Neurodevelopmental status and adaptive behavior of pediatric patients with mucopolysaccharidosis II: a longitudinal observational study.

BACKGROUND: Mucopolysaccharidosis (MPS) II is a rare, X-linked lysosomal storage disease. Approximately two-thirds of patients have central nervous system involvement with some demonstrating progressive cognitive impairment (neuronopathic disease). The natural history of cognitive and adaptive function in patients with MPS II is not well-defined. This 2-year, prospective, observational study evaluated the neurodevelopmental trajectories of boys with MPS II aged ≥ 2 years and < 18 years. RESULTS: Overall, 55 patients were enrolled. At baseline, mean (standard deviation [SD]) age was 5.60 (3.32) years; all patients were receiving intravenous idursulfase. Cognitive and adaptive function were assessed using the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) scores, respectively. Baseline mean (SD) DAS-II GCA and VABS-II ABC scores were 78.4 (19.11) and 83.7 (14.22), respectively, indicating low cognitive function and moderately low adaptive behavior. Over 24 months, modest deteriorations in mean (SD) scores were observed for DAS-II GCA (-3.8 [12.7]) and VABS-II ABC (-2.0 [8.07]). Changes in DAS-II GCA scores varied considerably, and data suggested the existence of four potential patient subgroups: (1) patients with marked early impairment and rapid subsequent decline, (2) patients with marked early impairment then stabilization, (3) patients with mild early impairment then stabilization, and (4) patients without impairment who remained stable. Subgroup analyses revealed numerically greater DAS-II GCA score reductions from baseline in patients aged < 7 years at baseline (vs. those aged ≥ 7 years) and in patients with DAS-II GCA scores ≤ 70 at baseline (vs. those with scores > 70); between-group differences were nonsignificant. No clear subgroups or patterns were identified for individual changes in VABS-II ABC scores. In total, 49 patients (89.1%) reported ≥ 1 adverse event (AE) and nine patients (16.4%) reported serious AEs. CONCLUSIONS: Some patients with MPS II had rapid declines in cognitive ability, whereas others remained relatively stable after an initial decline. These insights provide a basis for more detailed analyses of different patient subgroups, which may enhance the definition and understanding of factors that influence cognitive and adaptive function in MPS II. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01822184. Registered retrospectively: April 2, 2013.

Variables affecting outcomes after allogeneic hematopoietic stem cell transplant for cerebral adrenoleukodystrophy.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in early cerebral adrenoleukodystrophy can stabilize neurologic function and improve survival but has associated risks including transplant-related mortality (TRM), graft failure, and graft-versus-host disease (GVHD). An observational study of 59 patients with median age at allo-HSCT of 8 years addressed impact of donor source, donor match, conditioning regimen, and cerebral disease stage on first allo-HSCT outcomes. Efficacy analyses included 53 patients stratified by disease category: advanced disease (AD; n = 16) with Loes score >9 or neurological function score (NFS) >1 and 2 early disease (ED) cohorts (ED1 [Loes ≤4 and NFS ≤1; n = 24] and ED2 [Loes >4-9 and NFS ≤1; n = 13]). Survival free of major functional disabilities and without second allo-HSCT at 4 years was significantly higher in the ED (66%) vs AD (41%) cohort (P = .015) and comparable between ED1 and ED2 cohorts (P = .991). The stabilization of neurologic function posttransplant was greater in the ED vs AD cohort, with a median change from baseline at 24 months after allo-HSCT in NFS and Loes score, respectively, of 0 and 0.5 in ED1 (n = 13), 0.5 and 0 in ED2 (n = 6), and 2.5 and 3.0 (n = 4) in AD cohort. TRM was lower in the ED (7%) compared with the AD (22%) cohort; however, the difference was not significant (P = .094). Transplant-related safety outcomes were also affected by transplant-related characteristics: graft failure incidence was significantly higher with unrelated umbilical cord grafts vs matched related donors (P = .039), and acute GVHD and graft failure incidences varied by conditioning regimen. This study was registered at www://clinicaltrials.gov as #NCT02204904.

Methods of diagnosis of patients with Pompe disease: Data from the Pompe Registry.

