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Abnormal carbohydrate structures known as polyglucosan bodies (PGBs) are associated with neurodegenerative disorders, glycogen storage diseases (GSDs), and aging. A hallmark of the GSD Lafora disease (LD), a fatal childhood epilepsy caused by recessive mutations in the EPM2A or EPM2B genes, are cytoplasmic PGBs known as Lafora bodies (LBs). LBs result from aberrant glycogen metabolism and drive disease progression. They are abundant in brain, muscle and heart of LD patients and Epm2a(−/−) and Epm2b(−/−) mice. LBs and PGBs are histologically reminiscent of starch, semicrystalline carbohydrates synthesized for glucose storage in plants. In this study, we define LB architecture, tissue-specific differences, and dynamics. We propose a model for how small polyglucosans aggregate to form LBs. LBs are very similar to PGBs of aging and other neurological disorders, and so these studies have direct relevance to the general understanding of PGB structure and formation.

We report a case of two siblings with progressive myoclonus epilepsy whose parents were not consanguineous. Their clinical symptoms were typical of Lafora disease (LD), but skin biopsies revealed no Lafora bodies. Whole-exome sequencing identified a recurrent homozygous frameshift variant in the NHLRC1 gene in both siblings. The genetic analysis was useful for the diagnosis of LD, as neither consanguinity nor Lafora bodies were found.

11 páginas, 7 figuras. This is a pre-copyedited, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Rubio-Villena C., Viana R., Bonet J., Garcia-Gimeno M.A., Casado M., Heredia M.,Sanz P. (2018). Astrocytes: new players in progressive myoclonus epilepsy of Lafora type. Hum Mol Genet 27(7): 1290-1300, is available online at: http://dx.doi.org/10.1093/hmg/ddy044, Lafora disease (LD) is a fatal form of progressive myoclonus epilepsy characterized by the accumulation of insoluble poorly branched glycogen-like inclusions named Lafora bodies (LBs) in the brain and peripheral tissues. In the brain, since its first discovery in 1911, it was assumed that these glycogen inclusions were only present in affected neurons. Mouse models of LD have been obtained recently, and we and others have been able to report the accumulation of glycogen inclusions in the brain of LD animals, what recapitulates the hallmark of the disease. In this work we present evidence indicating that, although in mouse models of LD glycogen inclusions co-localize with neurons, as originally established, most of them co-localize with astrocytic markers such as glial fibrillary acidic protein (GFAP) and glutamine synthase. In addition, we have observed that primary cultures of astrocytes from LD mouse models accumulate higher levels of glycogen than controls. These results suggest that astrocytes may play a crucial role in the pathophysiology of Lafora disease, as the accumulation of glycogen inclusions in these cells may affect their regular functionality leading them to a possible neuronal dysfunction., This work was supported by grants from the Spanish Ministry of Economy and Competitiveness SAF2014-54604-C3-1-R, a grant from Generalitat Valenciana (PrometeoII/2014/029), a grant form Fundación Ramón Areces (XVIII Concurso Nacional Ayudas Investigacion Ciencias Vida y Materia) and a grant from the National Institute of Health (NIH-NINDS) P01NS097197, which established the Lafora Epilepsy Cure Initiative (LECI), to PS and grants SAF2016-75004-R and Contribution to COST Action CA15203 MITOEAGLE to MC.

In 1911, the Spanish neurologist-pathologist Gonzalo Lafora, working at the then Government Hospital for the Insane in Washington DC, first described the progressive myoclonus epilepsy that would later bear his name (Lafora, 1911). The journey to understand this disease started with Lafora’s detailed neuropathological description of the large and profuse inclusions (Fig. 1) that would come to be known as Lafora bodies. The odyssey has visited many a shore, and the latest and most mysterious is revealed by Javier Gayarre et al. (2014) in this issue of Brain . Figure 1 Lafora bodies as drawn by Lafora in his original manuscript (Lafora, 1911). Whereas the ‘amyloid’ plaques of Alzheimer’s disease are not in fact amyloid (starch), Lafora bodies, by contrast, are. Lafora bodies are composed of hyperphosphorylated and malformed glycogen molecules. These abnormal starch-like polyglucosans aggregate to form insoluble masses, which over time accumulate inside neuronal somata and dendrites. Lafora disease is caused by loss-of-function mutations in …

