Low bone mass in Pompe disease: Muscular strength as a predictor of bone mineral density

doi:10.1016/j.bone.2010.06.021

Bone

Volume 47, Issue 3, September 2010, Pages 643-649

https://doi.org/10.1016/j.bone.2010.06.021 Get rights and content

Abstract

Pompe disease is an inherited metabolic myopathy caused by deficiency of acid alpha-glucosidase. The introduction of enzyme replacement therapy as treatment for the disease may change prospects for patients and may require that more attention be paid to co-morbidities such as osteoporosis.

Methods

Bone mineral status was assessed in children and adults with Pompe disease and compared with reference values by means of dual energy X-ray absorptiometry (DXA) technology (GE Lunar DPX, GE Health Care). Bone mineral density (BMD) of the total body and the lumbar spine (L2–L4) was measured in adults and children; BMD of the femoral neck was measured in adults only. Exclusion criteria were: age < 4 years, severe contractures, and inability to transfer the patient.

Results

46 patients were enrolled in the study; 36 adults and 10 children. The BMD was significantly lower in Pompe patients than in healthy individuals. Sixty-seven percent of patients had a BMD Z-score below −1, 26% were classified as osteoporosis/low bone mass for chronological age (T-score < −2.5 in adults or Z-score < −2 in children), 66% had a BMD Z-score below −1 of the femoral neck, and 34% had a BMD Z-score below −1 for the lumbar spine. Osteoporosis/low bone mass for chronological age was more frequent in patients who were wheelchair-bound, but was also observed in ambulant patients. We found a significant correlation between proximal muscle strength and total body BMD. Of the 10 children, 8 (all four patients with the classic infantile form) had a low BMD.

Conclusion

Low BMD is a frequent finding in patients with Pompe disease and may be causally related to decreased proximal muscle strength. BMD should be monitored at regular intervals. Children deserve specific attention.

Introduction

Pompe disease (glycogen storage disease type II, acid maltase deficiency) (OMIM #232300) is an inherited metabolic myopathy caused by deficiency of acid α-glucosidase [1]. Deficiency of this lysosomal enzyme leads to glycogen accumulating in a variety of tissues. The GAA gene is located on chromosome 17q25.3. More than 200 mutations have been detected in this gene [1], [2]. Pompe disease presents as a broad clinical spectrum, ranging from the classic infantile form characterized by hypotonia, hypertrophic cardiomyopathy, and death within the first year of life [3], [4], to more slowly progressive forms in children and adults with proximal muscle weakness and respiratory problems [5], [6]. The most common genotype in children and adults with Pompe disease is the IVS1 c.-32-13T>G/null genotype [7], [8], which gives rise to 10–30% residual alpha-glucosidase activity and explains the milder phenotype.

Though the prognosis of patients is poor, this may change with the introduction of enzyme replacement therapy. The therapy has led to increased survival and improved motor outcome in patients with the classic infantile form [9], [10], [11]. Data on enzyme replacement therapy in children and adults are still limited, but early results indicate that muscle and respiratory function may stabilize or improve [12], [13]. These potential changes in outcome imply that better long-term clinical management programs will be needed for infants, children, and adults with Pompe disease. These programs should also focus on co-morbidities.

Decreased bone mineral density (BMD) and increased incidence of fractures have been observed in several myopathies [14], [15], [16] and lysosomal storage diseases [17], [18]. It seems likely that patients with Pompe disease are at a greater risk of acquiring osteoporosis—a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture [19]. There is evidence to suggest that bone fractures occur more frequently in infants and children with Pompe disease, especially in those who are immobile and bedridden [20]. However, no BMD data are available for child, adolescent, or adult Pompe disease patients. The goal of this study was therefore to systematically assess the bone mineral status in a cohort of forty-six patients with Pompe disease (children, adolescents, and adults) via dual-energy X-ray absorptiometry (DXA) technology, to ascertain the prevalence of osteoporosis/low bone mass for chronological age and to identify candidate causes of possible decreased BMD in this patient group.

Section snippets

Patients and methods

This study on bone mineral density was performed at the Erasmus MC University Medical Center in Rotterdam, the Netherlands, which is the Dutch national referral center and international expert center for patients with Pompe disease. The Ethical Committee of the Erasmus MC University Medical Center approved the research protocol. Written informed consent was obtained from all patients or their parents.

