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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.

This paper reported an unusual manifestation of a 19-year-old Chinese male patient presented with a complex phenotype of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome and Kearns–Sayre syndrome (KSS). He was admitted to our hospital with the chief complaint of “acute fever, headache and slow reaction for 21 days”. He was initially misdiagnosed as “viral encephalitis”. This Chinese man with significant past medical history of intolerating fatigue presented paroxysmal neurobehavioral attacks that started about 10 years ago. During this span, 3 or 4 attack clusters were described during which several attacks occurred over a few days. The further examination found that the hallmark signs of this patient included progressive myoclonus epilepsy, cerebellar ataxia, hearing loss, myopathic weakness, ophthalmoparesis, pigmentary retinopathy and bifascicular heart block (Wolff–Parkinson–White syndrome). By young age the disease progression is characterized by the addition of migraine, vomiting, and stroke-like episodes, symptoms of MELAS expression, which indicated completion of the MELAS/KSS overlap syndrome. The m. A3243G mitochondrial DNA mutation and single large-scale mtDNA deletions were found in this patient. This mutation has been reported with MELAS, KSS, myopathy, deafness and mental disorder with cognitive impairment. This is the first description with a MELAS/KSS syndrome in Chinese., Highlights • A 19-year-old Chinese man presented MELAS/KSS overlap syndrome. • A3243G mtDNA mutation and large-scale mtDNA deletions were in him. • This is the first description in Chinese.

Summary A 42‐year‐old male was admitted for refractory status epilepticus. At the age of 25, he had been diagnosed with juvenile myoclonic epilepsy. He had a stable clinical course for over a decade until a recent deterioration of behavior and epilepsy. After exclusion of acquired disorders, diagnostic work‐up included application of next‐generation sequencing (NGS), with a gene panel targeting progressive myoclonic epilepsies. This resulted in the diagnosis Lafora disease resulting from compound heterozygous NHLRC1 pathogenic variants. Although these pathogenic variants may be associated with a variable phenotype, including both severe and mild clinical course, the clinical presentation of our patient at this age is very unusual for Lafora disease. Our case expands the phenotype spectrum of Lafora disease resulting from pathogenic NHLRC1 variants and illustrates the value of using NGS in clinical practice to lead to a rapid diagnosis and guide therapeutic options.

Myoclonus epilepsy with ragged-red fibers (MERRFs), an inherited mitochondrial disorder, has characteristic morphological changes of ragged-red fibers (RRFs) in muscle biopsy, in the absence of which mitochondrial etiology is usually not considered in patients with phenotypes suggestive of MERRF. In these circumstances, MERRF can only be diagnosed using genetic analyses. The symptoms, pathological findings, and imaging results being age dependent, we can construct a protocol based on these characteristics to understand the disease’s natural course and to manage patients more effectively. The absence of RRFs should not preclude a MERRF diagnosis.

Myoclonus epilepsy associated with ragged-red fibers (MERRF) is traditionally characterized by myoclonus, generalized epilepsy and ragged-red fibers. We herein report a 42-year-old man who complained of falling after starting running, symptoms resembling those of paroxysmal kinesigenic dyskinesia. He showed only slight muscle weakness of the right quadriceps femoris. Muscle pathology and a genetic analysis identified him as having MERRF with a 8344AG mtDNA mutation. We diagnosed his symptoms as having been caused by slight quadriceps femoris muscle weakness and exercise intolerance. This case suggests that mitochondrial myopathy should be considered in cases with strong muscle symptoms for muscle weakness.

5-HT uptake by blood platelets was tested in patients with PME with no Lafora bodies. Blood platelets from patients with myoclonus epilepsy and those from healthy sex and age matched controls were incubated for 5 min with 0.1 microM 3H-5-HT in Krebs-Henseleit buffer at 37 degrees C. The radioactivity taken up by platelets was assayed by liquid scintillation counting. 5-HT uptake in platelets from patients tended to be slightly higher (19%, n = 18, P greater than 0.05). The kinetic pattern as revealed by the Lineweaver-Burk plot, was very similar in the two groups. All patients were on antiepileptic drugs (sodium valproate, clonazepam and phenobarbital), but no evidence was found in vitro that these drugs would have any direct effect on the uptake.

