Classic Infantile Pompe Disease Research Articles

High Sustained Antibody Titers in Patients with Classic Infantile Pompe Disease Following Immunomodulation at Start of Enzyme Replacement Therapy

To evaluate whether immunomodulation at start of enzyme replacement therapy induces immune tolerance to recombinant human acid alpha-glucosidase (rhGAA) in patients with classic infantile Pompe disease. Three patients (1 cross reactive immunologic material negative, 2 cross reactive immunologic material positive) were treated with 4 weekly doses of rituximab, weekly methotrexate, and monthly intravenous immunoglobulin and enzyme replacement therapy at 40 mg/kg/week. Antibody titers were measured using enzyme-linked immunosorbent assay. Neutralizing effects on rhGAA activity and cellular uptake were determined and combined with pharmacokinetic analysis. Clinical efficacy was evaluated by (ventilator-free) survival, reduction in left ventricular mass index, and improvement of motor function. Immunomodulation induced B cell depletion that was accompanied by absence of antibody formation in all 3 patients. Upon cessation of rituximab treatment, all 3 patients showed B cell recovery, which was accompanied by formation of very high sustained antibody titers in 2 patients. Neutralizing effects on infused rhGAA were low to mild/moderate. All patients were alive at study end, learned to walk, and showed (near) normalization of left ventricular mass index. Immunomodulation as recommended in the literature prevented formation of rhGAA antibodies only during B cell depletion but failed to induce immune tolerance in 2 out of 3 patients.

P.220 - Antibody formation to enzyme replacement therapy in classic infantile Pompe disease: effects of immunomodulation in naïve patients

P.220 - Antibody formation to enzyme replacement therapy in classic infantile Pompe disease: effects of immunomodulation in naïve patients

P 138 Normal cognitive performances in patients with late-onset Pompe disease

Background and objective In addition to increased glycogen accumulations in heart and sckeletal muscle cells, liver cells and lymphocytes, autopsy findings indicate glycogen accumulations in the brain of patients with Pompe disease ( DiRocco et al., 2007 ). Children with classic infantile Pompe disease also present a delayed cerebral myelination ( Chien et al., 2006 ). The cognitive development ranged from normal to mild retarded ( Lai et al., 2016 , Spiridigliozzi et al., 2012 , Ebbink et al., 2012 ). Also in the adult form of Pompe disease there are significant deficits in the executive functions ( Borroni et al., 2013 ). The objective of this study was to examine cognitive functions in patients with late-onset Pompe disease using different neuropsychological test methods. Methods A total of 9 patients (4 females, 5 males) aged 26–81 (M = 53.78, SD = 14.89), with late-onset Pompe disease were tested neuropsychologically in different cognitive domains. This included the examination of the verbal (AVLTtotal), nonverbal (RCFTdelayed) and episodic memory (AVLTdelayed), the attention and concentration (TMT A/B, SDMT), the executive functions (TMT B, BADSkey search, S-Wordsword fluency) and the visuoconstructive abilities (RFCTcopy). Additionally, the severity of depressive symptoms was investigated (ADS-K). Results Patients had no significant deficits in the verbal, nonverbal or episodic memory. The attention and concentration capabilities, executive functions and visuoconstructive abilities were within mean normal range. Furthermore, no pathological values were found in the questionnaire used to examine clinically relevant depressive symptoms. Conclusion Cognitive deficits seem not to be associated symptoms in the adult form of Pompe disease. Thus, the described glycogen accumulations in the brain have no influence on the cognition.

Neuropsychological profile of long-term treated patients with classic infantile Pompe disease

Neuropsychological profile of long-term treated patients with classic infantile Pompe disease

Rapidly Progressive White Matter Involvement in Early Childhood: The Expanding Phenotype of Infantile Onset Pompe?

Glycogen accumulation in the central nervous system of patients with classical infantile onset Pompe disease (IOPD) has been a consistent finding on the few post-mortems performed. While delays in myelination and a possible reduction in processing speed have previously been noted, it has only been recently that the potential for clinically significant progressive white matter disease has been noted. The limited reports thus far published infer that in some IOPD patients, this manifests as intellectual decline in the second decade of life. We present a CRIM negative patient, immunomodulated with rituximab and methotrexate at birth, who despite an initial good clinical response to ERT, at the age of just under 4 years, presented with evolving spasticity in the lower limbs. The investigation of which revealed progressive central nervous system involvement. Given both the earlier onset of the symptoms and consanguineous familial pedigree, extensive biochemical and genetic investigation was undertaken to ensure no alternative pathology was elucidated. In light of these findings, we review the radiology and post-mortems of previous cases and discuss the potential mechanisms that may underlie this presentation.

