Progressive myoclonic epilepsy: A clinical, electrophysiological and pathological study from South India

doi:10.1016/j.jns.2006.09.021

Journal of the Neurological Sciences

Volume 252, Issue 1, January 2007, Pages 16-23

https://doi.org/10.1016/j.jns.2006.09.021 Get rights and content

Abstract

Progressive myoclonic epilepsy (PME) is a syndrome complex encompassing different diagnostic entities and often cause problems in diagnosis. We describe the clinical, electrophysiological and pathological features of 97 patients with the diagnosis of PME evaluated over 25 years. Case records of confirmed patients of Neuronal ceroid lipofuscinosis (NCL = 40), Lafora body disease (LBD = 38), Myoclonic epilepsy with ragged red fibers (MERRF = 10), and probable Unverricht–Lundberg disease (ULD = 9) were reviewed. The mean age at onset in patients with NCL (n = 40) was 5.9 ± 9.1 years (M:F:: 28:12). Subtypes of NCL were: late infantile (n = 19), infantile (n = 8), juvenile (n = 11) and adult (n = 2) NCL. EEG (n = 37) showed varying degree of diffuse slowing of background activity in 94.6% and epileptiform discharges in 81.1% of patients. Slow frequency photic stimulation evoked photo-convulsive response in 5 patients only. Giant SSEP was demonstrated in 7 and VEP study revealed a prolonged P100 (2) and absent waveform (7). Electrophysiological features of neuropathy were present in 3 patients. Presence of PAS and Luxol Fast Blue (LFB) positive, auto fluorescent (AF) ceroid material in brain tissue (n = 12) and electron microscopy of brain (n = 5), skin (n = 28) and muscle (n = 1) samples showing curvilinear and lamellar bodies established the diagnosis. Patients of LBD (mean age of onset at 14.4 ± 3.9 years, M:F:: 24:14) with triad of PME symptoms were evaluated. EEG (n = 37) showed variable slowing of background activity in 94.6% and epileptiform discharges in 97.4%. Photosensitivity with fast frequency was observed only in 5 patients. CT (n = 32) and MRI (n = 4) revealed diffuse cortical atrophy. Giant SSEP was demonstrated in 24 patients of LBD while VEP study revealed a prolonged P100 (4) and absent waveform (8). Electrophysiological features of neuropathy were present in one patient. Diagnosis was established by the presence of PAS positive diastase resistant, Lugol's Iodine labeled inclusions in sweat glands of axillary skin (n = 35), brain (n = 2) and liver (n = 1). Ten patients with MERRF (mean age at onset: 14.6 ± 5.8 years; M: F:: 3:2) had triad of PME symptoms. Muscle biopsy revealed oxidative reaction product and classical ragged red fibers. In nine patients of PME without cognitive decline, probable diagnosis of ULD (mean age at onset: 13.8 ± 9.5 years) was considered after biopsy of skin and/or muscle excluded other forms of PMEs. Neuronal ceroid lipofuscinosis and Lafora body diseases were the common causes of PME in the series from south India. This is one of the largest series from the Indian subcontinent to the best of our knowledge. Photosensitivity is notably less common in LBD/NCL in this series distinctly different from those reported in the literature. Further exploration is required to determine whether different genotype is responsible. Morphological changes were helpful in diagnosis and could be confirmed by biopsy of peripheral tissues like skin and muscle in majority (60%). Electron microscopy was helpful in the diagnosis NCL and MERRF.

Introduction

Progressive myoclonic epilepsy (PME) is a syndrome complex that is characterized by the development of progressive myoclonus, cognitive impairment, ataxia and other neurological deficits. It encompasses different diagnostic entities and often causes problem in diagnosis leading to nosological confusion. However, recent advances have clarified the features of these disorders and facilitated a rational approach to diagnosis [1], [2], [3], [4], [5], [6]. Because of recent developments in molecular genetics, their natural history and biological basis may soon be better understood. The major causes of PME are Unverricht–Lundborg disease, myoclonic epilepsy with ragged-red fiber (MERRF) syndrome, Lafora body disease, neuronal ceroid lipofuscinoses, and sialidoses [3]. There are only few anecdotal case reports of these entities from Indian subcontinent [7], [8], [9], [10], [11], [12].

We describe the clinical, electrophysiological and pathological features of 97 patients of PME evaluated at a single tertiary care referral center from south India, where consanguineous parentage is common and highlight the homogeneous phenotypic features of each specific subgroups.

