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Review
. 2018 Oct;14(10):606-617.
doi: 10.1038/s41582-018-0057-0.

Lafora disease - from pathogenesis to treatment strategies

Affiliations
Review

Lafora disease - from pathogenesis to treatment strategies

Felix Nitschke et al. Nat Rev Neurol. 2018 Oct.

Abstract

Lafora disease is a severe, autosomal recessive, progressive myoclonus epilepsy. The disease usually manifests in previously healthy adolescents, and death commonly occurs within 10 years of symptom onset. Lafora disease is caused by loss-of-function mutations in EPM2A or NHLRC1, which encode laforin and malin, respectively. The absence of either protein results in poorly branched, hyperphosphorylated glycogen, which precipitates, aggregates and accumulates into Lafora bodies. Evidence from Lafora disease genetic mouse models indicates that these intracellular inclusions are a principal driver of neurodegeneration and neurological disease. The integration of current knowledge on the function of laforin-malin as an interacting complex suggests that laforin recruits malin to parts of glycogen molecules where overly long glucose chains are forming, so as to counteract further chain extension. In the absence of either laforin or malin function, long glucose chains in specific glycogen molecules extrude water, form double helices and drive precipitation of those molecules, which over time accumulate into Lafora bodies. In this article, we review the genetic, clinical, pathological and molecular aspects of Lafora disease. We also discuss traditional antiseizure treatments for this condition, as well as exciting therapeutic advances based on the downregulation of brain glycogen synthesis and disease gene replacement.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Fig. 1 |
Fig. 1 |. Causative mutations in Lafora disease.
EPM2A and NHLRC1 encode laforin and malin, respectively. Both genes are located on chromosome 6. Laforin contains an amino- terminal family 20 carbohydrate-binding module (CBM20) and a carboxy-terminal dual-specificity phosphatase (DSP) domain. Malin contains RING and NHL domains, which are typical for E3 ubiquitin ligases. Mutations — usually missense, nonsense or frameshift — in either of the two genes cause Lafora disease.
Fig. 2 |
Fig. 2 |. Impaired glycogen metabolism in Lafora disease.
a | The chemical basis of the polyglucans glycogen and starch. Glucan chains are formed by chain-elongating enzymes that incorporate glucosyl residues at terminal glucosyl C4 carbons of pre-existing chains, forming α−1,4 glycosidic linkages. Branching points are introduced by branching enzymes that cleave part of an existing chain, which is then reattached to form an α−1,6 glycosidic linkage. b | Laforin and malin act as a complex to prevent the accumulation of insoluble glycogen. In the absence of functional laforin or malin, normally soluble glycogen contains abnormally long chains and precipitates and aggregates as Lafora bodies, which drive Lafora disease progression. c | Glycogen metabolism. Glycogen is synthesized from glycogenin-containing glycogen primers by the concerted action of glycogen synthase (GS) and glycogen branching enzyme (GBE). This well-balanced reaction determines glycogen chain length and, hence, represents the pivot of glycogen structure. BOX 2 provides a more detailed explanation of glycogen metabolism. AGL, glycogen debranching enzyme; GAA, lysosomal α-giucosidase; GP, glycogen phosphorylase. Part a adapted with permission from REF, Elsevier. Part c adapted with permission from REF, CC-BY-4.0.
Fig. 3 |
Fig. 3 |. Mechanistic model for Lafora body formation and accumulation.
a | Glycogen is a heterogeneous mixture of molecules that differ in their long glucan chain content and possess different risks of precipitation. To prevent precipitation, a small proportion of molecules that are precipitation-prone (circled in red) might be modified by local reduction of chain elongation, which is achieved by the mechanism explained in part c. This modification leads to an increased relative branching frequency and a decreased risk of precipitation (horizontal arrow). b | If glycogen precipitation cannot be entirely prevented, precipitated glycogen accumulates over time, as observed in Lafora disease mice of different ages. Arrows indicate some typical Lafora bodies in diastase-resistant periodic acid-Schiff-stained sections of mouse hippocampus. c | A functional iaforin-maiin complex mediates a reduction in glycogen synthase (GS) activity by targeting GS and protein phosphatase 1 (PP1) subunit R5 to degradation, resulting in an increased branching frequency. Rather than affecting the entire GS protein population, this process might occur locally, that is, predominantly on the small proportion of glycogen molecules with a high risk of precipitation (red circle in part a). Parts a and c adapted with permission from REF, CC-BY-4.0.
Fig. 4 |
Fig. 4 |. Diagnosis of Lafora disease.
a | A 16 s EEG trace in an awake patient with Lafora disease (compound heterozygous for EPM2A: Arg241X and Pro211Leu) at age 20 years, 5 years into the disease. Note the slow background rhythms and generalized irregular spike-wave discharges associated with myoclonus. At this age, the patient was still conversant, but each thought and sentence was interrupted by myoclonic absences. b | EEG in the same patient at age 28 years in an unresponsive wakeful state. Grey shaded areas in parts a and b denote patient movements: 1, arm jerk; 2, head jerk; 3, head and arm jerk; 4, twitch; and 5, eyes upward and blinking. c | Skin biopsy in the same patient at age 20 years. Arrows indicate Lafora bodies in the myoepithelium of apocrine glands.The equally stained structures near the lumina of the glands are not Lafora bodies but the normal secretory materials of these cells. Owing to a lack of experience with the disease, many laboratories mistake these materials for Lafora bodies, leading to false-positive diagnoses. ECG, electrocardiogram
Fig. 5 |
Fig. 5 |. Overview of therapeutic strategies in Lafora disease.
In addition to the viral delivery of functional laforin or malin, the therapeutic options for Lafora disease include intracellular degradation of Lafora bodies by glucan-degrading enzymes such as α-amylase, as well as the downregulation of glycogen synthesis by targeting glycogen synthase (GS) or protein phosphatase 1 (PP1) subunit R5 at the gene, RNA or protein level. ASOs, antisense oligonucleotides; RNAi, RNA interference.

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