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Mucopolysaccaridosis IIIA (MPS IIIA) is a rare genetic disease that afflicts children and leads to neurocognitive degeneration. We develop a Bayesian disease progression model (DPM) of MPS IIIA that characterizes the pattern of cognitive growth and decline in this disease. The DPM is a repeated measures model that incorporates a nonlinear developmental trajectory and shape-invariant random effects. This approach quantifies the pattern of cognitive development in MPS IIIA and addresses differences in biological age, length of follow-up, and clinical outcomes across natural history subjects. The DPM can be used in clinical trials to estimate the percent slowing in disease progression for treatment relative to natural history. Simulations demonstrate that the DPM provides substantial improvements in power relative to alternative analyses., (© 2022 John Wiley & Sons Ltd.)

Introduction: Currently, there is no effective therapy for mucopolysaccharidosis IIIA (MPS IIIA). Intravenously-administered enzyme replacement therapies, while effective in other forms of MPS without neurological involvement, have not been successful in patients with MPS IIIA, as they are unable to cross the blood-brain barrier to improve neurological symptoms. We evaluated the long-term safety, tolerability, and clinical outcomes of recombinant human heparan-N-sulfatase (rhHNS) administered intrathecally (IT) in children with MPS IIIA in a phase 1/2 extension study., Methods: Patients aged ≥3 years with MPS IIIA who had previously completed a phase 1/2 study and received ≥5 of the 6 planned rhHNS infusions via IT administration, were eligible for inclusion. Patients who received 10 mg in the phase 1/2 study had their dose increased to 45 mg. Patients who were treated with 45 mg or 90 mg rhHNS IT in the phase 1/2 study remained on this monthly dose in the extension study. rhHNS was administered via an intrathecal drug delivery device (IDDD). Primary endpoints included the type and severity of adverse events, presence of anti-rhHNS antibodies in the CSF and serum, and changes in laboratory values. Secondary endpoints included standardized neurocognitive assessments and brain magnetic resonance imaging., Results: In the extension study, 12 patients with a mean (SD) age of 9.6 (7.3) years continued treatment with rhHNS IT for a median of 264.4 weeks. Ten of 12 patients completed the extension study. rhHNS IT was generally well-tolerated. All patients experienced at least one treatment-emergent adverse event (TEAE), most being mild or moderate in severity. No serious adverse events (SAEs) were considered related to the study drug, and no deaths occurred. Most SAEs were related to malfunctions of the IDDD. Declines from baseline in Bayley Scales of Infant Development, Third Edition or Kaufman Assessment Battery for Children, Second Edition, Nonverbal Index developmental quotient scores were evident at all rhHNS dosing groups: -17.97%, -18.99%, and -12.12% in the 10/45, 45, and 90 mg groups, respectively, at Month 54., Conclusions: Overall, rhHNS IT was well tolerated in the extension study. However, rhHNS IT was unable to slow the neurocognitive decline of patients with MPS IIIA. This study was subsequently terminated early because pre-specified efficacy criteria were not met, and the study did not yield clinical proof of concept. (Clinicaltrials.gov Identifier NCT01299727)., Competing Interests: Declaration of Competing Interest Dr. Wijburg reports grants, fees for consultations, and speaker fees from Takeda during the conduct of the study. Dr. Heap has received travel grants from Takeda. Dr. Rust has received a travel grant from Takeda. Dr. de Ruijter, Dr. Tump, and Dr. Marchal have nothing to disclose. Dr. Nestrasil reports research grants, personal fees, and other from Takeda, Genzyme, and Biomarin during the conduct of the study; other from Quantims LLC, outside the submitted work. Dr. Shapiro reports grants, personal fees, and other from Takeda during the conduct of the study; other from Shapiro Neuropsychology Consulting, LLC, outside the submitted work. Dr. Jones has received honoraria, travel grants, or research grants from Takeda. Dr. Alexanderian is an employee of Takeda Development Center Americas, Inc. and is a stockholder of Takeda Pharmaceuticals Company Limited outside of the submitted work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The majority of patients affected with lysosomal storage disorders (LSD) exhibit neurological symptoms. For mucopolysaccharidosis type IIIC (MPSIIIC), the major burdens are progressive and severe neuropsychiatric problems and dementia, primarily thought to stem from neurodegeneration. Using the MPSIIIC mouse model, we studied whether clinical manifestations preceding massive neurodegeneration arise from synaptic dysfunction. Reduced levels or abnormal distribution of multiple synaptic proteins were revealed in cultured hippocampal and CA1 pyramidal MPSIIIC neurons. These defects were rescued by virus-mediated gene correction. Dendritic spines were reduced in pyramidal neurons of mouse models of MPSIIIC and other (Tay-Sachs, sialidosis) LSD as early as at P10. MPSIIIC neurons also presented alterations in frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents, sparse synaptic vesicles, reduced postsynaptic densities, disorganized microtubule networks, and partially impaired axonal transport of synaptic proteins. Furthermore, postsynaptic densities were reduced in postmortem cortices of human MPS patients, suggesting that the pathology is a common hallmark for neurological LSD. Together, our results demonstrate that lysosomal storage defects cause early alterations in synaptic structure and abnormalities in neurotransmission originating from impaired synaptic vesicular transport, and they suggest that synaptic defects could be targeted to treat behavioral and cognitive defects in neurological LSD patients.

