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Lafora Disease
Introduction
Progressive myoclonic epilepsies are rare genetic disorders that most frequently present in late childhood or adolescence but can be seen in all age groups from infancy to adulthood. Conversely, epileptic encephalopathies start with polymorphic seizures in early infancy. These epilepsies are associated with progressive myoclonus, epileptic seizures, dementia ataxia, and, in the worst cases, death.[1] Progressive myoclonic epilepsies include Unverricht-Lundborg disease, Lafora disease, neuronal ceroid lipofuscinoses, sialidosis type I, myoclonus epilepsy, ragged red fibers (MERRF), Gaucher disease type 3, dentatorubral-pallidoluysian atrophy, and other rare progressive myoclonic epilepsies.[2][3][4]
Lafora disease is a severe, autosomal recessive, progressive myoclonus epilepsy commonly observed in previously healthy adolescents, with death occurring within 10 years of symptom onset. Genetic research has identified many hereditary etiologies, and others are expected to be found. In Lafora disease, the main cause is the loss-of-function mutations in EPM2A and NHLRC1 that encode laforin and malin, respectively. Lack of either protein results in poorly branched, hyperphosphorylated glycogen that precipitates, aggregates, and accumulates into Lafora bodies.[5] The presence of the pathognomic Lafora bodies in a tissue biopsy is diagnostic of Lafora disease.[6][7]
Characteristic features of Lafora disease include intractable myoclonic and photosensitive seizures, drop attacks, ataxia, apraxia, cortical blindness, rapidly progressive dementia, and neuropsychiatric symptoms. Pathologically, Lafora disease is associated with polyglucosan deposits, also known as Lafora bodies, in the brain, liver, muscles, and sweat glands. This disease is diagnosed through clinical, electrophysiological, histological, and genetic findings. No curative treatments or preventative interventions are available at present for Lafora disease. Management Lafora disease focuses on symptomatic relief of seizures and myoclonus, together with palliative, supportive, and rehabilitative measures. Antiepileptic drugs can be used for the management of myoclonus and seizures. However, patients can become drug-resistant over time, resulting in disease progression, increased seizure frequency, and a decline in neurologic function.[1][8][6][7]
Etiology
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Etiology
Lafora disease is a neurodegenerative disease with autosomal recessive inheritance. Heterozygotes are asymptomatic. EPM2A on chromosome 6q24.3 and EPM2B (ie, NHLRC1) on chromosome 6p22.3 are the known underlying genes leading to deficiencies in laforin and malin, respectively. They seem to contribute almost equally to the pathogenic variants. Most pathogenic variants have mutations resulting in a loss of function, including splice site mutations, missense mutations, nonsense deletions, small intragenic deletions, and insertion mutations.[5][9][10]
One study reviewed the function of laforin-malin as an interacting complex, suggesting that laforin recruits malin to parts of glycogen molecules where overly long glucose chains form to counteract further chain extension. Lack of either laforin or malin function may lead to water extrusion due to long glucose chains in specific glycogen molecules that extrude water, formation of double helices, and precipitation of those molecules, which accumulated into Lafora bodies over time.[11]
Other studies have found that many EPM2A variants were associated with late-onset or slower disease progression. Distinct functional classes were related to different outcomes, such as F321C and G279C mutations, which have attenuated functional defects and are associated with slow progression. This pipeline allowed rapid identification and classification of newly identified EPM2A mutations, which can guide clinicians and researchers on the genetic information in developing treatment of Lafora disease patients.[12] Another study characterized the EPM2A gene mutations in a patient with a slow progression form of Lafora disease. Findings also revealed severe impairment in the interaction with identified laforin-binding partners previously, which could indicate that the slow progression of Lafora disease present was either due to the specific biochemical properties of laforin N163D or to the presence of alternative genetic modifying factors separate from pathogenicity.[13]
Since Lafora disease results from mutations in the gene encoding either the glycogen phosphatase laforin or the E3 ubiquitin ligase malin, patients develop cytoplasmic, aberrant glycogen inclusions in nearly all tissues that more closely resemble plant starch than human glycogen.[14] PRMD8 is a recently discovered gene associated with Lafora disease that codes for a protein responsible for laforin and malin translocation to the nucleus, and the mutated form causes laforin and malin deficiency within the cytoplasm. This gene mutation is associated with early-onset Lafora disease.