Content, composition and molecular weight distribution of the urinary glycosaminoglycans (GAG) were determined in five patients with progressive myoclonus epilepsy (PME). In one patient (Family B) this syndrome was associated with cerebral Lafora bodies and in four siblings of Family A, no Lafora bodies were present in brain biopsy. Only one of the five patients had a moderate increase of urinary GAG excretion as expressed by 24-h output or creatinine. The heparan sulfate component of the GAG was moderately increased in two other patients. The molecular weight distribution of the urinary GAG was normal. The results do not support the contention that urinary GAG excretion is abnormal in PME. Among nine lysosomal enzymes in leucocytes, only the activity of alpha-mannosidase was increased 3-fold in the four siblings.

We studied brainstem auditory-evoked potentials of 11 patients suffering from the Finnish type of progressive myoclonus epilepsy (without Lafora bodies). All patients were ambulatory and had regular antiepileptic medication. The responses of 5 patients were interpreted as totally normal. In 6 cases there were slight deformations of the wave forms or of the amplitudes of the responses. The central conduction time of all patients was within the +/- 2 S.D. limits of the normal values. Postauricular muscular responses were not more prominent in patients than in controls. The results indicate that there is not any significant dysfunction in the cholinergic auditory pathways of the brainstem of these patients.

In 1995, we mapped a gene for Lafora's progressive myoclonus epilepsy in chromosome 6q23-25. In 1997 and 1998, we reduced the size of the locus to 300 kb, and an international collaboration identified mutations in the protein tyrosine phosphatase gene. Here, we examine for heterogeneity through the admixture test in 22 families and estimate the proportion of linked families to be 75 to 85%. Extremely low posterior probabilities of linkage (Wi), exclusionary LOD scores, and haplotypes identify 4 families unlikely to be linked to chromosome 6q24.

Editors' Note: In WriteClick this week, Dr. Carpenter and authors Pinto et al. debate whether the image on the cover of the September 22, 2015, issue of Neurology® is a Lafora body or a normal organelle. In reference to “Neuropsychological outcome after deep brain stimulation for Parkinson disease,” Dr. Massano and author Bronstein discuss the literature concerning the targeting of the subthalamic nucleus vs globus pallidus interna in deep brain stimulation. —Megan Alcauskas, MD, and Robert C. Griggs, MD …

Summary Lafora disease in man is an autosomal recessive defect which affects carbohy- drate metabolism and results in a progressive, ultimately fatal neurological condition. It is characterized histologically by intraneuronal cytoplasmic polyglucosan inclusions (Lafora bodies). Similar inclusions have been seen in association with neurological signs in other species, including the dog, the cockatiel and the cow. Polyglucosan bodies, however, are not always con- sidered to be disease specific, and have also been reported as an age-related change in cats, dogs and man. The only recorded case in cattle to date has been a single animal in the USA. The present report records a case study of two animals with Lafora inclusion bodies, together with a survey of the occurrence of non-specific polyglucosan bodies in aged cattle. It is concluded that the inclusions in the two putative cases of Lafora disease were not non-specific age-related changes, and that these cases represent the first report of the disease in cattle in the UK.

Polyglucosan bodies (Lafora bodies) were identified in a juvenile gray-headed flying fox ( Pteropus poliocephalus) with neurological signs. The structures were only noted in the brain stem, and no associated degenerative changes were present. These structures have not been previously identified in any species in the order Chiroptera.

