Progressive myoclonus epilepsies …

Epilepsy & Seizures

Updated 12.31.2023
Released 11.21.2011
Expires For CME 12.31.2026

Progressive myoclonus epilepsies

Authors: K P Vinayan MD DM, A S Jyotsna MBBS DNB DM

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Editor: Solomon L Moshé MD

Progressive myoclonus epilepsies

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Introduction

Overview

The progressive myoclonus epilepsies are a group of rare genetic disorders clinically characterized by the presence of myoclonic and generalized tonic-clonic seizures, myoclonic jerks, and progressive neurologic deterioration. In this article, the authors give a general overview of the main types of progressive myoclonus epilepsies and the advances in the understanding of their pathophysiology and management.

Key points

	• The progressive myoclonus epilepsies are a group of rare genetic disorders clinically characterized by the presence of typically refractory myoclonic seizures, generalized tonic-clonic seizures, and progressive neurologic deterioration.
	• Myoclonic jerks may be cortical or subcortical in origin.
	• Onset of symptoms is usually during childhood or adolescence.
	• Most progressive myoclonus epilepsies are caused by a pathogenic mutation in a gene inherited as an autosomal recessive trait. Less common progressive myoclonus epilepsies are inherited as an autosomal dominant trait or through mitochondrial inheritance.
	• Most of the known causative progressive myoclonus epilepsy genes encode lysosomal proteins or ion channels. Despite increasing knowledge of the etiology of most progressive myoclonus epilepsy disorders, the pathogenic mechanisms leading to neurodegeneration and epilepsy remain largely unknown.
	• Histological or genetic studies are frequently required to confirm the diagnosis.
	• Treatment is essentially symptomatic and limited to the management of the epileptic seizures, myoclonus, and intercurrent complications. Genetic counseling is mandatory.
	• Newer antiseizure medications like perampanel have been found to be useful in the management of myoclonus.
	• Disease modifying treatments like enzyme replacement and gene therapies have shown promise leading to a much better trajectory of the disease course.

Historical note and terminology

Progressive myoclonus epilepsy was first recognized as a clinical entity following original descriptions by Unverricht (74), Lundborg (44), and Lafora (42). Progressive myoclonus epilepsies were classically defined as progressive disorders presenting primarily with the association of epileptic generalized tonic-clonic seizures and multifocal, segmental, sometimes massive myoclonic jerks, with dementia being a less constant component. Cerebellar symptoms were reported in the original description of dyssynergia cerebellaris myoclonica, a mixup of forms of progressive myoclonus epilepsy described by Ramsay Hunt in 1921. However, cerebellar involvement is not always present in all the types of progressive myoclonus epilepsy. During the last century, many conditions were gradually added to the list of diseases that present as progressive myoclonus epilepsy. Most of them have clearly been clinically and genetically defined in the last 20 years.

Clinical manifestations

Presentation and course

The progressive myoclonus epilepsies are a group of heterogeneous and rare genetic disorders clinically characterized by the presence of myoclonic and generalized tonic-clonic seizures, myoclonus, and progressive neurologic deterioration that may include progressive dementia, cerebellar ataxia, neuropathy, and myopathy. Myoclonus in progressive myoclonus epilepsy is typically fragmentary and multifocal, often precipitated by posture, action, or external stimuli such as light, sound, or touch. Bilateral massive myoclonic jerks that tend to involve muscles of proximal limbs may also occur. The age of onset, presenting symptoms, relative predominance of symptoms as epileptic seizures, myoclonus, and dementia vary substantially across the different disorders (09).

The five major progressive myoclonus epilepsy entities are Unverricht-Lundborg disease, myoclonic epilepsy with ragged red fibers (MERRF), Lafora disease, the neuronal ceroid lipofuscinoses, and sialidoses type 1.

Unverricht-Lundborg disease is considered the commonest form of progressive myoclonus epilepsy. The age of onset is 6 to 15 years of age. Action and stimulus-sensitive myoclonic jerks are the initial symptoms in at least half of patients. The myoclonus is typically resistant to medications and progresses in severity. In late stages of the disease, it usually becomes severe enough to interfere with activities of daily living. Generalized tonic-clonic seizures are common. However, they are usually well controlled with antiepileptic drugs, and the frequency tends to decrease with age. Other seizure types such as absences may also be observed. With progression of the disease, patients develop ataxia, intention tremor, and dysarthria. Dementia is not a hallmark of this disease and is usually mild (38).