Cognitive decline in classic infantile Pompe disease, an underacknowledged challenge

La copertura delle perdite di sostanza dell’arto inferiore è una chirurgia difficile, soprattutto perché esistono una moltitudine di traumi e, quindi, un’infinità di situazioni cliniche molto differenti in termini di localizzazione, di lesioni associate, di tipo di tessuto da ricostruire, dell’urgenza della copertura, delle possibilità di prelievo e così via. La storia della ricostruzione dell’arto inferiore segue la storia della chirurgia plastica passo per passo: lembi muscolari, lembi cutanei, microchirurgia, lembi perforanti e supermicrochirurgia; ma la questione cruciale dell’interesse della conservazione di un arto si pone ancora nella pratica corrente. Occorre spiegare ad alcuni traumatizzati molto gravi (lesioni del nervo tibiale posteriore in particolare) che la soluzione migliore, indipendentemente dal livello di capacità tecnica raggiunto in questo inizio di XXI secolo, resta, talvolta, l’amputazione precoce, che permette una rieducazione rapida. Trovare la soluzione più appropriata tenendo conto del paziente e del tipo di perdita sostanza è la sfida di questa chirurgia.

Effects of a higher dose of alglucosidase alfa on ventilator-free survival and motor outcome in classic infantile Pompe disease: an open-label single-center study.

BackgroundThough enzyme-replacement therapy (ERT) with alglucosidase alfa has significantly improved the prospects for patients with classic infantile Pompe disease, some 50 % of treated infants do not survive ventilator-free beyond the age of 3 years. We investigated whether higher and more frequent dosing of alglucosidase alfa improves outcome.MethodsEight cross-reactive immunological material (CRIM) positive patients were included in the study. All had fully deleterious mutations in both GAA alleles. Four received a dose of 20 mg/kg every other week (eow) and four received 40 mg/kg/week. Survival, ventilator-free survival, left-ventricular mass index (LVMI), motor outcome, infusion-associated reactions (IARs), and antibody formation were evaluated.ResultsAll eight patients were alive at study end, seven of them remained ventilator-free. The patient who became ventilator dependent was treated with 20 mg/kg eow. Three of the four patients receiving 20 mg/kg eow learned to walk; two of them maintained this ability at study end. All four patients receiving 40 mg/kg/week acquired and maintained the ability to walk at study end (ages of 3.3–5.6 years), even though their baseline motor functioning was poorer. There were no apparent differences between the two dose groups with respect to the effect of ERT on LVMI, the number of IARs and antibody formation.ConclusionsOur data may suggest that a dose of 40 mg/kg/week improves outcome of CRIM positive patients over that brought by the currently recommended dose of 20 mg/kg eow. Larger studies are needed to draw definite conclusions.

G.P.10 - A higher dose of alglucosidase alpha in classic infantile Pompe disease positively affects ventilator-free survival and motor outcome: An open-label single-center study

G.P.10 - A higher dose of alglucosidase alpha in classic infantile Pompe disease positively affects ventilator-free survival and motor outcome: An open-label single-center study

Lower Urinary Tract Symptoms and Incontinence in Children with Pompe Disease.

Pompe disease (PD) is a disorder of lysosomal glycogen storage. The introduction of enzyme replacement therapy (ERT) has shifted the focus of care from survival to quality of life. The presence of lower urinary tract symptoms (LUTS) and incontinence has not been previously described in children with PD. Children with PD followed in the Duke Lysosomal Storage Disease Clinic completed a validated bladder control symptom score (BCSS) and additional questions regarding urinary tract infections (UTIs), giggle, and stress incontinence. Descriptive statistics were used to discriminate urinary symptoms between gender, age, and different types of PD. Sixteen of 23 children (aged 4-14 years) seen in our clinic participated. Seven were girls; ten had classic infantile PD, two atypical infantile PD, and four childhood presentation late-onset PD (LOPD). When stratified by PD subtype, median BCSS was worst for the classic PD subtype followed by atypical PD and LOPD. Daytime urinary incontinence accompanied by constipation was noted in six. Eight reported urinary incontinence with laughing: giggle incontinence in six and stress incontinence in two. Four girls reported a history of UTI. Longitudinal follow-up in 11 patients showed stable BCSS in six, improvement in three, and worsening in two. Worsening corresponded with changes in bowel function and improvement with increase in ERT dose or treatment of constipation. LUTS and incontinence are common in children with PD with greater symptoms noted with infantile-type PD. Improved bowel function and increase in ERT dose may lead to improvements in BCSS.

