Knowledge on rare diseases and orphan drugs

Lafora disease is ultrarare, with an estimated frequency of < 1 case per million individuals in the world. Prevalence rates are the highest in Mediterranean countries as well as North Africa, the Middle East, and some regions of Southern India.

Onset typically occurs during late childhood or adolescence, with generalized tonic-clonic seizures, myoclonus, and often focal occipital seizures with visual symptoms. Seizures gradually become difficult-to-treat and worsen, leading to episodes of status epilepticus. Myoclonus is a key feature and may present as myoclonic seizures but also as resting, action, and stimulus-induced myoclonus, becoming almost continuous in the advanced stages of the disease. Ataxia contributes to motor disability. Cognitive decline is invariably present; it manifests initially with school difficulties and progresses to dementia.

Lafora disease is caused by biallelic mutations in the EPM2A or NHLRC1 (also known as EPM2B) genes, encoding the proteins laforin and malin, respectively, which are implicated in glycogen metabolism. Loss of function of either protein results in the build-up of insoluble polyglucosan aggregates known as Lafora bodies in different organs. Neurodegeneration and clinical manifestations are primarily due to the accumulation of Lafora bodies in the brain.

At onset, the electroencephalogram (EEG) has a normal background, with generalized and, often, focal occipital epileptiform discharges that may be activated by photic stimulation. With time, the EEG background slows, and epileptiform abnormalities increase in prevalence becoming abundant or subcontinuous. Brain MRI is often unremarkable or shows variable degrees of cerebral and cerebellar atrophy. Brain FDG-PET can reveal extensive areas of decreased glucose metabolism that may correlate with disease progression. Targeted genetic testing of EPM2A and NHLRC1 is currently the reference standard to confirm the diagnosis in suspected cases. Biopsy of skin or other tissues might reveal Lafora bodies, but is fraught with false positive and false negative results.

At onset, Lafora disease may mimic juvenile myoclonic epilepsy, which does not have a progressive course. In later disease stages, the clinical picture becomes quite characteristic, facilitating diagnosis. Atypical cases with slow progression may be confused with Unverricht-Lundborg disease.

Prenatal testing is possible for families in which the diagnosis has been confirmed by molecular testing.

Genetic counseling is recommended to inform parents of the autosomal recessive inheritance pattern; if both parents are carriers there is a 25% chance with each pregnancy that their child will develop the condition, a 50% chance that their child will be a carrier, and a 25% chance that their child will not be a carrier or have the condition.

There is currently no cure for Lafora disease; antiseizure medications are used to manage both seizures and myoclonus. Psychological and social support is also essential for patients and their families. Metformin appears to slow disease progression. Various etiological therapies that may alter the course of Lafora disease are being developed, including gene or antisense oligonucleotide therapies and antibody-enzyme conjugates that can break down Lafora bodies.

Loss of autonomy usually occurs in late adolescence and death in young adulthood; half of the patients lose autonomy within 6 years and die within 11 years of disease onset. Death commonly results from status epilepticus or aspiration pneumonia and other complications of chronic neurodegeneration. Certain genetic variants can impact the prognosis and lead to either a more rapidly or slowly progressive form of the disease.

Last update: October 2024 - Expert reviewer(s): Pr Francesca BISULLI | EpiCARE* - Dr Ieva MICULE | EpiCARE* - Dr Lorenzo MUCCIOLI | EpiCARE* - Dr José SERRATOSA FERNÁNDEZ | EpiCARE*

* European Reference Network