Epidemiology
Most patients diagnosed with Lafora disease are from the Mediterranean (e.g., Spain, France, and Italy), Northern African, or Central Asian (eg, India and Pakistan) regions. The disease has been found in >250 families worldwide, resulting from EPM2A, responsible for laforin, and EPM2B, responsible for E3 ubiquitin-protein ligase NHLRC1 mutations. The prevalence is estimated to be 4 cases per 1,000,000 individuals; however, the number of misdiagnosed and undiagnosed patients may be higher, especially in developing countries.
The epidemiology of Lafora disease in Germany was studied to characterize the genotypes and phenotypes of Lafora disease patients. This revealed patients with the novel variants had typical disease onset during adolescence and manifested classical disease courses. The findings also help approximate the prevalence of Lafora disease in Germany to 1.69 per 10 million people.[15]
Pathophysiology
Glycogen synthesis plays a crucial role in disposing of excess glucose. The degradation of excess glucose is vital for providing energy during exercise and times of need. The significance of glycogen metabolism is also underlined by human genetic disorders caused by enzyme mutations and disruptions that may result in liver, muscle, heart, kidney, and brain dysfunction. In progressive Lafora disease, patients accumulate inclusion bodies in several tissues containing glycogen with increased phosphorylation, longer chain lengths, and irregular branch points. This accumulation becomes toxic to neurons, resulting in cell death.[16] The impairment in the role of glycogenolysis in neural functioning is also observed in Lafora disease. Determining glycogenolysis alterations can be made mainly through DNA analysis and electron microscopy of the liver and skeletal muscle biopsies.[17]
In typical individuals, malin, an E3 ubiquitin ligase, binds laforin, a dual specificity protein phosphatase, and interacts in a cellular pathway that protects against intracytoplasmic polyglucosan accumulation. Mutations in EPM2A and EPM2B (NHLRC1) genes that encode those proteins could lead to Lafora disease. Defects in the cellular clearance systems and autophagic processes are thought to lead to the accumulation of glycogen-derived particles within the cytoplasms, known as Lafora bodies. These insufficiently branched and long-chained glycogen form and precipitate into insoluble polyglucosan bodies called Lafora bodies, which leads to neuroinflammation, neurodegeneration, and epilepsy.[18]
The distinctive morphological feature of Lafora disease is the presence of polyglucosane bodies or Lafora bodies in brain tissue, myocardium, liver, or epithelium of the sweat gland ducts. The diagnosis of Lafora disease was confirmed in studies by genetic analysis by the presence of a homozygous mutation in the second exon of the EPM2A gene laforin (chr6:146007412G>A, rs137852915).[19] Studies have also indicated that Lafora bodies are present in astrocytes. Blocking glycogen synthesis in astrocytes impedes Lafora body accumulation and prevents the increase in neurodegeneration markers, autophagy impairment, and metabolic changes. These results revealed the deleterious consequences of the deregulation of glycogen metabolism in astrocytes, changing the belief that neuron alterations solely cause Lafora disease.[20]
A study revealed evidence of the decreased amount of phosphatidylinositol-3P, possibly caused by defective regulation of the autophagic PI3KC3 complex in the absence of a functional laforin-malin complex. It also demonstrated that the laforin-malin complex interacts physically and colocalizes intracellularly with core components of the PI3KC3 complex (ie, beclin1, vps34, and vps15. This interaction is specific and results in the polyubiquitination of these proteins. There was also polyubiquitination of the ATG14L and UVRAG in the laforin/malin complex. Lastly, the study showed that overexpression of the laforin-malin complex increased PI3KC3 activity.[21]
Another study used mitochondrial uncouplers and respiratory chain inhibitors to investigate human fibroblasts as a possible alteration in the selective degradation of damaged mitochondria, or mitophagy, in Lafora disease. Results showed partial impairment in the induced mitochondrial degradation in the dysfunctional mitochondria of Lafora disease fibroblasts due to a partial defect in the autophagic response but not in the canonical mitophagy signaling pathways.[22]
