Effect of alglucosidase alfa dosage on survival and walking ability in patients with classic infantile Pompe disease: a multicentre observational cohort study from the European Pompe Consortium.

BACKGROUND: Enzyme replacement therapy (ERT) with alglucosidase alfa has been found to improve outcomes in patients with classic infantile Pompe disease, who without treatment typically die before the age of 1 year. Variable responses to the standard recommended dosage have led to alternative dosing strategies. We aimed to assess the effect of real-world ERT regimens on survival and walking ability in these patients. METHODS: In this observational cohort study, we obtained data collected as part of a collaborative study within the European Pompe Consortium on patients with classic infantile Pompe disease from France, Germany, Italy, and the Netherlands diagnosed between Oct 26, 1998 and March 8, 2019. Eligible patients had classic infantile Pompe disease with a disease onset and proven diagnosis before age 12 months, and a hypertrophic cardiomyopathy. A proven diagnosis of classic infantile Pompe disease was defined as a confirmed deficiency of α-glucosidase in leukocytes or lymphocytes, fibroblasts or muscle, or two pathogenic GAA variants in trans, or both. We collected data on demographics, GAA variants, ERT dosage, age at death, and walking ability. We analysed the effects of ERT dosage on survival and walking ability using Cox regression, Kaplan-Meier curves, and log-rank tests. FINDINGS: We included 124 patients with classic infantile Pompe disease, of whom 116 were treated with ERT (median age at start of treatment 3·3 months [IQR 1·8-5·0, range 0·03-11·8]). During follow-up (mean duration 60·1 months [SD 57·3]; n=115), 36 (31%) of 116 patients died. 39 different ERT dosing regimens were applied. Among the 64 patients who remained on the same dosage, 16 (52%) of 31 patients on the standard dosage (20 mg/kg every other week), 12 (80%) of 15 patients on an intermediate dosage (20 mg/kg per week or 40 mg/kg every other week), and 16 (89%) of 18 patients on the high dosage (40 mg/kg per week) were alive at last follow-up. Survival was significantly improved in the high dosage group compared with the standard dosage group (hazard ratio [HR] 0·17 [95% CI 0·04-0·76], p=0·02). No significant difference in survival was identified between the intermediate dosage group and the standard dosage group (HR 0·44 [0·13-1·51], p=0·19). Of the 86 patients who reached 18 months of age, 44 (51%) learned to walk. Ten (53%) of 19 patients on the standard dosage regimen, six (67%) of nine patients on intermediate dosage regimens, and 14 (93%) of 15 patients on high dosage regimens learnt to walk, but the differences between groups were not statistically significant. INTERPRETATION: Patients with classic infantile Pompe disease treated with the high ERT dosage of 40 mg/kg per week had significantly improved survival when compared with patients treated with the standard recommended ERT dosage of 20 mg/kg every other week. Based on these results, we suggest that the currently registered dosage should be reconsidered. FUNDING: Prinses Beatrix Spierfonds and Wishdom Foundation.

Long-term benefit of enzyme replacement therapy with alglucosidase alfa in adults with Pompe disease: Prospective analysis from the French Pompe Registry.

Despite a wide clinical spectrum, the adult form of Pompe disease is the most common one, and represents more than 90% of diagnosed patients in France. Since the marketing of enzyme replacement therapy (alglucosidase alfa, Myozyme), all reports to date in adults demonstrated an improvement of the walking distance, and a trend toward stabilization of respiratory function, but the majority of these studies were less than 5 years of duration. We report here the findings from 158 treated patients included in the French Pompe Registry, who underwent regular clinical assessments based on commonly used standardized tests (6-minute walking test, MFM scale, sitting vital capacity, MIP and MEP). For longitudinal analyses, the linear mixed effects models were used to assess trends in primary endpoints over time under ERT. A two-phase model better described the changes in distance traveled in the 6-minute walk test and MFM. 6MWT showed an initial significant increase (1.4% ± 0.5/year) followed by a progressive decline (-2.3%/year), with a cut-off point at 2.2 years. A similar pattern was observed in total MFM score (6.6% ± 2.3/year followed by a - 1.1%/year decline after 0.5 years). A single-phase decline with a slope of -0.9 ± 0.1%/year (P < .001) was observed for FVC, and MEP remained stable over the all duration of follow-up. This study provides further evidence that ERT improves walking abilities and likely stabilizes respiratory function in adult patients with Pompe disease, with a ceiling effect for the 6MWT in the first 3 years of treatment.

