Progressive myoclonus epilepsies are characterized by myoclonic seizures, tonic-clonic seizures, and progressive neurological dysfunction including ataxia and dementia. The document discusses several specific causes of progressive myoclonus epilepsy including Unverricht-Lundborg disease, Lafora's disease, myoclonus epilepsy with ragged-red fibers, sialidoses, neuronal ceroid lipofuscinoses, and others. It provides details on clinical features, pathogenesis, diagnosis, and genetic basis for several of these conditions.

1. Progressive myoclonus epilepsiesDR.SRIRAMA ANJANEYULU

2. INTRODUCTIONcharacterized by myoclonicseizures,tonic-clonic seizures and progressive neurological dysfunction(ataxia , dementia). Myoclonus is severe, with bilateral synchronous or multifocal .Convulsive seizures and neurological decline predominate over myoclonus.accounts for less than 1% of epilepsy cases at specialist centres. Geography and ethnic variations amongst the specific genetic disorders.UnverrichtLundborg Disease, has an incidence of 1:20,000 in Finland.

3. Classical PME Unverricht-Lundborg disease.Lafora's disease.Myoclonus epilepsy and red-ragged fibres (MERRF).Sialidoses. NCLs.RARE CAUSES OF PMEGaucher’s disease(non infantile neuronopathic form)GM2gangliosidosis(late infantile,juvenile)Biotin responsive encephalopathyNeuroaxonal dystrophy.Hallervordonspatz disease.Action myoclonus-renal failure syndromeDentatorubralpallidolusyian atrophy.PME with deafness.PME with lipomas.

4. Diagnosis was made according to the criteria presented by Koskiniemi(1974), so that at least three other criteria (Table 1) in addition to stimulus-sensitive myoclonus were present.Epilepsia, 20,503-510, 1979

5. Differential diagnosisMyoclonic seizures from non epileptic myoclonus.(asso.cli.features-GTCS,EEG).From benign idiopathic generalised epilepsies, such as juvenile myoclonic epilepsy , JAE (progressive neurological signs,intractable seizures or both).PGE with AED toxicity-ataxia,impairedmentation.Myoclonus in BG of fixed neurological deficit,no e/o detoriation.

6. Overview of myoclonus categorizations

7. Unverricht-Lundborg disease

8. ULDInitially described in Finland, subsequently recognized worldwide.Clinical features -onset at age 8-13 years with myoclonus , GTCS , absences -progression to ataxia ,dysarthria,intention tremor and dementia -neuronal loss with no evidence of storage material .Myoclonus –severe ,ppted by movement , stress,sensory stimulus , more in morning.Variable disease progression slow/ faster course, even within the same family. Periods of stabilization.IQ decline 10 points /decade. gene involved in ULD (EPM1) has been identified as CSTB on chr 21, which encodes cystatin B, an inhibitor of cysteineproteases,lysosomal protease (Pennacchio et al., 1996).neuroprotectiverole for cystatin B, Thirteen years since the identification of the causative defect in ULD, pathogenesis -mostly not understood.Improvement with sodium valproate,LVM whereas phenytoin can bedeleterious.

9. ULDIdentification of the clinical features is the first step in diagnosing the disease. When suggestive indications are found, mutational analysis of CSTB may be attempted. Genetic testing for prenatal diagnosis and for the identification of carriers among at-risk individuals.

10. Lafora's disease

11. Lafora Diseaseseizures, myoclonus, and dementia.Onset is in adolescence(10-18yrs), rapidly progressive,death occurring before 25 years of age.Insidious, near-simultaneous appearance of headaches, difficulties in school work, MJ, generalized seizures, and, in many cases, visual hallucinations of both epileptic and psychotic origin.The myoclonus, seizures, and hallucinations gradually worsen and become intractable.dementia sets in, and by 10 years after onset the patient is in nearcontinuousmyoclonus with absences, frequent generalized seizures, and profound dementia or vegetative state (Minassian, 2001; Striano et al., 2008).

12. LDLafora bodies, round, basophilic, strongly PAS-positive intracellular inclusions seen in the cerebral cortex, SN, thalamus, GP, and dentate nucleus. Polyglucosan bodies are also seen in muscle, liver, heart, skin, and retina.Polyglucosans-poorly branched forms of glycogen that could arise from imbalance between the enzymatic activities of glycogen synthase and branching enzyme.Gene (EPM2A) on chromosome 6q24 ,30 pathogenic mutations .