Preconception expanded carrier screening (ECS) aims to detect carrier couples of autosomal recessive (AR) disorders before pregnancy in order to increase reproductive autonomy of prospective parents. Genetic knowledge and knowledge gained from experience influence decision making on participation in genetic testing and understanding carrier test results. In this study we assessed whether parents and relatives of patients with the severe AR condition mucopolysaccharidosis type III (MPS III), who are expected to have genetic and experiential knowledge, have more positive attitudes toward ECS than the Dutch reference group. Parents of all MPS III patients known to the Dutch expert center were invited to participate and asked to invite first and second degree relatives. The online questionnaire started with an educational text, and assessed attitudes toward ECS, genetic knowledge and perceived MPS III severity. Results were compared with the Dutch population. Parents and relatives of MPS III patients (n = 159) scored higher on the genetic knowledge test and perceived MPS III as more severe compared with the general Dutch population (n = 781). Parents and relatives reported to be more likely to participate in ECS (84.3% and 62.5%, respectively) compared with the public (31%) (p < 0.001). Being a relative of a MPS III patient was the strongest variable in the regression analyses for intended ECS participation. Our results show that genetic knowledge influences ECS decision making. Therefore, appropriate information on ECS and genetic counseling is needed to enable prospective parents from the general population, including relatives of patients with severe hereditary disorders, to make informed decisions.