Section snippets

Patient and methods

In this retrospective study, case records of histopathologically confirmed patients (n = 97) of various types of progressive myoclonic epilepsy (PME), evaluated at the Neurological services at National Institute of Mental Health and NeuoSciences (NIMHANS), Bangalore, India, were analyzed. Patients with i) Clinical evidence of myoclonus, other seizures, cognitive decline, ataxia and other neurological deficits in variable combinations, ii) Supportive electrophysiological features and iii)

Results

There were 63 males and 34 females in this cohort. Their mean age at onset of illness was 10.7 ± 8.2 years (median: 11 years, range: 6 month to 48 years). The duration of illness at the time initial presentation was 2.5 ± 2.2 years. Most of them presented with the classical triad of myoclonus, cognitive decline and neurological deficits. Family history of similar illness was present in 9 patients (9.3%). History of consanguineous parentage was evident in 60 patients (61.8%). Some of the clinical

Discussion

Over last two decades, considerable developments had occurred in the field of PMEs and are now recognized as a group of syndromes with specific aetiologies [1], [3], [6], [14] Genetic tests had further enhanced the understanding of the disease process. According to Berkovic et al, five important causes of PMEs are: Unverricht–Lundborg disease, MERRF syndrome, Lafora body disease, neuronal ceroid lipofuscinoses, and sialidoses [3]. Sialidosis was conspicuously absent in the present series,

