Ability change across multiple domains in mucopolysaccharidosis (Sanfilippo syndrome) type IIIA.

The objective of this paper is 1) to expand the scope of the domains previously published in a natural history study of Mucopolysaccharidosis IIIA (Sanfilippo syndrome type A) (MPS IIIA) and 2) to present evidence regarding the capacity of a new metric, Growth Scale Values (GSVs), in comparison with traditional metrics, to show changes in skills as assessed by the Bayley Scales of Infant Development -III (BSID-III) and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). We re-analyzed a cohort of 25 children, 20 with rapid progressing disease and 5 with slow progression, who had been followed over two years using the BSID-III, and the VABS-II. Previously findings were reported using age equivalent scores; now we are also presenting findings with GSVs. For the re-analysis, Language and Motor scores were added to the Cognitive scale on the BSID-III, and Domain- and Subdomain-level scores added to the Total VABS-II score (i.e., ABC Composite). We evaluated raw scores, age equivalent scores, and GSVs (and standard scores for the VABS-II only). Individual patient data can be found in the appendices to this publication. Results indicate that 1) Cognition as measured by GSVs was the most sensitive to decline; 2) GSVs showed significant decline in the range of 4 to 6 years of age; 3) For children under 4 years of age, positive growth occurs on most scales and most metrics, with the exception of language which slows somewhat earlier; 4) Other than the Cognitive scale, Receptive Language on the BSID-III and Receptive Communication on the VABS-II showed the most sensitivity to change; 5) Gross Motor skills showed the least decline over time and appeared to lack sensitivity to MPS IIIA motor concerns; and 6) No evidence for sensitivity to change for any metric was found in time intervals less than one year. We conclude that GSVs are a precise measurement of change to detect decline in function, and they are a valuable method for future clinical trials in MPS IIIA. Evidence continues to support cognition as a primary endpoint. Additional work is needed to identify sensitive measures of meaningful endpoints to families.

Quantitative brain MRI morphology in severe and attenuated forms of mucopolysaccharidosis type I.

OBJECTIVE: To assess our hypothesis that brain macrostructure is different in individuals with mucopolysaccharidosis type I (MPS I) and healthy controls (HC), we conducted a comprehensive multicenter study using a uniform quantitative magnetic resonance imaging (qMRI) protocol, with analyses that account for the effects of disease phenotype, age, and cognition. METHODS: Brain MRIs in 23 individuals with attenuated (MPS IA) and 38 with severe MPS I (MPS IH), aged 4-25 years, enrolled under the study protocol NCT01870375, were compared to 98 healthy controls. RESULTS: Cortical and subcortical gray matter, white matter, corpus callosum, ventricular and choroid plexus volumes in MPS I significantly differed from HC. Thicker cortex, lower white matter and corpus callosum volumes were already present at the youngest MPS I participants aged 4-5 years. Age-related differences were observed in both MPS I groups, but most markedly in MPS IH, particularly in cortical gray matter metrics. IQ scores were inversely associated with ventricular volume in both MPS I groups and were positively associated with cortical thickness only in MPS IA. CONCLUSIONS: Quantitatively-derived MRI measures distinguished MPS I participants from HC as well as severe from attenuated forms. Age-related neurodevelopmental trajectories in both MPS I forms differed from HC. The extent to which brain structure is altered by disease, potentially spared by treatment, and how it relates to neurocognitive dysfunction needs further exploration.

The natural history of neurocognition in MPS disorders: A review.