13. LDClinical diagnosis is not usually difficult when the disease is fully developed. Lafora bodies -skin biopsies constitute a unique marker.Although the screening of EPM2A for mutations can be carried out easily. Mutational screening of EPM2A is of critical importance for prenatal diagnosis and carrier identification.

14. MERRF

15. MERRF mitochondrial disorder -broad clinical spectrum and intrafamilial variability in severity and age of onset.deafness , short stature, optic atrophy , neuropathy,migraine and myopathy . Decreased metabolism for glucose and oxygen on PET and an increase in organic phosphate in resting muscle.biochemical assays of mitochondrial respiratory enzymes may be normal and red-ragged fibres absent, suggesting a complex pathogenesis.

16. MERRFmaternal line as a paradigmatic example of mitochondrial inheritance. Clinical variability is dependent on the amount of mutated mt DNA. In this perspective, MERRF may also manifest as a sporadic condition. A missense mutation (A8344G) affecting the tRNAlys, and, consequently, the translation of all genes encoded by the mtDNA, has been described. The mutation produces multiple deficiencies in the enzyme complexes of the respiratory chain, most prominently involving NADH-CoQreductase (complex I) and cytochrome C oxidase (complex IV)

17. MERRFAlthough increased levels of piruvate, lactate and red-ragged fibres are often found, identification of clinical signs is crucial for diagnosis. Genetic testing may also be used to perform prenatal diagnosis and to identify at-risk individuals.

18. Sialidoses

19. AR lysosomial disorders -complex phenotypes subgrouped into sialidosis type I and type II.Sialidosis I occurrs in the second decade of life, presents with cherry-red macular spots, progressive severe myoclonus, gradual visual impairment,lensopacieies,mild PN, tonic-clonic seizures and ataxia without dementia .Sialidosis type II includes complex phenotypes showing additional clinical symptoms such as coarse facies, dysostosismultiplex,corneal clouding, mental impairment and hearing loss, and may be subdivided into juvenile and infantile forms depending on the age of onset.

21. Neuronal lipidosis and vacuolated Kupffer cells .diagnosis can be confirmed by elevated urinary sialylil-oligosaccharides and a deficiency of N-acetyl neuroaminidase in leukocytes and cultured skin fibroblasts .In some cases of type II sialidosis — predominantly in Japanese 3-galactosidase deficiency is found in addition to neuroaminidase deficiency .Complementation between neuroaminidase-deficient cells and combined neuroaminidase/3-galactosidase deficiency suggests different genetic aetiology and pathogenesis .Classification of sialidoses into type I and II has only a clinical value, whereas the definition of neuroaminidase deficiency and galactosialidosis best describes the aetiology and pathogenesis of sialidoses.

22. A direct implication of the neuroaminidase gene (NEU) on chromosome 6p has been detected in neuroaminidase deficiency .In galactosialidosis mutations were found within the cathepsin A gene on chromosome 20q encoding a 32-kDa protein (PPGB, protective protein for 3-galactosidase, which is required to protect galactosidase from degradation and to promote the catalytic action of neuroaminidase .

23. Biochemical assays focus on measuring the activity levels of neuroaminidase and 3-galactosidase. Mutational screening of the NEU and PPGB genes is a powerful tool for confirming the clinical diagnosis in probands and may be applied in prenatal diagnosis and carrier identification.

24. NCLs

25. NCL’SAR neurodegenerative disorders characterized by accumulation of ceroidlipopigment of granular, curvilinear or fingerprint appearance in the lysosomes of various tissues.CLN2, CLN3 and CLN4 are most commonly involved in PME. CLN5, CLN6 and CLN8 are very rare disorders restricted to specific geographical areas.

