LOPD Patients Research Articles

Intracranial vasculopathy: an important organ damage in young adult patients with late-onset Pompe disease

BackgroundLate-onset Pompe disease (LOPD) is mainly characterized by progressive limb-girdle muscle weakness and respiratory impairment, whereas stroke and cerebrovascular abnormalities have been insufficiently studied in LOPD. This study aimed to evaluate the frequency and pattern of intracranial artery and brain parenchyma abnormalities in LOPD patients.ResultsNeuroimaging data from 30 Chinese adult LOPD patients were collected from our center. Seven patients (7/30) had acute cerebral infarction or hemorrhage. Brain magnetic resonance angiography (MRA) or computed tomography angiography (CTA) revealed artery abnormalities in 23 patients (23/30). Dilative arteriopathy was found in 19 patients (19/30), with vertebrobasilar dolichoectasia found in 17 patients and dilatation of the anterior circulation arteries found in 8 patients. The maximum diameter of the basilar artery was correlated with disease duration (p < 0.05). In addition, aneurysms (7/30) and fenestrations (3/30) were discovered. There were 14 patients with arterial stenosis (14/30), and both anterior and posterior circulation involvement occurred in 9 patients (9/14). Stenosis and dilative arteriopathy simultaneously occurred in 10 patients (10/30). White matter hyperintensities were present in 13 patients (13/28). Microbleeds, predominantly located in the cerebellum and brainstem, were detected in 7 patients (7/22) via susceptibility-weighted imaging.ConclusionsIntracranial vasculopathy involving both large arteries and small vessels is an important organ damage in LOPD patients. LOPD should be considered a key differential diagnosis in young adults with cryptogenic stroke, and a series of imaging evaluations of the brain and intracranial blood vessels is recommended as a routine workup in adult LOPD patients.

Diaphragm weakness in late-onset Pompe disease: A complex interplay between lower motor neuron and muscle fibre degeneration

BackgroundLate-onset Pompe disease (LOPD) patients may still need ventilation support at some point of their disease course, despite regular recombinant human alglucosidase alfa treatment. This suggest that other pathophysiological mechanisms than muscle fibre lesion can contribute to the respiratory failure process. We investigate through neurophysiology whether spinal phrenic motor neuron dysfunction could contribute to diaphragm weakness in LOPD patients. Material and methodsA group of symptomatic LOPD patients were prospectively studied in our centre from January 2022 to April 2023. We collected both demographic and clinical data, as well as neurophysiological parameters. Phrenic nerve conduction studies and needle EMG sampling of the diaphragm were perfomed. ResultsEight treated LOPD patients (3 males, 37.5%) were investigated. Three patients (37.5%) with no respiratory involvement had normal phrenic nerve motor responses [median phrenic compound muscle action potential (CMAP) amplitude of 0.49 mV; 1st-3rd interquartile range (IQR), 0.48–0.65]. Those with respiratory failure (under nocturnal non-invasive ventilation) had abnormal phrenic nerve motor responses (median phrenic CMAP amplitude of 0 mV; 1st-3rd IQR, 0–0.15), and were then investigated with EMG. Diaphragm needle EMG revealed both myopathic and neurogenic changes in 3 (60%) and myopathic potentials in 1 patient. In the last one, no motor unit potentials could be recruited. ConclusionsOur study provide new insights regarding respiratory mechanisms in LOPD, suggesting a contribution of spinal phrenic motor neuron dysfunction for diaphragm weakness. If confirmed in further studies, our results recommend the need of new drugs crossing the blood-brain barrier.

