Cognitive decline in classic infantile Pompe disease: An underacknowledged challenge

Ebbink, Berendine J.; Poelman, Esther; Plug, Iris; Lequin, Maarten H.; Doorn, Pieter A. van; Aarsen, Femke K.; Ploeg, Ans T. van der; Hout, J. M. P. van den

doi:10.1212/wnl.0000000000002523

Cited by 42 publications

(35 citation statements)

References 5 publications

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“…As with infused rhGAA, the GAA secreted by liver does not normally cross the BBB (6). However, as reported for other lysosomal enzymes, high circulating GAA may lead to leakage across the BBB (55).…”

Section: Discussionmentioning

confidence: 99%

“…However, although a lifesaving therapy for some patients, enzyme replacement therapy has several limitations, leading to treatment failures and limited long-term efficacy. Specifically, the low uptake of the enzyme in skeletal muscle (5) and the inability of rhGAA to cross the blood-brain barrier (BBB) (6), together with the progressive impairment of autophagy (7), limit the ability of enzyme replacement therapy to fully ameliorate the symptoms of Pompe disease. In addition, rhGAA can also induce immune responses, potentially resulting in acute infusion reactions (4) and development of anti-GAA antibodies (8, 9).…”

Section: Introductionmentioning

confidence: 99%

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Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

et al. 2017

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Glycogen storage disease type II or Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme, acid α-glucosidase (GAA), which result in pathological accumulation of glycogen throughout the body. Enzyme replacement therapy is available for Pompe disease; however, it has limited efficacy, has high immunogenicity, and fails to correct pathological glycogen accumulation in nervous tissue and skeletal muscle. Using bioinformatics analysis and protein engineering, we developed transgenes encoding GAA that could be expressed and secreted by hepatocytes. Then, we used adeno-associated virus (AAV) vectors optimized for hepatic expression to deliver the GAA transgenes to Gaa knockout (Gaa−/−) mice, a model of Pompe disease. Therapeutic gene transfer to the liver rescued glycogen accumulation in muscle and the central nervous system, and ameliorated cardiac hypertrophy as well as muscle and respiratory dysfunction in the Gaa−/− mice; mouse survival was also increased. Secretable GAA showed improved therapeutic efficacy and lower immunogenicity compared to nonengineered GAA. Scale-up to nonhuman primates, and modeling of GAA expression in primary human hepatocytes using hepatotropic AAV vectors, demonstrated the therapeutic potential of AAV vector–mediated liver expression of secretable GAA for treating pathological glycogen accumulation in multiple tissues in Pompe disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

et al. 2017

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“…In childhood and adult forms of Pompe disease, skeletal muscle wasting is prominent, but cardiac abnormalities are more rare, and there is no evidence for CNS abnormalities 28, 29, 30. A recent report described the generation of myocytes, using MyoD overexpression, from iPSCs derived from adult Pompe patients who did not carry the IVS1 variant 26 .…”

Section: Discussionmentioning

confidence: 99%

GAA Deficiency in Pompe Disease Is Alleviated by Exon Inclusion in iPSC-Derived Skeletal Muscle Cells

Wal

Bergsma

Gestel

et al. 2017

Molecular Therapy - Nucleic Acids

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Pompe disease is a metabolic myopathy caused by deficiency of the acid α-glucosidase (GAA) enzyme and results in progressive wasting of skeletal muscle cells. The c.-32-13T>G (IVS1) GAA variant promotes exon 2 skipping during pre-mRNA splicing and is the most common variant for the childhood/adult disease form. We previously identified antisense oligonucleotides (AONs) that promoted GAA exon 2 inclusion in patient-derived fibroblasts. It was unknown how these AONs would affect GAA splicing in skeletal muscle cells. To test this, we expanded induced pluripotent stem cell (iPSC)-derived myogenic progenitors and differentiated these to multinucleated myotubes. AONs restored splicing in myotubes to a similar extent as in fibroblasts, suggesting that they act by modulating the action of shared splicing regulators. AONs targeted the putative polypyrimidine tract of a cryptic splice acceptor site that was part of a pseudo exon in GAA intron 1. Blocking of the cryptic splice donor of the pseudo exon with AONs likewise promoted GAA exon 2 inclusion. The simultaneous blocking of the cryptic acceptor and cryptic donor sites restored the majority of canonical splicing and alleviated GAA enzyme deficiency. These results highlight the relevance of cryptic splicing in human disease and its potential as therapeutic target for splicing modulation using AONs.