Purpose: To investigate neuronal dysfunction in the thalami of juvenile myoclonic epilepsy (JME) by using proton magnetic resonance spectroscopy (MRS). Methods: We performed single-voxel proton MRS over the right and the left thalami of 15 consecutive patients (10 women, 5 men) with JME (mean age 20.3 years) and 16 healthy volunteers (10 women, 6 men) (mean age 24.5 years). All patients had seizure onset in late childhood-teenage, normal neurologic examination, typical electroencephalogram (EEG) of JME and normal magnetic resonance imaging (MRI). We determined N-acetylaspartate (NAA) values and NAA over creatine-phosphocreatine (Cr) values. Mann-Whitney U-test was used to evaluate group differences. Results: Group analysis showed that echo time (TE) 270 integral value of NAA over left thalamus were significantly decreased in JME patients as compared with controls (34.6033 +/- 15.8386; 48.0362 +/- 22.2407, respectively, P = 0.019). Also group analysis showed that thalami NAA/Cr ratios were significantly decreased in JME patients (right side, 2.21 +/- 1.07; left side 2.00 +/- 0.72) as compared with controls (right side, 3.45 +/- 1.50; left side, 3.08. +/- 1.60; P = 0.011 and P = 0.030, respectively). Conclusion: In the previous studies, NAA values inpatients with JME found that they were not statistically lower in thalami than control group. But, in our study, NAA value was found tow as well. It has been known that NAA is a neuronal marker and hence it is a valuable metabolite in the neuron physiopathology. As a result, in the patients with JME we tried to support the theory that the underlying mechanism of the generalized seizures was the abnormal thalamocortical circuity, determining the thalamic neuronal dysfunction in MRS statistically.

A nine-year-old, neutered female beagle was presented with a history of progressive myoclonic jerks. Clinical signs included mental depression and paroxysmal jerks of the head and forelimbs, apparently elicited by changes in light, noise or movements. Electroencephalographic findings were in accordance with myoclonus epilepsy. Postmortem histopathological findings included multiple periodic acid-Schiff-positive inclusion bodies throughout the central nervous system, but especially in the cerebellum, confirming the suspected diagnosis of Lafora's disease.

Uma paciente de 16 anos apresentava epilepsia mioclônica causada pela doença de Lafora. A biopsia muscular mostrou padrão vacuolar nas fibras musculares com as reações nicotinamida adenina tetrazolium redutase desidrogenase, hematoxilina-eosina e PAS. O aspecto morfológico permite o diagnóstico através da biopsia muscular. Este é um procedimento menos agressivo que a biopsia de fígado e de cérebro. A microscopia eletrônica deve ser reservada para casos nos quais as alterações musculares à microscopia óptica são muito discretas deixando dúvidas quanto ao diagnóstico.

An autopsy case of progressive myoclonic epilepsy (PME) with unusual neuropathologic features is discussed. The patient was a 46 year old man who presented with prominent cerebellar ataxia and an intention tremor, in addition to myoclonic movements and grand mal seizures. He was clinically diagnosed as having PME, in particular dys-synergia cerebellaris myoclonica (DCM; Ramsay Hunt syndrome). A neuropathologic examination revealed severe degeneration of the cerebellar cortex, mild nerve cell loss with marked fibrillary gliosis of the dentate nucleus, and focal laminar necrosis and mild diffuse nerve cell loss in the frontal cortex. Other recent clinicopathologic studies have revealed that most patients with Ramsay Hunt syndrome are diagnosed pathologically as having either mitochondrial encephalomyopathy, especially myoclonus epilepsy with ragged red fiber (MERRF), or dentatorubral or dentatorubropallidoluysian atrophy (DRPLA). The present case is thought to be unusual in that no pathologic features of MERRF or DRPLA were demonstrated.