Background: Sanfilippo syndrome B (or mucopolysaccharidosis type IIIB [MPS IIIB]) is a severe inherited metabolic disorder caused by mutations in the NAGLU gene, encoding α-N-acetylglucosaminidase. Dysfunction of this enzyme results in impaired degradation of heparan sulfate, one of glycosaminoglycans, and accumulation of this complex carbohydrate in lysosomes. Severe symptoms occurring in this disease are related to progressive neurodegeneration and include extreme hyperactivity, sleeping problems, aggressive-like behavior, reduced fear, and progressive mental and cognitive deterioration. No cure is currently available for Sanfilippo disease., Methods: Clinical characterization of the patient's symptoms has been performed. Biochemical analyses included glycosaminoglycan level determination and measurement of α-N-acetylglucosaminidase activity. Molecular analyses included exome sequencing and detailed analysis of the NAGLU gene. Psychological tests included assessment of attention, communication and behavior., Results: We describe a patient with an untypically mild phenotype, who was diagnosed at the age of 13 years. Many cognitive, communication, and motoric functions were preserved in this patient, contrary to vast majority of those suffering from MPS IIIB. The patient is a compound heterozygote (c.638C>T/c.889C>T) in the NAGLU gene, and relatively high residual activity (about 25%) of α-N-acetylglucosaminidase was measured in serum (while no activity of this enzyme could be detected in dry blood spot)., Conclusions: We suggest that the mild phenotype might arise from the partially preserved function of the mutant enzyme (p.Pro213Leu), suggesting the genotype-phenotype correlation in this case., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Sanfilippo B syndrome is a progressive neurological disorder caused by inability to catabolize heparan sulfate glycosaminoglycans. We studied neurobehavior in male Sanfilippo B mice and heterozygous littermate controls from 16 to 20 weeks of age. Affected mice showed reduced anxiety, with a decrease in the number of stretch-attend postures during the elevated plus maze (p=0.001) and an increased tendency to linger in the center of an open field (p=0.032). Water maze testing showed impaired spatial learning, with reduced preference for the target quadrant (p=0.01). In radial arm maze testing, affected mice failed to achieve above-chance performance in a win-shift working memory task (t-test relative to 50% chance: p=0.289), relative to controls (p=0.037). We found a 12.4% reduction in mean acetylcholinesterase activity (p<0.001) and no difference in choline acetyltransferase activity or acetylcholine in whole brain of affected male animals compared to controls. Cholinergic pathways are affected in adult-onset dementias, including Alzheimer disease. Our results suggest that male Sanfilippo B mice display neurobehavioral deficits at a relatively early age, and that as in adult dementias, they may display deficits in cholinergic pathways., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Unlabelled: Mucopolysaccharidosis IIIA is a heritable neurodegenerative disorder resulting from the dysfunction of the lysosomal hydrolase sulphamidase. This leads to the primary accumulation of the complex carbohydrate heparan sulphate in a wide range of tissues and the secondary neuronal storage of gangliosides GM2 and GM3 in the brain. GM2 storage is associated with CNS deterioration in the GM2 gangliosidosis group of lysosomal storage disorders and may also contribute to MPS CNS disease. N-butyldeoxynojirimycin, an inhibitor of ceramide glucosyltransferase activity and therefore of ganglioside synthesis, was administered to MPS IIIA mice both prior to maximal GM2 and GM3 accumulation (early treatment) and after the maximum level of ganglioside had accumulated in the brain (late treatment) to determine if behaviour was altered by ganglioside level. Ceramide glucosyltransferase activity was decreased in both treatment groups; however, brain ganglioside levels were only decreased in the late treatment group. Learning in the water cross maze was improved in both groups and the innate fear response was also restored in both groups. A reduction in the expression of inflammatory gene Ccl3 was observed in the early treatment group, while IL1β expression was reduced in both treatment groups. Thus, it appears that NB-DNJ elicits a transient decrease in brain ganglioside levels, some modulation of inflammatory cytokines and a functional improvement in behaviour that can be elicited both before and after overt neurological changes manifest., Synopsis: NB-DNJ improves learning and restores the innate fear response in MPS IIIA mice by decreasing ceramide glucosyltransferase activity and transiently reducing ganglioside storage and/or modulating inflammatory signals., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Mucopolysaccharidoses (MPS) are characterized by mental retardation constantly present in the severe forms of Hurler (MPS I), Hunter (MPS II) and Sanfilippo (MPS III) diseases. On the contrary, mental retardation is absent in Morquio (MPS IV) and Maroteaux-Lamy (MPS VI) diseases and absent or only minimal in the attenuated forms of MPS I, II and III. Considering that MPS patients affected by mental disease accumulate heparan sulfate (HS) due to specific enzymatic defects, we hypothesized a possible correlation between urinary HS-derived glucosamine (GlcN) accumulated in tissues and excreted in biological fluids and mental retardation. 83 healthy subjects were found to excrete HS in the form of fragments due to the activity of catabolic enzymes that are absent or impaired in MPS patients. On the contrary, urinary HS in 44 patients was observed to be composed of high molecular weight polymer and fragments of various lengths depending on MPS types. On this basis we correlated mental retardation with GlcN belonging to high and low molecular weight HS. We demonstrate a positive relationship between the accumulation of high molecular weight HS and mental retardation in MPS severe compared to attenuated forms. This is also supported by the consideration that accumulation of other GAGs different from HS, as in MPS IV and MPS VI, and low molecular weight HS fragments do not impact on central nervous system disease.