Muscle ultrasound in classic infantile and adult Pompe disease: A useful screening tool in adults but not in infants

A cohort of 4 infantile and 15 adult Pompe patients has been investigated regarding correlation between strength and ultrasound of skeletal musculature. In adults, muscle ultrasound is useful to assess clinical and subclinical involvement of muscles. In this study, visible sonographic changes were found in every clinically affected muscle, using a modified Heckmatt scale. In some muscles morphologic changes preceded weakness. Regarding the anatomical pattern of involvement, our findings do not support the hypothesis of a specific pattern with a higher vulnerability of vastus intermedius than rectus femoris, which has been postulated before. A frequent sparing of triceps brachii could be confirmed. Intramuscular abnormalities occurred in a focal, a diffuse, or an intermediate pattern, with characteristics of both. In contrast to muscular dystrophies, bone echogencity was not markedly decreased in Pompe disease even in an advanced stage. In infants, muscle ultrasound showed no distinct pathology even in clinically severely affected children and should not be used as a screening method for infantile Pompe disease.

PO-0043 Classic Infantile-onset Pompe Disease: A Study Of 8 Cases

Introduction Classic infantile pompe disease is an autosomal recessive inherited disorder caused by a deficiency of alpha 1–4 glucosidase, resulting in accumulation of glycogen in skeletal muscle and heart. It’s characterised by hypotonia, cardiomegaly and hypertrophic cardiomyopathy, feeding difficulties and respiratory distress, all patients died in the first year of life. Patients and methods A retrospective study of cases of classic infantile pompe disease collected in the Department of Paediatrics, Hospital Hedi Chaker, Sfax over a period of 7 years (2008–2013). Results During the study period we collected 8 cases of the disease. The average age at diagnosis was 3 months and 6 days. All patients were eutrophic. Hypotonia was noted in all cases, Respiratory distress in seven cases, cyanosis in 4 cases and a systolic murmur in 5 cases. Hepatomegaly was constant, macroglossia was noted in one patient. Chest radiography showed cardiomegaly in all cases. Electrocardiogram, showed electrical signs of left ventricular hypertrophy, wide QRS complex, a shortening of the PR interval was seen in 4 cases. Echocardiography confirmed diagnosis of hypertrophic cardiomyopathy. The dosage of acid maltase activity practiced in 5 patients, showed no enzyme activity. The genetic study of 4 patients showed a mutation in the homozygous state of the GAA gene. Treatment was purely symptomatic involving propranolol, oxygen and antibiotics. All patients died. Conclusion The fatal evolution of the classic infantile form of Pompe disease is being changed by the advent of enzyme replacement therapy wich significantly increased the survival of these patients.

T.P.19: Effects of antibody formation during enzyme replacement therapy in 73 adult patients with Pompe disease

High sustained antibody titers against enzyme replacement therapy (ERT) with alglucosidase alfa adversely affect clinical outcome in classic-infantile Pompe disease. The long-term effects of antibody formation on therapeutic efficacy in non-classic Pompe disease are yet unknown. We studied whether the presence of anti-alglucosidase alfa antibodies has an impact on treatment outcome and occurrence of infusion-associated reactions (IARs) in a large cohort of adult patients. This prospective single-centre cohort study included 73 adult patients who were treated with 20 mg/kg alglucosidase alfa every other week and started to receive ERT at least 3 years ago. Antibody titers were measured at approximately 6, 12 and 36 months of ERT using ELISA and their effects on enzyme activity were measured in the medium and in cultured fibroblasts in vitro . Clinical parameters included muscle strength (MRC sumscore), pulmonary function (FVC in upright and supine positions), and IARs. 71 of the 73 (97%) patients developed antibodies against alglucosidase alfa. The mean titer peaked at 6 months to 1:1259 and thereafter declined to 1:270 at 36 months of treatment. Individual titers and titer courses varied, but in the majority (93%) of patients titers decreased or stabilized with continued ERT. Patients with high peak titers showed moderate to high levels of in vitro enzyme inhibition. An increased risk for IARs was found in patients with higher antibody peak titers as 7 (44%) of 16 patients with high titers (⩾1:31,250) experienced IARs, 5 (19%) of 27 patients with intermediate titers (1:1250 to p = 0.001). No relation was found with antibody titer and poorer clinical outcome for MRC sumscore and FVC in upright and supine positions after a 36 months treatment period. Antibody formation to alglucosidase alfa in non-classic Pompe patients increases the risk for infusion-associated reactions, but is not associated with unfavorable clinical outcome during 3 years of treatment.

