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Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies. 5th edition. New York: Oxford University Press; 2024. doi: 10.1093/med/9780197549469.003.0052
Progressive myoclonus epilepsies (PMEs) are a group of genetically and clinically heterogeneous diseases characterized by an invariable neurodegenerative decline leading to devastating disabilities and often fatal outcomes. Although there is a broad range of clinical manifestations, the shared features are encompassed within the name. Typically beginning in childhood and adolescence, patients present with very frequent myoclonus in addition to other types of epileptic seizures that very soon become refractory to medication. This is accompanied by a progressive neurocognitive decline along with other devastating changes including, but not limited to, vision loss, neuropathy, myopathy, and ataxia in a child that was otherwise previously normal. This chapter will review the potential therapeutic strategies for various PMEs.
Progressive myoclonus epilepsies (PMEs) are a group of genetically and clinically heterogeneous diseases characterized by an invariable neurodegenerative decline leading to devastating disabilities and often fatal outcomes. Although there is a broad range of clinical manifestations, the shared features are encompassed within the name. Typically beginning in childhood and adolescence, patients present with very frequent myoclonus in addition to other types of epileptic seizures that very soon become refractory to medication. This is accompanied by a progressive neurocognitive decline along with other devastating changes including, but not limited to, vision loss, neuropathy, myopathy, and ataxia in a child that was otherwise previously normal (Kalviainen, 2015).
Historically, therapeutic options have been limited to symptomatic management with antiseizure medications that are incompletely effective, and which often result in significant side effects and worsened quality of life. As these treatment strategies did not address the underlying etiology, the progressive nature of the disease could not be halted. However, as our knowledge of the pathophysiologic processes expands, we are not only approaching but also are actively living in an era of targeted therapeutic possibilities (Riva et al., 2020).
As the majority of PMEs are monogenic, they are an ideal candidate for therapies that target a single gene, function, or pathway (Ferlazzo et al., 2017). Additionally, as there is a “window of health” prior to significant neurodegeneration, our ability to intervene early with life-altering gene-empowered therapies provides real hope for many families who would have otherwise suffered. This chapter will review the potential therapeutic strategies for various PMEs.
The prototypic PMEs include Unverricht-Lundborg (ULD), Lafora disease (LD), neuronal ceroid lipofuscinosis (NCL), and myoclonic epilepsy with ragged red fibers (MERRF). However, the diagnosis of other forms can be challenging as there is often overlap with other neurodegenerative diseases and there are many phenotypic similarities despite genetic heterogeneity (Delgado-Escueta et al., 2001). Other than autosomal dominant dentatorubral-pallidoluysian atrophy (DRPLA), neuronal ceroid lipofuscinosis-4B (CLN4B) and MERRF, the majority of PMEs are autosomal recessive. These autosomal recessive PMEs can be further subdivided, as the majority are lysosomal diseases while Lafora disease is not (Ramachandran et al., 2009). Table 52–1 outlines the different PMEs and the genetic markers.
PME Type and Gene.
Unverricht-Lundborg disease (ULD) is an inherited form of progressive myoclonus epilepsy (PME), which is characterized by myoclonus, epilepsy, and progressive neurologic deterioration of varying degrees (Kalviainen et al., 2008; Crespel et al., 2016). It is the most common form of PME (Orsini et al., 2019). Its worldwide prevalence is unknown, but approximately 2 in 100,000 people are affected in Finland, and the disease has equal sex distribution (Sipila et al., 2020). Patients typically begin showing signs and symptoms between the ages of 6 and 16 (Kalviainen et al., 2008). ULD patients present with myoclonus and generalized tonic-clonic seizures (GTCSs) in initial stages of the disease (Crespel et al., 2016; Ferlazzo et al., 2007). Myoclonic jerks usually affect the whole body, are stimulus sensitive, and can be provoked by light, noise, or physical exertion; they are less severe at rest. Though myoclonus is the most devastating symptom, the patients are usually referred for the GTCSs (Lasek-Bal et al., 2019). As opposed to myoclonus, the GTCSs typically occur during sleep or at awakening. Although seizures can be controlled by the medications, myoclonus is usually medication resistant (Crespel et al., 2016; Chew et al., 2008). Regardless of the therapeutic approach, the disease is progressive, especially in the first several years following clinical onset. In addition to seizures and myoclonus, people with ULD develop ataxia, intention tremor, and dysarthria (Chew et al., 2008; Sipila et al., 2020). ULD patients may also develop emotional sensitivity, depression, and mild to moderate cognitive impairment over time. A recent study showed that ULD patients had impaired performance in most of the cognitive measures, especially in the executive function tests and psychomotor speed tests (Aikia et al., 2021; Sipila et al., 2020).