Clinical and Molecular Disease Spectrum and Outcomes in Patients with Infantile-Onset Pompe Disease.

OBJECTIVES: To evaluate the clinical and molecular spectrum, and factors affecting clinical outcome of patients in India diagnosed with infantile-onset Pompe disease (IOPD). STUDY DESIGN: In this multicenter, cross-sectional study, we evaluated the records of 77 patients with IOPD to analyze their clinical course, outcomes, and factors influencing the outcomes. RESULTS: Of the 77 patients with IOPD, phenotype data were available in 59; 46 (78%) had the classic phenotype. Overall, 58 of 77 (75%) and 19 of 77 (25%) patients were symptomatic before and after age 6 months, respectively. Alpha-glucosidase gene variant analysis available for 48 patients (96 alleles) showed missense variants in 49 alleles. Cross-reactive immunologic material (CRIM) status could be determined or predicted in 44 of 48 patients. In total, 32 of 44 patients (72%) were CRIM-positive, and 12 of 44 patients (27%) were CRIM-negative. Thirty-nine cases received enzyme-replacement therapy (ERT), alglucosidase alfa, and 38 patients never received ERT. Median age at initiation of ERT was 6.5 months. Response to ERT was better in babies who had CRIM-positive, non-classic IOPD. CONCLUSIONS: This study highlights the clinical spectrum of IOPD in India and provides an insight on various factors, such as undernutrition, feeding difficulties, and recurrent respiratory infection, as possible factors influencing clinical outcomes in these patients. The study also reiterates the importance of raising awareness among clinicians about the need for early diagnosis and timely treatment of IOPD.

Systemic Delivery of AAVB1-GAA Clears Glycogen and Prolongs Survival in a Mouse Model of Pompe Disease.

Pompe disease is an autosomal recessive glycogen storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). GAA deficiency results in systemic lysosomal glycogen accumulation and cellular disruption in muscle and the central nervous system (CNS). Adeno-associated virus (AAV) gene therapy is ideal for Pompe disease, since a single systemic injection may correct both muscle and CNS pathologies. Using the Pompe mouse (B6;129-GaaTm1Rabn/J), this study sought to explore if AAVB1, a newly engineered vector with a high affinity for muscle and CNS, reduces systemic weakness and improves survival in adult mice. Three-month-old Gaa-/- animals were injected with either AAVB1 or AAV9 vectors expressing GAA and tissues were harvested 6 months later. Both AAV vectors prolonged survival. AAVB1-treated animals had a robust weight gain compared to the AAV9-treated group. Vector genome levels, GAA enzyme activity, and histological analysis indicated that both vectors transduced the heart efficiently, leading to glycogen clearance, and transduced the diaphragm and CNS at comparable levels. AAVB1-treated mice had higher GAA activity and greater glycogen clearance in the tongue. Finally, AAVB1-treated animals showed improved respiratory function comparable to wild-type animals. In conclusion, AAVB1-GAA offers a promising therapeutic option for the treatment of muscle and CNS in Pompe disease.

Survival and long-term outcomes in late-onset Pompe disease following alglucosidase alfa treatment: a systematic review and meta-analysis.