A case study collected Lafora disease cases for diagnosis and confirmed the genetic spectrum of a family. Furthermore, whole-exome sequencing of the pedigree was conducted for molecular diagnosis. Results showed that a novel biallelic compound heterozygous c.333dupC chr6-18122504 (p.[Gly112ArgfsTer44]) and c.612dupT chr6-18122225 (p.[Gly205Trpfs*29]) mutation in the NHLRC1 gene was elucidated in the progressive myoclonic epilepsy of Lafora pedigree. This means that genetic analysis was helpful in the diagnosis of Lafora disease. Moreover, genetic analysis with alternative tissue biopsy was recommended for patients and close relatives.[23]
History and Physical
Clinical Features
Lafora disease is a severe form of progressive myoclonic epilepsy manifested by generalized seizures, myoclonus, intellectual decline, ataxia, spasticity, dysarthria, visual loss, and, in later stages, psychosis and dementia.[24] Most patients are asymptomatic until adolescence, but they undergo first insidious, then rapid progressive myoclonus epilepsy toward a vegetative state and death within a decade.[7] Patients usually present between the ages of 11 and 18 years. Progression of the disease varies, but total disability or death usually occurs within 10 years of symptom onset due to complications of central nervous system (CNS) degeneration and status epilepticus. Generally, the course of Lafora disease is progressive and characterized by increasing frequency and intractability of seizures. Status epilepticus with any of the previously mentioned seizure types is common. Cognitive decline and dementia, as well as dysarthria, usually start early in the disease. Spasticity may be evident in the late stages and associated with neuropsychiatric symptoms, including behavioral changes, depression, and apathy.
Myoclonus is usually the reason for early disability and wheelchair dependency. Myoclonus, which becomes progressive, continuous, generalized, and challenging to control over time, can be symmetric, asymmetric, partial, or generalized. Myoclonus can occur at rest but usually disappears with sleep and is worsened by action, photic stimulation, or emotional excitement. Both losses of tone and myoclonus can occur. Massive myoclonus with relative preservation of consciousness has also been reported. The main seizure types associated with Lafora disease include myoclonic seizures and occipital seizures. However, generalized tonic-clonic seizures, atypical absence seizures, atonic, and complex partial seizures may occur. Occipital seizures may present as transient blindness, simple or complex visual hallucinations, photo myoclonic, or convulsive photoresponses. Seizures can also present as a migraine with scintillating scotomata.
Evaluation
Diagnostic Studies
Periodic acid-Schiff stain and the presence of polyglucosan particles are pathognomonic for Lafora disease. Additionally, Lafora bodies usually accumulate in the skin, muscle, liver, and brain tissues of patients with Lafora disease. Therefore, the diagnosis can be confirmed by performing a biopsy from any of these organs. Still, the most commonly used and accessible site with high yield is the axillary skin region.[25][26] Histopathologic examination of affected tissue with the demonstration of Lafora bodies and pathologic mutation in EPM2A or NHLRC1 genes is adequate for diagnosing Lafora disease when clinically suspected. However, a case report on a patient with progressive neurologic symptoms and homozygous mutation in the NHLRC1 gene encoding malin revealed that skin biopsy was vital in making the final diagnosis by demonstrating Lafora bodies in sweat glands by histopathologic and electron microscopic examination.[27]
Genetic analysis helps diagnose Lafora disease if consanguinity or Lafora bodies are observed. A case was reported on siblings with progressive myoclonus epilepsy whose parents were not consanguineous. Their clinical symptoms were typical of Lafora disease. However, skin biopsies were negative for Lafora bodies. Also, whole-exome sequencing revealed a recurrent homozygous frameshift variant in the NHLRC1 gene in the patients.[28]
Electroencephalogram (EEG) in the early stages of the disease may be normal or show generalized slowing and loss of posterior dominant rhythm. With the progression of the disease, asymmetric, irregular, generalized spikes, and polyspikes, maximum over the anterior regions associated with photosensitivity on a slowed background can be seen. In the later stages of the disease, myoclonic jerks become almost continuous. EEG usually will show paroxysms of generalized and fast irregular spike-and-wave discharges, exaggerated by photic stimulation at low frequency. These paroxysms are predominantly occipital. Other electrophysiological studies may also be abnormal in Lafora disease, especially visual evoked potentials demonstrating increased latencies or no response. Somatosensory evoked potentials can reveal aberrant integration of somatosensory stimuli, and giant evoked potentials reflecting cortical hyperexcitability.
