Pompeʼs Disease (Diffuse Glycogenosis) With Neuronal Storage* † ‡

Mancall, Elliott L.; Aponte, Gonzalo E.; Berry, Richard G.

doi:10.1097/00005072-196501000-00008

Cited by 74 publications

(57 citation statements)

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“…In support of this hypothesis, neural dysfunction has been noted in animal models and in human subjects (Mancall et al, 1965;Gambetti et al, 1971;DeRuisseau et al, 2009;Burrow et al, 2010). Our preclinical work in a knockout mouse model (Gaa -/ -) revealed glycogen accumulation in phrenic motoneurons and diminished phrenic efferent activity (DeRuisseau et al, 2009;Mah et al, 2010).…”

supporting

confidence: 64%

Phase I/II Trial of Adeno-Associated Virus–Mediated Alpha-Glucosidase Gene Therapy to the Diaphragm for Chronic Respiratory Failure in Pompe Disease: Initial Safety and Ventilatory Outcomes

et al. 2013

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Pompe disease is an inherited neuromuscular disease caused by deficiency of lysosomal acid alpha-glucosidase (GAA) leading to glycogen accumulation in muscle and motoneurons. Cardiopulmonary failure in infancy leads to early mortality, and GAA enzyme replacement therapy (ERT) results in improved survival, reduction of cardiac hypertrophy, and developmental gains. However, many children have progressive ventilatory insufficiency and need additional support. Preclinical work shows that gene transfer restores phrenic neural activity and corrects ventilatory deficits. Here we present 180-day safety and ventilatory outcomes for five ventilatordependent children in a phase I/II clinical trial of AAV-mediated GAA gene therapy (rAAV1-hGAA) following intradiaphragmatic delivery. We assessed whether rAAV1-hGAA results in acceptable safety outcomes and detectable functional changes, using general safety measures, immunological studies, and pulmonary functional testing. All subjects required chronic, full-time mechanical ventilation because of respiratory failure that was unresponsive to both ERT and preoperative muscle-conditioning exercises. After receiving a dose of either 1 · 10 12 vg (n = 3) or 5 · 10 12 vg (n = 2) of rAAV1-hGAA, the subjects' unassisted tidal volume was significantly larger (median [interquartile range] 28.8% increase [15.2-35.2], p < 0.05). Further, most patients tolerated appreciably longer periods of unassisted breathing (425% increase , p = 0.08). Gene transfer did not improve maximal inspiratory pressure. Expected levels of circulating antibodies and no T-cell-mediated immune responses to the vector (capsids) were observed. One subject demonstrated a slight increase in anti-GAA antibody that was not considered clinically significant. These results indicate that rAAV1-hGAA was safe and may lead to modest improvements in volitional ventilatory performance measures. Evaluation of the next five patients will determine whether earlier intervention can further enhance the functional benefit.

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supporting

confidence: 64%

Phase I/II Trial of Adeno-Associated Virus–Mediated Alpha-Glucosidase Gene Therapy to the Diaphragm for Chronic Respiratory Failure in Pompe Disease: Initial Safety and Ventilatory Outcomes

et al. 2013

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“…Several early and also more recent studies (Burrow et al 2010;Chen et al 2004;Crome et al 1963;Engel et al 1973;Gambetti et al 1971;Lee et al 1996;Mancall et al 1965;Martin et al 1973) point to abnormalities in the CNS and PNS, leading to a slowly progressive neurodegenerative process. Chien et al reported myelination delay on MRI in five patients started on ERT later than 5.5 months of age (Chien et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…The phenotype of Pompe disease is heterogeneous and primarily characterized by accumulation of glycogen in skeletal and cardiac muscle associated with progressive skeletal muscle weakness in all variants of the disease and by rapidly progressive hypertrophic cardiomyopathy and early death at about the age of 1 year in patients with the severe infantile variant (Hirschhorn and Reuser 2001;Kishnani and Howell 2004;Kishnani et al 2006a). Glycogen accumulation, however, has also been well documented in central (CNS) and peripheral (PNS) nervous systems (Gambetti et al 1971;Mancall et al 1965;Martin et al 1973;Sakurai et al 1974), also leading to cochlear dysfunction with subsequent hearing loss . In patients with clinical symptoms suggestive for Pompe disease, diagnosis is based on marked reduction of GAA activity in purified peripheral blood lymphocytes (Winchester et al 2008).…”