A number of studies have assessed the efficacy of alglucosidase alfa as an enzyme replacement therapy (ERT) on motor and respiratory endpoints in patients with late-onset Pompe disease (LOPD). A previous review evaluated the clinical efficacy and safety of alglucosidase alfa; however, it is difficult to draw inferences from individual studies due to small patient populations, particularly in evaluating the benefit on survival. To evaluate the current evidence on the long-term efficacy of alglucosidase alfa with regard to survival, motor, and respiratory function in patients with LOPD in relation to the natural progression of the disease, a new systematic literature review was performed identifying studies that assessed either mortality, percent predicted forced vital capacity (% FVC), or the 6-min walk test (6MWT) among treated and untreated LOPD patients. Patient overlap was avoided by removing smaller studies or ensuring the use of only one conflicting study per outcome. Mortality was modeled using Poisson models for each treatment group. Outcomes were modeled using first- and second-order fractional polynomial meta-analysis with fixed- and random-effects. Meta-regression was used to explore sources of heterogeneity. Twenty-two publications pertaining to 19 studies/trials were selected, including 438 patients when accounting for overlaps, with the average study duration being 45.7 months. Patients treated with alglucosidase alfa in these studies had a nearly five-fold lower mortality rate than untreated patients (rate ratio: 0.21; 95 % credible interval: 0.11, 0.41). On average, % FVC declined consistently among untreated patients, including a 2.3 % decline after 12 months follow-up and 6.2 % decline after 48 months. This is in contrast to alglucosidase alfa-treated patients, who, on average, improved rapidly, with an increase of 1.4 % FVC after 2 months, followed by a slow regression back to baseline over a three-year period. Nonetheless, the relative difference between those treated and not grew over time, from 4.5 % FVC after 12 months to 6 % FVC after 48 months. In the 6MWT, alglucosidase alfa-treated patients on average had the largest improvement over the first 20 months of treatment of approximately 50 meters increase over baseline, with its substantial stabilization in the following years. By comparison, untreated patients do not show 6MWT improvement over time. Alglucosidase alfa has a beneficial effect in LOPD patients as demonstrated by improvements in survival and ambulation maintained over time, as well as prevention of deterioration in respiratory function.

Response of 33 UK patients with infantile-onset Pompe disease to enzyme replacement therapy.

BACKGROUND: Enzyme replacement therapy (ERT) for infantile-onset Pompe disease has been commercially available for almost 10 years. We report the experience of its use in a cohort treated at three specialist lysosomal treatment centres in the UK. METHODS: A retrospective case-note review was performed, with additional data being gathered from two national audits on all such patients treated with ERT. The impact on the outcome of various characteristics, measured just prior to the initiation of ERT (baseline), was evaluated using logistic regression. RESULTS: Thirty-three patients were identified; 13/29 (45%) were cross-reactive immunological material (CRIM) negative, and nine were immunomodulated. At baseline assessment, 79% were in heart failure, 66% had failure to thrive and 70% had radiological signs of focal pulmonary collapse. The overall survival rate was 60%, ventilation-free survival was 40% and 30% of patients were ambulatory. Median follow-up of survivors was 4 years, 1.5 months (range 6 months to 13.5 years). As with previous studies, the CRIM status impacted on all outcome measures. However, in this cohort, baseline failure to thrive was related to death and lack of ambulation, and left ventricular dilatation was a risk factor for non-ventilator-free survival. CONCLUSION: The outcome of treated patients remains heterogeneous despite attempts at immunomodulation. Failure to thrive at baseline and left ventricular dilation appear to be associated with poorer outcomes.

CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy.

PURPOSE: Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) prolongs survival in infantile Pompe disease (IPD). However, the majority of cross-reactive immunologic material (CRIM)-negative (CN) patients have immune responses with significant clinical decline despite continued ERT. We aimed to characterize immune responses in CN patients with IPD receiving ERT monotherapy. METHODS: A chart review identified 20 CN patients with IPD treated with ERT monotherapy for ≥6 months. Patients were stratified by anti-rhGAA antibody titers: high sustained antibody titers (HSAT; ≥51,200) at least twice; low titers (LT; <6,400) throughout treatment; or sustained intermediate titers (SIT; 6,400-25,600). RESULTS: Despite early initiation of treatment, the majority (85%) of CN patients developed significant antibody titers, most with HSAT associated with invasive ventilation and death. Nearly all patients with HSAT had at least one nonsense GAA mutation, whereas the LT group exclusively carried splice-site or frameshift mutations. Only one patient in the HSAT group is currently alive after successful immune modulation in the entrenched setting. CONCLUSION: Immunological responses are a significant risk in CN IPD; thus induction of immune tolerance in the naive setting should strongly be considered. Further exploration of factors influencing immune responses is required, particularly with the advent of newborn screening for Pompe disease.

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

BACKGROUND: Enzyme-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. METHODS: Eleven patients were genotyped and their CRIM status was determined. Antibody formation and clinical outcome were assessed for a minimum of 4 years. RESULTS: ERT 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. CONCLUSION: Antibody 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.

Pompe disease: early diagnosis and early treatment make a difference.