Summary A longitudinal clinicoelectrophysiologic study was undertaken of a 15-year 2-month-old girl with Lafora disease who was diagnosed by skin biopsy and an immunohistochemical method with antisera against Lafora bodies. From age 10 years 5 months, 4 months after onset, EEG disclosed progressive deterioration of background activity and incremental increase in epileptic discharges. Photosensitivity was unique: Occipital spikes and diffuse spike-wave discharges were provoked by low-frequency repetitive photic stimuli but without elicitation of myoclonic seizures. Photosensitivity completely disappeared after age 13 years 10 months. High-voltage somatosensory evoked potentials (SEPs) and high-voltage flash visual evoked potentials (F-VEPs) were seen before age 13. After age 13, progressive prolongation of I-III and I-V interpeak latencies of auditory brainstem responses (ABRs), progressive prolongation of latencies of photoevoked eyelid microvibrations, delayed latencies of pattern-reversal visual evoked potentials, and a decrease in the V/I amplitude ratio of ABRs and the previously high F-VEP amplitudes were observed. RESUME Les auteurs ont suivi une jeune fille âgee de 15 ans et 2 mois, Presentant une maladie de Lafora diagnostiquee par biopsie cutanee et etude immunohistochimique au moyen d'un serum reagissant sur les corps de Lafora. A partir de l'âge de 10 ans et 5 mois, 4 mois apres le debut de la maladie, l'EEG a mis en evidence une deterioration progressive de l'activite de fond et une augmentation progressive des decharges epileptiques. Une photosensibilite tres particuliere a ete mise en evidence: des Pointes occipitales et des pointes-ondes diffuses etaient provoquees par la stimulation lumineuse intermittente a basse frequence, sans provoquer toutefois de crises myocloniques, cette photosensibilite a disparu completement apres l'âge de 13 ans et 10 mois. Des potentiels evoques somato-sensitifs de haut voltage et des potentiels evoques visuels au flash de haut voltage ont ete enregistres avant l'âge de 13 ans. Apres cet âge, les auteurs ont constate un allongement progressif des latences interpics I-III et I-IV des potentiels evoques auditifs precoces, un allongement progressif des latences des microvibrations palpebrales evoquees par la lumiere, un allongement des latences des potentiels evoques visuels par inversion de pattern, et une diminution de l'amplitude du rapport V/I des potentiels evoques auditifs precoces et des amplitudes des potentiels evoques visuels au flash. RESUMEN Se ha realizado un estudio longitudinal clinico-electrofisiologico en una nina de 15 anos y 2 meses de edad que padecia la enfermedad de Lafora diagnosticada mediante una biopsia cutanea y un metodo histoquimico con antisuero anticuerpos de Lafora. Desde la edad de 10 anos y 5 meses, 4 meses despues del comienzo de la enfermedad, aaparecio un deterioro progresivo de la actividad de fondo con un incremento de las descargas epilepticas. La fotosensibilidad fue muy especial: puntas occipitales y descargas difusas punta-onda fueron provocadas mediante estimulacion fotica repetitiva efectiva, de baja frecuencia, pero sin que se observaran ataques mioclonicos. La fotosensibilidad desaparecio completamente despues de la edad de 13 anos y 10 meses. Antes de la edad de 13 anos se observaron potenciales evocados somatosensoriales de alto voltaje y potenciales evocados visuales (F-VEPs) tras flash de alto voltaje. Despues de la edad de 13 anos se observaron: una progresiva prolongacion de las latencias interpicos de I-III y I-V de las respuestas auditivas de tronco cerebral (APRs), una prolongacion progresiva de las latencias de las vibraciones de los parpados evocadas foticamente, un retraso de las latencias de los potenciales evocados visuales inducidos por patrones graficos y una reduccion de la relacion V-I de los ABRs y de las previas amplitudes de los F-VEP. ZUSAMMENFASSUNG Eine klinisch-elektrophysiologische Langzeitstudie wurde bei einem jetzt 15 Jahre alten Madchen mit Lafora-Erkrankung durch gefuhrt. Die Diagnose war durch Hautbiopsie un durch immunhistochemische Methoden mit Antiseren gegen Laforakorper gestellt worden. Im Alter von 10,5 Jahren, 4 Monate nach Auftreten der Erkrankung, zeigte das EEG einen progredienten Abbau der Grundaktivitat und allmahliche Zunahme epileptischer Entladungen. Die Fotosensibilitat war auffallig: durch langsame repetitive Stimuli wurden occipitale spikes und diffuse spike-waves Entladungen provoziert ohne Auslosung einer myoklonischen Reaktion. Im Alter von 13,10 Jahren verschwand die Fotosensibilitat vollstandig. Amplitudenhohe somatosensorische EP und hohe Blitz-VEP wurden vor dem Alter von 13 Jahren und danach beobachtet. Die AEP zeigten allmahliche Verlangerung der I-III und I-V Latenzen, ferner eine Verlangerung der Licht-evozierten Augenlid-Mikrovibrationen und verzogerte Latenzen der VEP bei Musterumkehr. Ein Abfall der Amplitudenkorrelation V/1 der AEP und der Amplituden der F-VEP wurde ebenfalls festgestellt.