26. NCL’SThe NCLs are PMEs, because they affect previously normal children, are progressive, and include worsening myoclonus during these children’s short lives. They are grouped together on pathologic grounds due to the common presence of neuronal and extraneuralautofluorescent pigment accumulations. Under the electron microscope, the accumulated material takes three different forms: granular osmiophilic deposits (GRODs), curvilinear profiles, and fingerprint bodies. N Ramachandran et al,Theautosomal recessively inherited progressive myoclonus epilepsies and their genes,Epilepsia, 50(Suppl. 5):29–36, 2009

27. CLN1First symptoms appear between 8 and 18 months of age with irritability, and the baby becomes difficult to comfort.This is followed by rapid psychomotor deterioration, central hypotonia, and deceleration of head growth. Myoclonic jerks and other seizures are present, and blindness occurs, with optic atrophy. Hand-wringing often develops during the disease course, which, along with the slowing of head growth and developmental regression, raises the relatively optimistic differential of Rett syndrome, but unlike the latter, CLN1 does not stabilize, continuing instead to deteriorate until death in early childhood (Mole et al., 2005).

28. Neuronal ceroidlipofuscinosislate infantile type (CLN2)Myoclonic, tonic-clonic, atonic or atypical absence seizures between 2.5 and 4 years of age.Psychomotor delay and ataxia appear a few months later, whereas visual failure develops as the disease progresses.Prognosis is very poor, in that seizures are intractable, dementia is relentless and death usually occurs by the age of 5 years .The gene localized on chromosome 11 and identified as encoding tripetidyl peptidase 1 (TPP1) . In the past, electron microscopic detection of typical curvilinear lipidic inclusions was used to confirm the clinical diagnosis and to reach a prenatal diagnosis in uncultured amniocytes. The recent cloning of the gene has provided a further tool for the diagnosis of late infantile NCL.

29. Neuronal ceroidlipofuscinosis, juvenile type or Batten's disease (CLN3)Appears between 5 and 10 years of age, with rapid deterioration of vision and progressive dementia.Loss of vision and intellectual deterioration occur rapidly, followed by seizures and psychosis . Ocular pathology is initially a pigmentary retinopathy often misdiagnosed as retinitis pigmentosa .In adolescence, speech, mobility, and cognitive skills deteriorate and seizures set in. Children have behavioral problems such as aggressiveness, psychosis, mood disturbance, and anxiety. Speech becomes dysarthric and dysfluent with echolalia. As the disease progresses, myoclonic jerks and parkinsonian features and gait develop.Clinical course may vary among patients, death usually occurs within about 10-12 years of onset .Gene encodes for an integral membrane protein (CLN3) that is primarily localized in the Golgi apparatus. >20 different mutations have been observed . Diagnosis may be established by electron microscopy examination of curvilinear and rectilinear bodies and fingerprint profiles in skin biopsies. Mutational screening of CLN3 may also be attempted for the molecular diagnosis of Batten's disease.

30. Neuronal ceroidlipofuscinosis, adult type(CLN4, Kufs'disease)Kufs' disease is a very rare disorder characterized by generalized seizures with onset around 30 years of age and a subsequent cerebellar syndrome presenting with myoclonic jerks and extrapyramidal symptoms. Notably, fundoscopy examination is normal and blindness is absent.Death occurs within about 10-12 years of onset.The pattern of inheritance is still unclear, in that both autosomal dominant and autosomal recessive inheritance have been described.Since the Kufs' disease gene has not yet been localized or cloned, electron microscopy examination of muscle biopsies to detect curvilinear bodies is the only diagnostic test available.

31. Action Myoclonus–Renal Failure Syndrome (AMRF)This disorder may present with proteinuria and glomerulosclerosis as early as 9 years of age. The neurologic syndrome does not manifest until early adulthood, after age 17 but before age 25. The neurological syndrome begins with bilateral hand tremor worsened with activity. Progresses to include myoclonus that is highly inducible by a wide range of stimuli, highly emotionally enhanced, and rapidly progressive and debilitating.Dementia is minimal to not present in most patients, but ataxia is pronounced. The renal syndrome (collapsing glomerulopathy) is also progressive and, if not treated with transplantation, fatal.The neurologic phenotype is not connected to the renal failure, as it progresses unaltered after renal function is corrected by transplantation (Badhwar et al., 2004).Pathology reveals some accumulation of autofluorescent material seemingly not in neurons, perhaps in astrocytes, in contradistinction to the NCL where the material is very much neuronal (Badhwar et al., 2004; Berkovic et al., 2008).

