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Progressive myoclonus epilepsy
Handbook of Clinical Neurology, Vol. 113 (3rd series) Pediatric Neurology Part III O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V. All rights reserved
Chapter 178
Progressive myoclonus epilepsy JEAN-MARIE GIRARD, JULIE TURNBULL, NIVETHA RAMACHANDRAN, AND BERGE A. MINASSIAN* Division of Neurology, Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada
INTRODUCTION Progressive myoclonus epilepsy (PME) is a dreaded category of pediatric epilepsy. The term “progressive” distinguishes among countless epileptic children the few who will not get better, but will get worse in a continuous uninterrupted fashion and ultimately die. Progressive also implies neurodegenerative. Amidst the neurodegeneration of PME, there is dramatic prominence of two particular symptoms, myoclonus and epilepsy, suggesting that in this group of diseases there is either particular degeneration of neural pathways related to myoclonus and epilepsy, or that the underlying genetic disturbances are, separate from being neurodegenerative, also myoclonoand epileptogenic. Most pediatric PME are genetic diseases inherited in autosomal recessive fashion. Exceptions are some cases of mitochondrial disease, reviewed in Chapter 168, and the most severely affected members of families with the autosomal dominant Huntington’s disease, and dentatorubropallidoluysian atrophy (Yamada et al., 2006). A nongenetic PME occurs in the course of subacute sclerosing panencephalitis (SSPE), discussed in Chapter 123. Autosomal recessive PME can be subgrouped pathologically into nonlysosomal PME (Lafora disease and the newly characterized ataxia-PME disease) and lysosomal PME (Unverricht–Lundborg disease and certain forms of sialidosis, Gaucher disease, and the vast family of neuronal ceroid lipofuscinoses (NCL)). This chapter reviews the autosomal recessive PME, with the exception of the NCL, which merit their own section, Chapter 173.
LAFORA DISEASE Onset of Lafora disease is between 8 and 18 years of age. The first symptoms are headaches, difficulties in school, myoclonic jerks, generalized seizures, and in many cases visual hallucinations of both epileptic and psychotic origin.
Myoclonus is distal, erratic, triggered by light and sound stimulation, and enhanced with emotion. EEG shows slowing of background activity, generalized irregular spikewaves with photosensitivity and low amplitude spikes in posterior head regions (Figure 178.1). The myoclonus, seizures, and hallucinations gradually worsen and become intractable. For many years, patients maintain contact and communication, interrupted by extremely frequent myoclonic absence seizures. They remain conscious of their deterioration until late in the course of the disease and often exhibit depression. Gradually, dementia sets in and by the tenth year after onset the patient is in near-continuous myoclonus with absences, frequent generalized seizures, and profound dementia. Death is frequently secondary to aspiration pneumonia during status epilepticus (Lafora, 1911; Minassian, 2001; Andrade et al., 2005; Striano et al., 2008). Gonzalo Rodriguez-Lafora, an eminent Spanish neurologist and student of Cajal, Marie, Dejerine, Alzheimer, Oppenheim, and Kraeplin, described Lafora disease when he was a neuropathologist at the Government Hospital for the Insane in Washington DC (Nanduri et al., 2008). He not only discovered the pathognomonic inclusion bodies in the brain which later took his name, he also fully described the disease clinical features, course, and inheritance pattern. The only major neurological facet he did not address was the EEG, which had not yet been invented. Figure 178.2 shows drawings of Lafora bodies made by Lafora in his first publication (Lafora, 1911). Lafora bodies are dense accumulations of malformed and insoluble glycogen molecules termed polyglucosans that differ from normal glycogen in lacking the symmetric branching that allows glycogen to be soluble. They are present in all brain regions and in most neurons, specifically in neuronal cell bodies and dendrites (Fig. 178.3) (Lafora, 1911; Van Heycop Ten Ham, 1975; Cavanagh, 1999; Minassian, 2001; Striano et al., 2008). They are not present in glia. Remarkably,
*Correspondence to: Berge A. Minassian, MD, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: [email protected]
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Fig. 178.1. Ten seconds of EEG on a 14-year-old girl with Lafora disease at earliest onset of symptoms. Note the slow occipital background, irregular and wide generalized spike-waves, and low amplitude and posterior location of spikes. At the time of EEG, the child was experiencing frequent headaches and a decline in school performance. The first myoclonia and generalized convulsions appeared soon after this EEG. The EEG was done because her older sister, 23 years of age, had florid Lafora disease. A homozygous mutation in the EPM2A gene was found in both girls (c.799-800insA; N267fs). This was the first ever Lafora disease mutation.