Unveiling MRI markers for Parkinson’s Disease: GABAergic dysfunction and cortical changes

ObjectiveThe study aimed to investigate changes in basal levels of the inhibitory γ-aminobutyric acid (GABA) neurotransmitter in the sensorimotor cortex (SMC) and cortical gyrification in patients with Parkinson’s disease (PD), which could further identify potential imaging biomarkers for PD, particularly in patients with early-onset Parkinson’s disease (EOPD). MethodFifty patients with PD (EOPD: 10, late-onset Parkinson’s disease [LOPD]: 40) and fifty-two age- and gender-matched healthy controls (HC) underwent GABA-edited 1H MRS of the SMC and high-resolution 3D T1-weighted brain imaging. GABA levels and local gyrification index (LGI) were calculated to assess GABAergic and cortical gyrification deficits in PD. ResultThe Pearson correlation coefficients revealed significant negative associations between eight indicators, including GABA/Cr level and local gyrification index (LGI) of specific cortical regions (precentral, postcentral, entorhinal, superiortemporal, posteriorcingulate, cuneus, and transversetemporal cortex), and the likelihood of Parkinson’s disease (r < -0.4, p < 0.001). Additionally, GABA levels were significantly lower in the SMC region of both EOPD and LOPD patients compared to healthy controls (mean ± SD [u.i.]: EOPD=0.081 ± 0.022 vs. Young-HC=0.112 ± 0.021, p = 0.003; LOPD=0.054 ± 0.024 vs. Old-HC=0.099 ± 0.021, p < 0.001). The logistic regression model was established by using multivariate analysis, identifying two statistically significant indicators: GABA/Cr and LGI of the transversetemporal. The combined model exhibited the highest AUC values in both younger and older populations. ConclusionGABAergic dysfunction may play an important role in the pathogenesis of PD patients. Changes in neurotransmitter and morphological may serve as potential markers for the preclinical diagnosis and progression of PD, including EOPD.

Transcriptomic characterization of clinical skeletal muscle biopsy from late-onset Pompe patients.

Pompe disease is a rare lysosomal storage disorder arising from recessive mutations in the acid α-glucosidase gene and resulting in the accumulation of glycogen, particularly in the cardiac and skeletal muscle. The current standard of care is administration of enzyme replacement therapy in the form of alglucosidase alfa or the recently approved avalglucosidase alfa. In order to better understand the underlying cellular processes that are disrupted in Pompe disease, we conducted gene expression analysis on skeletal muscle biopsies obtained from late-onset Pompe disease patients (LOPD) prior to treatment and following six months of enzyme replacement with avalglucosidase alfa. The LOPD patients had a distinct transcriptomic signature as compared to control patient samples, largely characterized by perturbations in pathways involved in lysosomal function and energy metabolism. Although patients were highly heterogeneous, they collectively exhibited a strong trend towards attenuation of the dysregulated genes following just six months of treatment. Notably, the enzyme replacement therapy had a strong stabilizing effect on gene expression, with minimal worsening in genes that were initially dysregulated. Many of the cellular process that were altered in LOPD patients were also affected in the more clinically severe infantile-onset (IOPD) patients. Additionally, both LOPD and IOPD patients demonstrated enrichment across several inflammatory pathways, despite a lack of overt immune cell infiltration. This study provides further insight into Pompe disease biology and demonstrates the positive effects of avalglucosidase alfa treatment.

Age at Onset Influences Progression of Motor and Non-Motor Symptoms during the Early Stage of Parkinson's Disease: A Monocentric Retrospective Study.

The interactions between the age at onset with other pathogenic mechanisms and the interplays between the disease progression and the aging processes in Parkinson's disease (PD) remain undefined, particularly during the first years of illness. Here, we retrospectively investigated the clinical presentation and evolution of the motor and non-motor symptoms and treatment-related complications during the first 5 years of illness in subjects categorized according to age at onset. A total of 131 subjects were divided into "Early-Onset-PD" (EOPD; onset ≤49 years), "Middle-Onset-PD" (MOPD; onset 50-69 years) and "Late-Onset-PD" (LOPD; onset ≥70 years). The T0 visit was set at the time of the clinical diagnosis; the T1 visit was 5 years (±5 months) later. At T0, there were no significant differences in the motor features among the groups. At T1, the LOPD patients displayed a significantly higher frequency of gait disturbances and a higher frequency of postural instability. Moreover, at T1, the LOPD subjects reported a significantly higher frequency of non-motor symptoms; in particular, cardiovascular, cognitive and neuropsychiatric domains. The presented results showed a significantly different progression of motor and non-motor symptoms in the early course of PD according to the age at onset. These findings contribute to the definition of the role of age at onset on disease progression and may be useful for the pharmacological and non-pharmacological management of PD.