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The involvement of Purkinje cells in progressive myoclonic epilepsy: Focus on neuronal ceroid lipofuscinosis
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The progressive myoclonic epilepsies (PMEs) are a group of rare neurodegenerative diseases characterized by myoclonus, epileptic seizures, and progressive neurological deterioration with cerebellar involvement. They include storage diseases like Gaucher disease, Lafora disease, and forms of neuronal ceroid lipofuscinosis (NCL). To date, 13 NCLs have been reported (CLN1-CLN8, CLN10-CLN14), associated with mutations in different genes. These forms, which affect both children and adults, are characterized by seizures, cognitive and motor impairments, and in most cases visual loss. In NCLs, as in other PMEs, central nervous system (CNS) neurodegeneration is widespread and involves different subpopulations of neurons. One of the most affected regions is the cerebellar cortex, where motor and non-motor information is processed and transmitted to deep cerebellar nuclei through the axons of Purkinje cells (PCs). PCs, being GABAergic, have an inhibitory effect on their target neurons, and provide the only inhibitory output of the cerebellum. Degeneration of PCs has been linked to motor impairments and epileptic seizures. Seizures occur when some insult upsets the normal balance in the CNS between excitatory and inhibitory impulses, causing hyperexcitability. Here we review the role of PCs in epilepsy onset and progression following their PME-related loss. In particular, we focus on the involvement of PCs in seizure phenotype in NCLs, highlighting findings from case reports and studies of animal models in which epilepsy can be linked to PC loss.
Clinical and molecular characterization of Unverricht–Lundborg disease among Egyptian patients
2021, Epilepsy Research
Citation Excerpt :
To the best of our knowledge, our study detected CSTB gene mutation in 14 patients from 8 unrelated families, as shown in Table 2. Moreover, five studies from Finland, Maghreb (Tunisia, Algeria, and Morocco), and Western Mediterranean countries reported more than 20 patients (Canafoglia et al., 2017; Genton et al., 1990; Gouider et al., 1998; Hyppönen et al., 2015; Norio and Koskiniemi, 1979; Sipilä et al., 2020); most previous studies included one patient up to ≤20 patients (Bosak et al., 2020; Canafoglia et al., 2012; de Haan et al., 2004; Kim et al., 2018; Kobayashi et al., 2014; Magaudda et al., 2006; Mohamadpour et al., 2017; Saadah et al., 2014; Sinha et al., 2007). In our study, seven families (87.5 % of the patients) were from governorates proximate to the Mediterranean Sea, whereas only one family originated from a governorate in Southern Egypt.
Unverricht-Lundborg disease (ULD) is a common type of progressive myoclonic epilepsy (PME). It is caused mostly by biallelic dodecamer repeat expansions in the promoter region of CSTB gene. Despite highly prevalent in the Mediterranean countries, no studies have been reported from Egypt. This article study the presence of CSTB gene mutations among Egyptian patients clinically suspected with ULD, and describes the clinical and genetic characteristics of those with confirmed gene mutation.
Medical records of patients following up in two specialized epilepsy clinics in Cairo, Egypt were retrospectively reviewed. Twenty patients who belonged to 13 unrelated families were provisionally diagnosed with ULD based on the clinical presentation. Genetic testing was done. Clinical characteristics, demographic data and EEG findings were documented.
Genetic studies confirmed the presence of the CSTB dodecamer repeat expansion in 14 patients from 8 families (frequency 70 %). The mean duration of the follow-up was 5 years. Male to female distribution was 1:1 with a mean age of onset 9.7 years. Consanguinity was noted in 4 families. Eight patients had their first seizure between the age of 10 and 20 years. Myoclonic jerks ranged in severity from mild in three unrelated patients to severe in one. Only 3 had cognitive impairment.
Our study confirms the presence of CSTB mutation among Egyptian patients suspected with ULD. There was no clear phenotype-genotype correlation among the studied group of patients. In addition, we noticed variable inter and intra familial severity among patients from the same family.
Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study
2015, Brain and Development
Patau syndrome, trisomy 13, is the third commonest autosomal trisomy. It is associated with a 25–50% prevalence of epilepsy, but detailed electroclinical descriptions are rare. The occurrence of early-onset photosensitivity has recently been reported in single patients.
We collected electroclinical data on 8 infants (age range from 2 months to 3 years and 9 months, median: 17 months) with Patau syndrome referred for an EEG in our Clinical Neurophysiology Department between 1991 and 2011.
All EEGs, case-notes, cytogenetic diagnosis and neuroimaging when available were reviewed; data on the occurrence of seizures, epileptiform discharges, photoparoxysmal response and their characteristics in terms of positive frequencies, latencies, grade and duration were noted and analysed.
Two patients had been previously diagnosed with epilepsy (one with tonic spasms and one with multiple seizure types). We found 3 patients with photosensitive myoclonic epilepsy (37.5%), and one with non-photosensitive myoclonic epilepsy. We also recorded non-epileptic myoclonic jerks in one patient known to suffer from epileptic spasms. Among photosensitive patients we found self-limited, Waltz’s grade 2–4, spike-wave/polyspike-wave discharges in low, medium and high frequency ranges in two patients and in the high frequency range in the third patient, with latencies and duration from less than 1 s to a maximum of 9 s.
In our cohort of Patau syndrome patients, we found a high prevalence of spasms and photic-induced myoclonic jerks. Photosensitivity shows an unusual early age of onset.
Clinical, electrophysiological, imaging, and ultrastructural description in 68 patients with neuronal ceroid lipofuscinoses and its subtypes
2014, Pediatric Neurology
Citation Excerpt :
An association among the presence of signal changes, atrophy, seizures, giant SSEP, and visual impairment had statistical significance, which may point toward clinical diagnosis of NCL (P < 0.05). The presence of inclusions under electron microscopy is essential for diagnosis and is helpful in subtyping NCL in the absence of genetic studies.6,10,11,13,27,43,44 Brain biopsies showed prominent involvement of cortical neurons with complete sparing of white matter.
We evaluated the clinical, electrophysiological, imaging, and ultrastructural features of neuronal ceroid lipofuscinoses and its subtypes.
The clinical, electrophysiological, imaging, histopathological, and ultrastructural features of 68 (age at onset: 4.3 ± 5.4 years) neuronal ceroid lipofuscinoses and its subtypes (infantile neuronal ceroid lipofuscinoses [9], late infantile neuronal ceroid lipofuscinoses [34], juvenile neuronal ceroid lipofuscinoses [23], and adult neuronal ceroid lipofuscinoses [2] were evaluated. Skin (n = 56), brain (n = 12), muscle (n = 4) and nerve (n = 1) biopsies confirmed the diagnosis.
Clinical manifestations were milestone regression (93%), involuntary movements (92%), seizures (89%), myoclonus (79%), and visual impairment (68%). Response to anticonvulsants was unsatisfactory. Electroencephalography (n = 59) was abnormal in 90%: background slowing (90%); epileptiform discharges (71%), and photoparoxysmal response (4/21). Visual-evoked (n = 33) and somatosensory evoked (n = 40) potentials were abnormal in 62% and 63% of patients. Cranial computed tomography (n = 33) showed diffuse cerebral (61%) and cerebellar (27%) atrophy. Magnetic resonance imaging was abnormal in all 43 patients who were scanned: diffuse atrophy (100%), cerebellar atrophy (40%), leukoencephalopathy (65%), and thalamic T2 W hypointensity (33%). Dermal inclusions such as curvilinear inclusions were the most common abnormality: late infantile neuronal ceroid lipofuscinoses (97%), juvenile neuronal ceroid lipofuscinoses (100%), and infantile neuronal ceroid lipofuscinoses (88%). Additional fingerprint inclusions were noted: juvenile neuronal ceroid lipofuscinoses (43%), late infantile neuronal ceroid lipofuscinoses (15%), and infantile neuronal ceroid lipofuscinoses (13%). Granular osmiophilic deposits were noted in 50% of infantile neuronal ceroid lipofuscinoses. In 75% of patients, there was good correlation between the clinical subtype and ultrastructural inclusion pattern. In 27% of neuronal ceroid lipofuscinoses, multiple inclusions were noted.
The diagnosis of neuronal ceroid lipofuscinoses should be considered in individuals with characteristic clinical presentations and characteristic ultrastructural dermal inclusions. Three fourths showed morphological correlation of the inclusions with neuronal ceroid lipofuscinoses subtype.
Neuronatin-mediated aberrant calcium signaling and endoplasmic reticulum stress underlie neuropathology in Lafora disease
2013, Journal of Biological Chemistry
Lafora disease (LD) is a teenage-onset inherited progressive myoclonus epilepsy characterized by the accumulations of intracellular inclusions called Lafora bodies and caused by mutations in protein phosphatase laforin or ubiquitin ligase malin. But how the loss of function of either laforin or malin causes disease pathogenesis is poorly understood. Recently, neuronatin was identified as a novel substrate of malin that regulates glycogen synthesis. Here we demonstrate that the level of neuronatin is significantly up-regulated in the skin biopsy sample of LD patients having mutations in both malin and laforin. Neuronatin is highly expressed in human fetal brain with gradual decrease in expression in developing and adult brain. However, in adult brain, neuronatin is predominantly expressed in parvalbumin-positive GABAergic interneurons and localized in their processes. The level of neuronatin is increased and accumulated as insoluble aggregates in the cortical area of LD brain biopsy samples, and there is also a dramatic loss of parvalbumin-positive GABAergic interneurons. Ectopic expression of neuronatin in cultured neuronal cells results in increased intracellular Ca²⁺, endoplasmic reticulum stress, proteasomal dysfunction, and cell death that can be partially rescued by malin. These findings suggest that the neuronatin-induced aberrant Ca²⁺ signaling and endoplasmic reticulum stress might underlie LD pathogenesis.
Lafora disease ubiquitin ligase malin promotes proteasomal degradation of neuronatin and regulates glycogen synthesis
2011, Neurobiology of Disease
Lafora disease (LD) is the inherited progressive myoclonus epilepsy caused by mutations in either EPM2A gene, encoding the protein phosphatase laforin or the NHLRC1 gene, encoding the ubiquitin ligase malin. Since malin is an ubiquitin ligase and its mutations cause LD, it is hypothesized that improper clearance of its substrates might lead to LD pathogenesis. Here, we demonstrate for the first time that neuronatin is a novel substrate of malin. Malin interacts with neuronatin and enhances its degradation through proteasome. Interestingly, neuronatin is an aggregate prone protein, forms aggresome upon inhibition of cellular proteasome function and malin recruited to those aggresomes. Neuronatin is found to stimulate the glycogen synthesis through the activation of glycogen synthase and malin prevents neuronatin-induced glycogen synthesis. Several LD-associated mutants of malin are ineffective in the degradation of neuronatin and suppression of neuronatin-induced glycogen synthesis. Finally, we demonstrate the increased levels of neuronatin in the skin biopsy sample of LD patients. Overall, our results indicate that malin negatively regulates neuronatin and its loss of function in LD results in increased accumulation of neuronatin, which might be implicated in the formation of Lafora body or other aspect of disease pathogenesis.

