Postmortem Findings and Clinical Correlates in Individuals with Infantile-Onset Pompe Disease

Peña, Loren; Proia, Alan D.; Kishnani, Priya S.

doi:10.1007/8904_2015_426

Cited by 41 publications

(51 citation statements)

References 34 publications

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“…Follow-up MRI and IQ (patients 1,6,7,9,10) To study the relationship between MRI and IQ, the IQs of the patients assessed with the Griffiths and WISC-III-NL were related to brain MRIs performed at similar ages (time between MRI and IQ assessment <1y, range 0.5-9mo). In patients with involvement of the centrum semiovale and periventricular white matter only, intelligence was normal to mildly delayed (patients' ages 2y 8mo-7y 6mo).…”

Section: Intelligencementioning

confidence: 99%

“…However, small amounts of glycogen are also stored in the brain. [6][7][8][9][10][11][12] Therefore, we looked at the potential consequences of glycogen storage in the central nervous system (CNS) using neuropsychological tests and brain magnetic resonance imaging (MRI) from the start of therapy. Previously we found that intelligence ranged from normal to mildly delayed.…”

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confidence: 99%

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Classic infantile Pompe patients approaching adulthood: a cohort study on consequences for the brain

Ebbink

Poelman

Aarsen

et al. 2018

Develop Med Child Neuro

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Aim To examine the long‐term consequences of glycogen storage in the central nervous system (CNS) for classic infantile Pompe disease using enzyme replacement therapy. Method Using neuropsychological tests and brain magnetic resonance imaging (MRI), we prospectively assessed a cohort of 11 classic infantile Pompe patients aged up to 17 years. Results From approximately age 2 years onwards, brain MRI showed involvement of the periventricular white matter and centrum semiovale. After 8 years of age, additional white‐matter abnormalities occurred in the corpus callosum, internal and external capsule, and subcortical areas. From 11 years of age, white‐matter abnormalities were also found in the brainstem. Although there seemed to be a characteristic pattern of involvement over time, there were considerable variations between patients, reflected by variations in neuropsychological development. Cognitive development ranged from stable and normal to declines that lead to intellectual disabilities. Interpretation As treatment enables patients with classic infantile Pompe disease to reach adulthood, white‐matter abnormalities are becoming increasingly evident, affecting the neuropsychological development. Therefore, we advise follow‐up programs are expanded to capture CNS involvement in larger, international patient cohorts, to incorporate our findings in the counselling of parents before the start of treatment, and to include the brain as an additional target in the development of next‐generation therapeutic strategies for classic infantile Pompe disease. What this paper adds In our long‐term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white‐matter abnormalities. Cognitive development varied from stable and normal to declines towards intellectual disabilities.

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Section: Intelligencementioning

confidence: 99%

mentioning

confidence: 99%

Classic infantile Pompe patients approaching adulthood: a cohort study on consequences for the brain

Ebbink

Poelman

Aarsen

et al. 2018

Develop Med Child Neuro

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“…Therefore, the currently available ERT treatment with rhGAA may not effectively target neural tissue [83] because rhGAA cannot cross the blood-brain barrier. Furthermore, although ERT has significantly improved survival and quality of life of patients with Pompe disease, some patients on ERT still have mild to moderate accumulation of glycogen in the diaphragm [84], intercostal muscles [84], and airway smooth muscle [25,85] and pathology in respiratory control neurons [85]. Therefore, novel therapies need to target both muscle and neuronal pathology in order to treat the respiratory dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…The diaphragm of Pompe mice lack GAA activity and have accumulation of glycogen that disrupts the structure of the myofibrils and results in muscle weakness [39,40,45,51,52,56,57,86,87]. Similarly, post-mortem studies of patients with both IPD and LOPD reveal glycogen accumulation in the diaphragm [84,[88][89][90]. In some patients, there is severe disruption of the diaphragm myofibrils with degeneration and large vacuoles of glycogen evident on post-mortem studies [89][90][91].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the neuromuscular junctions of Pompe mouse models have irregular distribution of acetylcholine receptor clusters as well as limited colocalization of presynaptic and post synaptic labels [46,64]. Similarly, post-mortem studies of LOPD and IPD patients reveal glycogen accumulation and swelling in neurons in the anterior horns of the spinal cord [49,84,86,[93][94][95]. In addition, post-mortem phrenic nerve analysis in an LOPD patient case revealed abnormal glycogen accumulation in Schwann cells [88].…”