Fig. 178.2. The first ever Lafora bodies seen. Drawings of Lafora bodies by Lafora (Lafora, 1911).
even this was noted by Lafora, at a time when pathological distinction of neurons and glia was only starting to be made. It is currently thought that the gradual occupation of dendrites by Lafora bodies leads eventually to the onset and then the irrevocable progression of the epilepsy and the other neurological symptoms. The dendritic location is considered important, because in the only other disease in which Lafora bodies are found, adult polyglucosan body disease, caused by mutations in the glycogen branching enzyme gene, the bodies are in axons and the patients have dementia, upper and lower neuron signs, but no epilepsy (Robitaille et al., 1980; Lossos et al., 1998). Extraneural tissues, including skeletal muscle, heart, liver and skin, also contain Lafora bodies in Lafora disease, but these organs are not clinically affected in the life span of the patient. In skin, biopsy of which is often used for diagnosis, Lafora bodies are present in two very particular locations: in ducts of eccrine sweat glands and in the myoepithelium surrounding apocrine sweat glands. Interpretation of skin biopsy is prone to an important pitfall (Fig. 178.4) (Andrade et al., 2003), which if avoided makes this an excellent diagnostic modality next to gene sequencing. Lafora disease is caused by autosomal recessively inherited mutations in either the EPM2A or EPM2B gene, encoding respectively the laforin carbohydrate-binding dual-specificity phosphatase and the malin ubiquitin E3 ligase (Minassian et al., 1998; Chan et al., 2003). Mutations in each gene contribute approximately equally (45%) to cases of Lafora disease (Lafora Gene Mutation Database: Ianzano et al., 2005). The remaining 10% is thought to be caused by mutations in an as yet undiscovered gene (Chan et al., 2004; Singh et al., 2008). Based on the disease genes a
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Fig. 178.3. Lafora bodies in the brain. (A) Several large Lafora bodies are labeled LB. Note in the one to the right of the image the typical juxtanuclear location and the denser core of the structure. Numerous pink puncta are Lafora bodies in neuronal processes, usually in dendrites. Stain, periodic acid-Schiff with diastase pretreatment. Diastase is amylase which digests normal glycogen, but in the short time of these preparations is unable to digest the densely packed polyglucosans comprising the Lafora bodies. Bar, 50 mm. The mutation in this patient is homozygous EPM2B c.C205G (P69S). This is the most common Lafora disease mutation in the EPM2B gene. (B) Electron micrograph of Lafora bodies (LB) in neuronal processes. Note the fibrillar nature of the polyglucosans. Several axons are recognized by their synaptic vesicles. Bar, 500 nm. Note the absence of LB in the axons. The mutation in this patient is EPM2B c.T98C (F33S). This was the first EPM2B mutation identified.
that have excessively long strands and inadequate branching. This abnormal glycogen, polyglucosan, is insoluble and precipitates and accumulates to form the Lafora bodies (Lohi et al., 2005; Vilchez et al., 2007). In the second pathogenic model, laforin acts directly on glycogen, dephosphorylating its excess phosphate. In the absence of laforin, the excess phosphate distorts the double helices of glycogen strands and the molecule’s symmetric branch pattern, both of which are necessary for its solubility. Again, the abnormal glycogen precipitates and accumulates into Lafora bodies (Gentry et al., 2007; Tagliabracci et al., 2009). Whether both processes are important and complementary or not awaits further studies.
UNVERRICHT^LUNDBORG DISEASE (UNVERRICHT DISEASE) Fig. 178.4. Lafora bodies in apocrine glands. The Lafora bodies are in the myoepithelium of the gland, that is at the base of the gland (arrow). Periodic acid-Schiff structures at the luminal side (arrowhead) should not be confused with Lafora bodies. They are normal secretory material. Bar, 50 mm.
large amount of work has been done, which presently brings forth two chief pathogenic hypotheses. In the first, the laforin–malin complex is suggested to regulate glycogen synthase. In the absence of either protein, glycogen synthase is overactive, exceeding glycogen branching enzyme activity and thus resulting in glycogen molecules
Onset of Unverricht disease is between 6 and 13 years of age. This disease differs from other PME in that it is progressive only in adolescence, with dramatic and increasing myoclonus in the first 6 years. Jerks consist of action myoclonus triggered by any attempt to voluntary movement, posture, stress, and external stimulation; the adolescent is sometimes suspected of conversion, and is soon confined to the wheelchair. Seizures occur more often on awakening and usually respond to medications during this time, but myoclonus does not. EEG shows generalized spike-waves triggered by photic stimulation, but the basic background rhythm remains normal.