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Severe progressive neurological paediatric disease mucopolysaccharidosis III type C is caused by mutations in the HGSNAT gene leading to deficiency of acetyl-CoA: α-glucosaminide N-acetyltransferase involved in the lysosomal catabolism of heparan sulphate. To understand the pathophysiology of the disease we generated a mouse model of mucopolysaccharidosis III type C by germline inactivation of the Hgsnat gene. At 6-8 months mice showed hyperactivity, and reduced anxiety. Cognitive memory decline was detected at 10 months and at 12-13 months mice showed signs of unbalanced hesitant walk and urinary retention. Lysosomal accumulation of heparan sulphate was observed in hepatocytes, splenic sinus endothelium, cerebral microglia, liver Kupffer cells, fibroblasts and pericytes. Starting from 5 months, brain neurons showed enlarged, structurally abnormal mitochondria, impaired mitochondrial energy metabolism, and storage of densely packed autofluorescent material, gangliosides, lysozyme, phosphorylated tau, and amyloid-β. Taken together, our data demonstrate for the first time that deficiency of acetyl-CoA: α-glucosaminide N-acetyltransferase causes lysosomal accumulation of heparan sulphate in microglial cells followed by their activation and cytokine release. They also show mitochondrial dysfunction in the neurons and neuronal loss explaining why mucopolysaccharidosis III type C manifests primarily as a neurodegenerative disease., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Mucopolysaccharidoses (MPS) are inborn metabolic disorders caused by a deficiency of glycosaminoglycan degrading enzymes. Although intravenous enzyme replacement therapy is a viable approach for the treatment of non-neuronopathic forms of MPS, its effectiveness in the central nervous system (CNS) is limited by the blood-brain barrier. Alternatively, enzyme replacement therapies and other therapies that directly target the brain represent approaches that circumvent the blood-brain barrier and, in the case of gene therapies, are intended to negate the need for repetitive dosing., Methods: In the present study, gene therapy was targeted to the brains of young adult mice affected by mucopolysaccharidosis type IIIA (MPS IIIA) by bilateral delivery of two different therapeutic lentivirus vectors to the cerebral lateral ventricles. One vector expressed codon optimised murine sulphamidase, whereas the other co-expressed sulphamidase and sulfatase modifying factor-1., Results: Six months after gene delivery, bladder distension was prevented in all treated animals, and behavioural deficits were improved. Therapeutic enzyme activity from the most efficacious vector, which was also the simpler vector, ranged from 0.5- to four-fold normal within the brains of treated animals, and the average amount of integrated vector ranged from 0.1-1 gene copies per cell. Consequently, levels of ganglioside and lysosomal β-hexosaminidase, both of which are characteristically elevated in MPS IIIA, were significantly reduced, or were normalised., Conclusions: The present study demonstrates the efficacy of the intraventricular injection as a tool to target the brain with therapeutic genes in adult MPS IIIA mice, and provides evidence supporting this approach as a potentially effective means of treating CNS pathology in MPS IIIA patients., (Copyright © 2014 John Wiley & Sons, Ltd.)

Objective: To describe the natural history of Sanfilippo syndrome type A., Methods: We performed a retrospective review of 46 children (21 boys, 25 girls) with Sanfilippo syndrome type A evaluated between January 2000 and April 2013. Assessments included neurodevelopmental evaluations, audiologic testing, and assessment of growth, adaptive behavior, cognitive behavior, motor function, and speech/language skills. Only the baseline evaluation was included for patients who received hematopoietic stem cell transplantation., Results: Median age at diagnosis was 35 months, with a median delay between initial symptoms to diagnosis of 24 months. The most common initial symptoms were speech/language delay (48%), dysmorphology (22%), and hearing loss (20%). Early behavioral problems included perseverative chewing and difficulty with toilet training. All children developed sleep difficulties and behavioral changes (e.g., hyperactivity, aggression). More than 93% of the children experienced somatic symptoms such as hepatomegaly (67%), abnormal dentition (39%), enlarged tongue (37%), coarse facial features (76%), and protuberant abdomen (43%). Kaplan-Meier analysis showed a 60% probability of surviving past 17 years of age., Conclusions: Sanfilippo type A is characterized by severe hearing loss and speech delay, followed by a rapid decline in cognitive skills by 3 years of age. Significant somatic disease occurs in more than half of patients. Behavioral difficulties presented between 2 and 4 years of age during a rapid period of cognitive decline. Gross motor abilities are maintained during this period, which results in an active child with impaired cognition. Sleep difficulties are concurrent with the period of cognitive degeneration. There is currently an unacceptable delay in diagnosis, highlighting the need to increase awareness of this disease among clinicians.