The disease progression usually halts, and patients stabilize with a varying degree of disability within 5 to 10 years from the disease onset (Magaudda et al., 2006; Crespel et al., 2016). The outcome of disease can widely vary. Some patients stay independent with minimal lifestyle impairment, while others become incapacitated and bedridden at early ages. A recent study conducted in Finland showed that ULD patients have poorer survival outcome during long-term follow-up with a median death age of 54 years (Sipila et al., 2020). The risk of death is higher in patients with early disease onset (Sipila et al., 2020).
The main signs of brain pathology seen in ULD patients are progressive atrophy. The atrophy is seen in all white matter tracts including cerebellar tracts. Motor, sensory, and somatosensory areas in the cerebral cortex also show signs of atrophy in ULD patients. The degree of the atrophy of the cerebral cortex correlates with the severity of the myoclonus (Manninen et al., 2013; Koskenkorva et al., 2009). The signs and symptoms of patients, along with electroencephalogram (EEG) recordings and brain imaging, are used for clinical diagnosis, and demonstration of pathogenic mutations in CSTB gene is required to confirm the diagnosis (Crespel et al., 2016; Joensuu et al., 2007).
Currently available treatments aim to control symptoms and increase the quality of life. There is no targeted or disease-modifying therapy available. The first line of treatment for GTCS is usually an antiseizure medication (ASM), typically valproic acid (VPA). Although VPA is effective in suppressing most GTCS and photosensitivity, it has a minimal effect on myoclonus. Once the diagnoses of ULD is confirmed, the patients commonly receive a polytherapy of ASMs to control both seizures and myoclonus. The most effective therapeutic approach is often a combination of valproic acid, clonazepam, and levetiracetam. Zonisamide, topiramate, and brivaracetam are commonly used as add-on therapies (Crespel et al., 2016). Use of some ASMs, including phenytoin, sodium channel blockers (carbamazepine, oxcarbazepine), and GABAergic drugs (tiagabine, vigabatrin), are avoided due to their paradoxical exacerbating effects on myoclonus and myoclonic seizures, in addition to the cerebellar degeneration (Eldridge et al., 1983; Medina et al., 2005). Additionally, avoiding extreme stimuli, including excessive light, noise, and stress, can have some extra benefits to some patients. Notably, ULD patients need lifelong social support in addition to medical treatment.
ULD is caused by the loss-of-function mutations in the CSTB gene and is inherited autosomal recessively. The most common mutation is a dodecamer repeat expansion in the CSTB gene (upstream to the promoter) which leads to a reduction in Cystatin B protein. Patients with repeat expansion mutations usually retain 5%–10% of Cystatin B activity (Joensuu et al., 2008). Homozygosity of other types of loss-of-function mutations in the CSTB gene result in complete loss of Cystatin B, and these patients present with exceedingly early-onset severe phenotypes with microcephaly and developmental delay (O’Brien et al., 2017). Cystatin B, a cysteine protease inhibitor, is a small (11 kD) protein and it is expressed ubiquitously. There is no consensus on Cystatin B’s subcellular localization and its function. So far, studies have reported different localizations of CSTB, dependent on cell cycle and cell type, spanning from mitochondrial to diffuse cytoplasmic to nuclear (Alakurtti et al., 2005; Maher et al., 2014). Similarly, many different theories are proposed for the function of CSTB and pathogenesis of ULD. Studies have revealed the role of oxidative stress and different pathological mechanisms, including disruption of serotonin metabolism, defective inhibitory neurotransmission, and precocious microglial activation (Gilloux, 1966; Buzzi et al., 2012; Tegelberg et al., 2012).