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Treatment at that stage by a combination of valproate, zonisamide, levetiracetam and especially high dose piracetam may be effective. By adulthood, the disease stabilizes and myoclonus and ataxia may improve. Seizures remain controlled and there is minimal or no cognitive decline. Adulthood is characterized by ongoing, sometimes severe, but no longer progressive myoclonus, almost normal cognitive functions, controlled epilepsy, and the possibility of a normal life span (Unverricht, 1891; Magaudda et al., 2006; Kalviainen et al., 2008; Santoshkumar et al., 2008). Unverricht described the neurological features and the autosomal recessive inheritance pattern of this disease in detail in a large Baltic family from present-day Estonia (Unverricht, 1891). He did not describe pathological findings, and there are none beyond nonspecific apoptotic cell loss and brain atrophy. The disease is relatively common in Finland (1:20 000) (Kalviainen et al., 2008) and was known as Baltic myoclonus until it was shown that Mediterranean and other populations with the same phenotype have the same genotype. Lundborg described a Swedish family with an altogether different disease with, in addition to myoclonus, progressive tremor, rigidity, and ultimately paralysis resembling in his words, “paralysis agitans” (Parkinson’s disease) (Puschmann, 2008). Lundborg was racist (Puschmann, 2008) above and beyond the racism so prevalent in the Europe he lived in. Whether this disqualifies him from an eponym can be discussed, but clearly, even though he wrote extensively on PME, given that he did not describe a family with Unverricht–Lundborg disease, and that his own term for PME was “Unverricht’s myoclonus” (Lundborg, 1903), it seems that a simplification of the name of this disease to Unverricht disease is warranted. Unverricht disease was the first of the PME to be described. In the time of Unverricht and Lundborg, in the absence of effective antiepileptic and antimyoclonic medications, it was clearly a progressive disease. Later, when patients were treated with phenytoin, they developed a dramatic progressive ataxia, because, as we now know, their cerebellar Purkinje cells are dramatically vulnerable to this medication. In our time, as described above, this prototypical PME has thankfully all but lost its “progressive” status. The Unverricht disease gene is CSTB (alias EPM1) (Pennacchio et al., 1996). The disease is due to massive downregulation (to less than 10% of normal) but not complete loss of CSTB. The cause of the downregulation is a particularity of the human genome in the promoter of CSTB, the presence of a dodecamer repeat that occasionally expands, and when it does so drastically reduces transcription of the gene. Few patients have other mutations within the gene, but only on one allele. An
Unverricht disease patient necessarily has the dodecamer repeat expansion in at least one of the two alleles (Virtaneva et al., 1997; Joensuu et al., 2008). The CSTB product is cystatin B, so named because it interacts with and inactivates certain lysosomal proteases, cathepsins B, L, S, and H (Turk and Bode, 1991). It is thought that cystatin B protects cells from these cathepsins if they find their way out of the lysosome. Recently, a new function of the protein has been delineated, namely protection of the cell against oxidative stress (Lehtinen et al., 2009). Whether the two functions, protection against lysosomal hydrolases and protection against oxidants, are separate or part of a yet unknown interconnection between cathepsins and oxidative cell damage awaits further study.
ATAXIA-PME DISEASE Between 2005 and 2006, three groups described an autosomal recessive neurological disease in three separate large Arab families from nearby villages straddling the northern Israel–Jordan border. In one family, the patients were adolescents and adults exhibiting primarily a PME, so closely resembling Unverricht’s disease that it was called EPM1B (Berkovic et al., 2005). In the other two families, the affected individuals were children manifesting an ataxia (Straussberg et al., 2005; El-Shanti et al., 2006). A collaborative reevaluation of the families showed that two shared the same last name, that the children who had presented with ataxia were exhibiting myoclonus as they grew older, and that the adolescents and adults with myoclonus had in fact had ataxia earlier in life. All patients had the same missense mutation (R104Q) in the PRICKLE1 gene (Bassuk et al., 2008). The phenotype appears to be as follows: ataxia soon after walking in the first half of the second year of life, tremor starting at 3 or 4 years of age, seizures after 8 years, and myoclonus soon after. Most patients also have upward gaze palsy, and some have exhibited a sensory neuropathy. The core features of ataxia and myoclonus are progressive and the adults are wheelchair-dependent with florid myoclonus. Seizures are well controlled and there is no dementia. MRI shows no atrophy even of the cerebellum. Peripheral tissues exhibit no inclusions material, and brain has not yet been studied (Berkovic et al., 2005; Straussberg et al., 2005; El-Shanti et al., 2006; Bassuk et al., 2008). The gene product appears to influence the REST and Wnt pathways, separate signaling cascades that regulate gene expression, including neuronal genes (Bassuk et al., 2008). The questions of which genes are controlled by PRICKLE1 and how their dysregulation causes a progressive neurological disease without brain atrophy wait to be tackled.
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TYPE I SIALIDOSIS (CHERRY-RED SPOT MYOCLONUS SYNDROME) AND TYPE IIIA GAUCHER DISEASE Mutations of the gene encoding neuraminidase, a lysosomal enzyme that removes sialic acid from various macromolecules, cause severe infantile disease with bony deformities, dysmorphism, myoclonus, cherry-red spot in the fundus, and early lethality. Some mutations cause a variant phenotype (type I sialidosis) which presents as typical PME with a wide range of age of onset. This seems to have a higher frequency of occurrence in Italian patients, but has also been seen elsewhere (Chen et al., 2006). Ataxia is prominent, and the presence of a cherry-red spot on funduscopy is highly indicative of the disease in the context of a PME. The disease can be diagnosed by the presence of sialo-oligosaccharides in urine (Bonten et al., 2000). Gaucher disease, caused by mutations of GD1, which encodes the glucocerebrocidase lysosomal enzyme, is characterized by hepatosplenomegaly, anemia, thrombocytopenia, bone pain, and other systemic features. In some patients, the central nervous system is involved, and in a subgroup of these patients the neurological presentation is a typical PME (type IIIA Gaucher disease). Occasionally, the systemic disease in this type is so mild that it is unrecognized and the PME is initially confused for juvenile myoclonic epilepsy, and then for Lafora disease (Filocamo et al., 2004). Splenomegaly, even mild, and upward gaze palsy, are important clues towards considering type IIIA Gaucher disease in a patient with PME.
