Clinical Signs in 166 Beagles with Different Genotypes of Lafora.

Lafora disease (LD) is a genetic disease affecting beagles, resulting in seizures in combination with other signs. The aim of this study was to describe the clinical signs of LD in beagles with different NHLRC1 genotypes. One hundred and sixty-six beagles were tested for an NHLRC1 gene defect: L/L (n = 67), N/L (n = 32), N/N (n = 67). Owners were asked to participate in a survey about the clinical signs of LD in their dogs. These were recorded for the three possible genotypes in the two age groups, <6 years and ≥6 years. In all genotypes, nearly all the signs of LD were described. In the age group ≥ 6 years, however, they were significantly more frequent in beagles with the L/L genotype. If the following three clinical signs occur together in a beagle ≥ 6 years-jerking of the head, photosensitivity and forgetting things he/she used to be able to do-98.2% of these dogs are correctly assigned to the L/L genotype. If one or two of these signs are missing, the correct classification decreases to 92.1% and 13.2%, respectively. Only the combination of certain signs truly indicates the L/L genotype. Yet, for many dogs, only genetic testing will provide confirmation of the disease.

Lafora progressive myoclonus epilepsy: Disease mechanism and therapeutic attempts.

Lafora disease (LD) is a life-threatening autosomal recessive and progressive neurodegenerative disorder that primarily affects adolescents, resulting in mortality within a decade of onset. The symptoms of LD include epileptic seizures, ataxia, dementia, and psychosis. The underlying pathology involves the presence of abnormal glycogen inclusions in neurons and other tissues, which may contribute to neurodegeneration. LD is caused by loss-of-function mutations in either the EPM2A gene or the NHLRC1 gene. These two genes, respectively, code for laforin phosphatase and malin ubiquitin ligase, and are thought to function, as a functional complex, in diverse cellular pathways. One of the major pathways affected in LD is glycogen metabolism; defects here lead to abnormally higher levels of glycogen and its hyperphosphorylation and aggregation, resulting in the formation of Lafora inclusion bodies. Currently, there is no effective therapy for LD. Studies, particularly from animal models, provide distinct insights into the fundamental mechanisms of diseases and potential avenues for therapeutic interventions. The purpose of this review is to present a comprehensive overview of our current knowledge regarding the disease, its genetics, the animal models that have been developed, and the therapeutic strategies that are being developed based on an understanding of the disease mechanism.

[Lafora disease with a fatal outcome]. / Bolezn' Lafory s letal'nym iskhodom.

Lafora disease is a rare hereditary genetic pathology of the nervous system (a group of progressive myoclonic epilepsies). The distinctive morphological feature of this disease is the presence of specific abnormal structures - polyglucosane bodies («Lafora bodies¼) in the brain tissue, myocardium, liver, and epithelium of the sweat gland ducts. The article discusses the clinical data of the course of Lafora's disease in an 18-year-old patient with a fatal outcome and the results of a post-mortem examination. The diagnosis of Lafora disease was confirmed by genetic analysis data - the presence of a homozygous mutation in the 2nd exon of the EPM2A gene - laforin (chr6:146007412G>A, rs137852915). When analyzing literature, we did not find a description of Lafora's disease cases with a fatal outcome with the presentation of macroscopic examination data at autopsy, as well as the results of a pathohistological examination of altered organ tissues with the morphological manifestations specific for this pathology (Lafora bodies in the the brain, heart, sweat gland epithelium).

Lafora Body Epilepsy: A Challenging Diagnosis.

Lafora body disease (LBD) is a progressive myoclonic genetic epilepsy syndrome characterized by the presence of Lafora inclusion bodies within neurons and other cells. It is a complex neurodegenerative disease presenting in adolescence with seizures, myoclonus, and rapid cognitive decline. Diagnosis is often challenging requiring a thorough history including family history, identification of Lafora bodies in apocrine sweat glands of axillary skin, and specific DNA sequencing. There is no cure and management is mainly supportive. We present one of the only few cases from Pakistan of LBD based on characteristic biopsy findings, history of similar ailment in siblings, and EPM2B mutation. This case emphasizes the need for physicians and neurologists to be aware of diagnostic challenges associated with LBD and its characteristic findings. Key Words: Lafora body, Progressive epilepsy, Myoclonus, Axillary skin biopsy, EPM2B.

