Caregiver-reported outcome measures (CROMs) complement clinical assessments of neurodevelopmental functions (NDF) in pediatric rare disease trials. This scoping review summarizes use of CROMs of NDF across bodily function, activity, and participation domains of the International Classification of Functioning, Disability, and Health (ICF) model in pediatric lysosomal storage disorders (LSDs), characterizes assessed neurodevelopmental domains, and outlines considerations for CROM selection within a comprehensive functional assessment strategy. We applied JBI methodology and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Primary articles reporting CROM of NDF use in children with LSDs ≤ 12 years old were identified. Study characteristics, design, and CROMs utilized were extracted. CROMs were classified as condition-general or disease-specific. CROM content was mapped to neurodevelopmental domains (activities of daily living [ADL], cognition, communication, physical, social-emotional function). Ninety-eight articles published in the last 10 years reported on 38 distinct CROMs of NDF across > 20 LSDs. Nearly all studies (93%) used ≥ 1 condition-general CROM of NDF, most commonly the Vineland Adaptive Behavioral Scales or the Pediatric Quality of Life Inventory. Eleven disease-specific CROMs were reported, typically alongside condition-general measures. Physical, ADL, and social-emotional domains were indexed most consistently. CROMs were endpoints in 32 LSD clinical trials. Findings illustrate the variety and common trends of CROMs of NDF used in pediatric LSD studies. This review informs selection of complementary caregiver-reported endpoints in LSD trials based on a well-defined, clinically meaningful construct; alignment with other endpoints and expert consensus; and operational practicality.
Chenodeoxycholic acid (CDCA) is an essential drug for patients with rare metabolic disease cerebrotendinous xanthomatosis (CTX). To ensure continuation of treatment, the Amsterdam UMC hospital pharmacy developed pharmacy compounded CDCA capsules when the authorized CDCA capsules were no longer available for Dutch patients. This study reports the safety of pharmacy compounded CDCA through pharmacovigilance monitoring and assesses its effectiveness by evaluating biochemical outcome measures, both in patients who were previously treated with authorized CDCA and subsequently switched to the compounded formulation and in new patients. Data were generated during routine patient care and collected retrospectively. Adverse events were reported by 45% of the patients; the most reported adverse events were diarrhea (16%), constipation (7%), and fatigue (7%). Biochemically, plasma cholestanol levels and urinary bile alcohol levels remained normalized before and after switching from the authorized product to pharmacy compounded capsules. It can be concluded that the pharmacy compounded CDCA capsules are well tolerated by patients with CTX and that the desired biochemical effect was maintained, supporting the use of a compounded formulation when the authorized product is unavailable.
Mucopolysaccharidosis II is a rare, X-linked disease, with very few reports of affected female patients. Natural history data describe a predominantly male population, and appropriate disease characterization in female patients is lacking. This analysis explores the somatic disease burden and clinical progression of female patients with MPS II enrolled in the Hunter Outcome Survey (HOS; NCT03292887), a global disease registry. In total, 15 female patients were identified, representing 1.1% of the total patients in HOS. The median ages at first symptom onset and diagnosis were 1.8 and 3.1 years, respectively. A total of 8/14 (57.1%) of patients had cognitive impairment at the latest visit. X-chromosome abnormalities were reported in two patients. Most patients (11/15, 73.3%) had received at least one dose of idursulfase, which was generally well tolerated; no serious adverse events during follow-up were considered treatment-related. Musculoskeletal and ear symptoms were present in all 14 patients with data recorded. Almost all females also experienced neurological, abdominal/gastrointestinal, and pulmonary disease, similar to the symptomatology reported in males. Most patients underwent surgery (41 procedures in 12 patients). Two participants had a male sibling with MPS II who was also enrolled in HOS. Both sibling sets had missense variants and demonstrated several differences in signs/symptoms between the male and female siblings. Notably, only the female siblings displayed cognitive impairment. This report illustrates the disease burden in female patients with MPS II, helping to inform clinicians about the likely prognosis for this extremely rare subgroup of patients.
Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of phenylalanine hydroxylase (PAH), leading to the accumulation of phenylalanine (Phe) and an increased risk of developmental disorders. Treatment involves a Phe-restricted diet, amino acid supplements, and for a subset of patients, a tetrahydrobiopterin (BH4) chaperone. Managing PKU during pregnancy is challenging due to changing protein and energy needs, stricter Phe control, nausea, and unpalatable supplements. In rare cases of simultaneous maternal and fetal PKU, Phe tolerance may increase less throughout gestation, raising the demands on the patient and caregivers. There are few reports and no guidelines on the management of PKU during pregnancies in which both mother and fetus have PKU, hereafter referred to as maternal-fetal PKU (mfPKU). This report outlines our approach for successfully managing two consecutive mfPKU pregnancies. We emphasize a patient-centered approach, focusing on patient education and close collaboration with a multidisciplinary metabolic team. This involves regular monitoring of body weight, blood Phe levels, and calorie intake through an online food diary to tailor individual recommendations for natural protein restriction and amino acid supplements.
Although several advances in glycogen storage disorder (GSD) management have been made over the years, there is still increased morbidity and mortality in these patients, particularly among those with GSD type I (GSDI). Here, we describe a case series of five patients with GSDIa who presented with severe lactic acidosis and passed away without a clearly identified etiology, despite some having adequate metabolic control at baseline. Based on these presentations and emerging literature, we posit that progressive, secondary mitochondrial dysfunction plays an important role in placing GSDIa patients at increased risk for GSDI-related complications, including fulminant metabolic crisis. Both G6PC1 knockout mice and human GSDIa plasma and urinary samples exhibit markers of mitochondrial dysfunction. Our observations of refractory lactic acidosis despite hyper- or eu-glycemia potentially suggest mitochondrial dysfunction as a unique feature of the metabolic decompensation experienced by the patients of this report. Thus, underlying mitochondrial dysfunction may set up certain GSDIa patients for multiorgan failure that is unresponsive to conventional therapies. Further research into the mitochondrial function of GSDIa patients across the lifespan is warranted. By introducing surveillance strategies for mitochondrial dysfunction in GSDI, existing antioxidant therapies could be harnessed to maintain or improve mitochondrial function in this patient population. In turn, the integration of mitochondrial therapies into GSD care may improve quality of life and avoid the development of fulminant metabolic crisis.
Sialidosis, also known as Mucolipidosis Type I, is a rare condition caused by defects in the NEU1 gene which causes the accumulation of sialylated peptides, oligosaccharides, and glycoproteins leading to neurological decline. Haematopoetic stem cell transplantation has been performed in the symptomatic phase twice in the literature but has failed to prevent deterioration. We report on a case where a 4-year-old child was diagnosed with pre-symptomatic sialidosis due to investigation following the incidental detection of a cherry-red spot prior to the onset of neurological symptoms. We performed haematopoetic stem cell transplantation with a matched unrelated cord blood unit with optimal timing prior to clinical decline, achieving full donor engraftment with a largely uneventful post-transplant recovery followed by a period of relative clinical stability. However, subsequent neurological decline detailed by clinical history and radiological findings has occurred suggesting a lack of disease responsiveness to transplantation despite optimal timing. We go on to provide supporting laboratory investigations detailing sialidosis fibroblast culture as part of a novel cross-correction assay and compare results to other transplant responsive lysosomal storage disorders such as mucopolysaccharidosis type 1-H and detail a lack of cross-correction in concordance with our clinical findings. We conclude that conventional allogeneic haematopoetic stem cell transplantation is not a viable disease-modifying treatment option in sialidosis, even when performed optimally in the pre-symptomatic phase, and suggest that alternative treatment options must be explored to improve outcomes in this condition.
Diagnostic delay is common in mitochondrial disease, and its drivers remain unclear despite advances in molecular diagnostics. We retrospectively analyzed 61 individuals with molecularly confirmed mitochondrial disease at the Mount Sinai Mitochondrial Disease Clinic, diagnosed after 2016. Diagnostic delay was partitioned into intervals from symptom onset to clinical suspicion, and from suspicion to molecular diagnosis. Demographic, phenotypic, and genetic data were abstracted from health records, and Human Phenotype Ontology terms were compared before and after diagnosis using ClinPhen. Most delays occurred between symptom onset and clinical suspicion (mean 8.17 years) rather than after suspicion (mean 1.28 years), yielding a mean total delay of 8.22 years (median 3.0). Delay decreased sharply by year of birth (r = -0.99, p < 49.92 × 10-39) and symptom onset (r = -0.96, p < 8.14 × 10-27), but showed no meaningful trend with year of diagnosis. Canonical features such as seizures, hypotonia, and stroke were frequently documented years before suspicion, underscoring missed opportunities. Diagnostic delay may reflect missed recognition rather than testing limitations. Systematic capture of early phenotypes and AI/NLP-based mining of electronic health records could proactively flag patients for reflexive sequencing, shortening diagnostic delay.