Several names (“Cortical Tremor” = Crt Tr, Familial Adult Myoclonic Epilepsy = FAME, Benign Adult Familial Myoclonic Epilepsy = BAFME, Autosomal Dominant Cortical Myoclonus and Epilepsy = ADCME, Familial Cortical Myoclonic Tremor = FCMT, Familial Cortical Tremor with Epilepsy = FCTE, Familial Essential Myoclonus and Epilepsy = FEME, Familial Benign Myoclonus Epilepsy of Adult onset = FMEA, Heredofamilial Tremor and Epilepsy = THE) have been used to define a unique entity, Familial Myoclonic Cortical Tremor with Epilepsy (FCMTE), as proposed by van Rootselaar et al. (2005). All patients with FCMTE criteria share clinical and electrophysiological features. In contrast, Familial Infantile Myoclonic Epilepsy (FIME) and Adult-onset Myoclonic Epilepsy (AME) cannot yet be considered as FMCTE (Striano et al. 2009a).

Objective: To report the detection of mutations in the SCARB2 gene in a previously described patient with progressive myoclonus epilepsy (PME) and demyelinating peripheral neuropathy. Design: Case report. Setting: Epilepsy Genetics Research Laboratory and Epilepsy Service in a tertiary care center. Patient: A 27-year old male patient with PME with preserved intellect and peripheral neuropathy. Results: We have solved a previously reported case of PME, preserved intellect, and demyelinating peripheral neuropathy. The patient is a compound heterozygote for 2 mutations in the SCARB2 gene, which has recently been found to be a cause of PME. Conclusions: Demyelinating neuropathy is a clinical clue to the presence of SCARB2 mutations in PME. Refereed/Peer-reviewed

Myoclonus epilepsy with ragged-red fibers (MERRF) is a maternally inherited mitochondrial disorder defined by: myoclonus, generalized epilepsy, ataxia, and ragged-red fibers in muscle biopsies. About 80% of MERRF patients harbor an m.8344A > G mutation in the tRNA-Lys gene.

Interpretation: Mutations in SCARB2 are an important cause of hitherto unsolved cases of PME resembling ULD at onset. SCARB2 should be evaluated even in the absence of renal involvement. Onset is in teenage or young adult life. Molecular diagnosis is important for counseling the patient and family, particularly as the prognosis is worse than classical ULD. Methods: We reviewed cases of PME referred for diagnosis over two decades in which a molecular diagnosis had not been reached. Patients were classified according to age of onset, clinical pattern, and associated neurological signs into "ULD-like" and "not ULD-like." After exclusion of mutations in cystatin B (CSTB), DNA was examined for sequence variation in SCARB2 and PRICKLE1. Objective: Mutations in SCARB2 were recently described as causing action myoclonus renal failure syndrome (AMRF). We hypothesized that mutations in SCARB2 might account for unsolved cases of progressive myoclonus epilepsy (PME) without renal impairment, especially those resembling Unverricht-Lundborg disease (ULD). Additionally, we searched for mutations in the PRICKLE1 gene, newly recognized as a cause of PME mimicking ULD. Results: Of 71 cases evaluated, 41 were "ULD-like" and five had SCARB2 mutations. None of 30 "not ULD-like" cases were positive. The five patients with SCARB2 mutations had onset between 14 and 26 years of age, with no evidence of renal failure during 5.5 to 15 years of follow-up; four were followed until death. One living patient had slight proteinuria. A subset of 25 cases were sequenced for PRICKLE1 and no mutations were found. Refereed/Peer-reviewed

We describe a patient who presented with parkinsonism associated with the A8344G myoclonus epilepsy, ataxia, and myopathy with ragged red fibers mutation in the tRNA Lys gene. In addition, neurogenic changes and mitochondrial myopathy with ragged red fibers were observed. Neither myoclonus epilepsy nor other clinical signs described in association with A8344G were noted. Similar to previously reported patients with parkinsonism and mtDNA deletions, the symptoms of our patient responded favorably to levodopa therapy.