Pompe disease (glycogen storage disease type II or acid maltase deficiency) is a lysosomal disorder in which acid α-glucosidase (GAA) deficiencies lead to intralysosomal accumulation of glycogen in all tissues; most notably in skeletal muscles. Both the patient's age at the onset of Pompe disease symptoms and the rate of deterioration caused by the disease can vary considerably. In classical infant-onset Pompe disease (IOPD), symptoms start very early in life, and death occurs soon afterward if the disease remains untreated. In later-onset Pompe disease, symptoms are slower to appear, and patients often progress to wheelchair confinement and eventual respiratory failure. A diagnosis can be made by screening for GAA in dried blood samples, followed either by GAA assessment in lymphocytes or in fibroblasts or by the genetic analysis of mutations. Treatment by enzyme replacement therapy (ERT) with alglucosidase alfa was approved for human use in 2006. In classical IOPD, treatment significantly lengthens survival and improves motor development and cardiac function. The sooner ERT begins, the better are the results. Newborn screening aims to take advantage of different technologies for diagnosing and treating newborns early on and it yields better outcomes. However, newborns diagnosed early and other long-term survivors may encounter fresh problems, making up a new phenotype of IOPD patients. Further modifications of the treatment, such as a decrease in immune responses to ERT, a higher dosage, a better uptake formulation, and gene therapy delivered locally or systemically are being explored.

The cost-effectiveness of enzyme replacement therapy (ERT) for the infantile form of Pompe disease: comparing a high-income country's approach (England) to that of a middle-income one (Colombia).

OBJECTIVES: Determining the cost-effectiveness of enzyme replacement therapy (ERT) for the classical infantile form of Pompe disease (complete acid a-glucosidase deficiency-related) in two different settings: England and Colombia. Pompe disease is very rare (1:40,000 births incidence). METHODS: A literature review was made and historic databases searched for National Health Service (NHS) reimbursed costs in England and by health insurers in Colombia; expert opinion was elicited. Two Markov models were constructed for comparing both countries; alive with symptoms and dead were the transition states used. Patients aged < 6 months receiving ERT were assumed to have 75 % survival rate and better health-related quality of life (HR-QoL) compared to those without treatment (0.700 HR- QoL using the EQ-5D scale). RESULTS: The incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained was £234,307.7 for England and £109,991 for Colombia. Uncertainty about Anal HR-QoL with ERT, disease progression and cost from palliative care had the biggest impact on the ICER in both models. If ERT costs were reduced to 10,000 times per dose and HR-QoL was 0.750-0.820 ICER, then £165,000 could be attainable for England and £65,000 for Colombia. Transaction costs per case in Colombia were high. CONCLUSIONS: ERT was more effective than no ERT in treating infantile Pompe disease, but high levels of uncertainty still remain about survival and progression rates and QoL in the long-run. ICERs were high compared to CE thresholds. Manufacturers' ERT costs and monopoly had a major impact on Anal CEA results.

The cost-effectiveness of enzyme replacement therapy (ERT) for the infantile form of Pompe disease: comparing a high-income country's approach (England) to that of a middle-income one (Colombia) / Costo-Efectividad de la terapia del reemplazo enzimático (TRE) para la forma infantil de la enfermedad Pompe: perspectiva económica comparativa de un país ingresos altos (Inglaterra) vs uno de ingresos medios (Colombia)

Objectives Determining the cost-effectiveness of enzyme replacement therapy (ERT) for the classical infantile form of Pompe disease (complete acid a-glucosidase deficiency-related) in two different settings: England and Colombia. Pompe disease is very rare (1:40,000 births incidence). Methods A literature review was made and historic databases searched for National Health Service (NHS) reimbursed costs in England and by health insurers in Colombia; expert opinion was elicited. Two Markov models were constructed for comparing both countries; alive with symptoms and dead were the transition states used. Patients aged < 6 months receiving ERT were assumed to have 75 % survival rate and better health-related quality of life (HR-QoL) compared to those without treatment (0.700 HR- QoL using the EQ-5D scale). Results The incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained was £234,307.7 for England and £109,991 for Colombia. Uncertainty about Anal HR-QoL with ERT, disease progression and cost from palliative care had the biggest impact on the ICER in both models. If ERT costs were reduced to 10,000 times per dose and HR-QoL was 0.750-0.820 ICER, then £165,000 could be attainable for England and £65,000 for Colombia. Transaction costs per case in Colombia were high. Conclusions ERT was more effective than no ERT in treating infantile Pompe disease, but high levels of uncertainty still remain about survival and progression rates and QoL in the long-run. ICERs were high compared to CE thresholds. Manufacturers' ERT costs and monopoly had a major impact on Anal CEA results.