GM1 gangliosidosis is a lysosomal storage disease (LSD) caused by β-galactosidase deficiency, characterized by the accumulation of gangliosides in various tissues. Among different GM1 forms (infantile form, late-infantile and juvenile form, and late-onset form), the infantile form is the most severe: despite an early clinical onset with rapid neurodegeneration, coarse face, abdominal visceromegaly and skeletal abnormalities, the diagnosis is usually delayed, given the lack of recognized early disease-specific markers. We report the case of a newborn presenting with mild edema of hands and feet, mild transient hypoalbuminemia and isolated hyperphosphatasemia at three weeks of life. The first cardiological evaluation showed mild mitral regurgitation. Despite the absence of neurological symptoms, organomegaly, or a coarse face, the turgid consistency of the limbs, together with mitral regurgitation and persistent hyperphosphatasemia, led to multiorgan investigations with discovery of bilateral cherry-red spots and a beak-shaped lumbar vertebra. The cardiological follow-up revealed a dysplastic mitral valve. In the suspicion of a lysosomal disease, biochemical investigations were planned. An altered profile of urinary oligosaccharides, along with low β-galactosidase activity in leukocytes, led to the diagnosis of infantile GM1 gangliosidosis at 3 months of age. The GLB1 gene analysis confirmed the diagnosis. Genetic testing for GLB1 should be considered in cases of persistent hyperphosphatemia, especially if it is associated with any other clinical indicator of GM1, such as limb edema.
Maple syrup urine disease (MSUD) is a rare, autosomal recessive metabolic disorder resulting from a deficiency of the branched-chain α-ketoacid dehydrogenase complex. This leads to the accumulation of branched-chain amino acids and their corresponding ketoacids, causing acute metabolic crises and progressive neurological damage if untreated. The impact of founder variants, high consanguinity, and limited access to metabolic care pose challenges in medically underserved populations, such as in Palestine. We conducted a retrospective analysis of 11 patients from eight Palestinian families referred to the main Metabolic Unit in the West Bank. Clinical data, biochemical profiles, and molecular findings were reviewed to characterize the presentation and outcomes of MSUD. Management strategies, including dietary intervention and liver transplantation, were also evaluated. Acute metabolic crises were the initial presentation in 91% of cases, typically within the first days of life. Diagnostic delay averaged 47 days in families without prior MSUD history, compared to 2.3 days in those with affected siblings. Founder pathogenic variants were identified in multiple unrelated families, reflecting genetic homogeneity due to community structure; novel variants were also detected. Timely diagnosis facilitated early referral and improved outcomes. Patients who underwent liver transplantation, especially when performed early, exhibited favorable developmental trajectories, increased leucine tolerance, and fewer hospitalizations. One participant diagnosed prenatally remained free of metabolic crises until transplantation at age six, with excellent neurocognitive outcomes. This study highlights the importance of integrating prenatal screening and early diagnosis, timely dietary intervention, and liver transplantation to improve MSUD outcomes in resource-limited settings.
Phenylketonuria (PKU) is an inborn error of metabolism leading to phenylalanine (Phe) accumulation and consequent neurological, neurocognitive, and psychiatric symptoms. Pegvaliase, a pegylated recombinant phenylalanine ammonia lyase that metabolizes Phe, effectively reduced blood Phe in phase III studies in the United States. This multicenter, open-label, phase III study (jRCT2080224573) evaluated efficacy and safety of up to 4 years of pegvaliase treatment in 12 adult Japanese participants with PKU (blood Phe > 600 μmol/L). Subcutaneous pegvaliase followed an induction/titration/maintenance dosing regimen up to a maximum of 60 mg/day. After Week 52, diet and pegvaliase dose could be adjusted if blood Phe was ≤ 360 μmol/L. Mean (standard deviation [SD]) treatment duration was 166.4 (66.5) weeks. At Week 192 (n = 10), mean (SD) blood Phe was 296.2 (430.7) μmol/L, a 71.2% decrease from baseline, and daily protein intake from intact and medical food was 49.9 (21.4) g (68.0% increase) and 7.6 (16.2) g (64.2% decrease), respectively. All participants had ≥ 1 treatment-emergent adverse event (TEAE) during induction/titration, most commonly injection site erythema and injection site swelling (83.3% each); nine of 10 had a TEAE during maintenance. Of 395 TEAEs recorded during maintenance, 82 occurred between the 2-year interim analysis and the 4-year final analysis. One serious TEAE (allergic arthritis) was considered pegvaliase related. The exposure-adjusted rate of pegvaliase-related events was 17.0 per person-year (41.2 during induction/titration, 8.9 during maintenance). Pegvaliase effectively lowered blood Phe in Japanese participants with PKU, with no new safety issues with long-term treatment, and many participants were able to liberalize their diet.