Lafora disease is a severe form of progressive myoclonus epilepsy that typically presents during late childhood or adolescence. Seizure types include myoclonus, visual seizures, atypical absences, and generalized tonic-clonic seizures. Myoclonus is typically fragmentary, asymmetric, arrhythmic, and progressively disabling. Cognitive decline, dysarthria, and ataxia appear early and invariably evolve, leading to severe disabilities. The course is usually rapid with a fatal outcome from status epilepticus or respiratory problems, usually within a decade of onset (77; 09).

Myoclonus epilepsy with ragged red fibers (MERRF) typically begins in childhood or adolescence. MERRF is characterized by myoclonus, generalized epilepsy, ataxia, and a constellation of symptoms that include myopathy, neuropathy, and dementia. Patients may develop deafness and optic atrophy. As a mitochondrial disease, the clinical symptoms are variable and the syndrome exhibits intrafamilial variation in age of onset and clinical severity. Less common features include cardiomyopathy, pigmentary retinopathy, pyramidal signs, ophthalmoparesis, multiple lipomas, and diabetes (19; 22). There is an overlap with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, but MERRF usually has a longer course and is associated with milder behavioral and cognitive deficits.

The neuronal ceroid lipofuscinoses comprise a large group of inherited, progressive neurodegenerative disorders characterized by the accumulation of an abnormal lipopigment in lysosomes. Historically, the neuronal ceroid lipofuscinoses were clinically categorized by age of onset into congenital, infantile (Santavuori-Haltia), late-infantile (Jansky-Bielschowsky), juvenile (Batten disease, Spielmeyer-Vogt), adult (Kufs and Parry disease), and Northern epilepsy. Increasing recognition of genetic and phenotypic heterogeneity prompted a new classification scheme that encompasses the advances in genetic and biochemical techniques (85). Currently, 13 known genes cause neuronal ceroid lipofuscinoses. Collectively, symptoms include a progressive myoclonic epilepsy syndrome, progressive visual impairment, a characteristic movement disorder, loss of cognitive/developmental skills, and, in older children, a neuropsychiatric disorder. The adult form (Kufs disease), which usually manifests at around 30 years of age, may present with progressive myoclonus epilepsy (type A) or motor disability and dementia (type B), but there is no visual impairment. Northern epilepsy syndrome is characterized by epilepsy and cognitive decline but does not present as a progressive myoclonus epilepsy (52; 51).

Sialidoses type 1 begins at 8 to 25 years of age and is characterized by progressive visual loss and disabling progressive myoclonus epilepsy with preserved cognitive status. The presence of a cherry-red spot on funduscopy is characteristic (61; 43; 26).

The syndrome of action myoclonus with or without renal failure syndrome is a fatal form of progressive myoclonus epilepsy characterized by onset at 15 to 25 years of age, prominent and debilitating action myoclonus, ataxia, and renal failure, but no cognitive deterioration (02; 05).

Spinal muscular atrophy and progressive myoclonic epilepsy (SMAPME) is a rare recessive disorder characterized by the combination of progressive myoclonic epilepsy and low motor neuron disease. A subtype with ASAH1 mutations presents with onset in early childhood with proximal muscular weakness followed by generalized epilepsy with myoclonic and absence seizures in late childhood or early adolescence and cognitive impairment of variable degree. The course is progressive with muscle wasting and uncontrolled epileptic seizures (32; 87; 30; 65).

Myoclonic epilepsy and ataxia due to potassium (K+) channel mutation (MEAK) is a described progressive myoclonus epilepsy phenotype (55). The disease is heralded by myoclonus, with an onset between the age of 6 to 14 years. Progressive worsening of myoclonus is accompanied by motor and gait problems. Cognitive difficulties before seizure onset are uncommon, The initial clinical manifestations and temporal evolution of MEAK resembles that of Unverricht-Lundborg disease (ULD). However, MEAK can be distinguished from Unverricht-Lundborg disease, as patients with MEAK usually exhibit a more severe course.

Several new genes have been implicated to cause the progressive myoclonus epilepsy phenotype. The latest entrants to the list have been DHDDS gene (39), ATP6V0A1 gene (11), and the IFRBPL gene (28).