Lafora disease: a case report.

BACKGROUND: Lafora disease is a rare genetic disorder involving glycogen metabolism disorder. It is inherited by autosomal recessive pattern presenting as a progressive myoclonus epilepsy and neurologic deterioration beginning in adolescence. It is characterized by Lafora bodies in tissues such as brain, skin, muscle, and liver. CASE PRESENTATION: We report a rare case of Lafora disease in a 16-year-old Albanian girl who presented at a tertiary health care center with generalized tonic-clonic seizures, eyelid twitches, hallucinations, headache, and cognitive dysfunction. She was initially treated for generalized epilepsy and received an antiepileptic drug. However, owing to resistance of seizures to this antiepileptic drug, a second drug was introduced. However, seizures continued despite compliance with therapy, and general neurological status began to deteriorate. The child began to have hallucinations and decline of cognitive function. She developed dysarthria and unsteady gait. When admitted to the hospital, blood tests and imaging examinations were planned. The blood tests were unremarkable. There was no relevant family history and no consanguinity. Electroencephalography showed multifocal discharges in both hemispheres, and brain magnetic resonance imaging revealed no abnormality. Axillary skin biopsy revealed inclusion bodies in apocrine glands. Consequently, the child was referred to an advanced center for genetic testing, which also confirmed diagnosis of Lafora disease with a positive mutation on NHLRC1 gene. CONCLUSIONS:  Even though rare as a condition, Lafora disease should be considered on differential diagnosis in progressive and drug-refractory epilepsy in adolescents, especially when followed by cognitive decline.

[Efficacy of zonisamide in Lafora's disease case and brief review of its use in progressive myoclonic epilepsy]. / Eficacia de la zonisamida en un caso de enfermedad de Lafora y breve revisión en la epilepsia mioclónica progresiva.

INTRODUCTION: Mioclonic progressive epilepsy (MPE) includes a clinical and genetical heterogeneous group of neuro-degenerative disorders that associate spontaneous and action-induced myoclonus as well as progressive cognitive impairment. Lafora`s disease is a subtype of MPE with autosomical recessive inheritance due to a mutation in EPM2A or EPM2B genes. Seizures, especially myoclonus, are often refractary to antiepileptic drugs (AD). CASE REPORT: In this article we report a patient with Lafora´s disease diagnosis, previously resistant to several AD tested with good and sustained response to zonisamide. Indeed, we describe a brief review about the efficacy of zonisamida in MPE. CONCLUSION: Zonisamide may be considered as a good therapeutic alternative in MPE.

TITLE: Eficacia de la zonisamida en un caso de enfermedad de Lafora y breve revisión en la epilepsia mioclónica progresiva.Introducción. La epilepsia mioclónica progresiva constituye un grupo complejo de enfermedades neurodegenerativas clínica y genéticamente heterogéneas que asocian mioclonías espontáneas o inducidas por la acción y el deterioro neurológico progresivo. Dentro de estas entidades se encuentra la enfermedad de Lafora, una patología autosómica recesiva causada por mutación en el gen responsable de la síntesis de una proteína llamada laforina (EPM2A) o el gen responsable de la síntesis de la proteína malina (EPM2B o NHLRC1). Son entidades cuyas crisis, en especial las mioclonías, son frecuentemente resistentes a los fármacos anticrisis epilépticas. Caso clínico. Presentamos el caso de una paciente con diagnóstico de enfermedad de Lafora que, tras varios regímenes terapéuticos ineficaces, presentó buena respuesta a la introducción de la zonisamida, con una respuesta favorable mantenida en el tiempo. Asimismo, hacemos una breve revisión de la eficacia de la zonisamida en cuadros de epilepsia mioclónica progresiva. Conclusión. La zonisamida puede ser una buena alternativa en el tratamiento de cuadros con epilepsia mioclónica progresiva.