One study reviewed the electro-clinical features of Lafora disease among patients with mutations in EPM2A and NHLRC1 genes during the late stage of Lafora disease. All patients manifested with gait ataxia, becoming bedbound with severe dementia. Associated daily symptoms of myoclonus include drug-resistant myoclonic seizures, myoclonic absence, and tonic-clonic seizures with EEG and polygraphic findings revealing diffusely slow activity with epileptiform abnormalities, usually associated with myoclonic jerks. Dominant features are seizure emergencies with motor cluster status epilepticus and medical complications. Other significant complications identified include dysphagia, aspiration pneumonia, acute respiratory failure, sepsis, immobility, and spasticity with bedsores.[29]
Imaging Studies
Neuroimaging, including brain magnetic resonance imaging (MRI), usually has normal findings at the time of diagnosis; however, fluorodeoxyglucose positron emission tomography (FDG-PET) had positive findings in 2 reported cases of Lafora disease with posterior hypometabolism early in the disease. Cerebral glucose metabolism patterns, as assessed by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), found that FDG-PET seemed highly sensitive to Lafora disease evaluation at any stage and may correlate with disease progression. There are extensive areas of decreased glucose metabolism in Lafora disease, which usually involves the multiple cortical and subcortical regions; the most severely affected areas were demonstrated to be the thalamus, temporal, frontal, and parietal lobes.[30] The generation and characterization of laforin nanobodies, with a fragment being a laforin inhibitor, were also noted. Their binding epitopes use hydrogen-deuterium exchange (HDX) mass spectrometry. The studies concluded that the generated and characterized laforin nanobodies, with 1 nanobody being a laforin inhibitor, are vital tools that can open new avenues to define unresolved glycogen metabolism questions.[31]
The retina is an accessible neural tissue that may offer alternative methods to assess neurological diseases quickly and noninvasively. A study was conducted to describe the retina of patients with Lafora disease using noninvasive retinal imaging. Findings revealed that patients with previous seizure activity demonstrated reduced retinal thickness. Nummular reflectivity at the retinal nerve fiber layer level was observed using adaptive optics scanning light ophthalmoscopy in the macula and near the optic nerve head. This phenotype has not been observed previously and may contribute to the characteristic change produced by the neurodegenerative process.[32] Further evidence of early retinal alterations in Lafora disease patients by evaluating retinal cone and rod dysfunction among Lafora disease patients was done in another study. Analysis revealed a global mild to severe generalized cone dysfunction in all patients. Therefore, the cone and rod dysfunction grade is related to disease duration. At the same time, a full-field electroretinogram was found to be an essential modality in identifying the disease stage, allowing the evaluation of either natural or treatment-related disease progression minimally invasively.[33]
Treatment / Management
Unfortunately, there is no cure available for Lafora disease. Management is supportive, targeting seizure control and improving the patient's functional status. Given the diversity of seizure types (eg, generalized tonic-clonic seizures), a wide spectrum of antiepileptic drugs, including levetiracetam, sodium valproate, topiramate, and benzodiazepines, are usually considered.[34][35][6]
Seizure Management
Valproate is the monotherapy treatment of choice, with a dosage ranging from 15 to 60 mg/kg, depending on the clinical response. However, valproate should be avoided in patients with suspected mitochondrial disorders due to the inhibition of cytochrome C oxidase (complex IV), leading to decreased respiratory chain activity and carnitine uptake in addition to high ammonia blood levels. Clonazepam is effective in treating myoclonic seizures and can be used in Lafora disease, usually as add-on therapy, at dosages ranging from 3 to 16 mg/day.