Association of AQP4 single nucleotide polymorphisms (rs335929 and rs2075575) with Parkinson’s disease: A case-control study

ObjectiveThe glymphatic system plays an important role in brain waste removal and is functionally and structurally dependent on astrocyte aquaporin-4 (AQP4). Genetic variation in the AQP4 gene has therefore been hypothesized to be associated with genetic susceptibility to neurodegenerative diseases. This study aimed to investigate whether two specific single nucleotide polymorphisms (SNP) in the AQP4 gene, rs335929, and rs2075575, are associated with the risk and clinical features of PD. MethodsA total of 950 participants, including 475 patients with sporadic PD and 475 independent healthy controls, were included in this case-control study. Two SNPs (rs335929 and rs2075575) of the AQP4 gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Sanger sequencing was used to determine whether the genotyping results were accurate. A chi-square (χ2) test was used to compare the frequencies of alleles and genotypes between patients and controls. Logistic regression was used to calculate dominance ratios (OR) and 95% confidence intervals (CI). ResultsThe difference between rs2075575 in the dominant model (GG vs GA + AA: P = 0.019) and the overdominant model (GG + AA vs GA: P = 0.013) was statistically significant. Subgroup analysis showed that the frequency of the rs2075575 A allele was significantly higher in female PD patients than in matched female controls (P = 0.017). rs2075575 A allele was significantly more frequent in LOPD patients than in matched elderly controls (P = 0.033). rs335929 polymorphism was not significantly correlated with PD susceptibility in either the overall or subgroup analysis. Haplotype analysis between the two SNPs did not show an association with PD susceptibility. In addition, we found that the rs2075575 G allele was significantly associated with Rapid Eye Movement Behaviour Disorder (RBD) (P = 0.044), and the rs335929 A allele with memory impairment (P = 0.028) in PD. ConclusionThe AQP4 gene rs2075575 polymorphism may be associated with PD susceptibility, but not the rs335929 polymorphism. rs2075575 is associated with RBD and rs335929 is associated with memory cognition. Regulation of the glymphatic system by interfering with the genetics of AQP4 and thus influencing the pathology of PD may be a direction worth investigating. Studies in larger sample sizes and across ethnicities are essential for further understanding the potential association between AQP genes and PD pathogenesis.

P.85 Analysis of Juvenile onset Pompe disease patients included in the Spanish Pompe Registry

Late Onset Pompe patients (LOPD) is the main phenotype on Pompe disease that start with symptoms from the age of two years to late in the adulthood. Because of the heterogeneity of the disease, it has been described the Juvenile Onset Pompe Disease (JOPD) subgroup, who become symptomatic between 2 and 18 years old. We describe the demographic and clinical features of all JOPD patients and their progression (using six-minute walking test -6MWT-, forced vital capacity -FVC- and Creatin Kinase -CK- values and comparing it with the other LOPD patients) registered at the Spanish Pompe Registry (SPR), with 121 patients registered in Spain. We identified 28 JOPD patients (18.8%) in the SPR, with 16 males (57%), median age of symptoms onset was 8.5 years. The most frequent mutation was c.32-13T>G in 19 patients (68%). HyperCKemia was the most common reason for diagnosis in 17 (61%) patients. 19 patients (68%) developed muscle symptoms, being lower limbs weakness the most predominant (13). 9 (34.6%) developed respiratory symptoms, 2 (7%) of them before 18 years. All JOPD received Enzyme Replacement Therapy. JOPD patients showed significantly baseline higher CK values compared to LOPD (p<0.001) but tended to decline over time, without any significant difference of the progression of CVF and 6MWT (Mann-Whitney test). Most of the JOPD patients in the SPR were diagnosed because of hyperckemia, and lower limbs muscle weakness before 18 years old. We have not identified differences in the progression of the disease between JOPD patients and LOPD patients.

