Progressive Myoclonus Epilepsy as an Inborn Error of Metabolism Comparable to Storage Disease

Edgar, G. W. F.

doi:10.1111/j.1528-1157.1963.tb05215.x

Cited by 32 publications

(6 citation statements)

References 16 publications

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“…S3D). Similar PAS-positive granular material has been reported in fixed tissue sections from patient brain biopsies or LD mice, which are referred to as dust-like particles, or simply "dust" (40,(58)(59)(60).…”

Section: Isolation and Characterization Of Lbs From Ld Micesupporting

confidence: 58%

“…S3E. LBs have been reported in LD patient cardiac tissue: in fixed and stained tissue sections, they are irregularly shaped or elongated with pointed ends (59,(61)(62)(63). Although these reports do not discuss dust-like particles in the heart, they appear to be present in the micrographs, particularly in the studies that involve immunostaining with an LB-specific antibody (61,62).…”

Section: Isolation and Characterization Of Lbs From Ld Micementioning

confidence: 99%

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Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion

Brewer

Uittenbogaard

Austin

et al. 2019

Preprint

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One Sentence Summary: An antibody-enzyme fusion delivering an amylase degrades the toxic polyglucosan bodies that cause Lafora disease, a fatal childhood epilepsy.Abstract: Lafora disease (LD) is a fatal childhood epilepsy and a non-classical glycogen storage disorder with no effective therapy or cure. LD is caused by recessive mutations in the EPM2A or EPM2B genes that encode the glycogen phosphatase laforin and an E3 ubiquitin ligase malin, respectively. A hallmark of LD is the intracellular accumulation of abnormal and insoluble α linked polysaccharide deposits known as Lafora bodies (LBs) in several tissues, including most regions of the brain. In mouse models of LD, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Since multiple groups have confirmed that neurodegeneration and epilepsy result from LB accumulation, a major focus in the field has shifted toward the development of therapies that reduce glycogen synthesis or target LBs for degradation with the goal of treating LD. Herein, we identify the optimal enzymes for degrading LBs, and we develop a novel therapeutic agent by fusing human pancreatic α -amylase to a cellpenetrating antibody fragment. This antibody-enzyme fusion (VAL-0417) degrades LBs in vitro, shows robust cellular uptake, and significantly reduces the LB load in vivo in Epm2a-/-mice. VAL-0417 is a promising therapeutic for the treatment of LD and a putative precision therapy for an intractable epilepsy. Antibody-enzyme fusions represent a new class of antibody-based drugs that could be utilized to treat glycogen storage disorders and other diseases. The progressive myoclonic epilepsies (PMEs) are a group of inherited disorders characterized by recurrent seizures, myoclonus, and progressive neurological decline. There are currently no treatments for PMEs, and anti-epilepsy drugs are palliative at best (1). Lafora disease (LD; epilepsy, progressive myoclonus type 2, EPM2) is a severe form of PME that typically manifests with tonic-clonic seizures and myoclonic jerks in the early teen years followed by rapid neurological deterioration, increasingly severe and frequent epileptic episodes, dementia and death within ten years of onset (OMIM: 254780). LD is caused by mutations in the EPM2A or EPM2B genes that encode laforin, a glycogen phosphatase, and malin, an E3 ubiquitin ligase that ubiquitinates enzymes involved in glycogen metabolism (reviewed in (2)). LD is distinguishable from other PMEs by the presence of cytosolic polysaccharide inclusions known as Lafora bodies (LBs) most notably in the brain, where they are found in neuronal cell bodies and dendrites and astrocytic processes, and in other tissues such as muscle, heart, and liver (3-5). Among the PMEs LD is uniquely considered a non-classical glycogen storage disease (GSD) (6, 7). Independent studies from multiple groups demonstrate that Epm2a-/-and Epm2b-/-mice recapitulate disease symptoms with respect to LB formation, neurodegeneration, neurological impairments, and susceptibil...