CONCLUSION At the present time, some 120 years after the writings of Unverricht and Lundborg on PME, the first PME, Unverricht disease, is no longer considered to be progressive, because we have worked out which seizure medications to use and which not to use. Lafora disease is, however, just as progressive and fatal as ever. From Unverricht disease we have teased out a new phenotype with its own genotype (ataxia-PME disease), and we have discerned PME in a fraction of patients with sialidosis and the common Gaucher disease. We have likewise clarified the PME phenotypes within the large multifaceted neuronal ceroid lipofuscinoses, mitochondrial cytopathies, and trinucelotide repeat expansion diseases, and we have immunized most of humanity against SSPE. Finally, we have exposed the causes of all these disorders and are now racing to use this knowledge to eliminate them. We expect that Lundborg would agree that we have not done so badly as a human race. Hopefully, we will all achieve what remains to be done fast.
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ACKNOWLEDGMENTS This work was supported by funds from the Canadian Institutes for Health Research and the Canada Research Chairs Program. We thank Drs. Cameron Ackerley and Pasquale Striano for the biopsy and autopsy samples and Ms. Nela Pencea for help with preparing the images. Dr. Berge Minassian holds the University of Toronto Michael Bahen Chair in Epilepsy Research.
REFERENCES Andrade DM, Ackerley CA, Minett TS et al. (2003). Skin biopsy in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology 61: 1611–1614. Andrade DM, del Campo JM, Moro E et al. (2005). Non-epileptic visual hallucinations in Lafora disease. Neurology 64: 1311–1312. Bassuk AG, Wallace RH, Buhr AR et al. (2008). A homozygous mutation in human PRICKLE1 causes an autosomal recessive progressive myoclonic epilepsy-ataxia syndrome. Am J Hum Genet 83: 572–581. Berkovic SF, Mazarib A, Walid S et al. (2005). A new clinical and molecular form of Unverricht–Lundborg disease localized by homozygosity mapping. Brain 128: 652–658. Bonten EJ, Arts WF, Beck M et al. (2000). Novel mutations in lysosomal neuraminidase identify functional domains and determine clinical severity in sialidosis. Hum Mol Genet 9: 2715–2725. Chan EM, Young EJ, Ianzano L et al. (2003). Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat Genet 35: 125–127. Chan EM, Omer S, Ahmed M et al. (2004). Progressive myoclonus epilepsy with polyglucosans (Lafora disease): evidence for a third locus. Neurology 63: 565–567. Chen CM, Lai SC, Chen IC et al. (2006). First report of two Taiwanese siblings with sialidosis type I: a 10-year follow-up study. J Neurol Sci 247: 65–69. Cavanagh JB (1999). Corpora-amylacea and the family of polyglucosan diseases. Brain Res Brain Res Rev 29: 265–295. El-Shanti H, Daoud A, Sadoon AA et al. (2006). A distinct autosomal recessive ataxia maps to chromosome 12 in an inbred family from Jordan. Brain Dev 28: 353–357. Filocamo M, Mazzotti R, Stroppiano M et al. (2004). Early visual seizures and progressive myoclonus epilepsy in neuronopathic Gaucher disease due to a rare compound heterozygosity (N188S/S107L). Epilepsia 45: 1154–1157. Gentry MS, Dowen RH, 3rd., Worby CA et al. (2007). The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease. J Cell Biol 178: 477–488. Ianzano L, Zhang J, Chan EM et al. (2005). Lafora progressive Myoclonus Epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes. Hum Mutat 26: 397. Joensuu T, Lehesjoki AE, Kopra O (2008). Molecular background of EPM1–Unverricht–Lundborg disease. Epilepsia 49: 557–563.