Other rare diseases that can occasionally manifest as progressive myoclonus epilepsies are summarized in Table 1.

Table 1. Other Rare Diseases That May Present as a Progressive Myoclonus Epilepsy

• Celiac disease
• Dentatorubral-pallidoluysian atrophy
• Familial encephalopathy with neuroserpin inclusion bodies
• Galactosialidosis
• Gaucher disease type 3 (non-neuronopathic form)
• GM1 and GM2 gangliosidosis
• Huntington disease (juvenile form)

Prognosis and complications

The prognosis of a progressive myoclonus epilepsy is disease-specific and, thus, highly variable. On the mildest in the spectrum is Unverricht-Lundborg disease, with approximately half of the patients leading a normal life. The prognosis of MERRF and the neuronal ceroid lipofuscinoses is highly variable, even in individuals from the same family harboring the same mutation. The prognosis in sialidoses is poor, mainly resulting from the development of severe myoclonus in a few years. Lafora disease, progressive myoclonus epilepsy related to SCARB2 mutations (with or without renal failure), and SMAPME associated with mutations in ASAH1 lead to unavoidable incapacity and death, usually within a decade of disease onset.

Biological basis

Etiology and pathogenesis

Most progressive myoclonus epilepsies are caused by a pathogenic mutation in a gene inherited as an autosomal recessive trait. Less common progressive myoclonus epilepsies are inherited as an autosomal dominant trait (ie, some forms of adult neuronal ceroid lipofuscinosis) or through mitochondrial inheritance (ie, MERRF). The genes responsible for the most common types of progressive myoclonus epilepsy and their products are summarized in Table 2.

In addition, new phenotypes have been identified in some families or individuals harboring novel mutations in other genes (Table 3).

Table 2. Most Common Types of Progressive Myoclonus Epilepsy

Progressive myoclonus epilepsy type	Gene	Gene product	Common mutations
Unverricht-Lundborg disease	CSTB	Cystatin B	GC-rich dodecamer expansion
Lafora disease
	EPM2A	Laforin	Point mutations, deletions
	EPM2B	Malin	Point mutations, deletions
Neuronal ceroid lipofuscinoses
Congenital	CLN10/CTSD	Cathepsin D	Point mutations
Infantile
Classical (Haltia-Santavuori)	CLN1/PPT1	PPT1	Point mutations, deletions
Late infantile
Classical (Jansky- Bielschowsky)	CLN2	TPP1	Point mutations, deletions
Variants late-infantile	CLN5, CLN6, CLN8	CLN5, CLN6, CLN8	Point mutations, deletions
	CLN7/MFSD8	MFSD8	Point mutations
Juvenile
Spielmeyer-Sjögren-Vogt	CLN3	Battenin	1 Kb deletion, point mutations
Adult
Parry disease (AD)	DNAJC5	CSPα	Point mutations, deletions
Kufs type A (AR)	CLN6	CLN6	Point mutations
Sialidosis type 1	NEU1	Sialidase 1	Point mutations
MERFF	MT-TK	tRNA lysine	Point mutations
AD: autosomal dominant; AR: autosomal recessive; CSPα: co-chaperone cysteine string protein-α; DNAJC5: DnaJ homolog subfamily C member 5; MFSD8: major facilitator superfamily domain-containing protein 8; MT-TK: mitochondrially encoded tRNA lysine; PPT1: palmitoyl-protein thioesterase 1; TPP1: tripeptidyl-peptidase 1

Table 3. New Forms of Progressive Myoclonus Epilepsy

PME subtype (EPM designation in OMIM)	Gene	Protein function	Inheritance	References
PME type 1B (EPM1B)	PRICKLE1	Nuclear receptor	AR	(06)
AMRF (EPM4)	SCARB2	Lysosomal membrane protein	AR	(08; 20)
PME type 3 (EPM3)	KCTD7/CLN14	Modulation of potassium ion channel function	AR	(75; 72)
North Sea PME (EPM6)	GOSR2	Cathepsin D	AR	(16)
MEAK (EPM7)	KCNC1	Neuronal voltage-gated potassium ion channel	AD/de novo	(55)
PME type 8 (EPM8)	CERS1	Ceramide synthase-1	AR	(78)
PME type 9 (EPM9)	LMNB2	Nuclear lamin protein	AR	(18)
PME type 10 (EPM10)	PRMD8	Unknown function	AR	(73)
AD: autosomal dominant; AMRF: action myoclonus with or without renal failure; AR: autosomal recessive; MEAK: myoclonic epilepsy with ataxia due to potassium channel mutation