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in one of four enzymes involved in the catabolism of the glycosaminoglycan heparan sulphate. It is a degenerative disorder, with a progressive decline in children's intellectual and physical functioning. There is currently no cure for the disorder. To date there is a paucity of research on how this disorder impacts parents psychological functioning. Specifically, research in the area has failed to employ adequate control groups to assess if the impact of this disorder on parents psychological functioning differs from parenting a child with intellectual disability (ID). The current study examined child behaviour and parental psychological functioning in 23 parents of children with MPS III and 23 parents of children with ID. Parents completed postal questionnaires about their child's behaviour and abilities and their own psychological functioning. Parents of children with MPS III reported fewer behavioural difficulties as their child aged, more severe level of intellectual disability, and similar levels of perceived social support, coping techniques, stress, anxiety and depression levels as parents of children with ID. Both groups of parents scored above the clinical cut off for anxiety and depression. Parents of children with MPS III rated themselves as significantly less future-orientated and goal directed than parents of children with ID. Services should develop support packages for parents of children with MPS III that incorporate an understanding of the unique stressors and current-difficulty approach of this population. Future research should examine gender differences between parental psychological functioning, using mixed qualitative and quantitative approaches, and utilise matched developmental level and typically developing control groups.

Mucopolysaccharidosis Type IIIA (MPS IIIA) is a neurodegenerative disease with behavioral symptoms unique among the mucopolysaccharidoses. Children with MPS IIIA reportedly mouth things, explore novel environments almost continuously, disregard danger, and empathize/socialize and comply less with parents. These characteristics resemble Klüver-Bucy syndrome (K-Bs). To test the K-Bs hypothesis, 30 children with MPS IIIA were compared to 8 "posttransplant" mucopolysaccharidosis Type IH patients in an experimental "risk room." The room contained attractive and mildly frightening objects, exposure to a 92-dB startle noise triggered by contact with an attractive toy, mother's return after a brief absence, and compliance with her cleanup directive. Children with MPS IIIA: (a) left mother sooner, (b) wandered more, (c) were more likely to approach frightening objects, (d) were less likely to respond to loud noise with whole body startle, (e) were less likely to avoid the toy associated with the startle noise, (f) interacted less with mother upon her return, and (g) complied less with her cleanup command. K-Bs is associated with loss of amygdala function. Brain magnetic resonance imaging (MRI) of a subset of the children with MPS IIIA showed volume loss that was greater in the amygdala than in the hippocampus; only amygdala loss correlated with reduced fearfulness. MPS IIIA may be the first identified pediatric disease presenting systematically as a K-Bs variant. If validated by further studies, the K-Bs hypothesis of MPS IIIA would provide important clinical and theoretical information for the guidance of families as well as markers for natural disease progression and treatment effects.

Objective: Sanfilippo B is a rare autosomal recessive mucopolysaccharidosis (MPS IIIB) caused by a deficiency of N-acetyl-alpha-D-glucosaminidase (NAGLU)., Method: A mild mentally retarded elderly female patient is described with a slowly progressive dementia who had given birth to a daughter who developed normally., Results: Metabolic screening revealed an enhanced concentration of heparan sulfate in urine. Enzymatic assay demonstrated deficiency of N-acetyl-alpha-D-glucosaminidase. Mutations in the NAGLU gene were found. One mentally retarded and hospitalized elder brother was also found to have MPS IIIB, whereas a second brother, who had died earlier, is suspected to have had the same metabolic disorder. Prior to the development of dementia, both the patient and her brother showed autistic like features, signs of ideomotor apraxia and weakness in verbal comprehension., Conclusion: Screening for metabolic disorders, in particular MPSes, should always be considered in patients with a history of mental deficit and dementia or progressive functional decline.