Enzyme replacement therapy (ERT) in pompe disease

Pompe disease (OMIM 232300) is an AR glycogenosis due to deficiency of the lysosomal enzyme alpha-glucosidase (GAA). As a result, glycogen storage occurs in muscles and patients present a wide clinical spectrum ranging from early onset severe cardiomyopathy (EOPD) to adult onset forms (LOPD). Severe loss of GAA activity correlates with early onset and severe phenotypes. Residual enzyme activity warrants later onset and a slowly progressive course, although a strict correlation is not always observed. Patients with Classic infantile Pompe disease show hypotonia, macroglossia, respiratory insufficiency and early death for cardiorespiratory failure. The availability of enzyme replacement therapy (ERT) with alglucosidase alfa ( human recombinant GAA) has changed the natural history of the disease allowing most children with EOPD a longer survival and a longer preserved muscle performance with increased quality of life in LOPD. The experience of the Regional referral Center for Metabolic Diseases, University of Catania, concerns 11 patients ( 9 months to 65 years at the time of the diagnosis). Their clinical and laboratory follow-up included eye tracking and Muscle MRI. EOPD, with a severe clinical picture since the first weeks of life and cardiomyopathy was observed in a newborn who died at age 4 months, despite early started and high dosage ERT. Another girl with EOPD is on ERT since the age of 9 months and, today, after 7 years of treatment shows only mild signs of muscle weakness and no cardiac involvement. Five more LOPD patients on ERT had a significant improvement of blood parameters including transaminases, LDH and CPK. No progression of muscle impairment was seen after 5 to 8 years of treatment, except for one 35 years old man, who was already severely compromised and did not show any benefit in terms of respiratory ventilation. In a recently performed Italian survey of classical Pompe disease treated with ERT, a substantial improvement in cardiac parameters and gross motor function was observed, even if residual muscle weakness still exist and gross motor function remain below age-appropriate levels. The different response to ERT depends on several factors mainly on timing of treatment (worse outcome if started later than 5 months of age) and cross reactive immune material (CRIM-negative status associated with less good response to ERT). Although some residual mild weakness is present in treated patients, ERT has demonstrated its effects on respiration, lowering nocturnal apneas and allowing patients a better quality of life.

Are evoked potentials in patients with adult-onset pompe disease indicative of clinically relevant central nervous system involvement?

Pompe disease is a multisystem autosomal recessive glycogen storage disease. Autoptic findings in patients with classic infantile and late-onset Pompe disease have proven that accumulation of glycogen can also be found in the peripheral and central nervous system. To assess the functional role of these pathologic findings, multimodal sensory evoked potentials were analyzed. Serial recordings for brainstem auditory, visual, and somatosensory evoked potentials of 11 late-onset Pompe patients were reviewed. Data at the onset of the enzyme replacement therapy with alglucosidase alfa were compared with follow-up recordings at 12 and 24 months. Brainstem auditory evoked potentials showed a delayed peak I in 1/10 patients and an increased I-III and I-V interpeak latency in 1/10 patients, respectively. The III-V interpeak latencies were in the normal range. Visual evoked potentials were completely normal. Median somatosensory evoked potentials showed an extended interpeak latency in 3/9 patients. Wilcoxon tests comparing age-matched subgroups found significant differences in brainstem auditory evoked potentials and visual evoked potentials. We found that the majority of recordings for evoked potentials were within the ranges for standard values, therefore reflecting the lack of clinically relevant central nervous system involvement. Regular surveillance by means of evoked potentials does not seem to be appropriate in late-onset Pompe patients.