Utilization of skin biopsy for diagnosis in a case of Lafora disease.

Lafora disease is a rare inherited neurodegenerative disease with onset in adolescence. Patients present with progressive myoclonic seizures and cognitive decline. The disease is linked to mutations in either of the two genes encoding malin and laforin, and it is associated with the accumulation of polyglucosan inclusions (Lafora bodies [LBs]) in various tissues, such as brain, liver, muscle, and skin, with the skin being particularly accessible for biopsy. Histopathologic examination of affected tissue with demonstration of LBs, together with the presence of pathologic mutation in EPM2A or NHLRC1 genes, is sufficient for diagnosis of this neurologic disorder when clinically suspected. Here, we report the case of a 16-year-old female with progressive neurologic symptoms and homozygous mutation in the NHLRC1 gene encoding malin. The skin biopsy was instrumental in reaching the final diagnosis by showing LBs in sweat glands by histopathologic and electron microscopic examination.

Compound heterozygosity for novel variations of the NHLRC1 Gene in a family with Lafora disease.

PURPOSE: NHLRC1 gene mutations are present in a varied proportion of patients with Lafora disease (LD). Compound heterozygosity for novel variations of the gene has been reported in progressive Lafora myoclonic epilepsy of Lafora pedigree. METHODS: The clinical data of the cases were collected for diagnosis, and the genetic spectrum of the family was confirmed. For molecular diagnosis, whole-exome sequencing (WES) of the pedigree was performed. RESULTS: 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 identified in our progressive myoclonic epilepsy of Lafora pedigree. CONCLUSIONS: The genetic analysis was useful for the diagnosis of LD. Genetic analysis is recommended for patients and close relatives, and tissue biopsy is an alternative.

The second family affected with a PRDM8-related disease.

INTRODUCTION: Lafora disease (LD) is a severe form of progressive myoclonus epilepsy characterized by generalized seizures, myoclonus, intellectual decline, ataxia, spasticity, dysarthria, visual loss, and in later stages, psychosis and dementia. To date, mutations in the EPM2A and EPM2B/NHLRC1 genes have been identified as the common causes of LD. However, a mutation in PRDM8 has been reported only once in a Pakistani family affected with early-onset Lafora disease. In the present study, we report the second family with a PRDM8 mutation. METHODS: Two affected individuals of an Iranian family initially diagnosed as complicated hereditary spastic paraplegia (HSP) underwent careful neurologic examination. Homozygosity mapping and whole-exome sequencing were performed. Based on the results of genetic analysis to detection of Lafora bodies, a skin biopsy was done. RESULTS: The clinical features of the patients were described. Linkage to chromosome 4 and a mutation in the PRDM8 gene were identified, suggesting the patients may be affected with early-onset LD. However, like the Pakistani family, the search for Lafora bodies in their skin biopsies was negative. Their electroencephalograms showed generalized epileptiform discharges in the absence of clinical seizures. CONCLUSIONS: The current study increases the number of PRDM8-related cases and expands the phenotypic spectrum of mutations in the PRDM8 gene. Both reported PRDM8-related families presented intra and inter-familial heterogeneity and they have originated from the Middle East. Thus, it seems the PRDM8 mutations should be considered not only in LD but also in other neurodegenerative disorders such as a complicated HSP-like phenotype, especially in this region.

A retrospective case series of clinical signs in 28 Beagles with Lafora disease.