Electromyographic findings in patients with late-onset pompe disease

Background Pompe disease is an autosomal recessive disorder caused by mutations in the GAA gene encoding the enzyme acid alpha-glucosidase. The late-onset form (LOPD) is characterized by most prominent proximal muscles involvement at four limbs. Electrophysiological study is a diagnostic tool still applied in the diagnostic work up of patients with suspected LOPD. Aim of the study is to evaluate EMG findings including the distribution of involved muscles looking for distal muscle involvement, in a cohort of LOPD patients.

The impact of interrupting enzyme replacement therapy in late-onset Pompe disease

BackgroundLate-onset Pompe disease (LOPD) is a rare autosomal recessive disorder caused by mutations in the GAA gene, leading to progressive weakness of locomotor and respiratory muscles. Enzyme replacement therapy (ERT), administered every second week, has been proven to slow down disease progression and stabilize pulmonary function. Due to the COVID-19 pandemic in Germany, ERT was interrupted at our centre for 29 days. As reports on ERT discontinuation in LOPD are rare, our study aimed to analyse the impact of ERT interruption on the change in clinical outcome.MethodsWe performed a prospective cohort study in 12 LOPD patients. Clinical assessments were performed after ERT interruption and after the next three consecutive infusions. We assessed motor function by muscle strength testing, a 6-minute-walk-test, pulmonary function tests, and adverse events. For statistical analysis, an estimated baseline was calculated based on the individual yearly decline.ResultsThe mean time of ERT interruption was 49.42 days (SD ± 12.54). During ERT interruption, seven patients reported 14 adverse events and two of them were severe. Frequent symptoms were reduced muscle endurance/increased muscle fatigability and shortness of breath/worsening of breathing impairment. After ERT interruption, significant deterioration was found for MIP%pred (p = 0.026) and MRC%pred, as well as a trend to clinical deterioration in FVC%pred and the 6MWT%pred.ConclusionInterruption of ERT was associated with a deterioration in the core clinical outcome measures. Therefore, an interruption of ERT should be kept as short as possible.

Distinct Changes in Global Brain Synchronization in Early-Onset vs. Late-Onset Parkinson Disease.

Early- and late-onset Parkinson’s disease (EOPD and LOPD, respectively) have different risk factors, clinical features, and disease course; however, the functional outcome of these differences have not been well characterized. This study investigated differences in global brain synchronization changes and their clinical significance in EOPD and LOPD patients. Patients with idiopathic PD including 25 EOPD and 24 LOPD patients, and age- and sex-matched healthy control (HC) subjects including 27 younger and 26 older controls (YCs and OCs, respectively) were enrolled. Voxel-based degree centrality (DC) was calculated as a measure of global synchronization and compared between PD patients and HC groups matched in terms of disease onset and severity. DC was decreased in bilateral Rolandic operculum and left insula and increased in the left superior frontal gyrus (SFG) and precuneus of EOPD patients compared to YCs. DC was decreased in the right putamen, mid-cingulate cortex, bilateral Rolandic operculum, and left insula and increased in the right cerebellum-crus1 of LOPD patients compared to OCs. Correlation analyses showed that DC in the right cerebellum-crus1 was inversely associated with the Hamilton Depression Scale (HDS) score in LOPD patients. Thus, EOPD and LOPD patients show distinct alterations in global synchronization relative to HCs. Furthermore, our results suggest that the left SFG and right cerebellum-crus1 play important roles in the compensation for corticostriatal–thalamocortical loop injury in EOPD and LOPD patients, whereas the cerebellum is a key hub in the neural mechanisms underlying LOPD with depression. These findings provide new insight into the clinical heterogeneity of the two PD subtypes.