Exclusion criteria comprised age < 4 years, severe contractures and inability to transfer the

Patients

Forty-six patients (23 males, 23 females) were enrolled in this study. Thirty-six were adults and ten were children/adolescents. The most common genotype c.-32-13T>G (IVS1-13T>G) mutation was present in 84% of the patients. The patient characteristics are summarized in Table 1.

DXA scanning

Table 2 shows the BMD Z-scores of the children/adolescents and adults compared with the reference values of healthy individuals. The Z-scores for total body and femoral neck were significantly lower in the Pompe patients.

Discussion

With the changing perspectives for Pompe disease patients, supportive care and prevention of co-morbidities such as osteoporosis are becoming more important. The results of the current study shows that low bone mineral density, a possible indicator of the co-morbidity osteoporosis, is a common feature in patients with Pompe disease. Thirty-one of the forty-six patients (67%), that we investigated had a BMD Z-score below −1. Remarkably, this group included eight of the 10 participating

Acknowledgments

We thank the patients for participating in this study as well as all who have given their support: J.F. Hardon, H.A. Nelisse, J.P. Sluimer.

The Research on Pompe disease at Erasmus MC was financially supported by the Prinses Beatrix Fonds (Grant OP07-08), the 7th Frame Program “EUCLYD-a European Consortium for Lysosomal Storage Diseases" [health F2/2008 grant agreement 201678], ZonMw-Dutch Organization for Healthcare Research and Innovation of Care [Grant 152001005], and Genzyme.

The authors'