32. Gaucher DiseaseCharacterized by hepatosplenomegaly, anemia, thrombocytopenia, bone pain, and other systemic features. When the central nervous system is involved, the disease is classified as type II (early onset and severe) or type III (late onset and slowly progressive).Patients with types IIIB and IIIC have aggressive systemic Gaucher and relatively mild neurologic features that do not include myoclonus.Patients with type IIIA have relatively mild systemic Gaucher and a PME (Patterson et al., 1993; Bohlega et al., 2000). Occasionally, the systemic disease in type IIIA is so mild that it is unrecognized for some time into the course of the PME, and the disease is confused for a pure PME such as LD (Filocamo et al., 2004).

33. SCHINDLER DISEASEAR disorder of the lysosomal enzyme a-N-acetyl galactosaminidase, has two clinical phenotypes. Type I disease is a severe neurodegenerative disorder with normal development for the first nine to 12 months. A period of developmental delay is followed by rapid regression, myoclonus, cortical blindness, spasticity and decorticate posturing, with a vegetative state reached by 3-4 years. Urinary oligosaccharides are abnormal and the diagnosis can be confirmed by specific enzyme assays in white cell pellets or cultured skin fibroblasts. Ultrastructurally autonomic axons of the myenteric plexus from a rectal biopsy tissue show a typical tubulovesicular storage material, making type I Schindler disease the only inherited neuraxonal dystrophy for which the specific biochemical and molecular defects have been identified. The gene for a-N-acetyl galactosaminidase, which maps to chromosome 22q13.1 -ql3.2, has been totally characterized and mutations identified.There is no effective treatment for this disorder.

34. ALPERS DISEASEAlpers disease usually has its onset between 1 and 2 years of age, and is characterized initially by developmental delay and then by seizures, which may be of a myoclonic or tonic-clonic type. Psychomotor regression becomes evident, accompanied by spasticity, nystagmus, areflexia, abnormal respiratory pattern and liver dysfunction. Myoclonic seizures and liver disease often worsen in the terminal stages, with death occurring in 3-4 years. Like Leigh disease there may be clinical worseningduring infection and spongiform degeneration of the brain develops, but these degenerative changes are in distinct and different regions of the brain to those seen in Leigh disease.About half of the patients have a disorder of oxidative phosphorylation,pyruvatedehydrogenase deficiency or the Krebs cycle. Inheritance is uncertain but could be mitochondrial or mendelian

35. DENTATORUBRAL PALLIDOLUYSIAN ATROPHYDRPLA is a rare and recently described autosomal dominant neurodegenerative disorder. Onset is in the third decade with myoclonic epilepsy, dementia, gait disturbance and choreoathetosisDeath occurs approximately 20 years later. The genetic defect is an unstable expansion of a CAG repeat in a gene of unknown function located on the short arm of chromosome 12 . There appears to be a correlation between the size of the (CAG)n repeat and age of onset. Pedigrees with DRPLA demonstrate genetic anticipation and phenotypic heterogeneity which is typical of the dynamic mutation disorders. Patients with larger repeats tend to show a PME phenotype and earlier age.

36. TREATMENTCurrently, VPA is the treatment of choice for patients with PME. However, children require monitoring while on VPA because of the potential for hepatic and pancreatic dysfunction. Some of the newer AEDs, including ZNS and levetiracetam (LEV), have been under investigation for possible use in the treatment of PME.

37. Number of patients with 50% and 75% decrease in myoclonic seizure frequency from baseline in an open-label study of zonisamide therapy in patients with PME (48). Average counts represent the average morning, afternoon, and evening counts for patients counting seizures in 10-min epochs (n = 14). Twentyfour– hour counts represent patients counting seizures over 24-h periods (n = 6.

38. Case reports or uncontrolled studies in PME of L-J-HTP plus carbidopa or L-tryptophan plus a monoamine oxidase inhibitor . M. R. Pranzatelli Et al ,Neuropharmacology of Progressive M yoclonus Epilepsy: Response to 5-Hydroxy-~-Tryptophant,Epilepsia, 36(8):783-791, 1995

40. Progressive myoclonic epilepsies: Recent genetic advances CJ ELLAWAY et al J. Paediatr. Child Health (1 997) 33, 91 -95

41. Progressive myoclonic epilepsy: A clinical, electrophysiologica and pathological study from sout IndiaS Sinha et al Neurology Asia 2004; 9 (Supplement 1) : 95 – 96