Deferoxamine mesylate improves splicing and GAA activity of the common c.-32-13T>G allele in late-onset PD patient fibroblasts

Pompe disease (PD) is an autosomal recessive lysosomal storage disorder due to deficient activity of the acid alpha glucosidase enzyme (GAA). As a consequence of the enzymatic defect, undigested glycogen accumulates within lysosomes. Most patients affected by the late-onset (LO) phenotype carry in at least one allele the c.-32-13T>G variant, which leads to exon 2 exclusion from the pre-mRNA. These patients display a variable and suboptimal response to enzyme replacement therapy. To identify novel therapeutic approaches, we developed a fluorescent GAA exon 2 splicing assay and screened a library of US Food and Drug Administration (FDA)-approved compounds. This led to the identification of several drugs able to restore normal splicing. Among these, we further validated the effects of the iron chelator deferoxamine (Defe) in c.-32-13T>G fibroblasts. Defe treatment resulted in a 2-fold increase of GAA exon 2 inclusion and a 40% increase in enzymatic activity. Preliminary results suggest that this effect is mediated by the regulation of iron availability, at least partially. RNA-seq experiments also showed that Defe might shift the balance of splicing factor levels toward a profile promoting GAA exon 2 inclusion. This work provides the basis for drug repurposing and development of new chemically modified molecules aimed at improving the clinical outcome in LO-PD patients.

Body composition and 6 minute walking ability in late-onset pompe disease patients after 9 years of enzyme replacement therapy

Objective Pompe disease is a rare autosomal recessive disorder caused by the deficiency of acid α-glycosidase resulting in accumulation of glycogen in the lysosomes. The late-onset form of the disease (LOPD) causes primarily progressive muscle weakness and respiratory insufficiency. Enzyme replacement therapy (ERT) introduced in 2006, showed mild improvement or stabilization of the symptoms although long-term data are limited. Aim of the study was to describe the progression of body composition and walking ability in LOPD patients receiving ERT consistently for 9 years. Methods Lean body mass, bone mineral density, body fat and 6 min walking distance were assessed in three male and three female LOPD patients (height 165.8 ± 11.2 cm, age 42.3 ± 11.8yrs, body mass 71.1 ± 20.8 kg, at study entry), every three years, for 9 years since ERT initiation (T0, T3, T6, T9). Results Total body and upper extremities’ lean mass remained unchanged (p < 0.05), but it was decreased for the lower extremities (T3:13.06 ± 3.848 kg vs. T9:11.63 ± 3.49 kg, p < 0.05). Lean body mass was not significantly different after 9 years of ERT compared to before the ERT initiation (T0 to T9). Bone mineral density remained unchanged. Percent body fat increased (T0:39.1 ± 10.3%, vs. T9:43.1 ± 10.4%, p < 0.05). Six minute walking distance tended to increase after 3 years of ERT and decreased gradually thereafter, with no difference between T0-T9. Lean mass of the lower extremities adjusted for body weight was significantly correlated with 6 min walking distance (r = 0.712, p < 0.05). Conclusion The current data show that enzyme replacement therapy may preserve lean body mass, bone mineral density and walking capacity in LOPD patients.

Quantitative whole-body magnetic resonance imaging in children with Pompe disease: Clinical tools to evaluate severity of muscle disease.