Mucopolysaccharidosis IIIA (MPS IIIA) is a lysosomal storage disorder characterized by progressive mental deterioration and severe behavioral problems. We conducted an open-label, crossover study of the efficacy and safety of Risperidone on behavioral disorder in children with MPS IIIA. A total of 12 patients (5.5+/-2.2 years) with enzymatic diagnosis of MPS IIIA were randomly assigned to receive Risperidone (0.125-2mg/d) for 6 months. The hyperactivity and disruptive behavior level of children before and after treatment was evaluated regarding the scores from Turgay DSM IV Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S). Clinic Global Impression Scale - Severity (CGIS-S) was used for all cases for determining the psychiatric disorder severity. The anxiety and depression levels of mothers before and after treatment were evaluated using Hamilton Anxiety Scale (HAM-A) and Beck Depression Inventory (BDI). The adverse effects were evaluated by monitoring weight, serum prolactin, glucose and lipid levels. The response to the treatment was measured by decrease in values of CGI-S (from 6+/-1.12 to 2.91+/-0.66, p=0.001). According to T-DSM-IV-S scores the best improvement was observed in hyperactivity scores (16.25+/-8.57/11.58+/-7.26, p=0.001), followed by opposition/defiance (6.66+/-5.92/5.08+/-4.88, p=0.032), and conduct disorder scores (1.00+/-1.85/0.41+/-.99, p=0.67). No clinically relevant elevations in weight and serum prolactin, glucose or lipid levels have been documented (p>0.05). There was a significant decrease in anxiety and depression scores of mothers (HAM-A: 20.33+/-8.28/17.91+/-6.89, BDI: 23.58+/-7.14/20.5+/-5.93, p<0.001). To our knowledge, research on the pharmacological treatment of MPS IIIA with Risperidone has not been reported. According to our data, Risperidone appeared to be safe and effective in MPS IIIA patients., (2008 Elsevier B.V. All rights reserved.)

Background: We report the case of a 16-year-old male with Mucopolysaccharidosis III type A (Sanfilippo syndrome) who was commenced on risperidone for behaviour management. He rapidly developed extrapyramidal symptoms that have not resolved., Method: The medication histories of 20 patients with Mucopolysaccharidosis III seen at a Lysosomal Storage Diseases Clinic were reviewed to determine the incidence of extrapyramidal side effects., Results: Six patients had been treated with risperidone, olanzapine, or lamotrigine. Five of these patients developed extrapyramidal side effects., Conclusions: The incidence of extrapyramidal side effects was considerably higher than expected. We suggest that these medications be used with considerable caution in these patients.

Mucopolysaccharidosis (MPS) IIIB is an inherited lysosomal storage disease, caused by the deficiency of alpha-N-acetylglucosaminidase (NaGlu), resulting in severe global neurological involvement with high mortality. One major hurdle in therapeutic development for MPS IIIB is the presence of the blood-brain barrier, which impedes the global central nervous system (CNS) delivery of therapeutic materials. In this study, we used a minimal invasive strategy, combining an intravenous (i.v.) and an intracisternal (i.c.) injection, following an i.v. infusion of mannitol, to complement the CNS delivery of adeno-associated viral (AAV) vector for treating MPS IIIB in young adult mice. This treatment resulted in a significantly prolonged lifespan of MPS IIIB mice (11.1-19.5 months), compared with that without treatment (7.9-11.3), and correlated with significantly improved behavioral performances, the restoration of functional NaGlu, and variable correction of lysosomal storage pathology in the CNS, as well as in different somatic tissues. This study demonstrated the great potential of combining i.v. and i.c. administration for improving rAAV CNS gene delivery and developing rAAV gene therapy for treating MPS IIIB in patients.

At present, there is no widely available, safe and effective treatment for lysosomal storage disorders (LSD) that affect the brain. We have used a naturally occurring mouse model of mucopolysaccharidosis type IIIA (MPS IIIA) or Sanfilippo syndrome, to evaluate the effect of repeated injection of recombinant human sulfamidase (rhSGSH) into the cerebrospinal fluid via the cisterna magna (CM) on central nervous system (CNS) pathology and behavioral function. Mice received up to seven injections of rhSGSH (5-20 microg rhSGSH per injection) or vehicle on a fortnightly or monthly basis. A dose-dependent reduction in the level of a heparan sulfate-derived monosulfated disaccharide was observed within the brain (up to 62% reduction compared with vehicle-treated MPS IIIA mice) and spinal cord (up to 71% reduction). Ultrastructural examination revealed a reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) axonal spheroids were observed in several brain regions. The biochemical changes were accompanied by improved behavior, particularly in mice-treated more frequently. A humoral immune response to rhSGSH was observed in treated animals. Intra-CM injection of lysosomal enzyme may therefore represent an immediately applicable method of treating the CNS effects of this and potentially other LSD that affect the brain.