Lafora bodies (polyglucosan deposits) were identified in the brain of a young adult cat with neurologic signs characterized by intermittent but progressively worsening head and body tremors. The cerebellar cortex was the most severely affected area of brain, and the deposits were identified within Purkinje cell bodies and processes and throughout the neuropil. The association of Lafora bodies with neurologic signs, occurrence of deposits within neuronal perikarya, and distribution primarily within the cerebellar cortex are features distinct from the more commonly recognized situation in which Lafora bodies occur as incidental lesions in cats.

Lafora disease (LD) is an inherited and fatal form of neurodegenerative disorder characterized by the presence of an abnormal form of glycogen inclusions, called Lafora bodies, in neurons and other tissues. While Lafora bodies have been thought to underlie the neuropathology in LD, the specific process by which these inclusions might affect the neuronal functions was not very well understood. Here we review one of our recent studies on the LD animal model, wherein we have shown that the Lafora bodies might contribute to the impairment in the endosomal-lysosomal and autophagy pathways.

Background Lafora Disease (LD) is a fatal teenage-onset progressive myoclonus epilepsy. It is characterized by the formation of Lafora bodies (LBs), deposits of abnormally branched, insoluble, hyperphosphorylated glycogen-like polymers that are generally believed to trigger the development of the clinical symptoms of LD. 58% and 35% of the LD cases are caused by mutations in EPM2A (laforin) and EPM2B (malin), respectively. However, little is known about their function in LB formation. Two different mechanisms have been proposed to explain the accumulation of insoluble LBs: first, excessive glycogen phosphorylation and, second, an imbalance between glycogen synthesizing enzymes. The present study aims at the identification of proteins involved in the molecular mechanisms leading to LB formation and appearance of LD and the phosphorylation of glycogen.

Summary: Since age 12 years, a 25-year-old woman had a syndrome with myoclonic epilepsy, cerebellar signs, and spontaneous myoclonus. Skin biopsy showed typical Lafora bodies (LB), but she lacked a progressive course and mental impairment, hallmarks of Lafora disease. Lysosomal enzyme assays showed low level arylsulfatase A (ASA) activity. DNA study disclosed a homozygous ASA Pd genotype. Both parents carried one Pd allele. The still-unknown relationship between the pathologic level of ASA activity and myoclonic epilepsies suggests introduction of ASA assays in patients with PME. RESUMEN Desde la edad de 12 anos una mujer de 25 anos padecio un sindrome con epilepsia mioclonica, trastornos cerebelosos y mioclonias espontaneas. La biopsia cutanea mostro tipicos cuerpos de Lafora pero no presento un cuadro progresivo ni alteraciones mentales, sintomas fundamentales de la enfermedad de Lafora. Los ensayos de enzima lisosomial mostraron niveles bajos de actividad ASA. El estudio de DNA revelo un genotipo homozigotico ASA Pd. Ambos familiares eran portadores del allelo Pd. Todavia permanece desconocida la relacion entre el nivel patologico de la actividad de la ASA y las epilepsias mioclonicas lo que sugiere la introduccion de los ensayos ASA en los pacientes con epilepsia mioclonica progresiva. ZUSAMMENFASSUNG Eine 25 jahrige Frau litt seit ihrem 12. Lebensjahr an einem Syndrom mit myoklonischer Epilepsie, zerebellaren Zeichen und spontanem Myoklonus. Die Hautbiopsie zeigte typische Laforakorper, die Patientin zeigte jedoch keinen progressiven Verlauf und mentalen Abbau, wie sie typisch fur dei Lafora-Erkrankungen sind. Die Bestimmung der lysosomalen Enzyme zeigte eins erniedrigts ASA-Aktivitat. DNA-Untersuchungen schlossen einen homozygoten ASA Pd Genotyp aus. Beide Eltern trugen sin Pd Allel. Die bislang unbekannte Beziehung zwischen pathologischen ASA Werten und myoklonischen Epilepsien legen nahe, ASA Assays bei Patienten mit PME durchzufuhren.

Massive occurrence of polyglucosan bodies (PBs) was found within the surgically removed temporal lobe of a 34 year old woman with complex partial seizures. This peculiar feature is very unusual in neuropathological examinations of epileptogenic foci. This patient could not be included in any of the classic diseases in which PBs are found. She exhibited a localised form of glycogen storage disease.