MPS disorders are associated with a wide spectrum of neurocognitive effects, from mild problems with attention and executive functions to progressive and degenerative neuronopathic disease. Studies of the natural history of neurocognition are necessary to determine the profile of abnormality and the rates of change, which are crucial to select endpoints for clinical trials of brain treatments and to make clinical recommendations for interventions to improve patients' quality of life. The goal of this paper is to review neurocognitive natural history studies to determine the current state of knowledge and assist in directing future research in all MPS disorders. There are seven different types of MPS diseases, each resulting from a specific enzyme deficiency and each having a separate natural history. MPS IX, will not be discussed as there are only 4 cases reported in the literature without cognitive abnormality. For MPS IH, hematopoietic cell transplant (HCT) is standard of care and many studies have documented the relationship between age at treatment and neurocognitive outcome, and to a lesser extent, neurocognitive status at baseline. However, the mortality and morbidity associated with the transplant process and residual long-term problems after transplant, have led to renewed efforts to find better treatments. Rather than natural history, new trials will likely need to use the developmental trajectories of the patients with HCT as a comparators. The literature has extensive data regarding developmental trajectories post-HCT. For attenuated MPS I, significant neurocognitive deficits have been documented, but more longitudinal data are needed in order to support a treatment directed at their attention and executive function abnormalities. The neuronopathic form of MPS II has been a challenge due to the variability of the trajectory of the disease with differences in timing of slowing of development and decline. Finding predictors of the course of the disease has only been partially successful, using mutation type and family history. Because of lack of systematic data and clinical trials that precede a thorough understanding of the disease, there is need for a major effort to gather natural history data on the entire spectrum of MPS II. Even in the attenuated disease, attention and executive function abnormalities need documentation. Lengthy detailed longitudinal studies are needed to encompass the wide variability in MPS II. In MPS IIIA, the existence of three good natural history studies allowed a quasi-meta-analysis. In patients with a rapid form of the disease, neurocognitive development slowed up until 42 to 47 months, halted up to about 54 months, then declined rapidly thereafter, with a leveling off at an extremely low age equivalent score below 22 months starting at about chronological age of 6. Those with slower or attenuated forms have been more variable and difficult to characterize. Because of the plethora of studies in IIIA, it has been recommended that data be combined from natural history studies to minimize the burden on parents and patients. Sufficient data exists to understand the natural history of cognition in MPS IIIA. MPS IIIB is quite similar to IIIA, but more attenuated patients in that phenotype have been reported. MPS IIIC and D, because they are so rare, have little documentation of natural history despite the prospects of treatments. MPS IV and VI are the least well documented of the MPS disorders with respect to their neurocognitive natural history. Because, like attenuated MPS I and II, they do not show progression of neurocognitive abnormality and most patients function in the range of normality, their behavioral, attentional, and executive function abnormalities have been ignored to the detriment of their quality of life. A peripheral treatment for MPS VII, extremely rare even among MPS types, has recently been approved with a post-approval monitoring system to provide neurocognitive natural history data in the future. More natural history studies in the MPS forms with milder cognitive deficits (MPS I, II, IV, and VI) are recommended with the goal of improving these patients' quality of life with and without new brain treatments, beyond the benefits of available peripheral enzyme replacement therapy. Recommendations are offered at-a-glance with respect to what areas most urgently need attention to clarify neurocognitive function in all MPS types.

Can serial cerebral MRIs predict the neuronopathic phenotype of MPS II?

OBJECTIVE: To advance the prediction of the neurocognitive development in MPS II patients by jointly analyzing MRI and neurocognitive data in mucopolysaccharidosis (MPS) II patients. METHODS: Cognitive ability scores (CAS) were obtained by neuropsychological testing. Cerebral MRIs were quantified using a disease-specific protocol. MRI sumscores were calculated for atrophy, white-matter abnormalities (WMA) and Virchow-Robin spaces (VRS). To distinguish between atrophy and hydrocephalus the Evans' index and the callosal angle (CA) were measured. A random effects repeated measurement model was used to correlate CAS with the three MRI sumscores. RESULTS: MRI (n = 47) and CAS scores (n = 78) of 19 male patients were analyzed. Ten patients were classified as neuronopathic and nine as non-neuronopathic. Neuronopathic patients had normal cognitive development until age 3 years. Mental age plateaued between ages 3 and 6, and subsequently declined with loss of skills at a maximum developmental age of 4 years. MRIs of neuronopathic patients showed abnormal atrophy sumscores before CAS dropped below the threshold for intellectual disability (<70). White-matter abnormalities (WMA) and brain atrophy progressed. The calculated sumscores were inversely correlated with CAS (r = -.90 for atrophy and -.69 for WMA). This was not biased by the influence of hydrocephalus as shown by measurement of the Evans' and callosal angle. Changes over time in the Virchow-Robin spaces (VRS) on MRI were minimal. CONCLUSION: In our cohort, brain atrophy showed a stronger correlation to a decline in CAS when compared to WMA. Atrophy-scores were higher in young neuronopathic patients than in non-neuronopathic patients and atrophy was an important early sign for the development of the neuronopathic phenotype, especially when observed jointly with white-matter abnormalities.