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Progressive myoclonic epilepsy: A clinical, electrophysiological and pathological study from South India

Abstract

Introduction

Section snippets

Patient and methods

Results

Discussion

Lancet Neurol

Seizure

J Neurol Sci

Biochim Biophys Acta

Progressive myoclonus epilepsies: specific causes and diagnosis

N Engl J Med

Progressive myoclonus epilepsies and related disorders — a clinical and pathological appraisal

Neurol India

Progressive myoclonic epilepsies: clinical and genetic aspects

Epilepsia

Diseases of gray matter

Lysosomal and peroxisomal disorders

Progressive myoclonic epilepsies: the experience of a French epilepsy center

Neuropediatrics

Lafora's disease: a case report

Neurol India

Lafora's disease in south India — a clinical, electrophysiological and pathological study

Epilepsia

Atypical inclusion bodies with myoclonic epilepsy

Acta Neuropathol

Progressive myoclonic epilepsies without EEG abnormality

Neurol India

Consanguinity and the incidence of childhood genetic diseases in Karnataka

J Med Genet

Classification of progressive myoclonic epilepsies and related disorders

Ann Neurol

The NCL (Batten–Vogt syndrome)

Clinical classification of NCL subtypes

Am J Hum Genet

Progressive neurometabolic brain disease

The adult onset and a new late adult form of NCL

Acta Neuropathol (Berlin)

Kuf's disease — a critical appraisal

Brain