This report describes a sporadic late-onset myopathy in two unrelated adults which was marked by polyglucosan inclusions surrounded by abnormally structured mitochondria, the latter finding a localized, possibly reactive phenomenon. The polyglucosan material was characterized by a battery of histochemical and enzyme histochemical techniques; revealed common antigenicity with Lafora bodies, corpora amylacea and muscle fiber inclusions in types IV and VII glycogenoses; and contained ubiquitin. Additional lectin histochemical and associated digestion preparations disclosed the presence of alpha-glycosyl residues as apparently the sole carbohydrate component in polyglucosan bodies while the above mentioned common antigenicity with Lafora bodies and other inclusions suggests an additional, so far unidentified, protein component.

A 6-year-old Basset hound developed a progressive central nervous system disease culminating in epileptic seizures. Histologically, Lafora bodies were found in neurones of the middle and deeper cerebral cortex and midbrain, in Purkinje cells and their processes, and in glial cells of the molecular layer of the cerebellum. Many were also observed free in the neuropil. The ultrastructural and histochemical characteristics of the bodies were similar to those described in previous human and canine cases of Lafora's disease.

A cytochemical procedure for polysaccharides was carried out on a brain biopsy specimen, the thin-section study of which had shown excess glycogen granules and the corpora amylacea variety of polyglucosan bodies. Both granules and amyloid bodies were stained positively in contrast to the remaining structures of the brain tissue which remained unstained. This demonstrates that beta-granules as well as filamentous and amorphous components of amyloid bodies are just different aspects of the polysaccharide molecule. Up to now the same kind of cytochemical evidence has been supplied for Lafora bodies of human material and Lafora-like bodies of rat material. The present study on corpora amylacea of human material shows that amyloid, Lafora, and Lafora-like bodies all behave the same way when stained for polysaccharides.

Deposits similar to corpora amylacea were observed by electron microscopy and light microscopy within thin myelinated axons in the spinal gray matter in various diseases. By electron microscopy the deposits consisted of randomly interlacing short linear structures of various thickness which were different from tangles of neurofilaments. Sometimes they contained dense granules and electron-dense floccules. Though their incidence was relatively high in some cases of degenerative or metabolic disease of the central nervous system, they were not specific to any disease but seemed to be related to aging, indicating a peculiar aspect of chronic degeneration of the axons.