Long-term outcomes of systemic therapies for Hurler syndrome: an international multicenter comparison.

PURPOSE: Early treatment is critical for mucopolysaccharidosis type I (MPS I), justifying its incorporation into newborn screening. Enzyme replacement therapy (ERT) treats MPS I, yet presumptions that ERT cannot penetrate the blood-brain barrier (BBB) support recommendations that hematopoietic cell transplantation (HCT) treat the severe, neurodegenerative form (Hurler syndrome). Ethics precludes randomized comparison of ERT with HCT, but insight into this comparison is presented with an international cohort of patients with Hurler syndrome who received long-term ERT from a young age. METHODS: Long-term survival and neurologic outcomes were compared among three groups of patients with Hurler syndrome: 18 treated with ERT monotherapy (ERT group), 54 who underwent HCT (HCT group), and 23 who received no therapy (Untreated). All were followed starting before age 5 years. A sensitivity analysis restricted age of treatment below 3 years. RESULTS: Survival was worse when comparing ERT versus HCT, and Untreated versus ERT. The cumulative incidences of hydrocephalus and cervical spinal cord compression were greater in ERT versus HCT. Findings persisted in the sensitivity analysis. CONCLUSION: As newborn screening widens treatment opportunity for Hurler syndrome, this examination of early treatment quantifies some ERT benefit, supports presumptions about BBB impenetrability, and aligns with current guidelines to treat with HCT.

Cognitive and adaptive measurement endpoints for clinical trials in mucopolysaccharidoses types I, II, and III: A review of the literature.

Sensitive, reliable measurement instruments are critical for the evaluation of disease progression and new treatments that affect the brain in the mucopolysaccharidoses (MPS). MPS I, II, and III have early onset clinical phenotypes that affect the brain during development and result in devastating cognitive decline and ultimately death without treatment. Comparisons of outcomes are hindered by diverse protocols and approaches to assessment including applicability to international trials necessary in rare diseases. We review both cognitive and adaptive measures with the goal of providing evidence to a Delphi panel to come to a consensus about recommendations for clinical trials for various age groups. The results of the consensus panel are reported in an accompanying article. The following data were gathered (from internet resources and from test manuals) for each measure and summarized in the discussion: reliability, validity, date and adequacy of normative data, applicability of the measure's metrics, cross cultural validity including translations and adaptations, feasibility in the MPS population, familiarity to sites, sensitivity to change, and interpretability. If, resulting from this consensus, standard protocols are used for both natural history and treatment studies, patients, their families, and health care providers will benefit from the ability to compare study outcomes.

Developmental and behavioral aspects of mucopolysaccharidoses with brain manifestations - Neurological signs and symptoms.

The mucopolysaccharidoses (MPS) are a group of rare, inherited lysosomal storage disorders, caused by mutations in lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). The resulting accumulation of GAGs in the body leads to widespread tissue and organ dysfunction. The spectrum, severity, and progression rate of clinical manifestations varies widely between and within the different MPS types. In addition to somatic signs and symptoms, which vary between the different MPS disorders, patients with MPS I, II, III, and VII present with significant neurological signs and symptoms, including impaired cognitive abilities, difficulties in language and speech, and/or behavioral and sleep problems. To effectively manage and develop therapies that target these neurological manifestations, it is of utmost importance to have a profound knowledge of their natural history and pathophysiology. This review describes the appearance and progression of neurological signs and symptoms in patients with MPS I, II, and III, based on presentations and discussions among an international group of experts during a meeting on the brain in MPS on April 28-30, 2016, and additional literature searches on this subject.