Phenobarbital is another wide-spectrum antiepileptic drug that can be used in Lafora disease. The dosage ranges from 3 to 8 mg in children and 30 to 200 mg in adults. Phenobarbital should be used with caution when added to valproate to avoid toxicity. Piracetam, a pyrrolidone derivative, is another effective medication for myoclonus with few adverse effects and a favorable tolerability profile. It has long been used for patients with progressive myoclonic epilepsies. A double-blinded, placebo-controlled trial of 20 patients with Unverricht-Lundborg disease showed significantly reduced myoclonic jerks and improved gait, particularly with dosages close to 24 g daily. A linear dose-effect relationship was also established in this study.
Levetiracetam is a potent wide-spectrum antiepileptic drug with few adverse effects. Like piracetam, levetiracetam is another pyrrolidone derivative that binds and stimulates synaptic vesicle protein 2A, inhibiting neurotransmitter release. The efficacy of levetiracetam, particularly in the treatment of generalized seizures and myoclonus, has been demonstrated in multiple studies and case series of patients with progressive myoclonic epilepsies. In a study involving 23 patients with Unverricht-Lundborg disease, clinical improvement was seen in over two-thirds of the patients on dosages ranging from 1000 to 4000 mg daily. Brivaracetam is a novel molecule with the exact mechanism as levetiracetam but at least a 10-fold higher affinity for the synaptic vesicle protein 2A binding site than levetiracetam. Brivaracetam was proposed as a drug with high potential efficacy for myoclonus. In an animal study done on rat models with seizures following cardiac arrest and anoxic brain injury, low-dose brivaracetam of 0.3 mg/kg was superior to 3 mg/kg of levetiracetam in controlling postanoxic seizures. Antiseizure activity for both antiepileptic drugs started 30 minutes following intraperitoneal administration and was maintained for 150 minutes.
Perampanel is a selective, noncompetitive antagonist of a type of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor that is usually used for the treatment of refractory focal onset seizures but is also effective for generalized epilepsy. The effectiveness of perampanel in Lafora disease was demonstrated by 2 case studies where it was used as first-line monotherapy and an add-on medication. In one case, a 15-year-old female with Lafora disease was treated with 10 mg of perampanel as monotherapy. The treatment resulted in a significant and dramatic decrease in seizure frequency and improved neurological and cognitive functioning. The second case was a 21-year-old Turkish female given 8 to 10 mg of perampanel in addition to a regimen that included clonazepam, levetiracetam, piracetam, valproate, zonisamide, a ketogenic diet, and vagal nerve stimulation. This was followed by seizure remission for more than 3 months and was associated with decreased epileptiform discharges on EEG.
Topiramate is another wide-spectrum antiepileptic drug composed of a sulfamate-substituted monosaccharide molecule, usually used for the treatment of refractory focal seizures as well as generalized seizures. The beneficial use of topiramate for seizure treatment in patients with progressive myoclonic epilepsies and Lafora disease stems primarily from case studies. Effectiveness in treating myoclonus and myoclonic seizure was demonstrated when used as add-on therapy. In another study, 5 out of 8 patients with progressive myoclonic epilepsy improved after adding topiramate to their antiepileptic drug regimen with myoclonic seizures and functional capacity improvement. However, topiramate efficacy tended to decrease over time, and the drug was discontinued in 2 out of 5 patients because of a rapid increase in cognitive impairment and vomiting.