Enzyme therapy and immune response in relation to CRIM status: the Dutch experience in classic infantile Pompe disease

BackgroundEnzyme-replacement therapy (ERT) in Pompe disease—an inherited metabolic disorder caused by acid α-glucosidase deficiency and characterized in infants by generalized muscle weakness and cardiomyopathy—can be complicated by immune responses. Infants that do not produce any endogenous acid α-glucosidase, so-called CRIM-negative patients, reportedly develop a strong response. We report the clinical outcome of our Dutch infants in relation to their CRIM status and immune response.MethodsEleven patients were genotyped and their CRIM status was determined. Antibody formation and clinical outcome were assessed for a minimum of 4 years.ResultsERT was commenced between 0.1 and 8.3 months of age, and patients were treated from 0.3 to 13.7 years. All patients developed antibodies. Those with a high antibody titer (above 1:31,250) had a poor response. The antibody titers varied substantially between patients and did not strictly correlate with the patients’ CRIM status. Patients who started ERT beyond 2 months of age tended to develop higher titers than those who started earlier. All three CRIM-negative patients in our study succumbed by the age of 4 years seemingly unrelated to the height of their antibody titer.ConclusionAntibody formation is a common response to ERT in classic infantile Pompe disease and counteracts the effect of treatment. The counteracting effect seems determined by the antibody:enzyme molecular stoichiometry. The immune response may be minimized by early start of ERT and by immune modulation, as proposed by colleagues. The CRIM-negative status itself seems associated with poor outcome.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-014-9707-6) contains supplementary material, which is available to authorized users.

Outcome of patients with classical infantile pompe disease receiving enzyme replacement therapy in Germany.

Enzyme replacement therapy (ERT) has been shown to improve outcome in classical infantile Pompe disease. The purpose of this study was to assess mortality, morbidity, and shortcomings of ERT in a larger cohort of patients treated outside clinical trials. To accomplish this, we retrospectively analyzed the data of all 23 subjects with classical infantile Pompe disease having started ERT in Germany between January 2003 and December 2010. Ten patients (43%) deceased and four others (17%) became ventilator dependent. Seven infants (30.5%) made no motor progress at all, while seven (30.5%) achieved free sitting, and nine (39%) gained free walking. Besides all the seven patients (100%) attaining no improvement of motor functions, four out of the seven (57%) achieving to sit without support, and three out of the nine (33%) being able to walk independently, secondarily deteriorated, and died or became ventilator dependent. Sustained reduction of systolic function despite reversal of cardiac hypertrophy (n = 3), gastroesophageal reflux (n = 5), swallowing difficulties or failure to thrive (n = 11), recurrent pneumonias (n = 14), port system complications (n = 4), anesthesia-related incidents (n = 2), severe allergic reactions (n = 6), hearing loss (n = 3), and orthopedic deformities (n = 4) were problems frequently encountered. Although this study has important shortcomings due to its retrospective nature and because important variables potentially influencing outcome were not available for a substantial amount of patients, these data suggest that classical infantile Pompe disease still remains a life-threatening condition associated with high morbidity and often dismal prognosis. Currently, a relevant number of patients do not benefit definitely from ERT.

Non-depleting anti-CD4 monoclonal antibody induces immune tolerance to ERT in a murine model of Pompe disease

Approximately 35–40% of patients with classic infantile Pompe disease treated with enzyme replacement therapy (ERT) develop high, sustained antibody titers against the therapeutic enzyme alglucosidase alfa, which abrogates the treatment efficacy. Induction of antigen-specific immune tolerance would greatly enhance ERT for these patients. Here we show that a short-course treatment with non-depleting anti-CD4 monoclonal antibody successfully induced long-term ERT-specific immune tolerance in Pompe disease mice. Our data suggest an effective adjuvant therapy to ERT.

Polysomnographic findings in infantile Pompe disease

Infantile Pompe disease is a rare, autosomal recessive disorder due to deficiency of the enzyme acid α-glucosidase that degrades lysosomal glycogen. Clinical features of diffuse hypotonia, cardiomyopathy, and weakness are present within the first days to months of life in patients with classic infantile Pompe disease. Progression of the disease often leads to respiratory failure. Although sleep apnea is reported in late-onset Pompe disease, sleep pathology is not well characterized in infantile disease. In this retrospective study, we analyzed nocturnal polysomnography results from 17 patients with infantile-onset Pompe disease. Obstructive sleep apnea and hypoventilation were common among this cohort, even in those that did not have symptoms of sleep-disordered breathing. All patients with infantile-onset Pompe disease should undergo polysomnography as a routine part of their care.