Summary Sixty-five patients with progressive myoclonus epilepsy without Lafora bodies were examined by the Wechsler Verbal or Terman-Merrill-Lehtovaara scale, and 25 were reexamined after a mean of 6 yr. Intelligence was relatively intact by contrast with the patients' poor physical condition. The estimated I.Q. at the onset was 92, in the low normal range, and it diminished by about 10 points in 10 yr. This diminution had begun before the appearance of clear clinical symptoms. Low test scores correlated significantly (p < 0.01) with duration of the disease and with age. On the Wechsler Verbal Scale, tests of similarities, information, and comprehension were least affected; scores on digit span and arithmetic tests were lowest. Speech was slow and dysarthric and became finally unintelligible. Personality was infantile and mood labile and often depressed. The surprisingly high intelligence differentiates these patients from those having the form of progressive myoclonus epilepsy that occurs with Lafora bodies. The two diseases seem to be distinct clinical and histopathologic entities. REsume 65 sujets avec une epilepsie myoclonique progressive sans corps de Lafora, ont ete examines avec l'echelle verbale Wechsler ou Terman-Merrill-Lehtovaara, et 25 ont ete examines a nouveau en moyenne 6 ans apres. L'intelligence etait relativement intacte en contraste avec les mauvaises conditions psychiques des sujets. Le Q.I. au debut etait environ G 92, dans les limites inferieures de la normale. Des pauvres performances etaient en correlation significative (p < 0.01) avec la duree de la maladie et l'âge. Dans l'echelle verbale de Wechsler, les tests de similitudes, l'information et la comprehension etaient moins atteints; les valeurs des tests, la memoire des chiffres et l'arithmetique, etaient les plus bas. Le langage etait ralenti et avec dysarthrie et devenait a la fin incomprehensible. La personnaliteetait infantile et l'heumeur labile et souvent depressive. Un niveau d'intelligence etonnament eleve differencie ces patients de ceux qui ont une forme de myoclono-epilepsie progressive avec corps de Lafora. Les deux maladies sont des entites distinctes du point de vue clinique et histo-pathologique. RESUMEN Utilizando la escala verbal de Wechsler o la de Terman-Merrill-Lehtovaara se han examinado 65 enfermos con epilepsyia mioclonica progresiva sin cuerpos de Lafora, 25 de los cuales fueron reexaminados despues de un promedio de 6 anos. La inteligencia estaba relativamente conservada, hecho que contrastaba con el considerable deterioro fisico de los enfermos. Al principio del estudio el Cociente Intelectual (IQ) fue de 92, normal bajo, disminuyendo 10 puntos al cabo de 10 anos. Se aprecio una significativa correlateon (p < 0.01) entre los IQ bajos, la duracion de la enfermedad y la edad de los enfermos. En la escala verbal de Wechsler, resultaron menos afectados los tests de semejanzas, information y comprension, mientras que los resultados mas bajos se obtuvieron en pruebas aritmeticas. El lenguaje era disartrico y lento llegando, finalmente, a ser incomprensible. La personalidad era infantil y el animo labil y frecuentemente deprimido. La inteligencia sorprendentemente alta diferencia a este tipo de enfermos con los que padecen la forma progresiva de epilepsyia mioclonica con cuerpos de Lafora. Estas dos enfermedades constituyen entidades clinicas e histopatologicas distintas. ZUSAMMEnfassung 65 Patienten mit progressiver Myoklonusepilepsie ohne Laforakorperchen wurden psychologisch untersucht mit dem verbalen Wechslertest oder der Terman-Merrill-Lehtovaara-Skala. 25 von ihnen wurden nach einer durchsehnittlichen Zeitdauer von 6 Jahren nachuntersucht. Im Gegensatz zu der schweren korperlichen Beeintrachtigung war die Intelligenz relativ intakt. Der durchschnittliche IQ lag im Beginn mit 92 im unteren Normbereich. Er verminderte sich um etwa 10 Punkte in 10 Jahren. Niedrige Testergebnisse korrelierten signifikant mit der Dauer der Erkrankung und mit dem Alter (p < 0.01). Im Wechslerverbaltest waren die Untertests fur Ahnlichkeiten, Informatione und Verstandnis am wenigsten beeintrachtigt. Die Scores fur Zahlennachsprechen und Rechnen lagen am niedrigsten. Die Sprache war langsam und dysarthrisch und wurde schliesslich unverstandlich. Die Personlichkeit war infantil, die Stimmung labil und haufig depressiv. Die uberraschenderweise hohe Intelligenz unterscheidet diese Patienten von solchen mit einer progressiven Myoklonusepilepsie, bei der Lafora-korperchen gefunden wurden. Beide Erkrankungen sind klinisch und histopathologisch zu unterscheidende Entitaten.

Lafora bodies were observed in the inner plexiform layer of the retina in cases of absolute or fereabsolute glaucoma. In the cases studied epilepsy and other neurological diseases could be excluded. On the basis of these findings it can be stated that Lafora bodies are not specific for one single disease.

A patient with advanced progressive myoclonic epilepsy (Unverricht type) with Lafora bodies is presented. Although the clinical history and symptoms were classical, the regional distribution of the cerebral involvement differed from the classical picture: the corpora mamillaria, the nucleus subthalamicus, and the nucleus ruber, which are normally reported to be spared, contained multiple Lafora bodies, whereas the lateral geniculate body, which is usually involved, was intact. The number of inclusions per cell, up to 25, was extremely high and correlated with the marked cortical atrophy and the prolonged clinical course. Using electron microscopy, type I and type II Lafora bodies were found, but the latter lacked the typical filamentous ultrastructure in the peripheral zone. The lack of visceral Lafora bodies in this case suggests that liver, muscle, and skin biopsies, which are widely used for the diagnosis, may lead to false negative results and cannot always replace a stereotactic brain biopsy. The differential diagnosis on polyglucosan bodies is emphasized.

Seven cases of progressive familial myoclonus epilepsy occurring in three families are presented. The patients were in different stages of the illness. The EEG was abnormal in all. It is suggested that these cases belong clinically to the Lafora bodies group. Nystagmus and optic atrophy, seen in one patient, have not been described previously. Myoclonic jerks did not respond to treatment with diazepam and ethosuximide.

We have studied four patients who had a clinical course compatible with Lafora disease. The diagnosis was confirmed in one by the presence of Lafora bodies in central nervous system neurons at autopsy and was supported in another by findings in the cerebral biopsy of a sibling. Our patients had no clinically apparent liver disease, but liver specimens in each instance showed a distinctive histological abnormality, with hepatocytes containing inclusions having a ground-glass appearance. The liver biopsy findings appear to be relatively specific for this disorder and can easily be differentiated from those in other liver diseases.