Section: Introductionmentioning

confidence: 99%

CRIM‐negative infantile Pompe disease: 42‐month treatment outcome

Rohrbach

Klein

Köhli-Wiesner

et al. 2010

J of Inher Metab Disea

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Pompe disease is a rare lysosomal glycogen storage disorder characterized by deficiency of acid !-glucosidase enzyme (GAA) and caused by mutations in the GAA gene. Infantile-type Pompe disease is a multiorgan disorder presenting with cardiomyopathy, hypotonia, and muscular weakness, which is usually fatal. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) has recently been shown to be effective and subsequently yielded promising results in cross-reactive immunologic material (CRIM)-positive patients. CRIM-negative patients showed a limited response to ERT and died or were ventilator dependant. Over a period of 44 months, we monitored cognitive and motor development, behavior, auditory function, and brain imaging of a CRIM-negative infantile Pompe disease patient on rhGAA and monoclonal anti-immunoglobulin E (anti-IgE) antibody (omalizumab) treatment due to severe allergic reaction. Cardiorespiratory and skeletal muscle response was significant, with almost normal motor development. Cognitive development-in particular, speech and language-deviated increasingly from normal age-appropriate development and was markedly delayed at 44 months, unexplained by moderate sensorineural hearing impairment. Brain magnetic resonance imaging (MRI) at 18, 30, and 44 months of age revealed symmetrical signal alteration of the deep white matter. Titer values of IgG antibodies to rhGAA always remained <1:800. The potential role of omalizumab in immune modulation remains to be

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“…However, a few Pompe case reports have demonstrated CNS glycogen accumulation (9)(10)(11)(12)(13)(14) and absent or diminished deep tendon reflexes (15,16). In particular, spinal motoneurons seem to be susceptible to excessive glycogen accumulation (10,13,15). The large, swollen appearance of these cells (10,12) suggests possible neurophysiological implications, such as altered excitability.…”

mentioning

confidence: 99%

“…In particular, spinal motoneurons seem to be susceptible to excessive glycogen accumulation (10,13,15). The large, swollen appearance of these cells (10,12) suggests possible neurophysiological implications, such as altered excitability. Accordingly, we postulated that GAA deficiency in the nervous system may contribute to respiratory insufficiency and tested the hypothesis that GAA-deficient mice (Gaa Ϫ/Ϫ ) would exhibit reduced ventilation, and this would be reflected by attenuated efferent phrenic motor discharge.…”

mentioning

confidence: 99%

Neural deficits contribute to respiratory insufficiency in Pompe disease

DeRuisseau¹,

Fuller

Qiu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

168

312

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Pompe disease is a severe form of muscular dystrophy due to glycogen accumulation in all tissues, especially striated muscle. Disease severity is directly related to the deficiency of acid ␣-glucosidase (GAA), which degrades glycogen in the lysosome. Respiratory dysfunction is a hallmark of the disease, muscle weakness has been viewed as the underlying cause, and the possibility of an associated neural contribution has not been evaluated previously. Therefore, we examined behavioral and neurophysiological aspects of breathing in 2 animal models of Pompe disease-the Gaa ؊/؊ mouse and a transgenic line (MTP) expressing GAA only in skeletal muscle, as well as a detailed analysis of the CNS in a Pompe disease patient. Glycogen content was elevated in the Gaa ؊/؊ mouse cervical spinal cord. Retrograde labeling of phrenic motoneurons showed significantly greater soma size in Gaa ؊/؊ mice vs. isogenic controls, and glycogen was observed in Gaa ؊/؊ phrenic motoneurons. Ventilation, assessed via plethysmography, was attenuated during quiet breathing and hypercapnic challenge in Gaa ؊/؊ mice (6 to >21 months of age) vs. controls. We confirmed that MTP mice had normal diaphragmatic contractile properties; however, MTP mice had ventilation similar to the Gaa ؊/؊ mice during quiet breathing. Neurophysiological recordings indicated that efferent phrenic nerve inspiratory burst amplitudes were substantially lower in Gaa ؊/؊ and MTP mice vs. controls. In human samples, we demonstrated similar pathology in the cervical spinal cord and greater accumulation of glycogen in spinal cord compared with brain. We conclude that neural output to the diaphragm is deficient in Gaa ؊/؊ mice, and therapies targeting muscle alone may be ineffective in Pompe disease.glycogenosis ͉ motor neuron ͉ muscular dystrophy ͉ myopathy

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Pompeʼs Disease (Diffuse Glycogenosis) With Neuronal Storage* † ‡

Cited by 74 publications

References 0 publications

Phase I/II Trial of Adeno-Associated Virus–Mediated Alpha-Glucosidase Gene Therapy to the Diaphragm for Chronic Respiratory Failure in Pompe Disease: Initial Safety and Ventilatory Outcomes

Phase I/II Trial of Adeno-Associated Virus–Mediated Alpha-Glucosidase Gene Therapy to the Diaphragm for Chronic Respiratory Failure in Pompe Disease: Initial Safety and Ventilatory Outcomes

CRIM‐negative infantile Pompe disease: 42‐month treatment outcome

Neural deficits contribute to respiratory insufficiency in Pompe disease

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