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Kalviainen R, Khyuppenen J, Koskenkorva P et al. (2008). Clinical picture of EPM1–Unverricht–Lundborg disease. Epilepsia 49: 549–556. Lafora GR (1911). Uber das vorkommen amyloider korperchen im innern der ganglienzellen: zugleich en beitrag zum stadium der amyloiden substanz im nervensystem. Virchows Arch Pathol Anat Physiol Klin Med 205: 295–303. Lehtinen MK, Tegelberg S, Schipper H et al. (2009). Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1. J Neurosci 29: 5910–5915. Lohi H, Ianzano L, Zhao XC et al. (2005). Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. Hum Mol Genet 14: 2727–2736. Lossos A, Meiner Z, Barash V et al. (1998). Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene. Ann Neurol 44: 867–872. Lundborg H (1903). Die progressive Myoklonus-Epilepsie (Unverricht’s Myoklonie). Almqvist und Wiksell’s Buchdruckerei-A-G, Uppsala. Magaudda A, Ferlazzo E, Nguyen VH et al. (2006). Unverricht–Lundborg disease, a condition with selflimited progression: long-term follow-up of 20 patients. Epilepsia 47: 860–866. Minassian BA (2001). Lafora’s disease: towards a clinical, pathologic, and molecular synthesis. Pediatr Neurol 25: 21–29. Minassian BA, Lee JR, Herbrick JA et al. (1998). Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat Genet 20: 171–174. Nanduri AS, Kaushal N, Clusman H et al. (2008). The maestro don Gonzalo Rodriguez-Lafora. Epilepsia 49: 943–947. Pennacchio LA, Lehesjoki AE, Stone NE et al. (1996). Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1). Science 271: 1731–1734. Puschmann A (2008). Unverricht–Lundborg disease – a misnomer? Mov Disord 24: 629–630. Robitaille Y, Carpenter S, Karpati G et al. (1980). A distinct form of adult polyglucosan body disease with massive involvement of central and peripheral neuronal processes
and astrocytes: a report of four cases and a review of the occurrence of polyglucosan bodies in other conditions such as Lafora’s disease and normal ageing. Brain 103: 315–336. Santoshkumar B, Turnbull J, Minassian BA (2008). Unverricht–Lundborg progressive myoclonus epilepsy in Oman. Pediatr Neurol 38: 252–255. Singh S, Satishchandra P, Shankar SK et al. (2008). Lafora disease in the Indian population: EPM2A and NHLRC1 gene mutations and their impact on subcellular localization of laforin and malin. Hum Mutat 29: E1–E12. Straussberg R, Basel-Vanagaite L, Kivity S et al. (2005). An autosomal recessive cerebellar ataxia syndrome with upward gaze palsy, neuropathy, and seizures. Neurology 64: 142–144. Striano P, Zara F, Turnbull J et al. (2008). Typical progression of myoclonic epilepsy of the Lafora type: a case report. Nat Clin Pract Neurol 4: 106–111. Tagliabracci VS, Girard JM, Segvich D et al. (2009). Abnormal metabolism of glycogen phosphate as a cause for Lafora disease. J Biol Chem 283: 33816–33825. Turk V, Bode W (1991). The cystatins: protein inhibitors of cysteine proteinases. FEBS Lett 285: 213–219. Unverricht H (1891). Die Myoclonie. Leipzig and Vienna, Franz Deuticke. Van Heycop Ten Ham M (1975). Lafora disease, a form of progressive myoclonus epilepsy. In: PJ Vinken, GW Bruyn (Eds.), The Epilepsies. Handbook of Clinical Neurology. vol.15. Elsevier, Amsterdam, pp. 382–422. Vilchez D, Ros S, Cifuentes D et al. (2007). Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat Neurosci 10: 1407–1413. Virtaneva K, D’Amato E, Miao J et al. (1997). Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1. Nat Genet 15: 393–396. Yamada M, Shimohata M, Sato T et al. (2006). Polyglutamine disease: recent advances in the neuropathology of dentatorubral-pallidoluysian atrophy. Neuropathology 26: 346–351.
Chapter 178
Progressive myoclonus epilepsy JEAN-MARIE GIRARD, JULIE TURNBULL, NIVETHA RAMACHANDRAN, AND BERGE A. MINASSIAN* Division of Neurology, Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada
INTRODUCTION Progressive myoclonus epilepsy (PME) is a dreaded category of pediatric epilepsy. The term “progressive” distinguishes among countless epileptic children the few who will not get better, but will get worse in a continuous uninterrupted fashion and ultimately die. Progressive also implies neurodegenerative. Amidst the neurodegeneration of PME, there is dramatic prominence of two particular symptoms, myoclonus and epilepsy, suggesting that in this group of diseases there is either particular degeneration of neural pathways related to myoclonus and epilepsy, or that the underlying genetic disturbances are, separate from being neurodegenerative, also myoclonoand epileptogenic. Most pediatric PME are genetic diseases inherited in autosomal recessive fashion. Exceptions are some cases of mitochondrial disease, reviewed in Chapter 168, and the most severely affected members of families with the autosomal dominant Huntington’s disease, and dentatorubropallidoluysian atrophy (Yamada et al., 2006). A nongenetic PME occurs in the course of subacute sclerosing panencephalitis (SSPE), discussed in Chapter 123. Autosomal recessive PME can be subgrouped pathologically into nonlysosomal PME (Lafora disease and the newly characterized ataxia-PME disease) and lysosomal PME (Unverricht–Lundborg disease and certain forms of sialidosis, Gaucher disease, and the vast family of neuronal ceroid lipofuscinoses (NCL)). This chapter reviews the autosomal recessive PME, with the exception of the NCL, which merit their own section, Chapter 173.