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“…The same group [19] later described the cognitive decline observed in a 9-year-old patient with IOPD (CRIM-positive), who had been treated with ERT since 5 weeks of age. Reportedly, his cognitive abilities were in the normal to mildly delayed range up through age 6.…”

Section: Introductionmentioning

confidence: 99%

“…These include delayed myelination, ventricular enlargement and subcortical white matter changes [9,19–22]. White matter abnormalities on MRI have been reported as early as 44 months [23].…”

Section: Introductionmentioning

confidence: 99%

Cognitive and academic outcomes in long-term survivors of infantile-onset Pompe disease: A longitudinal follow-up

Spiridigliozzi

Keeling

Ștefănescu

et al. 2017

Molecular Genetics and Metabolism

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This study examines the long-term cognitive and academic outcomes of 11 individuals with infantile onset Pompe disease (IOPD) (median age = 11 years, 1 month, range = 5 years, 6 months through 17 years of age) treated with enzyme replacement therapy from an early age. All participants (7 males, 4 females) were administered individual intelligence tests (Wechsler or Leiter scales or both), a measure of their academic skill levels (Woodcock-Johnson Tests of Achievement), and a screening measure of visual-motor integration ability (Beery-Buktenica). Consistent with our earlier findings, median IQ scores for the entire group on the Wechsler (median = 84) and Leiter (median = 92) scales continue to fall at the lower end of the average range compared to same-aged peers. The median scores for the group on a measure of visual-motor integration (median = 76), visual perception (median = 74) and motor coordination (median = 60) were below average. Two distinct sub-groups emerged based on participants’ average or below average performance on the majority of academic sub-tests. Those participants with below average academic skills (n = 6) demonstrated average nonverbal cognitive abilities on the Leiter, but had weaknesses in speech and language skills and greater medical involvement. Their profiles were more consistent with a learning disability diagnosis than an intellectual disability. Two of these participants showed a significant decline (15 and 23 points, respectively) on repeated Wechsler scales, but one continued to earn average scores on the Leiter scales where the verbal and motor demands are minimal. Participants with average academic skills (n = 5) demonstrated average cognitive abilities (verbal and nonverbal) on the Wechsler scales and less medical involvement. Their speech and language skills appeared to be more intact. However, both groups earned below average median scores on the Beery-Buktenica motor coordination task. This study highlights the importance of using appropriate tests to capture both verbal and nonverbal abilities, considering each individual’s motor skills, speech and language abilities, hearing status and native language. This will allow for a more accurate assessment of whether there is a learning disability or an intellectual disability. Long-term outcomes may be related to the stability of an individual’s expressive and/or receptive language abilities over time. Changes in the speech and language domain may account for the decline in IQ observed in some IOPD long-term survivors, reflecting a learning disability rather than a decline in overall cognition or an intellectual disability. These observations, in conjunction with neuroimaging, will further our understanding of the neurocognitive profile of long-term IOPD survivors.

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Cognitive decline in classic infantile Pompe disease: An underacknowledged challenge

Cited by 42 publications

References 5 publications

Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

GAA Deficiency in Pompe Disease Is Alleviated by Exon Inclusion in iPSC-Derived Skeletal Muscle Cells

Cognitive and academic outcomes in long-term survivors of infantile-onset Pompe disease: A longitudinal follow-up

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