Zonisamide, a sulfonamide derivative chemically distinct from any previously established antiepileptic drugs, is indicated for the treatment of refractory partial epilepsy but is also useful for a variety of generalized epilepsies, including epileptic encephalopathies, including Lennox-Gastaut and West syndromes. Some case reports, and small studies have suggested that zonisamide may be effective in treating patients with progressive myoclonic epilepsy. In long-term observation and clinical follow-up of a brother and a sister with Lafora disease who had resistant, repeated attacks of severe myoclonus, tonic, and tonic-clonic seizures, the use of oral zonisamide as add-on therapy resulted in dramatic seizure control for about 12 to 14 years in both patients, not only for myoclonus but generalized tonic-clonic seizures as well. More specifically, almost all patients with Unverricht-Lundborg disease who were treated with zonisamide as add-on therapy using dosages of up to 6 mg/kg per day showed a dramatic reduction in myoclonus and a marked improvement in generalized tonic-clonic seizures and functional capacity. However, efficacy tended to decrease over time.
Lamotrigine was noted as an effective treatment for infantile and juvenile neuronal ceroid lipofuscinosis. The use of lamotrigine, in addition to medications that affect gamma-aminobutyric acid neurotransmitters (eg, vigabatrin and tiagabine), could exacerbate myoclonus in patients with juvenile myoclonic epilepsy. Such exacerbation was also observed in 5 patients with Unverricht-Lundborg disease; therefore, the use of lamotrigine in progressive myoclonic epilepsies can be avoided. Clinicians also advised patients to avoid using other sodium channel blockers (eg, phenytoin, carbamazepine, and oxcarbazepine) for the same reason.
Video-EEG and polygraphic recordings in one study showed that status epilepticus with prominent motor symptoms of different subtypes is refractory to new intravenous antiseizure medications and responsive to intravenous phenytoin in patients with EPM2A mutations. Moreover, coordinated and multidisciplinary management of the patients with EPM2A mutations decreased seizure emergencies, medical complications, and days of hospitalization and a prolongation of the years of disease compared to those patients with NHLRC1 mutations.[29]
Alternative Seizure Therapies
Vagal nerve stimulation effectively reduces the seizure frequency in a few cases of Lafora disease. A low carbohydrate-high cholesterol ketogenic diet was proven effective in a variety of refractory epilepsies, including infantile myoclonic seizures and Lennox-Gastaut syndrome; however, this diet was shown to be ineffective in treating Lafora disease. In 5 patients in an Italian study, a ketogenic diet was unable to stop the disease progression.
Metformin consists of biguanide compounds widely used in type 2 diabetes treatment. Researchers in a study focused on the beneficial effects of metformin as a neuroprotective agent, especially among epileptic disorders and Lafora disease.[36] Recent works analyzed whether early treatment with metformin from conception to adulthood enhances the formation of Lafora bodies, improves the behavioral and neurological outcomes observed with late treatment, and evaluated the benefits of metformin in patients with Lafora disease. Findings revealed that early metformin was more effective than late metformin in Lafora disease, which improves neurological alterations like neuronal hyperexcitability, motor and memory alterations, neurodegeneration, and astrogliosis and decreases the formation of Lafora bodies. There was also a slow progression of the disease and slower deterioration of their daily living activities among patients receiving metformin had a slower progression of the disease.[37] (B3)
Another study collected data on patients with Lafora disease referred by Italian epilepsy centers. Findings from this study showed that metformin was considered safe in the small cohort of Lafora disease patients. Although the poor clinical outcome can be due to the advanced stage of the disease, the role of metformin in slowing down Lafora disease progression cannot be excluded. Therefore, based on the preclinical data, the authors believed that metformin treatment may be administered as early as possible among Lafora disease patients.[38]