LAFORA DISEASE Onset of Lafora disease is between 8 and 18 years of age. The first symptoms are headaches, difficulties in school, myoclonic jerks, generalized seizures, and in many cases visual hallucinations of both epileptic and psychotic origin.
Myoclonus is distal, erratic, triggered by light and sound stimulation, and enhanced with emotion. EEG shows slowing of background activity, generalized irregular spikewaves with photosensitivity and low amplitude spikes in posterior head regions (Figure 178.1). The myoclonus, seizures, and hallucinations gradually worsen and become intractable. For many years, patients maintain contact and communication, interrupted by extremely frequent myoclonic absence seizures. They remain conscious of their deterioration until late in the course of the disease and often exhibit depression. Gradually, dementia sets in and by the tenth year after onset the patient is in near-continuous myoclonus with absences, frequent generalized seizures, and profound dementia. Death is frequently secondary to aspiration pneumonia during status epilepticus (Lafora, 1911; Minassian, 2001; Andrade et al., 2005; Striano et al., 2008). Gonzalo Rodriguez-Lafora, an eminent Spanish neurologist and student of Cajal, Marie, Dejerine, Alzheimer, Oppenheim, and Kraeplin, described Lafora disease when he was a neuropathologist at the Government Hospital for the Insane in Washington DC (Nanduri et al., 2008). He not only discovered the pathognomonic inclusion bodies in the brain which later took his name, he also fully described the disease clinical features, course, and inheritance pattern. The only major neurological facet he did not address was the EEG, which had not yet been invented. Figure 178.2 shows drawings of Lafora bodies made by Lafora in his first publication (Lafora, 1911). Lafora bodies are dense accumulations of malformed and insoluble glycogen molecules termed polyglucosans that differ from normal glycogen in lacking the symmetric branching that allows glycogen to be soluble. They are present in all brain regions and in most neurons, specifically in neuronal cell bodies and dendrites (Fig. 178.3) (Lafora, 1911; Van Heycop Ten Ham, 1975; Cavanagh, 1999; Minassian, 2001; Striano et al., 2008). They are not present in glia. Remarkably,
*Correspondence to: Berge A. Minassian, MD, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: [email protected]
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Fig. 178.1. Ten seconds of EEG on a 14-year-old girl with Lafora disease at earliest onset of symptoms. Note the slow occipital background, irregular and wide generalized spike-waves, and low amplitude and posterior location of spikes. At the time of EEG, the child was experiencing frequent headaches and a decline in school performance. The first myoclonia and generalized convulsions appeared soon after this EEG. The EEG was done because her older sister, 23 years of age, had florid Lafora disease. A homozygous mutation in the EPM2A gene was found in both girls (c.799-800insA; N267fs). This was the first ever Lafora disease mutation.
Fig. 178.2. The first ever Lafora bodies seen. Drawings of Lafora bodies by Lafora (Lafora, 1911).
even this was noted by Lafora, at a time when pathological distinction of neurons and glia was only starting to be made. It is currently thought that the gradual occupation of dendrites by Lafora bodies leads eventually to the onset and then the irrevocable progression of the epilepsy and the other neurological symptoms. The dendritic location is considered important, because in the only other disease in which Lafora bodies are found, adult polyglucosan body disease, caused by mutations in the glycogen branching enzyme gene, the bodies are in axons and the patients have dementia, upper and lower neuron signs, but no epilepsy (Robitaille et al., 1980; Lossos et al., 1998). Extraneural tissues, including skeletal muscle, heart, liver and skin, also contain Lafora bodies in Lafora disease, but these organs are not clinically affected in the life span of the patient. In skin, biopsy of which is often used for diagnosis, Lafora bodies are present in two very particular locations: in ducts of eccrine sweat glands and in the myoepithelium surrounding apocrine sweat glands. Interpretation of skin biopsy is prone to an important pitfall (Fig. 178.4) (Andrade et al., 2003), which if avoided makes this an excellent diagnostic modality next to gene sequencing. Lafora disease is caused by autosomal recessively inherited mutations in either the EPM2A or EPM2B gene, encoding respectively the laforin carbohydrate-binding dual-specificity phosphatase and the malin ubiquitin E3 ligase (Minassian et al., 1998; Chan et al., 2003). Mutations in each gene contribute approximately equally (45%) to cases of Lafora disease (Lafora Gene Mutation Database: Ianzano et al., 2005). The remaining 10% is thought to be caused by mutations in an as yet undiscovered gene (Chan et al., 2004; Singh et al., 2008). Based on the disease genes a
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Fig. 178.3. Lafora bodies in the brain. (A) Several large Lafora bodies are labeled LB. Note in the one to the right of the image the typical juxtanuclear location and the denser core of the structure. Numerous pink puncta are Lafora bodies in neuronal processes, usually in dendrites. Stain, periodic acid-Schiff with diastase pretreatment. Diastase is amylase which digests normal glycogen, but in the short time of these preparations is unable to digest the densely packed polyglucosans comprising the Lafora bodies. Bar, 50 mm. The mutation in this patient is homozygous EPM2B c.C205G (P69S). This is the most common Lafora disease mutation in the EPM2B gene. (B) Electron micrograph of Lafora bodies (LB) in neuronal processes. Note the fibrillar nature of the polyglucosans. Several axons are recognized by their synaptic vesicles. Bar, 500 nm. Note the absence of LB in the axons. The mutation in this patient is EPM2B c.T98C (F33S). This was the first EPM2B mutation identified.