Despite some progress in understanding the biological function of Cystatin B, the disease mechanism remains unknown. This lack of understanding has presented a big challenge for therapy development. However, recent advancements in genetics and gene-based therapies opened a new path to developing treatments for monogenic diseases (Jensen et al., 2021; Privolizzi et al., 2021; Abulimiti et al., 2021). Currently, in such strategies, gene replacement therapy (GRT) is the standard and the most unsophisticated approach. GRT involves delivering a functional copy of the faulty gene to deficient cells using different vehicles. Adeno-associated viruses (AAVs) are the gold standard vectors for brain-targeted neurological disorders. AAVs are superior to other vectors in many ways, including higher transduction efficiency, lower immunogenicity, and limited genome integration (Wang et al., 2019). Despite their superiority, AAVs’ small packaging capacity (~4.7 kb) can be a limiting factor for many genes. Another caveat for some GRTs is the development of immunogenicity against the transgene product (Muhuri et al., 2021). The newly formed proteins are seen as foreign by the immune system in the case of null mutations.
Fortunately, Cystatin B (~13 kD) is relatively small, and the presence of minimum Cystatin B activity in patients makes the ULD a good candidate for GRT. We tested this gene therapy approach in a preclinical setting in the ULD mouse model. We observed that replacing CSTB might provide therapeutic benefits in the ULD mouse model by decreasing the severity of neuropathology (unpublished data). This approach could be further improved and developed as a therapy for human patients. Another possible gene therapy approach is targeting the dodecamer repeat expansion mutation by using more advanced gene-editing techniques like CRISPR-Cas9 to remove the expansion mutation or using Cas9-based activators to enhance gene expression bypassing the repeats (Wang et al., 2020).
While ULD was the first PME described and the prototypical example, Lafora disease followed suit in the first decade of the twentieth century as the second identified progressive myoclonus epilepsy (Verhalen et al., 2018). Lafora disease is an autosomal recessive and very severe form of PME with symptoms attributed to the accumulation of Lafora bodies within the brain, skeletal, and cardiac myocytes and other cell types. Loss-of-function mutations in EPM2A on chromosome 6q24.3 (which encodes laforin) and EPM2B, also known as NHLRC1, on chromosome 6p22.3 (which encodes malin) lead to deficiencies in laforin and malin, respectively (Minassian et al., 1998; Chan et al., 2003). Under normal circumstances, there is balanced activity between these two enzymes allowing glycogen particles to form spherically and therefore remain soluble. Lafora bodies, also known as polyglucosan, are malformed or excessively long and insufficiently branched glycogen strands and therefore insoluble glycogen molecules that are then accumulated within the brain, specifically within the dendrites and cell bodies of neurons (Turnbull et al., 2011; Striano et al., 2008). Although Lafora bodies are the pathognomonic finding upon tissue biopsy, targeted genetic testing is now the standard way to confirm diagnosis. Most recently PRMD8 has been identified as a gene mutation associated with early-onset Lafora disease (it codes for a protein responsible for Laforin and Malin translocation to the nucleus and the mutated form leads to deficiency of these enzymes within the cytoplasm) (Ibrahim et al., 2021).
As in other PMEs, symptoms begin in a child or adolescent who was previously healthy. With the onset of myoclonus and seizures by late childhood or early adolescence, these patients may be inappropriately diagnosed with juvenile myoclonic epilepsy (JME), a syndrome that carries a much more favorable outcome. Much to these families’ dismay, however, seizures are not well controlled by medication and as more medications are added to control seizures other symptoms are becoming prevalent, including visual manifestations, ataxia, and neurocognitive decline. Unlike JME, even in the early stages of LD, there is notable background slowing on EEG with intermixed multifocal and generalized irregular epileptiform discharges. With progression there is loss of normal sleep staging, and there is a significant increase in the spike burden often akin to an electrical firestorm (Markussen et al., 2021; Knupp et al., 2014). With no means to control the underlying pathogenesis, these patients historically die within approximately 10 years of onset (often secondary to complications from status epilepticus such as aspiration pneumonia, etc.) (Desdentado et al., 2019).