BACKGROUND: Clinical signs and their progression in Beagles with Lafora disease are poorly described. OBJECTIVES: To describe clinical signs in Beagles with Lafora disease. ANIMALS: Twenty-eight Beagles with Lafora disease confirmed by genetic testing or histopathology. METHODS: Retrospective multicenter case series. Data regarding signalment, clinical signs, diagnostic tests and treatment were retrieved from hospital data files. A questionnaire was sent to owners asking about neurological deficits, changes in cognitive functions, behavioral changes, response to treatment and survival time. RESULTS: Onset of clinical signs was 8.3 years (mean; range, 6.3-13.3). All dogs had myoclonic episodes as an initial clinical sign with tonic-clonic seizures in n = 11/28 (39%) and n = 12/28 (43%) later developing tonic-clonic seizures. Deficits of coordination (n = 21/25; 84%), impaired vision (n = 15/26; 58%), and impaired hearing (n = 13/26; 50%) developed later. Mental decline was observed as loss of house training (urination; n = 8/25; 32%), difficulties performing learned tasks (n = 9/25; 36%), and difficulties learning new tasks (n = 7/23; 30%). Common behavioral changes were: increased photosensitivity (n = 20/26; 77%), staring into space (n = 16/25; 64%), reduced stress resistance (n = 15/26; 58%), increased noise sensitivity (n = 14/26; 54%), and separation anxiety (n = 11/25; 44%). Twenty-one dogs were alive (median age 11.9 years; range, 9.8-18.6), and 7 dogs were dead (mean age 12.1 years; SD: 1.3; range, 10.5-12.6) at time of writing. CONCLUSIONS AND CLINICAL IMPORTANCE: Lafora disease in Beagles causes significant behavioral changes, and mental decline as well as neurological deficits in addition to myoclonic episodes and generalized tonic-clonic seizures. Nevertheless, a relatively normal life span can be expected.

Natural history of Lafora disease: a prognostic systematic review and individual participant data meta-analysis.

BACKGROUND: Lafora disease (LD) is a rare fatal autosomal recessive form of progressive myoclonus epilepsy. It affects previously healthy children or adolescents, causing pharmacoresistant epilepsy, myoclonus and severe psychomotor deterioration. This work aims to describe the clinical course of LD and identify predictors of outcome by means of a prognostic systematic review with individual participant data meta-analysis. METHODS: A search was conducted on MEDLINE and Embase with no restrictions on publication date. Only studies reporting genetically confirmed LD cases were included. Kaplan-Meier estimate was used to assess probability of death and loss of autonomy. Univariable and multivariable Cox regression models with mixed effects (clustered survival data) were performed to evaluate prognostic factors. RESULTS: Seventy-three papers describing 298 genetically confirmed LD cases were selected. Mean age at disease onset was 13.4 years (SD 3.7), with 9.1% aged ≥ 18 years. Overall survival rates in 272 cases were 93% [95% CI 89-96] at 5 years, 62% [95% CI 54-69] at 10 years and 57% [95% CI 49-65] at 15 years. Median survival time was 11 years. The probability of loss of autonomy in 110 cases was 45% [95% CI 36-55] at 5 years, 75% [95% CI 66-84] at 10 years, and 83% [95% CI 74-90] at 15 years. Median loss of autonomy time was 6 years. Asian origin and age at onset < 18 years emerged as negative prognostic factors, while type of mutated gene and symptoms at onset were not related to survival or disability. CONCLUSIONS: This study documented that half of patients survived at least 11 years. The notion of actual survival rate and prognostic factors is crucial to design studies on the effectiveness of upcoming new disease-modifying therapies.

The rare rs769301934 variant in NHLRC1 is a common cause of Lafora disease in Turkey.

Lafora disease (LD) is a severe form of progressive myoclonus epilepsy inherited in an autosomal recessive fashion. It is associated with biallelic pathogenic variations in EPM2A or NHLRC1, which encode laforin and malin, respectively. The disease usually starts with adolescent onset seizures followed by progressive dementia, refractory status epilepticus and eventually death within 10 years of onset. LD is generally accepted as having a homogenous clinical course with no considerable differences between EPM2A or NHLRC1 associated forms. Nevertheless, late-onset and slow progressing forms of the disease have also been reported. Herein, we have performed clinical and genetic analyses of 14 LD patients from 12 different families and identified 8 distinct biallelic variations in these patients. Five of these variations were novel and/or associated with the LD phenotype for the first time. Interestingly, almost half of the cases were homozygous for the rare rs769301934 (NM_198586.3(NHLRC1): c.436 G > A; p.(Asp146Asn)) allele in NHLRC1. A less severe phenotype with an onset at a later age may be the reason for the biased inflation of this variant, which is already present in the human gene pool and can hence arise in the homozygous form in populations with increased parental consanguinity.