ObjectiveSince the introduction of enzyme replacement therapy (ERT) with alglucosidase alfa, there has been increased survival in patients with Pompe disease. It is essential to characterize and quantify the burden of disease in these patients. Here, we report a measure of muscle fat infiltration in children with infantile and pediatric late‐onset Pompe disease (IPD and LOPD, respectively) to better understand the extent of muscle involvement.MethodsEleven pediatric patients with Pompe disease (five IPD, six LOPD), ages 7‐17 years, received whole‐body magnetic resonance imaging (WBMRI), muscle strength testing using the modified Medical Research Council (mMRC) scale, functional assessment using gait, stairs, gowers, chair (GSGC), and urine glucose tetrasaccharide (Glc4) testing. The intramuscular fat seen on WBMRI was quantified using proton density fat fraction (PDFF) and correlated to appropriate muscle strength and functional tests, and urine Glc4.ResultsPatients with IPD, although younger, had higher mean PDFF values than LOPD patients (11.61% vs 8.52%). Significant correlation existed between PDFF and the GSGC assessment (r = .9273, P = .0003). Moderate correlation existed between PDFF and mMRC (r = −.667, P = .0831), and PDFF and urine Glc4 (r = .6121, P = .0667). Anterior tibialis was in the top quartile of muscle involvement for patients with LOPD.ConclusionIn the past, physical therapy assessments alone have been used to track disease progression. Here, we show the clinical utility of WBMRI in quantifying muscle involvement in children with Pompe disease, especially regarding the novel involvement of anterior tibialis in children with LOPD, to better assess baseline muscle burden and mapping disease progression in children treated with ERT.

Characterization of Gait and Postural Regulation in Late-Onset Pompe Disease

Pompe disease is a multisystemic disorder with the hallmark of progressive skeletal muscle weakness that often results in difficulties in walking and balance. However, detailed characterization of gait and postural regulation with this disease is lacking. The objective of this investigation was to determine if differences exist between the gait and postural regulation of LOPD patients and a matched control group. The gaits of 16 patients with LOPD were assessed using a gait analysis mobile system (RehaGait) and a dynamometric treadmill (FDM-T 1.8). The Interactive Balance System (IBS) was used to evaluate postural regulation and stability. All measures were compared to individual reference data. Demographic (age, gender), morphological (body height, body mass) and clinical data (muscle strength according to the Medical Research Council Scale (MRC Scale), as well as the 6-min walking test and a 10-m fast walk) were also recorded. Compared to individual reference data, LOPD patients presented with reduced gait velocity, cadence and time in single stand. A total of 87% of LOPD patients had abnormalities during posturographic analysis presenting with differences in postural subsystems. This study provides objective data demonstrating impaired gait and posture in LOPD patients. For follow-up analysis and as outcome measurements during medical or physiotherapeutic interventions, the findings of this investigation may be useful.

Exercise training alone or in combination with high-protein diet in patients with late onset Pompe disease: results of a cross over study

BackgroundLate onset Pompe disease (LOPD) is a lysosomal neuromuscular disorder which can progressively impair the patients’ exercise tolerance, motor and respiratory functions, and quality of life. The available enzyme replacement therapy (ERT) does not completely counteract disease progression. We investigated the effect of exercise training alone, or associated with a high-protein diet, on the exercise tolerance, muscle and pulmonary functions, and quality of life of LOPD patients on long term ERT.MethodsThe patients were asked to participate to a crossover randomized study comprehending a control period (free diet, no exercise) followed by 2 intervention periods: exercise or exercise + diet, each lasting 26 weeks and separated by 13 weeks washout periods. Exercise training included moderate-intensity aerobic exercise on a cycle ergometer, stretching and balance exercises, strength training. The diet was composed by 25–30% protein, 30–35% carbohydrate and 35–40% fat. Before and after each period patients were assessed for: exercise tolerance test on a cycle-ergometer, serum muscle enzymes, pulmonary function tests and SF36 questionnaire for quality of life. Compliance was evaluated by training and dietary diaries. Patients were contacted weekly by researchers to optimize adherence to treatments.ResultsThirteen LOPD patients, median age 49 ± 11 years, under chronic ERT (median 6.0 ± 4.0 years) were recruited. Peak aerobic power (peak pulmonary O2 uptake) decreased after control, whereas it increased after exercise, and more markedlyafter exercise + diet. Serum levels of lactate dehydrogenase (LDH) significantly decreased after exercise + diet; both creatine kinase (CK) and LDH levels were significantly reduced after exercise + diet compared to exercise. Pulmonary function showed no changes after control and exercise, whereas a significant improvement of forced expiratory volume in 1 sec (FEV1) was observed after exercise + diet. SF36 showed a slight improvement in the “mental component” scale after exercise, and a significant improvement in “general health” and “vitality” after exercise + diet. The compliance to prescriptions was higher than 70% for both diet and exercise.ConclusionsExercise tolerance (as evaluated by peak aerobic power) showed a tendency to decrease in LOPD patients on long term ERT. Exercise training, particularly if combined with high-protein diet, could reverse this decrease and result in an improvement, which was accompanied by improved quality of life. The association of the two lifestyle interventions resulted also in a reduction of muscle enzyme levels and improved pulmonary function.