Methylmalonic acidemia (MMA) is a rare metabolic disorder with various subtypes, including Cobalamin B (cblB) disease. While cardiac complications are well-documented in propionic acidemia, their occurrence in MMA is less understood. Here, we report a 12-year-old child with cblB disorder who developed acute cardiomyopathy (CM). The patient presented with fever, tachycardia, and dyspnea. Echocardiography revealed depressed left ventricular function, which initially improved with standard treatment but rapidly deteriorated. Coenzyme Q10 (CoQ10) supplementation was initiated at a dose of 25 mg/kg/day, resulting in a remarkable improvement in cardiac function within 72 h. This report highlights the potential efficacy of CoQ10 in treating MMA-related cardiomyopathy, suggesting mitochondrial dysfunction as a key factor. The successful use of CoQ10 in this context is novel, as previous literature mainly focused on its application in propionic acidemia. This report proposes CoQ10 supplementation as a promising adjuvant therapy for cardiomyopathy in MMA, particularly in cblB disorder, and calls for further research to validate its benefits.
Pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency is characterized by early-onset epileptic encephalopathy refractory to standard antiseizure medications. It is caused by variants in the PNPO gene, resulting in deficient PNPO enzyme activity, which normally converts pyridoxine-5'-phosphate and pyridoxamine-5'-phosphate (two vitamers of vitamin B6) into the active cofactor, pyridoxal-5'-phosphate (PLP). Treatment relies on PLP or pyridoxine in some cases. Long-term outcomes remain suboptimal. We describe two cases of unrelated children treated with vitamin B6 (pyridoxine) in utero: one with a confirmed prenatal PNPO diagnosis and one at risk due to family history but ultimately unaffected. In utero pyridoxine, combined with early postnatal PLP treatment, allowed excellent seizure control and normal neurodevelopment in the long term. Notably, our first patient, treated from birth, is now 10 years old, representing the oldest reported PNPO-deficient individual treated from birth. Case 2 highlights the safety of prenatal B6 supplementation even in unaffected fetuses. These observations support prenatal pyridoxine supplementation as a safe and potentially beneficial strategy in at-risk PNPO pregnancies.
Cobalamin C (cblC) disease is the most common disorder of Vitamin B12 activation. The early-onset form presents within the first few months of life, with some patients identified through newborn screening (NBS). However, despite early detection and optimal treatment, patient outcomes remain poor, with intellectual impairment and progressive visual loss in the majority. We reviewed a cohort of 10 patients with cblC disease, all identified either by NBS or a neonatal clinical presentation. We reviewed their biochemical control and correlated this with clinical progress and treatment. The majority of the cohort (including four asymptomatic patients) was identified through NBS and had genotypes predictive of early-onset disease. Clinical outcomes improved with standard-of-care treatment (hydroxocobalamin, betaine, and folinic acid) but were suboptimal, with both neurocognitive (6/10) and ophthalmological manifestations (10/10) occurring in most patients. One patient died at 5 months of age, and it is unclear whether this was related to cblC disease or not. Across over 250 timepoints from 9 patients, there was minimal correlation between cumulative intramuscular hydroxocobalamin (OHCbl) dose and biomarkers, including methylmalonic acid (r 2 = 0.0031) and total homocysteine (r 2 = 0.2858) levels. This study provides comprehensive, longitudinal biochemical, and clinical follow-up of patients with cblC disease treated from soon after birth, often presymptomatically. Our findings corroborate previous observations regarding the lack of correlation of current biomarkers, both with disease progression and with standard (< 0.3 mg/kg/day) hydroxocobalamin dosing. Further investigation of the clinical impact of early high-dose OHCbl treatment is needed in larger cohorts of patients.