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Pompe disease is an autosomal recessive disorder caused by a deficiency of α-glucosidase, resulting in the accumulation of glycogen in smooth, cardiac, and skeletal muscles, leading to skeletal muscle dysfunction, proximal muscle weakness, and early respiratory insufficiency. Although many patients exhibit decreased bone mineral density (BMD) and increased fractures, there is currently no official protocol for surveillance and management of osteoporosis and osteopenia in late onset Pompe disease (LOPD). Enzyme replacement therapy (ERT) has therapeutic effects on muscle function; however, very few studies report on the effect of ERT on bone mineralization in LOPD patients. Our study included 15 Pompe patients from 25 to 76 years of age on ERT for variable durations. Progressive impact of ERT on BMD of the hips and spine, and the frequency of osteopenia or osteoporosis was studied using DEXA scanning, and correlations were made with age of initiation of ERT, duration of ERT and six-minute walk test. We found a significant positive correlation between the age of ERT initiation and age of the subject, with increases in the Z-scores for the femur and lumbar region. Females had a significantly higher risk for developing osteoporosis compared to males. These results highlight the significance of ERT on reducing progression of osteoporosis in LOPD patients.
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Twenty-one adults with GSD IIIa (14 F & 7 M) and four with GSD IIIb (1 F & 3 M) were included in this natural history study. At the most recent visit, the median (range) age and follow-up time were 36 (19–68) and 16 years (0–41), respectively. For the entire cohort: 40% had documented hypoglycemic episodes in adulthood; hepatomegaly and cirrhosis were the most common radiological findings; and 28% developed decompensated liver disease and portal hypertension, the latter being more prevalent in older patients. In the GSD IIIa group, muscle weakness was a major feature, noted in 89% of the GSD IIIa cohort, a third of whom depended on a wheelchair or an assistive walking device. Older individuals tended to show more severe muscle weakness and mobility limitations, compared with younger adults. Asymptomatic left ventricular hypertrophy (LVH) was the most common cardiac manifestation, present in 43%. Symptomatic cardiomyopathy and reduced ejection fraction was evident in 10%. Finally, a urinary biomarker of glycogen storage (Glc₄) was significantly associated with AST, ALT and CK.
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Fabry disease and Pompe disease are rare lysosomal storage disorders that belong to a heterogeneous group of more than 200 distinct inborn metabolic diseases. Mutations followed by loss of function of enzymes or transporters that are localised in the acidic environment of the lysosome may result in degradation of many substrates, such as glycosaminoglycans, glycosphingolipids, glycogen, cholesterol, oligosaccharides, glycoproteins, and peptides, or the excretion of the products degraded by the lysosome. Our aim was to identify the oral signs and symptoms of Fabry disease and Pompe disease from a systematic review made using MEDLINE/PubMed, and a hand search for relevant articles, following the PRISMA guidelines. Both diseases show various craniofacial and oral changes, including supernumerary teeth, dental agenesis, angiokeratoma, and telangiectases in Fabry disease; and macroglossia, teeth fusion, and taurodontism in Pompe disease. Common clinical signs of Fabry disease include hyposalivation, hypohidrosis, and xerophthalmia, and a generally reduced physical resilience was apparent in patients with Pompe disease. Oral and craniofacial changes in patients with both diseases extend over their entire lifetime and can be detected even in an infant. Lysosomal storage diseases should be taken into consideration in the differential diagnosis of relevant diverse symptoms, because treatment, when available, is most effective when started early. The main therapeutic concepts are enzymatic replacement for Pompe disease, whereas patients with Fabry disease require additional oral chaperone treatment or enzyme replacement.
Elevated Creatine Kinase in a 6-Year-Old Boy
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Dietician input is invaluable, particularly as swallowing and feeding difficulties can develop over time. Finally, calcium and vitamin D supplements should be considered given the high frequency of osteopenia in Pompe disease.13,15,33 JOPD, a rare inherited progressive myopathy, can present with insidious onset of symptoms in childhood, typically resulting from progressive skeletal and respiratory muscle weakness.
Paucisymptomatic or asymptomatic but persistently elevated serum creatine kinase is not an uncommon pediatric neurology referral question. The challenge is in promptly identifying etiologies with specific treatments, even if they are rare. The presenting features for a child or adolescent with juvenile-onset Pompe disease (JOPD) can be nonspecific and heterogeneous. Clinical manifestations can appear at any age after 2 years and before adulthood, with insidious onset of symptoms related to slowly progressive skeletal or respiratory muscle weakness. This reported case highlights the importance of screening for JOPD in children with “hyper-CK-emia.” Dried blood spot measuring acid α-glucosidase enzyme activity is reliable, rapid, noninvasive, and inexpensive, allowing early diagnosis. Diagnosis of JOPD is important as enzyme replacement therapy with alglucosidase alpha, an intravenous recombinant α-glucosidase, is available, and early treatment improves muscle function, quality of life, and long-term survival.
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Bone and skeletal muscle mass are highly correlated in mammals, suggesting the existence of common anabolic signaling networks that coordinate the development of these two anatomically adjacent tissues. The activin signaling pathway is an attractive candidate to fulfill such a role. Here, we generated mice with conditional deletion of activin receptor (ACVR) type 2A, ACVR2B, or both, in osteoblasts, to determine the contribution of activin receptor signaling in regulating bone mass. Immunohistochemistry localized ACVR2A and ACVR2B to osteoblasts and osteocytes. Primary osteoblasts expressed activin signaling components, including ACVR2A, ACVR2B, and ACVR1B (ALK4) and demonstrated increased levels of phosphorylated Smad2/3 upon exposure to activin ligands. Osteoblasts lacking ACVR2B did not show significant changes in vitro. However, osteoblasts deficient in ACVR2A exhibited enhanced differentiation indicated by alkaline phosphatase activity, mineral deposition, and transcriptional expression of osterix, osteocalcin, and dentin matrix acidic phosphoprotein 1. To investigate activin signaling in osteoblasts in vivo, we analyzed the skeletal phenotypes of mice lacking these receptors in osteoblasts and osteocytes (osteocalcin-Cre). Similar to the lack of effect in vitro, ACVR2B-deficient mice demonstrated no significant change in any bone parameter. By contrast, mice lacking ACVR2A had significantly increased femoral trabecular bone volume at 6 weeks of age. Moreover, mutant mice lacking both ACVR2A and ACVR2B demonstrated sustained increases in trabecular bone volume, similar to those in ACVR2A single mutants, at 6 and 12 weeks of age. Taken together, these results indicate that activin receptor signaling, predominantly through ACVR2A, directly and negatively regulates bone mass in osteoblasts.

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Low bone mass in Pompe disease: Muscular strength as a predictor of bone mineral density

Abstract

Methods

Results

Conclusion

Introduction

Section snippets

Patients and methods

Patients

DXA scanning

Discussion

Acknowledgments

Lancet

Neuromuscul Disord

Genet Med

J Clin Densitom

Neuromuscul Disord

Bone

Bone

Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency

The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature

Pediatrics

A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease

J Pediatr

The natural course of non-classic Pompe's disease; a review of 225 published cases

J Neurol

Clinical features of late-onset Pompe disease: a prospective cohort study

Muscle Nerve

Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II

Hum Mutat

Broad spectrum of Pompe disease in patients with the same c.-32-13T->G haplotype

Neurology

Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk

Pediatrics

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

Neurology

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

Pediatr Res

Enzyme replacement therapy with alglucosidase alfa in 44 patients with late-onset glycogen storage disease type 2: 12-month results of an observational clinical trial

J Neurol