Objetivo Determinar la costo-efectividad de la TRE como indicación para la forma clásica de la enfermedad de Pompe (relacionada con deficiencia completa de a-glucosidasa ácida) desde dos perspectivas, Inglaterra y Colombia. La enfermedad de Pompe es muy rara (incidencia 1:40000 nacimientos). Métodos Revisiónbibliográfica y bases de datos para calcular costosasociados al tratamiento en NHS en Inglaterra, aseguradores de salud en Colombia y opinión de expertos. Dos procesos de Markov fueron construidos para comparar entre países; los estados de transición fueron: vivo sintomático y fallecido. En pacientes de < 6 meses de edad con TRE, se asume un incremento de 75 % de sobrevida y mejor calidad de vida comparada con los que no reciben TRE (HR-QoL 0.700 usando EQ-5D). Resultados Inglaterra alcanzo ICER por QALY ganado £234307, 7 y Colombia £109991. Incertidumbre sobre HR-QoL con TRE, progresión de enfermedad y costo de cuidado paliativo tuvieron el mayor impacto en losICERs;sí el costo de TREfuera 10.000 menor y la HR-QoLalcanzara 0.750-0.820 ICERs de £165000y £65000 podrían obtenerse para Inglaterra y Colombia respectivamente. Los costos transaccionales en Colombia son representativos. Conclusiones La TRE es más efectiva que no dar tratamiento, pero incertidumbre sobre tasas desobrevida, progresión y HR-QoLpermanecen en el largo plazo. Los ICERsson altos comparados a los umbrales establecidos de CE. Los costos de TRE y el podermonopolístico del fabricante tienen un impacto importante en los resultados Anales de CEA. Investigación adicional debe realizarsea futuro.

Survival and associated factors in 268 adults with Pompe disease prior to treatment with enzyme replacement therapy.

BACKGROUND: Pompe disease is a rare lysosomal storage disorder characterized by muscle weakness and wasting. The majority of adult patients have slowly progressive disease, which gradually impairs mobility and respiratory function and may lead to wheelchair and ventilator dependency. It is as yet unknown to what extent the disease reduces the life span of these patients. Our objective was to determine the survival of adults with Pompe disease not receiving ERT and to identify prognostic factors associated with survival. METHODS: Data of 268 patients were collected in a prospective international observational study conducted between 2002 and 2009. Survival analyses from time of diagnosis and from time of study entry were performed using Kaplan-Meier curves and Cox-proportional-hazards regression. RESULTS: Median age at study entry was 48 years (range 19-79 years). Median survival after diagnosis was 27 years, while median age at diagnosis was 38 years. During follow-up, twenty-three patients died prior to ERT, with a median age at death of 55 (range 23-77 years). Use of wheelchair and/or respiratory support and patients' score on the Rotterdam Handicap Scale (RHS) were identified as prognostic factors for survival. Five-year survival for patients without a wheelchair or respiratory support was 95% compared to 74% in patients who were wheelchair-bound and used respiratory support. In a Dutch subgroup of 99 patients, we compared the observed number of deaths to the expected number of deaths in the age- and sex-matched general population. During a median follow-up of 2.3 years, the number of deaths among the Dutch Pompe patients was higher than the expected number of deaths in the general population. CONCLUSION: Our study shows for the first time that untreated adults with Pompe disease have a higher mortality than the general population and that their levels of disability and handicap/participation are the most important factors associated with mortality. These results may be of relevance when addressing the effect of ERT or other potential treatment options on survival.

The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease.