Despite the grim prognosis and ineffective therapeutic approaches, there is now much room for hope with the advent of exciting gene-based therapies (Privolizzi et al., 2021; Jensen et al., 2021; Vemana et al., 2021). LD is a suitable candidate for such therapeutic approaches and can benefit from targeted therapies from several fronts (Orsini et al., 2019; Markussen et al., 2021; Mitra et al., 2021). These targeted drug development strategies aim to prevent abnormal glycogen accumulation or to degrade LB (Lafora body) accumulates. The conventional approach would be a GRT to reinstate EPM2A or EPM2B into deficient cells. Theoretically, the GRT will revive normal glycogen formation and arrest further LB accumulation. Additionally, replacement therapy may also help to break down already formed LBs.
In addition to the GRTs, another promising approach is the reduction of brain glycogen synthesis by targeting glycogen synthase (GS) and preventing or stalling further LB accumulation. Inhibition of GS at DNA level using Crispr-Cas9 showed encouraging results in preclinical mouse models of the LD (Gumusgoz et al., 2021). Similar outcomes came from different studies using AAV (adeno-associated virus) mediated RNA interference (RNAi) or antisense oligonucleotide (ASO) to inhibit GS at the RNA level (Ahonen et al., 2021). While the Cas9 technology is still in its early stage of development for in vivo human therapies, both RNAi and ASO therapies have made considerable progress in recent years and are waiting to be turned into human clinical trials for LD patients soon.
Although only tested in mouse models, these new examples of precision medicine have the potential for providing a significant and life-altering clinical benefit to LD patients. Additionally, some of these therapeutics may help if they can be applied to many other glycogen storage diseases (GSDs).
Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurodegenerative disorders. NCLs are a group of genetically heterogenous lysosomal storage disorders and are the most usual form of childhood-onset degenerative brain disease (Schulz et al., 2013a, 2013b). The key features include progressive epilepsy, ataxia, motor, language, and cognitive neurologic deterioration with progressive dementia. In addition, visual deterioration caused by progressive retinal dystrophy is another common feature. Timelines of these events are variable in several types of NCLs. Age of disease onset can vary in range from infancy to adult onset. See Table 52–2.
NCL Type and Gene.
Historically NCL is classified clinically based upon the age of onset of symptoms: congenital, infantile, late infantile, juvenile, and adult onset. A new internationally developed and proposed system of classification is based upon age of onset and the identified underlying genetic variant (Williams et al., 2012). Pathogenic variants in 14 genes—PPT1, TPP1, CLN3, CLN4, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, GRN, and KCTD7—are known to cause NCL (Kousi et al., 2012).
These genes encode lysosomal proteins (CLN1, CLN2, CLN10, CLN13), a soluble lysosomal protein (CLN5), a protein in secretory pathway (CLN11), transmembrane protein (CLN3, CLN6, CLN7, CLN8, CLN12), and two cytoplasmic proteins (CLN4 and CLN14) (Mole et al., 2015).
Patients with congenital NCL are born with severe symptoms that include congenital microcephaly and intrauterine seizures or early seizures in newborn period are seen. CLN10 caused by cathepsin D deficiency presents with the clinical phenotype of congenital NCL.
The infantile form of NCL presents between 6 and 18 months (about 1.5 years) of age. Early development is normal until the onset of symptoms. Hypotonia, myoclonus, seizures, and visual failure are prominent features. Rapid psychomotor regression is seen over the course of a few months leading to blindness and acquired microcephaly by 2 years of age. Spasticity with loss of neurologic function is seen at the later stages with flat EEG. CLN1 is caused by PPT1 deficiency. CLN14 has been reported to manifest in infantile form as well.
Late infantile and variant late infantile NCL present between 2 and 5 years of age. Patients with classic late infantile NCL present with slowing of development around the second or third year of life. Seizure onset is seen between 4 and 6 years of age. Seizures become intractable shortly after the onset and mark the onset of neurodegenerative course with progressive psychomotor regression and dementia. The CLN2 gene has been classically linked with the clinical phenotype of late infantile NCL. Various variants of classic late infantile NCL are seen with CLN1, CLN5, CLN6, CLN7, CLN8, and CLN14.