Researchers at St Vincent's Hospital, Victoria, Australia, measured cortical excitability using transcranial magnetic stimulation in 157 patients with epilepsy (95 generalized and 62 focal) and their asymptomatic siblings and results were compared to those of 12 controls and 20 of their siblings.

Seizure disorders are among the most common neurological diseases. The clinical epileptic syndrome is determined by the anatomical localization and extent of the cerebral lesions. In the absence of exogenous cerebral damage or in the presence of a diffuse cerebral lesion, a primary generalized epilepsy is likely to develop as an expression of genetic factors. It is becoming increasingly apparent that many epileptic syndromes, both idiopathic and symptomatic, have a genetic background. Among the idiopathic forms, gene loci have been identified for juvenile myoclonus epilepsy and for benign familial neonatal convulsions. Epilepsy with dense microsphere accumulation is reported in Friedmann's Syndrome.

Although marked atrophy of the tegmentum of the mid-brain is a known computed tomography (CT) and magnetic resonance imaging (MRI) feature in patients with dentato-ruburo-pallido-luysian atrophy (DRPLA), this is the first report of marked high signal intensity of the globus pallidus on proton and T2-weighted MR images in a patient in the early stage of DRPLA of the myoclonus epilepsy type. We suggest that the globus pallidus may be involved in the early stage of DRPLA of this type. Magnetic resonance imaging is considered to be useful for the early detection of involvement of the globus pallidus and in the clinical diagnosis of DRPLA.

Lafora disease (EPM2A and EPM2B genes); myoclonus epilepsy with ragged red fibers; or MERRF (mtDNA tRNA genes), and Dentatorubral-pallidoluysian atrophy or DRPLA (ATNI gene) are three severe forms of progressive myoclonus epilepsy. The corresponding gene defects have been identified and molecular diagnosis is now widely available. Recent advances in genetics and molecular biology offer promising venues toward the development of new therapies. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at www.ncbi.nlm.nih.gov/ books).

Cytochrome c oxidase (CCO) activity was shown by biochemical and histochemical examination to be decreased in the skeletal muscles of twelve patients with mitochondrial myopathies, especially in 8 chronic progresssive external ophthalmoplegia (CPEO) cases, which included 2 Kearns-Sayre syndrome and 6 ocular myopathy patients. In 4 MELAS patients, NADH cytochrome c reductase activity was decreased. Immunocytochemical examination, using anti-CCO, anti-complex I and III rabbit sera revealed that CCO was stained more weakly in the muscle fibers of one of the CPEO patients than in those of the control.

A TRH analog, (γ-butyrolactone-γ-carbonyl-L-histidyl-L-pro-linamide citrate) was effective in improving myoclonus, cerebellar symptoms and psychic activity in one case of degenerative myoclonus epilepsy.The drug was found to exert an excellent effect on psychic activity, in-cluding volition and motivation. The drug also proved to have antimyoclonic and cerebellar symptom-improving actions.The drug markedly inhibited activation of paroxysmal discharges with photic stimulation, and completely eliminated the intermixing EMG from the basic pattern.The effects appeared after 3 to 4 days of treatment, and persisted for 30 to 40 days after withdrawal.