that have excessively long strands and inadequate branching. This abnormal glycogen, polyglucosan, is insoluble and precipitates and accumulates to form the Lafora bodies (Lohi et al., 2005; Vilchez et al., 2007). In the second pathogenic model, laforin acts directly on glycogen, dephosphorylating its excess phosphate. In the absence of laforin, the excess phosphate distorts the double helices of glycogen strands and the molecule’s symmetric branch pattern, both of which are necessary for its solubility. Again, the abnormal glycogen precipitates and accumulates into Lafora bodies (Gentry et al., 2007; Tagliabracci et al., 2009). Whether both processes are important and complementary or not awaits further studies.
UNVERRICHT^LUNDBORG DISEASE (UNVERRICHT DISEASE) Fig. 178.4. Lafora bodies in apocrine glands. The Lafora bodies are in the myoepithelium of the gland, that is at the base of the gland (arrow). Periodic acid-Schiff structures at the luminal side (arrowhead) should not be confused with Lafora bodies. They are normal secretory material. Bar, 50 mm.
large amount of work has been done, which presently brings forth two chief pathogenic hypotheses. In the first, the laforin–malin complex is suggested to regulate glycogen synthase. In the absence of either protein, glycogen synthase is overactive, exceeding glycogen branching enzyme activity and thus resulting in glycogen molecules
Onset of Unverricht disease is between 6 and 13 years of age. This disease differs from other PME in that it is progressive only in adolescence, with dramatic and increasing myoclonus in the first 6 years. Jerks consist of action myoclonus triggered by any attempt to voluntary movement, posture, stress, and external stimulation; the adolescent is sometimes suspected of conversion, and is soon confined to the wheelchair. Seizures occur more often on awakening and usually respond to medications during this time, but myoclonus does not. EEG shows generalized spike-waves triggered by photic stimulation, but the basic background rhythm remains normal.
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Treatment at that stage by a combination of valproate, zonisamide, levetiracetam and especially high dose piracetam may be effective. By adulthood, the disease stabilizes and myoclonus and ataxia may improve. Seizures remain controlled and there is minimal or no cognitive decline. Adulthood is characterized by ongoing, sometimes severe, but no longer progressive myoclonus, almost normal cognitive functions, controlled epilepsy, and the possibility of a normal life span (Unverricht, 1891; Magaudda et al., 2006; Kalviainen et al., 2008; Santoshkumar et al., 2008). Unverricht described the neurological features and the autosomal recessive inheritance pattern of this disease in detail in a large Baltic family from present-day Estonia (Unverricht, 1891). He did not describe pathological findings, and there are none beyond nonspecific apoptotic cell loss and brain atrophy. The disease is relatively common in Finland (1:20 000) (Kalviainen et al., 2008) and was known as Baltic myoclonus until it was shown that Mediterranean and other populations with the same phenotype have the same genotype. Lundborg described a Swedish family with an altogether different disease with, in addition to myoclonus, progressive tremor, rigidity, and ultimately paralysis resembling in his words, “paralysis agitans” (Parkinson’s disease) (Puschmann, 2008). Lundborg was racist (Puschmann, 2008) above and beyond the racism so prevalent in the Europe he lived in. Whether this disqualifies him from an eponym can be discussed, but clearly, even though he wrote extensively on PME, given that he did not describe a family with Unverricht–Lundborg disease, and that his own term for PME was “Unverricht’s myoclonus” (Lundborg, 1903), it seems that a simplification of the name of this disease to Unverricht disease is warranted. Unverricht disease was the first of the PME to be described. In the time of Unverricht and Lundborg, in the absence of effective antiepileptic and antimyoclonic medications, it was clearly a progressive disease. Later, when patients were treated with phenytoin, they developed a dramatic progressive ataxia, because, as we now know, their cerebellar Purkinje cells are dramatically vulnerable to this medication. In our time, as described above, this prototypical PME has thankfully all but lost its “progressive” status. The Unverricht disease gene is CSTB (alias EPM1) (Pennacchio et al., 1996). The disease is due to massive downregulation (to less than 10% of normal) but not complete loss of CSTB. The cause of the downregulation is a particularity of the human genome in the promoter of CSTB, the presence of a dodecamer repeat that occasionally expands, and when it does so drastically reduces transcription of the gene. Few patients have other mutations within the gene, but only on one allele. An
Unverricht disease patient necessarily has the dodecamer repeat expansion in at least one of the two alleles (Virtaneva et al., 1997; Joensuu et al., 2008). The CSTB product is cystatin B, so named because it interacts with and inactivates certain lysosomal proteases, cathepsins B, L, S, and H (Turk and Bode, 1991). It is thought that cystatin B protects cells from these cathepsins if they find their way out of the lysosome. Recently, a new function of the protein has been delineated, namely protection of the cell against oxidative stress (Lehtinen et al., 2009). Whether the two functions, protection against lysosomal hydrolases and protection against oxidants, are separate or part of a yet unknown interconnection between cathepsins and oxidative cell damage awaits further study.