The well-described genes causing progressive myoclonus epilepsy encode lysosomal proteins. Despite increasing knowledge of the genes and proteins involved in progressive myoclonus epilepsy disorders, little was known about the pathogenic mechanisms leading to neurodegeneration and epilepsy (60). Recent basic neuroscience studies have thrown more light into the molecular pathomechanisms of the classically described progressive myoclonus epilepsies, ie, Unverricht-Lundborg disease, Lundborg disease, and neuronal ceroid lipofuscinoses. However, with the ever expanding genotypic and phenotypic spectrum in progressive myoclonus epilepsies, pathological heterogeneity becomes a rule rather than exception.

Neuroinflammation is being increasingly proven as a common trait in most of the neurodegenerative disorders of childhood. Neuroinflammation is supposed to trigger a cascade of events that ultimately results in neuronal hyperexcitability and seizures (66). Seizures in turn upregulate the proinflammatory cytokines contributing to a positive feedback loop (80). Several mechanisms of neuroinflammation have been proposed based on the studies on animal models of progressive myoclonus epilepsies. The most recurrent finding has been the activation and immune dysregulation mediated by the astrocytes and microglia. There have been strikingly common proinflammatory cytokines that have been detected in all three major progressive myoclonus epilepsies, ie, Unverricht-Lundborg disease, Lundborg disease, and neuronal ceroid lipofuscinoses. One disease specific chemokine is the Cxcl13 in Unverricht-Lundborg disease, which is also being studied as a possible biomarker (58). The exact trigger of such a diffuse glial response activation is not clear. Proposed mechanisms are the accumulation of intracellular deposits in Lundborg disease, neuronal ceroid lipofuscinoses, and mitochondrial dysfunction, along with oxidative stress-related injury in Unverricht-Lundborg disease and Lundborg disease. The end result of a long standing activation of a diffuse glial response is neurodegeneration.

Lafora disease is caused by mutations in either EPM2A or EPM2B, which encode the interacting proteins laforin, a dual-specificity phosphatase, and malin, an ubiquitin E3 ligase (49; 69; 14). Laforin and malin regulate glycogen synthesis, and their malfunction results in the formation of an abnormal glucose polymer that accumulates in the brain and other tissues (Lafora bodies) (42). This accumulation, other malfunctioning pathways where laforin and malin are involved, or both, results in progressive neurodegeneration and epileptic seizures. Experimental work has shown that neurons have the enzymatic mechanism for synthesizing glycogen, but that it is suppressed by the laforin-malin complex. Disturbance of this mechanism, as a consequence of mutations in laforin or malin, would explain the accumulation of a poorly branched glycogen. This abnormal glycogen might result in the activation of the apoptotic program (81). Lafora bodies are seen to accumulate in many different tissues, such as muscle, heart, and liver. Other systemic symptoms are very rarely seen.

Classical Unverricht-Lundborg disease is caused by mutations in the CSTB gene encoding cystatin B. The most prevalent genetic defect is the expansion of an unstable polymorphic dodecamer repeat in the promoter region of CSTB, which accounts for more than 90% of mutated alleles (59; 36). Because of the role of cystatin B as an inhibitor of lysosomal cysteine proteases, the defective protein is presumed to lead to increased abnormal apoptosis or altered redox homeostasis, leading to neuronal degeneration and death.

Mutations in the 13 genes known to cause neuronal ceroid lipofuscinosis lead to defects of lysosomal enzymes or transmembrane proteins whose functions are not yet defined. Despite genetic and clinical heterogeneity, the different forms are grouped together on the basis of pathologic grounds due to the common presence of neuronal and extraneural autofluorescent pigment deposits. Under the electron microscope, the accumulated material takes three different forms: granular osmiophilic deposits, curvilinear profiles, and fingerprint bodies. The form that predominates in a particular patient may correlate with the particular genetic type of neuronal ceroid lipofuscinosis (53).

