perspective.

UNLABELLED: Lysosomal storage diseases and related disorders (LSRDs) are a heterogeneous group of rare diseases caused by genetic mutations that result in deficiencies of specific lysosomal enzymes. Some of these enzymes are necessary for normal development of the central and peripheral nervous systems. Because of the heterogeneity in clinical presentation and complexity of these disorders, evaluation of disease progression poses unique challenges. In recent years, recombinant enzyme replacement therapy and haematopoietic stem cell transplantation have been developed to treat some of these diseases. With the development of specific therapies and screening programmes, there is a need to systematically follow the natural course and effects of treatment in these disorders with standardized and validated tools. This review describes the limitations of currently available neurobehavioural tools in longitudinally tracking disease outcomes in patients with neurodegenerative LSRDs. A multidisciplinary team reviewed over 750 evaluations in 274 patients. These patients were found to have neurological, sensory and somatic problems that considerably influence the results of neurobehavioural testing. CONCLUSION: Treatment effects in patients with neurodegenerative LSRDs are best evaluated by repeated measures and longitudinal analysis of each domain of function.

The Emergence of Effortful Control in Young Boys With Fragile X Syndrome.

Effortful control, or the ability to suppress a dominant response to perform a subdominant response, is an early-emerging temperament trait that is linked with positive social-emotional development. Fragile X syndrome (FXS) is a single-gene disorder characterized by hallmark regulatory impairments, suggesting diminished effortful control. This study compared the development of effortful control in preschool boys with FXS ( n = 97) and typical development ( n = 32). Unlike their typical peers, the boys with FXS did not exhibit growth in effortful control over time, which could not be accounted for by adaptive impairments, FMR1 molecular measures, or autism symptoms. These results contribute to our understanding of the childhood phenotype of FXS that may be linked to the poor social-emotional outcomes seen in this group.

A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life.

BACKGROUND: Krabbe disease is a rare neurodegenerative disorder caused by a deficiency in the lysosomal enzyme galactocerebrosidase. Patients with Krabbe disease present with a variable disease course depending on their age of onset. The purpose of this prospective cohort study was to characterize the natural progression of Krabbe disease in a large group of patients with disease onset between 6 and 36 months of life who were evaluated with a standardized protocol. METHODS: All patients with Krabbe disease who had onset between 6 and 36 months of age and were prospectively evaluated between 2000 to 2017 were included. Standardized neurodevelopmental, physical, and neurological examinations were performed. Other assessments included neuroradiologic and neurophysiologic tests, enzyme level, cerebrospinal fluid analysis, and GALC pathogenic variants when available. Descriptive statistics were used for analysis. Survival curve was estimated using the Kaplan-Meier method. RESULTS: Thirty-five patients (26 boys, 9 girls) with disease onset between 6 and 36 months of age were evaluated. Median age at symptom onset was 11.5 months, with a median delay of 3.5 months between onset of symptoms and diagnosis. Of the 32 symptomatic patients, 23 presented with initial signs or symptoms of disease between 6 and 12 months of life; nine presented after 12 months. The most common initial signs and symptoms were loss of acquired developmental milestones, irritability, abnormal gait, motor delay, and abnormal muscle tone. The most common magnetic resonance imaging abnormality was increased T2 signal in the periventricular white matter. Nerve conduction velocity results were abnormal for 21 of 24 patients. Patients with onset after 12 months had less peripheral nerve involvement and slower disease progression. Abnormal cerebrospinal fluid protein levels were obtained for 13 of 16 symptomatic children. Protein levels were normal in all asymptomatic children. CONCLUSIONS: Based on our findings, we propose reclassifying the group of patients with onset ≤12 months as infantile and the > 12 month group as late-infantile. Patients with onset > 12 months are more likely to benefit from hematopoietic stem cell transplantation. The proposed change in classifications will allow physicians to improve their ability to recognize and diagnose patients and more precisely assess potential treatment effects after transplantation.