Auditory brain stem responses (BSR) were studied in five cases including 2 acoustic neurinomas, degenerative type of myoclonus epilepsy, pontine glioma and the 4-th ventricle tumor.They showed typical BSR suspecting of brain stem lesions, and the BSR patterns were compared with those of animal experiments for discussion of the topographical differential diagnosis. In two patients with acoustic neurinoma, nothing but wave I was recognized at the pathologic side, and normal BSR was recorded at the healthy side. The BSR was similar to that of a cat destructed ipsilateral cochlear nucleus.In the patient with degenerative type of myoclonus epilepsy, wave I was reconized only in both sides.In the patient with pontine glioma, wave 1, 2 and 3 at the right side and wave 1 and 2 at the left side were recognized, but the following components were obscured in both sides. The right side response was considered similar to BSR of a cat destructed bilat. inf. colliculus, and the left side one was similar to that of a cat with destruction of bilat. Sup. olivery nucleus complex.In the patient with the 4-th ventricle tumor, wave 1, 2, 3 and 4 were recognized in both sides, and probably wave 5 was depressed in both sides. BSR was considered similar to that of a cat with destruction of contralateral inf. colliculus or contralateral sup. olivery nucleus complex. It was considered that the BSR pattern was suggestive of a medial lesion of the upper portion of the brain stem.The data of animal experiments could not be applied to the clinical use, but it could be very useful for topographical differential diagnosis of the brain stem lesions.

SUMMARY A 28–year-old male of progressive my-oclonus epilepsy was reported, who had showed a gradual progression in myoclonus, mental retardation and cerebellar symptoms, and had been treated with a large dosage of diphenylhydantoin. Neuropathologically, slight degenerative changes of the cerebral cortex, especially in the IV layer, the external pallidum, and the dentate and olivary nuclei were observed. The most obvious change was diffuse reduction of Purkinje's and granular cells in the cerebellum. A congenital cyst was found with surrounding gliosis in the central teg-mental tract of the pons. A significant relationship between myoclonus and the cyst was proposed, and furthermore, influences of diphenylhydantoin intoxication on the clinicopathological development of myoclonus epilepsy were emphasized.

We report a case of Ramsay Hunt syndrome which was clinically characterized by myoclonus epilepsy, cerebellar ataxia, convulsions, and dementia. Major necropsy findings were dentatorubral-pallidoluysian atrophy. Dentatorubral-pallidoluysian atrophy may be associated with a variety of clinical symptoms, amongst which Ramsay Hunt syndrome can be included.

One hundred and twelve family histories, with mitochondrial cytopathies in which (‘vertical’) transmission from at least one generation to the other occurred, were reviewed. A paternal versus maternal transmission ratio of 2:3.4 was found. The mitochondrial cytopathies with ‘vertical’ transmission were split into a group with chronic progressive external ophthalmoplegia (CPEO) and a group without CPEO (83 and 29 families respectively). The paternal versus maternal transmission ratios amounted to 1:1.2 for the CPEO related cytopathies and 1:3.3 for the non-CPEO-related cytopathies with the exclusion of X-chromosomal myopathy and myoclonus epilepsy with ragged-red fibres (MERRF). For MERRF a mitochondrial heredity could not be excluded. For the other hereditary mitochondrial cytopathies a Mendelian form of hereditary transmission is most likely. For the CPEO related transmittable cytopathies an autosomal dominant heredity of a pleiotropic gene is the most probable form of transmission.

A 20-year-old man showed myoclonus epilepsy, cerebellar ataxia, and macular cherry-red spot. Assay of lysosomal enzymes demonstrated that the liver, leukocytes, and blood plasma were severely deficient in acid β-galactosidase. Partial deficiency of β-galactosidase activity was shown in kidney tissue. The plasma and leukocytes were also moderately deficient in β-galactosidase. There was an increase in the less acidic mucopolysaccharides in the patient's urine. A coarse face and the deformity of lumbar vertebrae also suggested a disturbance of mucopolysaccharide metabolism. The case resembles the ones reported recently from two laboratories, but the localization of the enzyme deficiency was different in each. These cases seem to be in a series of GM1-gangliosidosis variants caused by a localized deficiency of β-galactosidase.