ATAXIA-PME DISEASE Between 2005 and 2006, three groups described an autosomal recessive neurological disease in three separate large Arab families from nearby villages straddling the northern Israel–Jordan border. In one family, the patients were adolescents and adults exhibiting primarily a PME, so closely resembling Unverricht’s disease that it was called EPM1B (Berkovic et al., 2005). In the other two families, the affected individuals were children manifesting an ataxia (Straussberg et al., 2005; El-Shanti et al., 2006). A collaborative reevaluation of the families showed that two shared the same last name, that the children who had presented with ataxia were exhibiting myoclonus as they grew older, and that the adolescents and adults with myoclonus had in fact had ataxia earlier in life. All patients had the same missense mutation (R104Q) in the PRICKLE1 gene (Bassuk et al., 2008). The phenotype appears to be as follows: ataxia soon after walking in the first half of the second year of life, tremor starting at 3 or 4 years of age, seizures after 8 years, and myoclonus soon after. Most patients also have upward gaze palsy, and some have exhibited a sensory neuropathy. The core features of ataxia and myoclonus are progressive and the adults are wheelchair-dependent with florid myoclonus. Seizures are well controlled and there is no dementia. MRI shows no atrophy even of the cerebellum. Peripheral tissues exhibit no inclusions material, and brain has not yet been studied (Berkovic et al., 2005; Straussberg et al., 2005; El-Shanti et al., 2006; Bassuk et al., 2008). The gene product appears to influence the REST and Wnt pathways, separate signaling cascades that regulate gene expression, including neuronal genes (Bassuk et al., 2008). The questions of which genes are controlled by PRICKLE1 and how their dysregulation causes a progressive neurological disease without brain atrophy wait to be tackled.
PROGRESSIVE MYOCLONUS EPILEPSY
TYPE I SIALIDOSIS (CHERRY-RED SPOT MYOCLONUS SYNDROME) AND TYPE IIIA GAUCHER DISEASE Mutations of the gene encoding neuraminidase, a lysosomal enzyme that removes sialic acid from various macromolecules, cause severe infantile disease with bony deformities, dysmorphism, myoclonus, cherry-red spot in the fundus, and early lethality. Some mutations cause a variant phenotype (type I sialidosis) which presents as typical PME with a wide range of age of onset. This seems to have a higher frequency of occurrence in Italian patients, but has also been seen elsewhere (Chen et al., 2006). Ataxia is prominent, and the presence of a cherry-red spot on funduscopy is highly indicative of the disease in the context of a PME. The disease can be diagnosed by the presence of sialo-oligosaccharides in urine (Bonten et al., 2000). Gaucher disease, caused by mutations of GD1, which encodes the glucocerebrocidase lysosomal enzyme, is characterized by hepatosplenomegaly, anemia, thrombocytopenia, bone pain, and other systemic features. In some patients, the central nervous system is involved, and in a subgroup of these patients the neurological presentation is a typical PME (type IIIA Gaucher disease). Occasionally, the systemic disease in this type is so mild that it is unrecognized and the PME is initially confused for juvenile myoclonic epilepsy, and then for Lafora disease (Filocamo et al., 2004). Splenomegaly, even mild, and upward gaze palsy, are important clues towards considering type IIIA Gaucher disease in a patient with PME.
CONCLUSION At the present time, some 120 years after the writings of Unverricht and Lundborg on PME, the first PME, Unverricht disease, is no longer considered to be progressive, because we have worked out which seizure medications to use and which not to use. Lafora disease is, however, just as progressive and fatal as ever. From Unverricht disease we have teased out a new phenotype with its own genotype (ataxia-PME disease), and we have discerned PME in a fraction of patients with sialidosis and the common Gaucher disease. We have likewise clarified the PME phenotypes within the large multifaceted neuronal ceroid lipofuscinoses, mitochondrial cytopathies, and trinucelotide repeat expansion diseases, and we have immunized most of humanity against SSPE. Finally, we have exposed the causes of all these disorders and are now racing to use this knowledge to eliminate them. We expect that Lundborg would agree that we have not done so badly as a human race. Hopefully, we will all achieve what remains to be done fast.
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ACKNOWLEDGMENTS This work was supported by funds from the Canadian Institutes for Health Research and the Canada Research Chairs Program. We thank Drs. Cameron Ackerley and Pasquale Striano for the biopsy and autopsy samples and Ms. Nela Pencea for help with preparing the images. Dr. Berge Minassian holds the University of Toronto Michael Bahen Chair in Epilepsy Research.
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