In the late infantile variant form of the CLN5 disease, the first symptoms of behavior problems are seen around 2–4 years of age, followed by motor clumsiness and attention disturbances that can appear between 4 and 7 years of age and are followed by progressive visual failure, motor and mental decline, ataxia, myoclonus and epilepsy, and an early death between the second and fourth decades of life (Santavuori et al., 1982, 1991, 1993). The severity of the impact can vary from a mild, late-onset version with nonsyndromic visual deficits (Roosing et al., 2015) to a severe, early-onset version that manifests as neurological signs with progressive deterioration in intellectual and motor capabilities, seizures, muscle spasms, and visual deficits culminating in premature death (Aiello et al., 2009).
In juvenile NCL, onset of symptoms is typically reported between 4 and 7 years of age, though symptom onset has been reported until 16 years of age. Blindness is typically the first presenting symptom followed by behavioral outbursts and cognitive decline.
Juvenile-onset NCL is typically caused by mutations in the CLN3 gene. Other forms of Juvenile NCL are seen with CLN1, CLN2, CLN5, CLN7, CLN8, CLN10, and CLN12.
Adult-onset NCL presents after 18 years of age. Presenting symptoms include ataxia, dementia, and progressive myoclonic epilepsy. CLN4 and CLN6 present with adult NCL. CLN4 is the only NCL that is inherited in an autosomal dominant fashion while the rest are autosomal recessive.
Recent advances in defining genotype and phenotype in various types of NCLs has made it a favorable target for a precision therapeutic approach like GRT. Unlike many other lysosomal storage disorders, proteins in various NCLs are not secreted, which means that enzyme replacement therapy is not an effective therapeutic approach. In addition, bone marrow transplant or stem cell transplant is likely not an effective approach due to the blood–brain barrier. Various preclinical studies involving GRTs have shown in vivo and in vitro expression and distribution of missing protein across several types of NCLs.
Griffey et al. (2004) studied the effect of viral gene vector in a murine model of infantile NCL (ppt1–/–mice). Treated mice showed reduction in storage material in brain and showed improvement in brain weights with no decrease in brain volumes (Griffey et al., 2004). Shyng et al. (2017) used a synergistic approach in treating brain and spinal cord disease with improvement in life span and motor function in ppt1–/– mice (Shyng et al., 2017).
Katz el al. studied delivery of recombinant AAV2 expressing canine TPP1 (rAAV2-caTPP1) into the ventricular system to transduce ependymal cells. Intraventricular administration showed expression of TPP1 in ependymal cells and secretion into cerebrospinal fluid. Diseased dogs treated with rAAV.caTPP1 showed delays in onset of clinical signs and disease progression, protection from cognitive decline, and extension of life span (Katz et al., 2015).
In a study by Bosch et al., 1-month-old Cln3Δex7/8 mice received one systemic (intravenous) injection of scAAV9/MeCP2-hCLN3 or scAAV9/β-actin-hCLN3, with green fluorescent protein (GFP)-expressing viruses as controls. A promoter–dosage effect was observed in all brain regions examined, in which hCLN3 levels were elevated 3- to 8-fold in Cln3Δex7/8 mice receiving scAAV9/β-actin-hCLN3 versus scAAV9/MeCP2-hCLN3 scAAV9 construct driving low CLN3 expression (scAAV9/MeCP2-hCLN3) corrected motor deficits and attenuated microglial and astrocyte activation and lysosomal pathology (Bosch et al., 2016).
Mitchell et al. (2018) studied GRT in a naturally occurring sheep model of CLN5. Treated sheep showed preservation of cognitive and neurologic function and extension of life span. Visual deficit onset was also noted to be delayed (Mitchell et al., 2018).
Preclinical studies have demonstrated that a single intracerebroventricular injection of scAAV9.CB.CLN6 in mice model was not only safe but also induced sustained and significant protein expression which alleviated clinical symptoms in mouse model. This study became the basis of phase I/II clinical trial for CLN6.