SUMMARY In their totality, investigations on the clinical biochemistry of human epilepsy have not been conclusive and did not provide information useful for the diagnosis or treatment of this disease. There are good reasons to assume that the epileptic seizure is accompanied by disturbances in the metabolism of water, of some electrolytes, of fast-moving globulins in the central nervous system and in the CSF and perhaps also of some amino-acids. It is not possible, however, to specify these general assumptions. So far as myoclonus epilepsy is concerned, the possibility exists that further investigation into the metabolism of α2-globulins may give a better understanding of this genetical condition. REASUMEA Dans leur totaliteA, les recherches sur la biochimie clinique de l'eApilepsie humaine n'ont pas eAteA concluantes et n'ont pas fourni des renseignements utiles pour le diagnostic ou le traitement de cette affection. Il y a de bonnes raisons de supposer que la crise eApileptique est accompagneAe de troubles du meAtabolisme de l'eau, de quelques eAlectrolytes, des globulines qui migrent rapidement dans le systeGme nerveux central et dans le L.C.R. et, peut-eCtre aussi, de quelques amino-acides. II n'est pas possible cependant de preAciser ces hypotheGses geAneArales. En ce qui concerne l'eApilepsie myoclonique, il est possible qu'une recherche plus poussee dans le meAtabolisme des aL2-globulines puisse donner une meilleure compreAhension de cette maladie geAneAtique.

Intraganglionic inclusion bodies of presumably non-viral ongm have been associated with a range of defined neurologic disturbances, including myoclonus epilepsy (1), Pick's disease (2), and Parkinson's disease (3). In each of these entities the inclusions present a pattern of characteristics (histochemical and histologic properties, topographical distribution and size) which permits a degree of diagnostic differentiation. In the Parkinsonian states, the inclusion is typically intracytoplasmic, and most frequently encountered in the pigmented neurons of the mesencephalic and rhombencephalic nuclei (4). Two elderly patients with progressive dementia associated with quadriparesis in flexion, and without any Parkinsonian stigmata, have been studied, demonstrating at autopsy widely disseminated intracytoplasmic ganglionic inclusions morphologically and histochemically indistinguishable from those initially described by Lewy in Parkinson's disease (paralysis agitans).

A twenty-five-years-old man who had no hereditary abnormal trait but had a tendency to luxation of the omo-branchial joints since childhood. Convulsive seizures began to occur at thirteen years, myoclonia at fourteen years and cerebellar symptoms and dementia at about nineteen years, succumed to bronchopneumonia after eleven odd years of illness.Principal pathologic findings were splenomegaly (160 gm) and enlarged mesenteric lymph nodes in both of which Gaucher's cells containing histochemically demonstrable glycolipids were observed to be present.At autopsy gross pathologic examination failed to reveal any significant adverse findings for the brain. Microscopically, nerve cell of the cerebellar dentate nuclei were noted to be considerably defective, hence evidence of regional neuronophagia, and defect of Purkinje's cells was also noted. A histopathologic finding of particular note was vascular changes characterized by conspicuous enlargement and proliferation of adventitial cells which were frequent in the cerebral white matter, amygdaloid nuclei, claustrum and cerebellum. Some of the enlarged adventitial cells bore resemblance to Gaucher's cells and presented histochemical findings suggestive of the presence of glycolipids. Moreover, proliferation of blood vessels was prominent in the amygdaloid nuclei.These findings seems to represent a juvenile form of Gaucher's disease.

Summary The authors reported the clinical picture of myoclonus epilepsy occurred in three siblings of one family. In Case 1 the illness began at 14 years, and she is now still alive. In Case 2 the disease began at 7 years and death occurred at the age of 14 after the clinical course of about 7 years. In Case 3 (autopsy case), the onset of the disease was 6 years of age, and death occurred at 11 after the clinical history of 5 years. Autopsy revealed the degenerative lesions of the dentate and the olivary nucleus associated with gliosis of the pallidum due to a perinatal anoxic damage. In two siblings (Cases 2, 3) the duration of the disease is shorter, and the age of death is less advanced as compared with the cases of degenerative type of myoclonus epilepsy reported in the literature, and the authors discussed its reason.