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Section: Isolation and Characterization Of Lbs From Ld Micesupporting

confidence: 58%

Section: Isolation and Characterization Of Lbs From Ld Micementioning

confidence: 99%

Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion

Brewer

Uittenbogaard

Austin

et al. 2019

Preprint

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Section: Isolation and Characterization Of Lbs From Ld Micementioning

confidence: 60%

“…S3E). LBs have been reported in LD patient cardiac tissue: in fixed and stained tissue sections, they are irregularly shaped or elongated with pointed ends (Edgar, 1963;Van Heycop ten Ham and Jager, 1963;Yokota et al, 1987;Yokota et al, 1988). Although these reports do not discuss dust-like particles in the heart, they appear to be present in the micrographs, particularly in the studies that involve immunostaining with an LB-specific antibody (Yokota et al, 1987;Yokota et al, 1988).…”

Section: Isolation and Characterization Of Lbs From Ld Micementioning

confidence: 99%

Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion

et al. 2019

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“…The observation of a rarc patho-physiological symptom, such as myoclonus, in amaurotic idiocy made us compare the EEG of these cases to those of progressive myoclonus epilepsy described elsewhere (19). This comparison seems the more interesting since there are indications that the latter condition is aiso a type of storage disease (14). In our cases with progressive myoclonus epilepsy (19) the spikes were usually more prominent than in the cases with late-infamtile amaurotic idiocy.…”

Section: Diagnosismentioning

confidence: 61%

Amaurotic Idiocy and Epilepsy

Edgar¹,

Post²

1963

Epilepsia

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SUMMARY The infantile form of amaurotic idiocy or Tay‐Sachs disease is separated from all other forms of amaurotic idiocy on the basis of neuropathological and biochemical aspects. Hexosamine estimations in the grey matter of 7 cases of Tay Sachs disease and of 7 cases of other forms of amaurotic idiocy show that ganglioside accumulation is a specific characteristic of Tay‐Sachs disease. The clinical aspects in 4 patients suffering from late‐infantile amaurotic idiocy, 3 patients suffering from the juvenile form of amaurotic idiocy and 3 patients suffering from abortive or chronic forms of amaurotic idiocy, are compared. Attention is called to the combination of myoclonus, mental disturbance and epilepsy, which characterizes the patients with non‐infantile amaurotic idiocy before the clinical onset of retinal pathology. The neuropathological aspects in 3 patients with juvenile amaurotic idiocy, 1 patient with late‐infantile amaurotic idiocy and 1 patient with chronic amaurotic idiocy without amaurosis are compared to descriptions available in the literature. The significance of epilepsy in amaurotic idiocy is discussed. Epileptic symptomatology is more prominent in amaurotic idiocy, other than Tay‐Sachs disease, than in Tay‐Sachs disease and in other forms of lipidosis. In the absence of a satisfactory anatomical explanation for this observation, it is tentatively suggested that epileptic symptomatology in non‐infantile amaurotic idiocy might be causally related to the error of metabolism, rather than to diffuse neuronal damage of the nervous system. RÉSUMÉ La forme infantile de l'idiotie amaurotique ou maladie de Tay‐Sachs est mise à part de toutes les autres formes d'idiotie amaurotique sur la base de ses aspects neuro‐pathologiques et biochimiques. Les estimations de l'hexosamine dans la substance grise de 7 cas de maladie de Tay‐Sachs et de 7 cas de formes autres d'idiotie amaurotique revelent qu'une accumulation de ganglioside est une caractéristique spécifique de la maladie de Tay‐Sachs. Les aspects cliniques de 4 malades atteints d'idiotie amaurotique infantile tardive, de 3 malades atteints de la forme juvénile d'idiotie amaurotique et de 3 malades présentant une forme abortive ou chronique d'idiotie amaurotique, sont l'objet d'une comparaison. Les auteurs appellent l'attention sur la combinaison de myoclonus, trouble mental et épilepsie, laquelle caractérise les patients ayant une idiotie amaurotique non‐infantile avant le début clinique de la pathologie rétinienne. Les aspects neuropathologiques présentés par 3 enfants atteints d'idiotie amaurotique juvénile, 1 malade ayant une idiotie amaurotique infantile tardive et 1 autre une idiotie amaurotique sans amaurose sont comparés avec des cas publicés dans la littérature. Discussion de la signification de l'épilepsie dans l'idiotie amaurotique. La symp‐tomatologie épileptique est plus importante dans l'idiotie amaurotique autre que la maladie de Tay‐Sachs, que dans la maladie de Tay‐Sachs et autres formes de lipidose. Une explication anatomique satis...

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Progressive Myoclonus Epilepsy as an Inborn Error of Metabolism Comparable to Storage Disease

Cited by 32 publications

References 16 publications

Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion

Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion

Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion

Amaurotic Idiocy and Epilepsy

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