Assessments of neurocognitive and behavioral function in the mucopolysaccharidoses.

The mucopolysaccharidoses (MPS) are a group of rare, inherited lysosomal storage disorders in which accumulation of glycosaminoglycans (GAGs) leads to progressive tissue and organ dysfunction. In addition to a variety of somatic signs and symptoms, patients with rapidly progressing MPS I (Hurler), II, III, and VII can present with significant neurological manifestations, including impaired cognitive abilities, difficulties in language and speech, behavioral abnormalities, sleep problems, and/or seizures. Neurological symptoms have a substantial impact on the quality of life of MPS patients and their families. Due to the progressive nature of cognitive impairment in these MPS patients, neurocognitive function is a sensitive indicator of disease progression, and a relevant outcome when testing efficacy of therapies for these disorders. In order to effectively manage and develop therapies that address neurological manifestations of MPS, it is important to use appropriate neurocognitive assessment tools that are sensitive to changes in neurocognitive function in MPS patients. This review discusses expert opinions on key issues and considerations for effective neurocognitive testing in MPS patients. In addition, it describes the neurocognitive assessment tools that have been used in clinical practice for these patients. The content of this review is based on existing literature and information from a meeting of international experts with extensive experience in managing and treating MPS disorders.

Practical management of behavioral problems in mucopolysaccharidoses disorders.

The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes, resulting in progressive glycosaminoglycan (GAG) accumulation in cells and tissues throughout the body. Excessive GAG storage can lead to a variety of somatic manifestations as well as primary and secondary neurological symptoms. Behavioral problems (like hyperactivity, attention difficulties, and severe frustration) and sleeping problems are typical primary neurological symptoms of MPS caused by GAG accumulation in neurons, and are frequently observed in patients with MPS I, II, III, and VII. As these problems often place a significant burden on the family, proper management is important. This review summarizes current insights into behavioral and sleeping problems in MPS disorders and the most optimal management approaches, as presented and discussed during a meeting of an international group of experts with extensive experience in managing and treating MPS.

Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study.

Mucopolysaccharidosis type I-Hurler syndrome (MPS-IH) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Although hematopoietic cell transplantation (HCT) has been performed in these patients for more than 30 years, large studies on the long-term outcome of patients with MPS-IH after HCT are lacking. The goal of this international study was to identify predictors of the long-term outcome of patients with MPS-IH after successful HCT. Two hundred seventeen patients with MPS-IH successfully engrafted with a median follow-up age of 9.2 years were included in this retrospective analysis. Primary endpoints were neurodevelopmental outcomes and growth. Secondary endpoints included neurologic, orthopedic, cardiac, respiratory, ophthalmologic, audiologic, and endocrinologic outcomes. Considerable residual disease burden was observed in the majority of the transplanted patients with MPS-IH, with high variability between patients. Preservation of cognitive function at HCT and a younger age at transplantation were major predictors for superior cognitive development posttransplant. A normal α-l-iduronidase enzyme level obtained post-HCT was another highly significant predictor for superior long-term outcome in most organ systems. The long-term prognosis of patients with MPS-IH receiving HCT can be improved by reducing the age at HCT through earlier diagnosis, as well as using exclusively noncarrier donors and achieving complete donor chimerism.

A Prospective Natural History Study of Mucopolysaccharidosis Type IIIA.