Visual losses in early-onset and late-onset Parkinson's disease.

Patients with Parkinson's disease (PD) manifest visual losses. However, it is not known whether these losses are equivalent in both early-onset (EOPD) and late-onset (LOPD) patients. We evaluated contrast sensitivity and color vision in EOPD and LOPD patients and in age-matched controls. Losses occurred in both patient groups but were more pronounced in EOPD, consistent with the notion that non-motor symptoms are affected by age of symptom onset. More studies of visual function in EOPD and LOPD patients are needed to understand how aging is related to the pathophysiology of non-motor PD symptomatology. This would permit earlier diagnosis and, perhaps, better management of the disease.

Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease

PurposeTo characterize clinical characteristics and genotypes of patients in the ADVANCE study of 4000 L-scale alglucosidase alfa (NCT01526785), the largest prospective United States Pompe disease cohort to date. MethodsPatients aged ≥1 year with confirmed Pompe disease previously receiving 160 L alglucosidase alfa were eligible. GAA genotypes were determined before/at enrollment. Baseline assessments included histories/physical exams, Gross Motor Function Measure-88 (GMFM-88), pulmonary function tests, and cardiac assessments. ResultsOf 113 enrollees (60 male/53 female) aged 1–18 years, 87 had infantile-onset Pompe disease (IOPD) and 26 late-onset (LOPD). One hundred eight enrollees with GAA genotypes had 215 pathogenic variants (220 including combinations): 118 missense (4 combinations), 23 splice, 35 nonsense, 34 insertions/deletions, 9 duplications (1 combination), 6 other; c.2560C>T (n = 23), c.−32-13T>G (n = 13), and c.525delT (n = 12) were most common. Four patients had previously unpublished variants, and 14/83 (17%) genotyped IOPD patients were cross-reactive immunological material–negative. All IOPD and 6/26 LOPD patients had cardiac involvement, all without c.−32−13T>G. Thirty-two (26 IOPD, 6 LOPD) were invasively ventilated. GMFM-88 total %scores (mean ± SD, median, range): overall 46.3 ± 33.0% (47.9%, 0.0–100.0%), IOPD 41.6 ± 31.64% (38.9%, 0.0–99.7%), LOPD: 61.8±33.2 (70.9%, 0.0–100.0%). ConclusionADVANCE, a uniformly assessed cohort comprising most US children and adolescents with treated Pompe disease, expands understanding of the phenotype and observed variants in the United States.