Succinate dehydrogenase (SDH) serves a dual function as complex II of the electron transport chain and an enzyme of the tricarboxylic acid cycle. Pathogenic variants in subunits of SDH result in diverse clinical presentations, including typically autosomal recessive neurodegenerative disorders. Biallelic variants in the SDHA subunit most often cause Leigh syndrome. However, epilepsy phenotypes of these patients are ill-defined and there is only one prior report of epilepsy in a patient with SDHA deficiency. Here we report the seizure and EEG phenotypes of three autosomal recessive SDHA patients with refractory epilepsy, two of whom are siblings. These patients exhibit multiple seizure types and a variety of EEG findings, including a patient with rhythmic high-amplitude delta with superimposed spikes (RHADS), a finding closely associated with polymerase gamma (POLG)-related disorders.
Hyperammonemia is a medical emergency, and the cause must be identified quickly in order to treat appropriately. Malnutrition is a known risk factor for hyperammonemia; however, there are limited reliable lab indicators used to identify malnutrition. Early identification of the etiology of hyperammonemia is crucial to optimizing care, specifically reintroduction of appropriate amounts of protein into the diet. Herein, we discuss three patients with complex medical histories and clinical signs of malnutrition who presented with hyperammonemia. In all three patients, both hypoaminoacidemia and pyroglutamic aciduria were observed. Specifically, all patients had low tyrosine, tryptophan, methionine, and branched-chain amino acids. Recognizing this biochemical pattern could result in more rapid initiation of supplementing protein, a primary tenet of treatment in malnutrition-related hyperammonemia. We highlight the unique features of malnutrition-related hyperammonemia, propose mechanisms to explain the pattern, and suggest a framework for managing these cases.
Holocarboxylase synthetase deficiency is an autosomal recessive inborn error of metabolism characterised by life-threatening metabolic acidosis, ketoacidosis and hyperammonaemia through reduced biotin-dependent carboxylase activity. We report the presentation of a Polynesian neonate with severe metabolic acidosis secondary to holocarboxylase synthetase deficiency with the development of cholestatic liver disease thought to be secondary to holocarboxylase synthetase deficiency. This is only the second reported case of holocarboxylase synthetase deficiency associated with cholestatic liver disease. Both of these cases were a result of the same homozygous c.647T>G L216R pathogenic variants in the HLCS gene suggesting a possible genotype-phenotype correlation and broadening the phenotypic understanding of this disease.
Phenylketonuria (PKU) is an inherited metabolic disorder causing elevated phenylalanine (Phe) levels and neurocognitive impairment if left untreated. While dietary therapy remains the treatment standard, adherence declines during adolescence. Pegvaliase, an injectable enzyme therapy approved for adults > 18 years in the United States, lowers Phe levels while allowing dietary flexibility. This study examines pegvaliase use in adolescents, focusing on efficacy, discontinuation patterns, and predictors of success. We conducted a retrospective chart review from four metabolic centers with 53 individuals with PKU (age 14-22 years) who initiated pegvaliase through March 2025. Data included demographics, treatment response, side effects, and discontinuation reasons. Mean pretreatment Phe was 716 μmol/L, which decreased by 44% post-treatment initiation. Sixty-four percent of individuals achieved efficacy with a mean Phe of 231 μmol/L (60% decrease) after 14 months at mean dose of 37.4 mg/day. Common side effects included injection site reactions in 77%, joint pain in 64%, rash in 45%, headaches in 26%, fatigue in 19%, fever and/or chills in 13%, GI symptoms in 13%, and anaphylaxis in 9%. Discontinuation occurred in 24.5% of this cohort, with rates significantly higher in 12th graders (40%) and college students (32%) versus 9th-11th graders (5.5%). Pegvaliase may lower Phe levels in adolescents, reaching target blood Phe goals (≤ 360 μmol/L) once efficacy is achieved. Treatment showed better sustainability when initiated earlier in adolescence. The higher discontinuation during transitional years (12th grade/college) suggests treatment challenges increase during these periods. Earlier initiation, when family support is typically stronger, may improve outcomes. These findings support reconsidering current age restrictions for pegvaliase therapy.
Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency is a rare autosomal recessive gluconeogenesis disorder caused by variants in the PCK1 gene. Clinically, PEPCK-C deficiency is characterized by recurrent episodes of fasting-induced hypoglycemia, liver dysfunction, and seizures, with the first hypoglycemic episode typically occurring in the neonatal period or in early childhood. We report a case of PEPCK-C deficiency in an 8-year-old who presented with transient severe acute liver and kidney failure, accompanied by markedly elevated glutamine levels as the initial manifestation of the disease. The acute liver failure was reversible following continuous glucose infusion. Next-generation sequencing identified two variants in the PCK1 gene: one previously known pathogenic variant, c.925G>A p.(Gly309Arg), and a second previously unreported variant, c.1833_1834del p.(Glu611AspfsTer16). These variants were confirmed to be in a compound heterozygous state. Based on the patient's clinical presentation, the second variant was classified as likely pathogenic. Subsequent genetic testing of family members revealed that the patient's 12-year-old sister has the same PCK1 variants but remains asymptomatic to date. Given the clinical findings, we propose that the c.1833_1834del p.(Glu611AspfsTer16) variant in the PCK1 gene should be classified as likely pathogenic. We recommend considering molecular diagnostics for PEPCK-C deficiency in patients presenting with severe acute liver failure and elevated glutamine levels, as early diagnosis and intervention may lead to a reversible outcome.
Mucopolysaccharidosis Type IV is a multisystem lysosomal storage disease characterized by severe skeletal dysplasia resulting from impaired degradation of the glycosaminoglycans keratan sulfate and chondroitin-6-sulfate. The condition is classified into Types A and B based on the underlying enzyme deficiency. Low bone mineral density (BMD) is a feature of the skeletal phenotype, contributing to increased fracture risk. Extraskeletal manifestations include, among others, cardiovascular disease due to valvular stenosis and regurgitation, myocardial remodeling, coronary artery disease, and vascular stiffness, all associated with glycosaminoglycan accumulation. We report two adult patients with mucopolysaccharidosis Type IVB treated with the osteoanabolic agent teriparatide for an apparently low BMD. The first patient presented with a non-healing femoral fracture requiring BMD improvement prior to surgical fixation. This patient was treated with teriparatide for 2 years, which resulted in significant BMD gain, enabling successful surgical fixation. The second patient received teriparatide for only 6 months and showed stable BMD. Notably, both patients developed serious cardiac problems during teriparatide treatment: the first patient experienced rapidly progressive aortic stenosis, while the second patient developed dyspnea and polyuria due to worsening dynamic left ventricular outflow tract obstruction, which had previously been asymptomatic. Both patients required invasive cardiac interventions, which carry high risk in mucopolysaccharidosis due to unique anatomical and anesthetic challenges. The temporal association between teriparatide treatment and the onset of cardiac problems in both patients is noteworthy and raises the possibility of a treatment-related effect. Therefore, we recommend cautious use of teriparatide in patients with mucopolysaccharidosis Type IV.
Data from a phase 2/3, randomized, controlled, open-label, multicenter trial in children with neuronopathic mucopolysaccharidosis II (MPS II; Hunter syndrome) older than 3 years suggested a benefit of intrathecal idursulfase-IT on cognitive functioning in some patients. We describe a separate, parallel, open-label, single-arm, 52-week substudy of the same trial (NCT02055118) that investigated idursulfase-IT in children with MPS II younger than 3 years at enrollment and Bayley Scales of Infant and Toddler Development (BSID-III) quotient 55-85. This report describes a prespecified analysis of nine patients (aged 1.4-3.0 years) who had received 3-years' treatment with idursulfase-IT. BSID-III cognitive composite scores generally remained relatively stable over time. At the last available assessment, scores were "high average" (110; n = 1), "average" (100-90; n = 4), and "low average" (85-80; n = 4). Eight patients transitioned to the Differential Ability Scales (DAS-II) after ages ≥42 months, and scores decreased for all patients when the instrument for assessing cognitive function changed. However, DAS-II General Conceptual Ability scores were relatively stable for the remainder of the follow-up. At the last available assessment, scores were "average" (106; n = 1), "low average" (85-80; n = 3), and "very low" (69-43; n = 4). Cerebrospinal fluid concentrations of total glycosaminoglycans were markedly reduced from baseline levels (mean [range] 1278 [429-2660] ng/mL) by week 16 and remained low thereafter. Data suggest early enzyme replacement therapy may stabilize cognitive development or slow the progression of cognitive impairment in young patients with neuronopathic MPS II.