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.

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.

[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).

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.

Novel method for detection of glycogen in cells.

y: Glycogen, a branched polymer of glucose, functions as an energy reserve in many living organisms. Abnormalities in glycogen metabolism, usually excessive accumulation, can be caused genetically, most often through mutation of the enzymes directly involved in synthesis and degradation of the polymer leading to a variety of glycogen storage diseases (GSDs). Microscopic visualization of glycogen deposits in cells and tissues is important for the study of normal glycogen metabolism as well as diagnosis of GSDs. Here, we describe a method for the detection of glycogen using a renewable, recombinant protein which contains the carbohydrate-binding module (CBM) from starch-binding domain containing protein 1 (Stbd1). We generated a fusion protein containing g lutathione S-transferase, a cM c eptitope and the tbd1 BM (GYSC) for use as a glycogen-binding probe, which can be detected with secondary antibodies against glutathione S-transferase or cMyc. By enzyme-linked immunosorbent assay, we demonstrate that GYSC binds glycogen and two other polymers of glucose, amylopectin and amylose. Immunofluorescence staining of cultured cells indicate a GYSC-specific signal that is co-localized with signals obtained with anti-glycogen or anti-glycogen synthase antibodies. GYSC-positive staining inside of lysosomes is observed in individual muscle fibers isolated from mice deficient in lysosomal enzyme acid alpha-glucosidase, a well-characterized model of GSD II (Pompe disease). Co-localized GYSC and glycogen signals are also found in muscle fibers isolated from mice deficient in malin, a model for Lafora disease. These data indicate that GYSC is a novel probe that can be used to study glycogen metabolism under normal and pathological conditions.

Severe and rapidly-progressive Lafora disease associated with NHLRC1 mutation: a case report.

Lafora disease (LD), also known as progressive myoclonic epilepsy-2 (EPM2), is a rare, fatal autosomal recessive disorder typically starting during adolescence in otherwise neurologically normal individuals. It is clinically characterized by insidious of progressive neurological features including seizures, action myoclonus, visual hallucination, ataxia and dementia. Mutations in the laforin (EPM2A) gene on chromosome 6q24 or in the malin gene (NHLRC1) on chromosome 6p22 are responsible of LD phenotype. Diagnostic workup includes genetic analysis as well as axillary skin biopsy with evidence of typical periodic acid-Schiff (PAS)-positive polyglucosan inclusion bodies (Lafora bodies) in the apocrine glands and/or in the eccrine duct. Usually, genotype-phenotype correlations do not reveal substantial differences between patients carrying EPM2A and NHLRC1 mutations, but a few specific NHLRC1 mutations appear to correlate with a late onset and slow progressing LD. We report a case of LD due to compound heterozygote NHLRC1 mutation in an adolescent presenting with severe and atypical electro-clinical features, mimicking an autoimmune encephalopathy, and a rapidly progressive clinical course.

Clinical and genetic data on Lafora disease patients of Serbian/Montenegrin origin.

Lafora disease (LD) is an autosomal recessive, progressive disorder characterized by myoclonus and seizures, inexorable neurologic deterioration, cognitive decline and poor prognosis. LD is caused by mutations either in the EPM2A or in NHLRC1 genes. Here we report clinical and genetic findings on 14 LD patients from 10 families of Serbian/Montenegrin origin. Molecular diagnostics was performed by sequencing the coding regions of the EPM2A and NHLRC1 genes. In addition, haplotype analysis of the chromosomes carrying the two most frequent mutations (c.1048-1049delGA and deletion of the whole NHLRC1 gene) using eight different markers flanking the NHLRC1 gene was conducted. We identified one new mutation (c.1028T>C) along with the 3 previously reported mutations (c.1048-1049delGA, c.990delG, deletion of the whole NHLRC1 gene), all of which were located on the NHLRC1 gene. The two predominant mutations (c.1048-1049delGA and complete NHLRC1 gene deletion) appear to be founder mutations. In addition to documenting the genetic heterogeneity observed for LD, our study suggests that mutations in the NHLRC1 gene may be a common cause of LD in the Serbian/Montenegrin population, primarily because of a founder effect.

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.

Presentation of an unusual patient with Lafora disease.

Lafora disease is a rare, fatal, autosomal recessive progressive myoclonic epilepsy. The condition is characterised by seizures, myoclonus and dementia. In this case report, a patient who presented with generalised tonic-clonic seizures at the age of 30 is discussed. Until the age of 48, the patient did not have myoclonic jerks or ataxia clinically, but had well controlled seizures. He developed dementia and late extrapyramidal signs. Axillary skin biopsy revealed typical Lafora inclusion bodies. Genetic analysis showed a mutation in the EMP2B gene. To our knowledge, this is the first description of a patient suffering from a Lafora disease without disabling myoclonus and ataxia but rather rare seizures, extrapyramidal signs, and dementia.

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.

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.

[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.

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.

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.

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.

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.