RECENT advances in the diagnosis and classifcxation of epileptic seizures and epileptic syndromes, together with improvemenss in anticonvulsant therapy, have enabled the great majority of patients ...

Foram feitos estudos neuropatológicos em dois casos de pacientes que apresentaram encefalopatia mioclônica pós-anóxica (síndrome de Lance-Adams). O encéfalo mostrou lesões neuronais difusas, comprometendo principalmente o córtice, tálamo e estruturas sub-talâmicas, desde lesões discretas caracterizadas pela presença de vacúolos intracitoplasmáticos (primeira alteração vista na anoxia) até neurônios totalmente degenerados, notando-se vários neurônios com lesões clássicas de isquemia. A presença de material de inclusão anfofílica discretamente PAS positiva observado no citoplasma neuronal foi diferente das inclusões verificadas nos casos de epilepsia mioclônica com corpúsculos de Lafora. Não conseguimos identificar a constituição destas inclusões, apesar de serem feitos diferentes métodos de coloração. Não encontramos também, na literatura, referência a tal tipo de inclusão. Foram também encontradas alterações vasculares, consistindo de vasos proliferados com células endoteliais tumefeitas. Tais células apresentaram-se com disposição anárquica, provavelmente devidas à anoxia isquêmica. A diferença dos achados anatomopatológicos, entre os casos 1 e 2, são provavelmente decorrentes do mecanismo diverso da instalação da anoxia. Two cases of Lance-Adams syndrome with anatomopathologic study are reported. There were evidences of diffuse neuronal degeneration in the brain. These changes were most seen in the neurones of the cortical layers, thalamus and subthalamic nuclei. The cells changes were similar of those seen in ischaemic disease. Some neurones showed intracytoplasmatic inclusions staining with the P.A.S. method. These inclusions were readily distinguished from the Lafora bodies.

The Lafora type of progressive myoclonus epilepsy is a rare and fatal familial disease characterized by seizures, myoclonus, and dementia. This diagnosis was confirmed in 2 patients by demonstrating the presence of intracytoplasmic polygkicosan bodies, or Lafora bodies, in the peripheral portion of the eccrinc sweat gland duct. Exclusive use of the periodic acid-Schifl stain is recommended for demonstrating these diagnostic inclusions. Electron microscopy reveals fine pale-staining filaments, line clark-slaining granules, and dark-rimmed vacuoles within these non-inembranc-bound inclusions. Skin biopsy is the preferred method of confirming the diagnosis of Lafora disease.

Deposits similar to corpora amylacea were observed by electron microscopy within myelinated axons in the peripheral nerves in a case of familial spastic paralysis. Ultrastructurally the deposits consisted of randomly interlacing short filaments which were closely related to glycogen granules present in the periphery of the deposits. A possible relationship between the filamentous structures and glycogen granules is discussed. The significance of this inclusion and of related bodies is also discussed.

Bei einem 60 Jahre alt gewordenen Mann, mit einer bis in die Kindheit zuruckreichenden und extrem langsam progredienten, wahrscheinlich torsionsdystonischen bzw. choreoathetoiden Bewegungsstorung, fand sich eine isolierte Degeneration des auseren Pallidumgliedes mit intraneuronaler Ablagerung von Bielschowsky-Korperchen und nur geringgradigem Nervenzellausfall.

Both thecorpora amylacea and Lafora bodies have been described in the literature as filamentous structures. On electron microscopic examination they are often composed of ribbon-like fasciolar units. The ultrastructural appearance of these structures is discussed on the example of an amylopectin model. These fasciolar substructures are also encountered in Bielschowsky bodies and are then considered to be a sign of intracellular accumulation of dysmetabolic products. The histological and electron microscopical similarity ofcorpora amylacea, Lafora bodies and Bielschowsky bodies suggests that all these structures are an unspecific, nearly identical endproduct of various intracellular metabolic disturbances.

The authors present the case of a patient with Lafora disease proven by skin biopsy, who suffered two occipital seizures recorded on EEG and provoked by intermittent photic stimulation. On the basis of data in the literature and their present experience, the authors suggest the involvement of the occipital lobes as a whole in the epileptogenic activity.