Pompe disease is a rare, autosomal recessive disorder characterized by deficiency of lysosomal acid alpha-glucosidase and accumulation of lysosomal glycogen in many tissues. The variable clinical manifestations, broad phenotypic spectrum, and overlap of signs and symptoms with other neuromuscular diseases make diagnosis challenging. In the past, the diagnosis of Pompe disease was based on enzyme activity assay in skin fibroblasts or muscle tissue. In 2004, methods for measuring acid alpha-glucosidase activity in blood were published. To compare how diagnostic methods changed over time and whether they differed by geographic region and clinical phenotype, we examined diagnostic methods used for 1059 patients enrolled in the Pompe Registry in three onset categories (Group A: onset of signs/symptoms ≤ 12 months of age with cardiomyopathy; Group B: onset ≤ 12 months without cardiomyopathy and onset >1 year to ≤ 12 years; Group C: onset >12 years). Enzyme activity-based assays were used more frequently than other diagnostic methods. Measuring acid alpha-glucosidase activity in blood (leukocytes, lymphocytes, or dried-blood spot) increased over time; use of muscle biopsy decreased. The increased use of blood-based assays for diagnosis may result in a more timely diagnosis in patients across the clinical spectrum of Pompe disease.

Timing of diagnosis of patients with Pompe disease: data from the Pompe registry.

Diagnostic delays in Pompe disease are common. The diagnostic gap (the time from the onset of symptoms to the diagnosis of Pompe disease) and factors associated with diagnostic delays were examined among Pompe Registry patients in three onset categories: Group A, onset ≤12 months of age with cardiomyopathy; Group B, onset ≤12 months without cardiomyopathy and onset >12 months to ≤12 years; and Group C, onset >12 years. Of 1,003 patients, 647 were available for analysis. In all groups, musculoskeletal signs and symptoms were among the most frequent presenting signs and symptoms, in addition to cardiomyopathy in Group A, which was part of the group's definition. Diagnostic gaps existed in all three groups. Patients presenting with respiratory and musculoskeletal signs and symptoms concurrently had the shortest diagnostic gap, while those presenting with neither respiratory nor musculoskeletal signs and symptoms had the longest. Independent factors influencing the probability of a long diagnostic gap included presenting signs and symptoms (all three groups) and year of diagnosis and age at symptom onset (Groups B and C). Group B, which represents the infantile patients without cardiomyopathy and juvenile Pompe cases, had the longest median gap (12.6 years). Diagnostic testing methods used also were reviewed. Despite the availability of blood-based assays that can be used to quickly and accurately diagnose Pompe disease, diagnostic gaps in Pompe patients across the disease spectrum continue.

[Enzyme replacement therapy in the infantile form of Pompe disease: Argentinean experience in a seven-year follow up case]. / Terapia de reemplazo enzimático en la forma infantil de la enfermedad de Pompe: experiencia de un caso con 7 años de seguimiento en Argentina.

The infantile form of Pompe disease drives children to death before the first year of life due to cardiomyopathy and respiratory insufficiency. We present the seven-year follow-up experience with enzyme replacement therapy on a child with Pompe disease, being the longest follow-up in the country. The treatment was well tolerated without adverse reactions. The echocardiographic and electrocardiographic parameters clearly improved during the first year and remain stable. Motor milestones (like rolling over or sitting down without support) were initially achieved, but, after the third year were getting lost. The average age of ventilator dependence was also delayed (16 months). The 7-year old patient remains alive with severe generalized muscle weakness. The child notably overcame the average age of survival and onset of ventilator dependence. Although the cardiovascular improvement was clear, enzyme replacement therapy efficacy on skeletal muscle was limited in this patient.

Pompe disease (glycogen storage disease type II) in Argentineans: clinical manifestations and identification of 9 novel mutations.

Pompe disease is an autosomal recessive disorder caused by a deficiency in 1,4-alpha-glucosidase (EC.3.2.1.3), the enzyme required to hydrolyze lysosomal glycogen to glucose. While previous studies have focused on Pompe patients from Europe, the United States, and Taiwan, we have analyzed a group of South American Pompe patients to better understand the molecular basis of their disease. From 14 Argentinean patients diagnosed with either infantile or late-onset disease, we identified 14 distinct mutations in the acid alpha-glucosidase (GAA) gene including nine novel variants (c.236_246del, c.377G>A, c.1099T>C, c.1397T>G, c.1755-1G>A, c.1802C>G, c.1978C>T, c.2281delGinsAT, and c.2608C>T). Three different families displayed the c.377G>A allelic variant, suggesting a higher frequency among a subset of Argentineans. Comparison of patients with similar or identical variations in the GAA gene highlights the phenotypic diversity of late-onset disease and supports a role for other genetic and environmental factors in disease presentation.