OBJECTIVES: To characterize the clinical course of mucopolysaccharidosis type IIIA (MPS IIIA), and identify potential endpoints for future treatment trials. STUDY DESIGN: Children with a confirmed diagnosis of MPS IIIA, functioning above a developmental age of 1 year, were followed for up to 2 years. Cognitive status and brain atrophy were assessed by standardized tests and volumetric magnetic resonance imaging, respectively. Liver and spleen volumes and cerebrospinal fluid and urine biomarker levels were measured. RESULTS: Twenty-five children, from 1.1 to 18.4 years old, were enrolled, and 24 followed for at least 12 months. 19 exhibited a rapidly progressing (RP) form of MPS IIIA, and 5, a more slowly progressing form. Children with RP plateaued in development by 30 months, followed by rapid regression after 40-50 months. In patients with RP, cognitive developmental quotients showed consistent steep declines associated with progressive cortical gray matter atrophy. Children with slowly progressing had a similar but more prolonged course. Liver and spleen volumes were approximately double normal size, and cerebrospinal fluid and urine heparin sulfate levels were elevated and relatively constant over time. CONCLUSION: Developmental quotient and cortical gray matter volume are sensitive markers of disease progression in MPS IIIA, and may have utility as clinical endpoints in treatment trials. For optimal outcomes, treatment may need to be instituted in children before the onset of steep cognitive decline and brain atrophy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01047306.

Cognitive, medical, and neuroimaging characteristics of attenuated mucopolysaccharidosis type II.

UNLABELLED: The phenotype of attenuated mucopolysaccharidosis type II (MPS II), also called Hunter syndrome, has not been previously studied in systematic manner. In contrast to the "severe" phenotype, the "attenuated" phenotype does not present with behavioral or cognitive impairment; however, the presence of mild behavior and cognitive impairment that might impact long-term functional outcomes is unknown. Previously, significant MRI abnormalities have been found in MPS II. Recent evidence suggests white matter abnormalities in many MPS disorders. METHODS: As the initial cross-sectional analysis of a longitudinal study, we studied the association of brain volumes and somatic disease burden with neuropsychological outcomes, including measures of intelligence, memory, and attention in 20 patients with attenuated MPS II with a mean age of 15.8. MRI volumes were compared to 55 normal controls. RESULTS: While IQ and memory were average, measures of attention were one standard deviation below the average range. Corpus callosum volumes were significantly different from age-matched controls, differing by 22%. Normal age-related volume increases in white matter were not seen in MPS II patients as they were in controls. Somatic disease burden and white matter and corpus callosum volumes were significantly associated with attention deficits. Neither age at evaluation nor age at starting treatment predicted attention outcomes. CONCLUSIONS: Despite average intelligence, attention is compromised in attenuated MPS II. Results confirm an important role of corpus callosum and cortical white matter abnormality in MPS II as well as the somatic disease burden in contributing to attention difficulties. Awareness by the patient and caregivers with appropriate management and symptomatic support will benefit the attenuated MPS II patient.

Quantifying behaviors of children with Sanfilippo syndrome: the Sanfilippo Behavior Rating Scale.

The Sanfilippo Behavior Rating Scale (SBRS), a 68 item questionnaire, has been developed to assess the behavioral phenotype of children with Sanfilippo syndrome and its progression over time. Fifteen scales rate orality, movement/activity, attention/self-control, emotional function including anger and fear, and social interaction. Items within scales intercorrelate; measures of internal consistency are adequate. Twelve scales are grouped into 4 abnormality clusters: Movement, Lack of fear, Social/emotional and Executive Dysfunction. A Loess age-trajectory analysis showed that Lack of Fear, Social/Emotional and Executive Dysfunction increased steadily with age; Orality and Mood/Anger/Aggression leveled off. Movement peaked around 6years, then declined as children's excessive/purposeless actions stopped. Compared with standard scales, SBRS Movement was appropriately associated with the Vineland Motor scale; SBRS Lack of Fear had significant associations with the Autism Diagnostic Observation Schedule (ADOS), indicating a symptom overlap between Sanfilippo syndrome and autism. This suggests that reduced fearfulness may be the most salient/sensitive SBRS marker of disease progression. Volumetric MRI showed that increased Lack of Fear was significantly associated with reduced amygdala volume, consistent with our hypothesis that the behavior seen in Sanfilippo syndrome is a variant of Klüver-Bucy syndrome. Hippocampal volume loss had twice the effect on Social-Emotional Dysfunction as amygdala loss, consistent with a hippocampal role in attachment and social emotions. In conclusion, the SBRS assesses the Sanfilippo behavioral phenotype; it can measure behavior change that accompanies disease progression and/or results from treatment.