Aims: To determine the incidence, manifestations, and best management of sleep disturbance in Sanfilippo syndrome (mucopolysaccharidosis (MPS) type III)., Methods: Families were ascertained through the MPS societies of Australasia, the UK, and the USA. Questionnaires were sent by mail and were answered anonymously. Identical questions regarding sleep disturbance were asked about unaffected siblings to provide control data. Sleep disturbance was quantified by a total sleep disturbance score., Results: A total of 141 responses were received; 91.5% of children with Sanfilippo syndrome had sleep disturbance and this was significantly higher than for their unaffected sibs; 77.5% of parents had used medication for this problem, with melatonin and antihistamines being most commonly used. Melatonin and benzodiazepines were reported as the most efficacious. Many different environmental modifications had been employed for this problem and some parents reported success with behavioural therapies., Conclusions: Sleep disturbance is common, severe, and difficult to manage in Sanfilippo syndrome. Based on the parental responses and its safety profile, melatonin is the first line drug that should be tried. Behavioural therapy should be tried in all with Sanfilippo syndrome and sleep disturbance.

Sanfillippo B syndrome (mucopolysaccharidosis (MPS) III, type B) is characterized by mild expression of the characteristic 'Hurler' phenotype and a severe central nervous system involvement. We report three patients with Sanfilippo B syndrome, referred to our clinic because of peculiar facies, delay in language development and behavioral problems, at the ages of 4, 3 and 5 years, respectively. At presentation they manifested clinical features of MPS, severe developmental retardation, radiological features of dysostosis mutiplex, as well as neurophysiological findings suggestive of carpal tunnel syndrome and sensorineural hearing impairment. Due to marked urinary excretion of heparan sulfate, as well as deficiency of alpha-N-acetylglucosaminidase in leukocytes, the diagnosis of Sanfilippo B syndrome was made. Serial brain magnetic resonance imaging (MRI) at different ages demonstrated white matter abnormalities, cortical atrophy and ventricular enlargement in all three patients, while other findings included thickening of the diploe in two patients and callosal atrophy, basal ganglia involvement, cerebellar changes and dilatation of venous sinuses in one patient. Although the combination of the above MRI findings is highly suggestive of a MPS, they carry a little predictive value in the different clinical stages of MPS IIIB.

We report two women with Sanfilippo syndrome. Both had characteristic aggressiveness that was refractory to treatment with conventional agents. Both women improved on oral estrogen therapy and showed diminished aggressiveness.

This paper reports a study of the nature and prevalence of behaviour problems in 258 children with mucopolysaccharide disorders. Questionnaire data obtained through the post was supplemented by home visits to 42 families in the sample and by regular discussions with families at meetings of the Society for Mucopolysaccharide Diseases. High rates of behaviour problems were found, particularly in children with Sanfilippo's and Hunter's disease aged 5 to 9 years. These included destructiveness, restlessness, and aggressiveness. Sleep problems were common across subtypes with an overall prevalence of 66%. Parents reported that they received little or no support in the management of these difficult behaviours. It is concluded that behaviour problems are a primary feature of the mucopolysaccharide disorders and place a major strain on families. Services to help families cope with these problems are urgently needed.

Intrafamilial variability has not been reported previously in Hurler syndrome or Sanfilippo syndrome type A. We describe two families in which sibs with comparable deficiencies of alpha-iduronidase (Hurler) or sulfamidase (Sanfilippo type A) activities in vitro nonetheless have divergence in clinical severity and disease progression. These cases underscore the need for caution in counseling as well as the limitations of using sibs as controls in evaluating the outcome of treatment.

Allogeneic bone marrow transplantation was performed on twins with Sanfilippo B disease. They were the first two patients with this disorder to undergo the procedure. There was definite evidence of engraftment as shown by conversion to donor blood group antigen and tissue type, and increased leukocyte alpha-glucosaminidase activity. Nine years post transplant, neither twin is as handicapped as her untreated brothers were at the same age, although in one twin hyperactivity and behavioural problems, characteristic of the disorder, are present. Details of the twins' intellectual development and growth, their alpha-glucosaminidase activity and urinary glycosaminoglycan excretion are reported.

The results of a survey given to parents with Sanfilippo syndrome (MPS III) children (n = 30) are described with an emphasis in several areas. Developmental and degenerative patterns are outlined in detail and contrasted with developmental milestones of normal children. An essentially uniform pattern of behaviour problems was discovered and is discussed along with the efficacy of pharmacological and non-pharmacological approach to remediation. Finally, practical suggestions are offered for physicians and parents which are encountered by the daily management problems of children with this disorder.