A Case of Lafora Disease Diagnosed by Axillary Skin Biopsy.

Lafora disease is a severe form of progressive myoclonic epilepsy with autosomal recessive inheritance diagnosed by inclusion body in biopsy. A 26-year-old woman was admitted due to complaints of frequent twitches and fainting. The 0.5x0.3x0.3 cm axillary skin punch biopsy was subjected to routine histopathological evaluation. Cytoplasmic PAS-positive inclusion bodies were observed at the basal side of the eccrine and apocrine glands. The diagnosis of Lafora disease can also be made by the observation of the polyglycosan cytoplasmic inclusion bodies in the brain, liver and skeletal muscle biopsies. Although we need more work to understand the etiopathogenesis of Lafora disease, we would like to draw attention to the importance of skin biopsy in the differential diagnosis of young patients with clinically refractory epilepsy, myoclonus, and cognitive decline.

Lafora body disease: a case of progressive myoclonic epilepsy.

Progressive myoclonic epilepsy (PME) is a progressive neurological disorder. Unfortunately, until now, no definitive curative treatment exists; however, it is of utmost importance to identify patients with PME. The underlying aetiology can be pinpointed if methodological clinical evaluation is performed, followed by subsequent genetic testing. We report a case of PME that was diagnosed as Lafora body disease. This case emphasises that, suspecting and identifying PME is important so as to start appropriate treatment and reduce the probability of morbidity and prognosticate the family.

[Lafora disease in a Beagle - diagnosis and therapy]. / Lafora-Erkrankung bei einem Beagle ­ Diagnose und Therapie.

Lafora disease is an autosomal recessive lysosomal storage disorder leading to an accumulation of toxic glycogen bodies into the cells of the central nervous system and other tissues. In the progressive form of myoclonic epilepsy, clinical signs typically start around 7 years of age. Causal therapy is impossible, however, in the early stages the symptoms may at least be alleviated by modern antiepileptic drugs. In the case reported here, an approximately 7-year-old Beagle presented with daytime-dependent fasciculations, focal and generalized myoclonus ranging up to a brief tonic-clonic seizure. The signs could be triggered and augmented by stress, sounds and light. Histologic examination was performed on biopsy samples of skin, liver, muscle and nervous tissue to test for the clinical diagnosis of Lafora disease. Sarcoplasmic PAS-positive pla®ue deposits typical of Lafora bodies were detected in the muscle biopsies but not in any of the other specimens. Initial treatment with phenobarbital and imepitoin was unsuccessful. However, treatment with levetiracetam significantly alleviated the clinical signs. At time of writing this publication, 2 years following the diagnosis, the now 9-year-old dog shows occasional, stress-related increase in fokal myoclonic seizures. Episodes of collapse or tonic-clonic seizures did not occur to any further extent.

Brain proton magnetic resonance spectroscopy findings in a Beagle dog with genetically confirmed Lafora disease.

Cortical atrophy has been identified using magnetic resonance imaging (MRI) in humans and dogs with Lafora disease (LD). In humans, proton magnetic resonance spectroscopy (1HMRS) of the brain indicates decreased N-acetyl-aspartate (NAA) relative to other brain metabolites. Brain 1HMRS findings in dogs with LD are lacking. A 6-year-old female Beagle was presented with a history of a single generalized tonic-clonic seizure and episodic reflex myoclonus. Clinical, hematological, and neurological examination findings and 3-Tesla MRI of the brain were unremarkable. Brain 1HMRS with voxel positioning in the thalamus was performed in the affected Beagle. It identified decreased amounts of NAA, glutamate-glutamine complex, and increased total choline and phosphoethanolamine relative to water and total creatine compared with the reference range in healthy control Beagles. A subsequent genetic test confirmed LD. Abnormalities in 1HMRS despite lack of changes with conventional MRI were identified in a dog with LD.