PURPOSE: Enzyme replacement therapy with rhGAA (Myozyme®) has lead to improved survival, which is largely attributable to improvements in cardiomyopathy and skeletal muscle function. However, crossreactive immunologic material-negative patients have a poor clinical response to enzyme replacement therapy secondary to high sustained antibody titers. Furthermore, although the majority of crossreactive immunologic material-positive patients tolerize or experience a downtrend in anti-rhGAA antibody titers, antibody response is variable with some crossreactive immunologic material-positive infants also mounting high sustained antibody titers. METHODS: We retrospectively analyzed 34 infants with Pompe disease: 11 crossreactive immunologic material-negative patients, nine high-titer crossreactive immunologic material-positive patients, and 14 low-titer crossreactive immunologic material-positive patients. Clinical outcome measures were overall survival, ventilator-free survival, left ventricular mass index, Alberta Infant Motor Scale score, and urine Glc(4) levels. RESULTS: Clinical outcomes in the high-titer crossreactive immunologic material-positive group were poor across all areas evaluated relative to the low-titer crossreactive immunologic material-positive group. For the crossreactive immunologic material-negative and high-titer crossreactive immunologic material-positive groups, no statistically significant differences were observed for any outcome measures, and both patient groups did poorly. CONCLUSIONS: Our data indicate that, irrespective of crossreactive immunologic material status, patients with infantile Pompe disease with high sustained antibody titer have an attenuated therapeutic response to enzyme replacement therapy. With the advent of immunomodulation therapies, identification of patients at risk for developing high sustained antibody titer is critical.

Treatment of infantile Pompe disease with alglucosidase alpha: the UK experience.

Treatment of infantile Pompe disease with recombinant human acid α-glucosidase has shown substantial improvement in survival, and in cardiac, motor and respiratory functions. We analyzed the outcome of all patients with infantile Pompe disease treated in the United Kingdom since the availability of the enzyme, using a questionnaire-based survey circulated to all treating centres. A total of 20 infants were treated from 2000 to 2009. Median ages at diagnosis and treatment were 5.75 months (range 0.25-31 months) and 6.5 months (0.5-32 months), respectively. Median duration of treatment was 31 months (1-102 months). Overall ventilator-free survival was 35% (7/20 infants), while 35% (7/20) died at a median age of 10 months (5.75-15 months) and 30% (6/20) were alive but ventilator-dependent. Endotracheal intubation for acute deterioration carried a high risk of failure of extubation and progression to long-term ventilation (LTV), but elective general anaesthesia, in contrast, was well tolerated. Overall outcome was worse than in the pivotal clinical trials; possible causes include later diagnosis and treatment in our patients and a higher incidence of infants at the severe end of the clinical spectrum. Careful consideration must be given to all possible outcomes, including LTV, before commencing enzyme replacement therapy in newly diagnosed infants.

Antenatal diagnosis of pompe disease by fetal echocardiography: impact on outcome after early initiation of enzyme replacement therapy.

Hypertrophic cardiomyopathy (HCM) affects most infants with Pompe disease (PD), and may serve as a marker for its antenatal diagnosis (ANDx) by fetal echocardiography (FE). Fetuses diagnosed with HCM between 2006 and 2009 were included in this study. HCM, defined as Z-score of mean left ventricular wall thickness (LVWT) and/or mass (LVM) above 2, was detected in 5/1,268 fetuses (0.39%) carried by 1,137 pregnant women referred for FE. Three fetuses (0.24%) had postnatal confirmation of PD. Their gestational age and fetal weight at diagnosis was (mean ± standard deviation) 31 ± 3.6 weeks and 1.9 ± 0.2 kg, respectively. Fetal Z-score of LVM and LVWT was 3.8 ± 0.9 and 3.1 ± 0.6, respectively. Postnatally, acid α-glucosidase (GAA) enzyme activity was nearly absent in all patients, 2 were homozygous for the mutation 1327-2A>G in the GAA gene, and 1 was homozygous for 340insT. Enzyme replacement therapy (ERT) was initiated 4.9 ± 7.8 days after birth (range 2 h-14 days), and continued every 2 weeks. Two infants are alive at 4 and 31 months, and one died of aspiration pneumonia at 19 months. Cardiac hypertrophy resolved after 10-12 weeks of ERT in all patients, and none required any respiratory support. One patient had normal neurodevelopmental assessment at 25 months, and one had severe global delay at 15 months before death. ANDx of PD by FE is feasible based on fetal HCM. It promotes early initiation of ERT which may improve outcome in some patients. However, larger studies and longer follow-ups are required.

Pompe disease in infants: improving the prognosis by newborn screening and early treatment.