Algorithm for the early diagnosis and treatment of patients with cross reactive immunologic material-negative classic infantile pompe disease: a step towards improving the efficacy of ERT.

ObjectiveAlthough enzyme replacement therapy (ERT) is a highly effective therapy, CRIM-negative (CN) infantile Pompe disease (IPD) patients typically mount a strong immune response which abrogates the efficacy of ERT, resulting in clinical decline and death. This study was designed to demonstrate that immune tolerance induction (ITI) prevents or diminishes the development of antibody titers, resulting in a better clinical outcome compared to CN IPD patients treated with ERT monotherapy.MethodsWe evaluated the safety, efficacy and feasibility of a clinical algorithm designed to accurately identify CN IPD patients and minimize delays between CRIM status determination and initiation of an ITI regimen (combination of rituximab, methotrexate and IVIG) concurrent with ERT. Clinical and laboratory data including measures of efficacy analysis for response to ERT were analyzed and compared to CN IPD patients treated with ERT monotherapy.ResultsSeven CN IPD patients were identified and started on the ITI regimen concurrent with ERT. Median time from diagnosis of CN status to commencement of ERT and ITI was 0.5 months (range: 0.1–1.6 months). At baseline, all patients had significant cardiomyopathy and all but one required respiratory support. The ITI regimen was safely tolerated in all seven cases. Four patients never seroconverted and remained antibody-free. One patient died from respiratory failure. Two patients required another course of the ITI regimen. In addition to their clinical improvement, the antibody titers observed in these patients were much lower than those seen in ERT monotherapy treated CN patients.ConclusionsThe ITI regimen appears safe and efficacious and holds promise in altering the natural history of CN IPD by increasing ERT efficacy. An algorithm such as this substantiates the benefits of accelerated diagnosis and management of CN IPD patients, thus, further supporting the importance of early identification and treatment initiation with newborn screening for IPD.

Skeletal muscle pathology of infantile Pompe disease during long-term enzyme replacement therapy

BackgroundPompe disease is an autosomal recessive metabolic neuromuscular disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). It has long been believed that the underlying pathology leading to tissue damage is caused by the enlargement and rupture of glycogen-filled lysosomes. Recent studies have also implicated autophagy, an intracellular lysosome-dependent degradation system, in the disease pathogenesis. In this study, we characterize the long-term impact of enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) on lysosomal glycogen accumulation and autophagy in some of the oldest survivors with classic infantile Pompe disease (IPD).MethodsMuscle biopsies from 8 [4 female, 4 male; 6 cross-reactive immunologic material (CRIM)-positive, 2 CRIM-negative] patients with a confirmed diagnosis of classic IPD were examined using standard histopathological approaches. In addition, muscle biopsies were evaluated by immunostaining for lysosomal marker (lysosomal-associated membrane protein-2; LAMP2), autophagosomal marker (microtubule-associated protein 1 light chain 3; LC3), and acid and alkaline ATPases. All patients received rhGAA by infusion at cumulative biweekly doses of 20–40 mg/kg.ResultsMedian age at diagnosis of classic IPD was 3.4 months (range: 0 to 6.5 months; n = 8). At the time of muscle biopsy, the patients’ ages ranged from 1 to 103 months and ERT duration ranged from 0 (i.e., baseline, pre-ERT) to 96 months. The response to therapy varied considerably among the patients: some patients demonstrated motor gains while others experienced deterioration of motor function, either with or without a period of initial clinical benefit. Skeletal muscle pathology included fiber destruction, lysosomal vacuolation, and autophagic abnormalities (i.e., buildup), particularly in fibers with minimal lysosomal enlargement. Overall, the pathology reflected clinical status.ConclusionsThis is the first study to investigate the impact of rhGAA ERT on lysosomal glycogen accumulation and autophagic buildup in patients with classic IPD beyond 18 months of treatment. Our findings indicate that ERT does not fully halt or reverse the underlying skeletal muscle pathology in IPD. The best outcomes were observed in the two patients who began therapy early, namely at 0.5 and 1.1 months of age.