Section: Discussionmentioning

confidence: 99%

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The Respiratory Phenotype of Pompe Disease Mouse Models

Fusco

McCall

Dhindsa

et al. 2020

IJMS

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Pompe disease is a glycogen storage disease caused by a deficiency in acid α-glucosidase (GAA), a hydrolase necessary for the degradation of lysosomal glycogen. This deficiency in GAA results in muscle and neuronal glycogen accumulation, which causes respiratory insufficiency. Pompe disease mouse models provide a means of assessing respiratory pathology and are important for pre-clinical studies of novel therapies that aim to treat respiratory dysfunction and improve quality of life. This review aims to compile and summarize existing manuscripts that characterize the respiratory phenotype of Pompe mouse models. Manuscripts included in this review were selected utilizing specific search terms and exclusion criteria. Analysis of these findings demonstrate that Pompe disease mouse models have respiratory physiological defects as well as pathologies in the diaphragm, tongue, higher-order respiratory control centers, phrenic and hypoglossal motor nuclei, phrenic and hypoglossal nerves, neuromuscular junctions, and airway smooth muscle. Overall, the culmination of these pathologies contributes to severe respiratory dysfunction, underscoring the importance of characterizing the respiratory phenotype while developing effective therapies for patients.

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Long term survival in patients with classic infantile Pompe disease reveals a spectrum with progressive brain abnormalities and changes in cognitive functioning

van den Dorpel,

Mackenbach,

Dremmen

et al. 2024

J of Inher Metab Disea

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The aim of this longitudinal cohort study, is to provide more insight into the pattern of brain abnormalities, and possible consequences for cognitive functioning, in patients with classic infantile Pompe disease. We included 19 classic infantile Pompe patients (median age last assessment 8.9 years, range 1.5–22.5 years; 5/19 CRIM negative), treated with ERT. Using MR imaging of the brain (T1, T2, and FLAIR acquisitions), we classified progression of brain abnormalities on a 12‐point rating scale at multiple time points throughout follow‐up. Additionally we noted specific white matter patterns and examined atrophy. Cognitive development was studied using Wechsler IQ assessments obtained by certified neuropsychologists. The association between age and cognitive functioning, and MRI ratings and cognitive functioning was assessed by linear regression models. All but one patient developed brain abnormalities. The abnormalities progressed in a similar pattern throughout the brain, with early involvement of periventricular white matter, later followed by subcortical white matter, gray matter structures, and juxtacortical U‐fibers. We found a significant decline (p < 0.01), with increasing age for full scale IQ, performance IQ and processing speed, but not for verbal IQ (p = 0.17). Each point increment in the 12‐point MRI rating scale was associated with a significant decline (3.1–6.0 points) in all the IQ index scores (p < 0.05). The majority of long‐term surviving patients in our cohort develop incremental brain MRI abnormalities and decline in cognitive functioning. This highlights the need for new therapies that can cross the blood–brain barrier in order to treat this CNS phenotype.

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Postmortem Findings and Clinical Correlates in Individuals with Infantile-Onset Pompe Disease

Abstract: Pompe disease (OMIM 232300), a glycogen storage disorder caused by deficiency in the lysosomal enzyme acid alpha-glucosidase (EC 3.2

Cited by 41 publications

References 34 publications

Classic infantile Pompe patients approaching adulthood: a cohort study on consequences for the brain

Classic infantile Pompe patients approaching adulthood: a cohort study on consequences for the brain

The Respiratory Phenotype of Pompe Disease Mouse Models

Long term survival in patients with classic infantile Pompe disease reveals a spectrum with progressive brain abnormalities and changes in cognitive functioning

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