OBJECTIVE: Pompe disease causes progressive, debilitating, and often life-threatening musculoskeletal, respiratory, and cardiac symptoms. Favorable outcomes with early intravenous enzyme-replacement therapy and alglucosidase alfa have been reported, but early clinical diagnosis before the development of severe symptoms has rarely been possible in infants. METHODS: We recently conducted a newborn screening pilot program in Taiwan to improve the early detection of Pompe disease. Six of 206088 newborns screened tested positive and were treated for Pompe disease. Five had the rapidly progressive form of Pompe disease, characterized by cardiac and motor involvement, and were treated soon after diagnosis. The sixth patient was started on treatment at 14 months of age because of progressive muscle weakness. Outcomes were compared with treated patients whose disease was diagnosed clinically and with untreated historical control subjects. RESULTS: At the time of this report, patients had been treated for 14 to 32 months. The 5 infants who had early cardiac involvement demonstrated normalization of cardiac size and muscle pathology with normal physical growth and age-appropriate gains in motor development. The infant without cardiac involvement also achieved normal motor development with treatment. Survival in patients who had newborn screening was significantly improved compared with those in the untreated reference cohort (P = .001). Survival in the treated clinical comparators was reduced but not statistically different from that in the newborn screening group (P = .48). CONCLUSIONS: Results from this study indicate that early treatment can benefit infants with Pompe disease and highlight the advantages of early diagnosis, which can be achieved by newborn screening.

Early treatment with alglucosidase alpha prolongs long-term survival of infants with Pompe disease.

In a previous 52-wk trial, treatment with alglucosidase alpha markedly improved cardiomyopathy, ventilatory function, and overall survival among 18 children <7 mo old with infantile-onset Pompe disease. Sixteen of the 18 patients enrolled in an extension study, where they continued to receive alglucosidase alpha at either 20 mg/kg biweekly (n = 8) or 40 mg/kg biweekly (n = 8), for up to a total of 3 y. These children continued to exhibit the benefits of alglucosidase alpha at the age of 36 mo. Cox regression analyses showed that over the entire study period, alglucosidase alpha treatment reduced the risk of death by 95%, reduced the risk of invasive ventilation or death by 91%, and reduced the risk of any type of ventilation or death by 87%, compared with an untreated historical control group. Cardiomyopathy continued to improve and 11 patients learned and sustained substantial motor skills. No significant differences in either safety or efficacy parameters were observed between the 20 and 40 mg/kg biweekly doses. Overall, long-term alglucosidase alpha treatment markedly extended survival as well as ventilation-free survival and improved cardiomyopathy.

Alglucosidase alfa: new drug. Pompe disease: a short-term benefit.

(1) Pompe disease is the early-onset form of type 2 glycogenosis, a rare enzyme deficiency. Onset occurs in early infancy, and most patients die from cardiorespiratory failure before their first birthday. (2) The missing enzyme, alglucosidase alfa is now produced through biotechnology and is approved as replacement therapy for infants with Pompe disease. (3) According to a dose-finding study involving 19 infants, and a somewhat shaky historical comparison, alglucosidase alfa has a positive impact on survival at the age of 18 months. (4) The main known adverse effects of alglucosidase alfa are potentially severe infusion reactions and the development of anti-alglucosidase antibodies. (5) Treatment requires an intravenous infusion every two weeks. In France, it costs 4200 euros for a child weighing 10 kg. (6) Alglucosidase alfa replacement therapy is the only treatment that seems to improve the short-term survival of infants with Pompe disease. However, it should only be used within a context of continued assessment.

Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease.

BACKGROUND: Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid alpha-glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease. METHODS: Patients were diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy. Patients received IV infusions of rhGAA at 20 mg/kg (n = 9) or 40 mg/kg (n = 9) every other week. Analyses were performed 52 weeks after the last patient was randomized to treatment. RESULTS: All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. There was no clear advantage of the 40-mg/kg dose with regard to efficacy. Eleven of the 18 patients experienced 164 infusion-associated reactions; all were mild or moderate in intensity. CONCLUSIONS: Recombinant human acid alpha-glucosidase is safe and effective for treatment of infantile-onset Pompe disease. Eleven patients experienced adverse events related to treatment, but none discontinued. The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid alpha-glucosidase in which patients were older.