Pharmaceutical research explored the use of antibodies as targeting molecules or cell-penetrating tools. Antibody-directed therapies such as antibody-drug conjugates, immune modulators, and antibody-directed enzyme prodrugs were used extensively as a treatment for hematological, rheumatological, and oncological cases. Recently, this technology was used to treat glycogen storage disorders via an antibody-enzyme fusion platform to penetrate cells and deliver an enzyme to the cytoplasm, nucleus, and other organelles. This development may contribute to the management of patients with Lafora disease.[39]
Another study developed novel cationic liposomes as a nonviral gene delivery vector for treating Lafora disease. DLinDMA (1,2-dilinoleyloxy-3-dimethylaminopropane) and DOTAP (1,2-dioleoyl-3-trimethylammonium-propane) liposomes were designed and characterized for the delivery of gene encoding laforin and expression of functional protein in HEK293 and neuroblastoma cells. Findings revealed good physicochemical characteristics of liposomes with cationic lipids DLinDMA and DOTAP. Furthermore, nanosized DLinDMA liposomes showed desired transfection efficiency, negligible hemolysis, and minimal cytotoxicity. Western blotting confirmed successful expression, and the biological activity of laforin was determined through glucan phosphatase assay. Therefore, the study made a novel preclinical effort in formulating cationic lipoplexes with plasmid DNA for Lafora disease therapy.[40]
Differential Diagnosis
Other conditions that should be considered during Lafora disease evaluation include:
- Juvenile myoclonic epilepsy: Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome described as bilateral myoclonic and tonic-clonic seizures typically starting in adolescence and responding well to medication. Drug resistance can be the cause of the misdiagnosis of more severe progressive myoclonus epilepsy.[41]
- Myoclonic epilepsy with ragged red fibers
- Schizophrenia
- Sialidosis
- Subacute sclerosing panencephalitis
- Unverricht-Lundborg disease: Unverricht-Lundborg disease is the most common form of progressive myoclonus epilepsy characterized by myoclonus, generalized seizures, intellectual disability, ataxia, and dysarthria. EEG shows a posterior dominant rhythm with alpha variant, mild bilateral slowing, and anterior-predominant epileptiform abnormalities. Brain MRI often reveals mild cerebellar atrophy, and FDG-PET demonstrates hypometabolism to be more prominent in the posterior brainstem, thalami, frontal lobes, and parietal lobes.[41]
Pearls and Other Issues
Clinicians should keep some key factors in mind when managing Lafora disease. Lafora disease is an autosomal recessive disorder. Siblings have a 50% chance of being carriers and a 25% chance of having the disease. Therefore, genetic counseling for families is essential as prenatal testing and diagnosis is possible. Furthermore, Lafora disease affects previously healthy children or adolescents and causes resistance to antiepileptic drugs together with myoclonus and severe psychomotor deterioration. The mean survival rate was 11 years, while the median loss of autonomy was 6 years. Asians were found to have an age at onset of less than 18 years and emerged as negative prognostic factors, while the type of mutated gene and symptoms at onset were not related to survival or disability. The information on actual survival rates and prognostic factors can be a critical factor in designing studies on the effectiveness of upcoming new disease-modifying therapies.[42] Additionally, understanding the mechanisms underlying the pathogenesis of Lafora disease is crucial for developing appropriate treatment strategies. Lafora disease remains a disabling and potentially lethal condition that would undoubtedly benefit from more in-depth research and advancement in epilepsy therapy.
Enhancing Healthcare Team Outcomes
Management of Lafora disease is primarily supportive, targeting seizure control and improving the patient's functional status. The interprofessional approach to managing Lafora disease involves collaboration among physicians, advanced practitioners, nurses, pharmacists, and other health professionals. Neurologists and pediatricians lead patient management, focusing on supportive care for seizures. Pharmacists educate caregivers on the adverse effects of medications and compliance. Nurses play a crucial role in follow-ups, monitoring compliance, and identifying adverse reactions. Dietary consults may offer additional support, while geneticists provide counseling on screening for affected family members. This collaborative effort ensures patient-centered care, enhances outcomes, promotes safety, and optimizes team performance in addressing the complexities of Lafora disease.
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Level 1 (high-level) evidence