Neurocognition across the spectrum of mucopolysaccharidosis type I: Age, severity, and treatment.

OBJECTIVES: Precise characterization of cognitive outcomes and factors that contribute to cognitive variability will enable better understanding of disease progression and treatment effects in mucopolysaccharidosis type I (MPS I). We examined the effects on cognition of phenotype, genotype, age at evaluation and first treatment, and somatic disease burden. METHODS: Sixty patients with severe MPS IH (Hurler syndrome treated with hematopoietic cell transplant and 29 with attenuated MPS I treated with enzyme replacement therapy), were studied with IQ measures, medical history, genotypes. Sixty-seven patients had volumetric MRI. Subjects were grouped by age and phenotype and MRI and compared to 96 normal controls. RESULTS: Prior to hematopoietic cell transplant, MPS IH patients were all cognitively average, but post-transplant, 59% were below average, but stable. Genotype and age at HCT were associated with cognitive ability. In attenuated MPS I, 40% were below average with genotype and somatic disease burden predicting their cognitive ability. White matter volumes were associated with IQ for controls, but not for MPS I. Gray matter volumes were positively associated with IQ in controls and attenuated MPS I patients, but negatively associated in MPS IH. CONCLUSIONS: Cognitive impairment, a major difficulty for many MPS I patients, is associated with genotype, age at treatment and somatic disease burden. IQ association with white matter differed from controls. Many attenuated MPS patients have significant physical and/or cognitive problems and receive insufficient support services. Results provide direction for future clinical trials and better disease management.

Enzyme replacement is associated with better cognitive outcomes after transplant in Hurler syndrome.

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 < .001). 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.

Attention and corpus callosum volumes in individuals with mucopolysaccharidosis type I.

OBJECTIVE: Previous research suggests attention and white matter (WM) abnormalities in individuals with mucopolysaccharidosis type I (MPS I); this cross-sectional comparison is one of the first to examine the relationship of WM structural abnormalities as measured by corpus callosum (CC) volumes with attention scores to evaluate this relationship in a larger sample of patients with MPS I. METHODS: Volumetric MRI data and performance on a computerized measure of sustained attention were compared for 18 participants with the severe form of MPS I (MPS IH), 18 participants with the attenuated form of MPS I (MPS IATT), and 60 typically developing age-matched controls. RESULTS: The MPS I groups showed below-average mean attention scores (p < 0.001) and smaller CC volumes (p < 0.001) than controls. No significant associations were found between attention performance and CC volume for controls. Attention was associated with posterior CC volumes in the participants with MPS IH (p = 0.053) and total (p = 0.007) and anterior (p < 0.001) CC volumes in participants with MPS IATT. CONCLUSIONS: We found that attention and CC volumes were reduced in participants with MPS I compared to typically developing controls. Smaller CC volumes in participants with MPS I were associated with decreased attention; such an association was not seen in controls. While hematopoietic cell transplantation used to treat MPS IH may compound these effects, attention difficulties were also seen in the MPS IATT group, suggesting that disease effects contribute substantially to the clinical attentional difficulties seen in this population.

The Color Object Association Test (COAT): the development of a new measure of declarative memory for 18- to 36-month-old toddlers.

Few methods exist to measure declarative (explicit) memory in children during the toddler and preschool stages of development. We report the development and psychometric properties of a new measure of declarative memory for this age group, the Color Object Association Test (COAT). In pilot testing and large scale application of the test, the COAT was demonstrated to be a reliable and a valid measure of declarative memory for healthy children ages 18-36 months, living in a disadvantaged community. The test shows a linear developmental trajectory, which allows longitudinal examination of the development of declarative memory in children.

Beneath the floor: re-analysis of neurodevelopmental outcomes in untreated Hurler syndrome.