NCT00151216: Worgall et al. conducted a clinical trial for CLN2. AAV2cuhCLN2 vector was administered intracerebrally through six burr holes—three in each hemisphere—with 12 sites of injection. A total dose of 1.8-3.2 × 1012 particles with an average dose of 2.5 × 1012 was given to the study participants. Ten patients were enrolled in this study—five with moderate and five with severe disease. Although the study was limited by lack of a placebo-controlled group and being nonblinded, the study showed slowing of disease progression. Primary safety assessments: PE, neurologic exam, blood work, ophthalmologic assessments. EEG was added after a serious adverse event. Primary efficacy assessment included modified Hamburg scale and secondary efficacy assessments included magnetic resonance imaging (MRI) brain (Worgall et al., 2008).
NCT01161576: This is a follow-up study to the above trial, but with a slightly different viral vector. Group A received 9.0 × 1011 genome copies/subject. Per preliminary reports, five out of six subjects developed T2 hyperintensities with diffusion restriction correlating with vector administration site. While group B was supposed to receive a 2-fold higher dose, the dose was decreased for the remaining subjects.
NCT01414985: Extension of the above IRB (Institutional Review Board) protocol- expansion of the eligibility criteria.
NCT03770572: This is a phase 1/2, open-label, single-dose, dose-escalation study of AT-GTX-502 (AAV9-CLN3) administered intrathecally into the lumbar spinal cord region of pediatric patients with CLN3 Batten disease. This study consists of a one-time injection of AT-GTX-502 with follow-up visits on Day 7, 14, 21, and 30, followed by every 3 months through 1-year post-dose, and then every 6 months through the second and third years. There are two cohorts with a low dose and a high dose.
NCT02725580: Patients receive intrathecal injections of an AAV9-CLN6 vector (AT-GTX-501). This trial is sponsored by amicus therapeutics. Preliminary safety results and interim efficacy results were presented at the joint 16th Child Neurology Congress and 49th Annual Child Neurology Society meeting. Preliminary safety data revealed that AT-GTX-501 is well tolerated. No pattern of AE related to immunogenicity was reported. Interim efficacy data revealed stabilization of motor and language function in vLINCL6 compared to the natural history cohort.
NCT04737460: This is a phase 1, open-label, single administration of gene therapy agent AAV9/CLN7, administered intrathecally into the lumbar spinal cord region of pediatric patients with CLN7 Batten disease. This is currently an ongoing study. In this study, patients will receive a one-time dose of intrathecal AAV9/CLN7. Out of four patients, one will receive lower dose and the rest will be given higher dose at 1 × 1015. The primary objective is to evaluate safety, and the secondary objective is to determine the efficacy of intrathecal AAV9/CLN7.
PMEs are a group of disorders which are invariably linked to neurodegeneration over time along with major disease burden with multiple medical complexities. Historically, classifying genetic underpinnings of various PMEs has been challenging, and this has impacted clinical care where the mainstay of the treatment has remained supportive symptomatic therapy and palliative care. Recent advances in molecular diagnostic techniques have allowed better and efficient genetic understanding of these diseases in parallel with major scientific interest to develop disease course-altering interventional therapies. Among these therapies, GRTs have been favorable precision medicine strategies for several reasons. GRTs have been used as a research tool in the preclinical arena for over four decades. GRTs using certain vectors like rAAV have been deemed safe and well tolerated in many clinical studies. At this point, in order to keep advancing our knowledge, more studies and extensive preclinical and clinical scientific work are needed. Various critical considerations in assuring success of GRTs include choosing appropriate vector and capsid designs, tissue tropism and appropriate route of administration with effective delivery to the organs of interest, and aspects related to immunogenicity to vector and transgene product. In addition, on the clinical side, work is needed to broaden our knowledge of the natural histories of the various PMEs and bridge the gap in knowledge to help study the clinical impact of GRTs. These combined efforts promise a future with better and effective treatments, and potentially cures for PME and other rare brain disorders.
This is an open access publication, available online and distributed under the terms of a Creative Commons Attribution-Non Commercial-No Derivatives 4.0 International licence (CC BY-NC-ND 4.0), a copy of which is available at https://creativecommons.org/licenses/by-nc-nd/4.0/. Subject to this license, all rights are reserved.
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