Progress and challenges of gene therapy for Pompe disease

Pompe disease (PD) is a monogenic disorder caused by mutations in the acid alpha-glucosidase gene (Gaa). GAA is a lysosomal enzyme essential for the degradation of glycogen. Deficiency of GAA results in a severe, systemic disorder that, in its most severe form, can be fatal. About a decade ago, the prognosis of PD has changed dramatically with the marketing authorization of an enzyme replacement therapy (ERT) based on recombinant GAA. Despite the breakthrough nature of ERT, long-term follow-up of both infantile and late-onset Pompe disease patients (IOPD and LOPD, respectively), revealed several limitations of the approach. In recent years several investigational therapies for PD have entered preclinical and clinical development, with a few next generation ERTs entering late-stage clinical development. Gene therapy holds the potential to change dramatically the way we treat PD, based on the ability to express the Gaa gene long-term, ideally driving enhanced therapeutic efficacy compared to ERT. Several gene therapy approaches to PD have been tested in preclinical animal models, with a handful of early phase clinical trials started or about to start. The complexity of PD and of the endpoints used to measure efficacy of investigational treatments remains a challenge, however the hope is for a future with more therapeutic options for both IOPD and LOPD patients.

Characteristics of Pompe disease in China: a report from the Pompe registry

BackgroundPompe disease is a rare, progressive, autosomal recessive lysosomal storage disorder caused by mutations in the acid α-glucosidase gene. This is the first report of Chinese patients from the global Pompe Registry. Chinese patients enrolled in the Registry (ClinicalTrials.gov, NCT00231400) between Jan 2013 and 2 Sep 2016 with late onset Pompe disease (LOPD; presentation after 12 months of age or presentation at ≤12 months without cardiomyopathy) were included. Data analyses were descriptive.ResultsOf the 59 Chinese patients included, 86.4% had never received enzyme replacement therapy (ERT). The age at symptom onset and diagnosis was 14.9 (12.35) and 22.1 (10.08) years, which is younger than previous reports of LOPD patients from the rest of the world (28.4 [18.86] and 34.9 [20.03], respectively). The most common diagnosis methods were enzyme assay (79.7%) and/or DNA analysis (61.0%). Of the 36 patients diagnosed using DNA analysis, 31 had standardized variant data and among these patients the most common mutations were c.2238G > C (n = 18, 58.1%) and c.2662G > T (n = 5, 16.1%). Chinese LOPD patients appeared to have worse lung function versus patients from the rest of the world, indicated by lower forced vital capacity (37.2 [14.00]% vs. 63.5 [26.71]%) and maximal expiratory and inspiratory pressure (27.9 [13.54] vs. 51.0 [38.66] cm H2O, and 29.4 [12.04] vs. 70.5 [52.78] cm H2O).ConclusionsCompared with patients from the rest of the world, Chinese patients with LOPD appeared to have younger age at symptom onset and diagnosis, lower lung function, and the majority had not received ERT. The most common mutations were c.2238G > C and c.2662G > T.

Follow-up analysis of voice quality in patients with late-onset Pompe disease

BackgroundLate-onset Pompe disease (LOPD) is a metabolic myopathy disorder characterized by progressive muscle damage and among others dysfunction of the voice apparatus, which affects speech and – above all – voice quality. Symptoms include dysphonia, instability, glottic insufficiency, and tense voice. The aim of this study was to evaluate and compare voice quality disorder in a group of 15 LOPD patients who were first examined in 2014 and then re-examined in 2017.MethodsIn both 2014 and 2017, the same 15 LOPD patients, ranging in age from 15 to 57, from 10 different families, underwent the following examinations: perceptual assessment of voice quality on the RBH scale, electroglottographic recordings, and acoustic recordings. All the patients were on enzyme replacement therapy (ERT).ResultsThree years after the 2014 study, the LOPD patients demonstrated a deterioration in voice quality. A statistically significant increase in glottic insufficiency (p = 0.0399) and a shift towards tense voice (p = 0.0417) were observed. Two patients – out of three who had received presymptomatic treatment – demonstrated stable voice quality compared with 2014.ConclusionsThe results suggest increased muscle weakness and progression of LOPD. The parameters Closed Quotient (calculated on the basis of an electroglottographic signal) and Peak Slope (calculated on the basis of an acoustic signal) proved to be the most sensitive.