BACKGROUND: Hurler syndrome (MPS IH), the severe, neurodegenerative form of type one mucopolysaccharidosis, is associated with rapid neurocognitive decline during toddlerhood and multi-system dysfunction. It is now standardly treated with hematopoietic cell transplantation (HCT), which halts accumulating disease pathology and prevents early death. While norm-based data on developmental functioning in untreated children have previously demonstrated neurocognitive decline, advances in methodology for understanding the cognitive functioning of children with neurodegenerative diseases have highlighted that the previous choice of scores to report results was not ideal. Specifically, the lowest possible norm-based score is 50, which obscures the complete range of cognitive functioning at more advanced stages of neurodeterioration. To a set of cognitive data collected on a sample of untreated children, we applied a modern method of score analysis, calculating a developmental quotient based on age equivalent scores, to reveal the full range of cognitive functioning beneath this cutoff of 50, uncovering new information about the rapidity of decline and the profound impairment in these children. RESULTS: Among 39 observations for 32 patients with untreated Hurler syndrome, the full array of cognitive functioning below 50 includes many children in the severely to profoundly impaired range. The loss of skills per time unit was 14 points between age 1 and 2. There was a very large range of developmental quotients corresponding to the norm-based cutoff of 50. CONCLUSIONS: This report enables clarification of functioning at levels that extend beneath the floor of 50 in previous work. At the dawn of newborn screening and amidst a proliferation of new therapies for MPS I, these data can provide crucial benchmark information for developing treatments, particularly for areas of the world where transplant may not be available.

Previously unrecognized behavioral phenotype in Gaucher disease type 3.

OBJECTIVE: To provide a comprehensive description of abnormal behaviors in patients with Gaucher disease type 3 (GD3) and relate these behaviors to demographic, neurodevelopmental, and neurologic characteristics. METHODS: Thirty-four Egyptian patients with GD3 (mean age of 7.9 years) were enrolled in the study. They were selected based on parent report and/or physician observation of one or more abnormal behaviors documented in 2 settings and by 2 different individuals and/or by video recording. Behaviors were grouped into 4 categories: Crying/Withdrawal, Impatience/Overactivity, Anger/Aggression, and Repetitive Acts. Baseline and follow-up 6-12 monthly neurologic evaluations included IQ assessment and an EEG. All patients were receiving enzyme replacement therapy (30-60 IU/kg every 2 weeks) and were followed for periods of 3-10 years. RESULTS: Supranuclear palsy of horizontal gaze, and of both horizontal and vertical gaze, bulbar symptoms, seizures, convergent strabismus, abnormal gait, and neck retroflexion were present in 97.1%, 50%, 55.9%, 29.4%, 29.4%, 20.6%, and 4.4% of patients, respectively. The most abnormal behavioral features were excessive anger (88.2%) and aggression (64.7%), and both were significantly higher in males. Anger/Aggression scores were highly correlated with IQ but not with either EEG/Seizure status or neurologic signs. CONCLUSIONS: We describe behavioral problems with a unique pattern of excessive anger and aggression in patients with GD3. Defining these components using quantitative behavioral scoring methods holds promise to provide a marker of neurologic disease progression and severity.

[Formula: see text]Selecting measures for the neurodevelopmental assessment of children in low- and middle-income countries.

Diseases affecting millions of children in low- and middle-income countries (LMICs), such as malnutrition, micronutrient deficiency, malaria, and HIV, can lead to adverse neurodevelopmental outcomes. Thus, a key health outcome in children is neurodevelopmental status. In this paper, the neurodevelopmental screening and testing measures most commonly utilized in LMICs are reviewed, and a matrix is presented to help researchers and clinicians determine which measures may be most useful for various LMIC inquiries. The matrix is based on an Internet literature review of 114 publications for the period January 1998 to February 2016, reporting the psychometric properties of instruments tested in LMIC children. The measures are classified as screening tests or more detailed tests that include both comprehensive batteries of general development and tests of specific domains. For completeness, two experts have reviewed this paper, as well as the authors. An overview of the tests used to date is presented, including the benefits and drawbacks of each test, in order to provide researchers and developmental clinicians with a way to decide which tests may be best suited to their developmental assessment goals. Remarkable progress has been made in neurodevelopmental testing in children in LMICs over the past two decades but there remains a need for additional research in this area to develop new tests, better evaluate and adapt current tests, and assess test validity and reliability across cultures.