In sialidoses, the enzymatic deficiency of sialidase 1 results in lysosomal storage of sialylated glycopeptides and oligosaccharides (10). Sialidase 1 is a negative regulator of lysosomal exocytosis, thus, the impaired function of neuraminidase is related to exacerbation of lysosomal exocytosis (86). Light and electron microscopy reveals cytoplasmic vacuolation involving neurons and perineuronal and interfascicular oligodendroglia, endothelial, and perithelial cells. Vacuolations are associated with diffuse neuronal intracytoplasmic storage of lipofuscin-like pigment. These changes can be observed in the neocortex, basal ganglia, thalamus, brainstem, spinal cord, and also in organs outside the nervous system (01).

MERRF is caused by mutations in genes contained in mitochondrial DNA (mtDNA) and, thus, inherited by maternal inheritance. The A8344G mutation in the MT-TK gene encoding tRNA lysine is found in more than 80% of patients with MERRF. Less common mutations in the MT-TL1, MT-TH, and MT-TS1 genes have been described (70; 22). Neuropathological studies have revealed prominent loss of neurons in the cerebellum, brainstem, and spinal cord.

Action myoclonus-renal failure syndrome is caused by mutations in SCARB2, a gene encoding lysosome membrane protein 2, a chaperone that escorts glucocerebrosidase to the lysosome (08).

MEAK (EPM7), myoclonus epilepsy and ataxia due to a potassium channel dysfunction, is caused by a recurrent de novo heterozygous mutation (c.959G> A, p.Arg320His) in the KCNC1 gene coding for the Kv3.1 protein (a subunit of the Kv3 subfamily of voltage-gated potassium channels). Loss of function of this protein causes disruption of the firing properties of fast-spiking neurons, affects neurotransmitter release, and induces cell death. The most affected neurons include inhibitory GABAergic interneurons and cerebellar neurons that may contribute to the main clinical symptoms of seizures or myoclonus and ataxia or tremor respectively (55).

Diagnostic workup

The first stage of the diagnostic approach should be based on a detailed clinical evaluation considering age at onset; geographic and ethnic origin; family history; associated neurologic symptoms, and neurophysiologic features. Further specific laboratory analysis, molecular genetic testing, or histological studies should lead to the diagnosis of the specific disease in the majority of the patients (07).

Neurophysiology. The EEG background may be relatively well-preserved in the early phases, but as the condition progresses generalized slow activity appears, especially in progressive myoclonus epilepsies associated with cognitive impairment. Sleep patterns may become disorganized or even be absent generalized epileptiform abnormalities, such as fast spike-and-waves, multiple spike-and-waves, or multiple-spike discharges, are commonly recorded spontaneously or elicited by intermittent photic stimulation. Spontaneous myoclonic jerks may be associated with EEG paroxysms in routine recordings, although jerk-locked back averaging may be necessary to detect a time-locked EEG correlate. Focal epileptiform abnormalities with predominant posterior location are common in Lafora disease, but may also occur in Unverricht-Lundborg disease, MERRF, and juvenile neuronal ceroid lipofuscinosis (09). With a few exceptions, epileptiform activity is often less apparent than in the waking state.

Features that may be useful for specific diagnosis include the finding of vertex spikes and fast rhythms in sialidoses, activation of epileptiform abnormalities in non-REM sleep in sialidoses and in the late-infantile and juvenile forms of neuronal ceroid lipofuscinosis, photosensitivity to single flashes in late-infantile and adult neuronal ceroid lipofuscinosis, and absent electroretinogram in late-infantile and juvenile neuronal ceroid lipofuscinosis (09).

Somatosensory evoked potentials frequently show giant responses whereas visual and brainstem evoked responses are usually normal. Magnetic stimulation of the cortex and peripheral stimulation show an exaggerated effect of afferent input on motor cortical excitability (63).

Laboratory findings. Routine biochemical tests are not helpful, with the exception of elevated lactate levels in blood and CSF in some cases of MERRF and proteinuria with impaired renal function in the action myoclonus-renal failure syndrome.

Some useful, specific tests are urinary thin-layer chromatographic oligosaccharide screen for the sialidosis and urinary sediment dolichol estimation for the neuronal ceroid lipofuscinoses. Specific enzyme assays using fibroblast cultures and specific substrates may be useful to confirm the diagnosis in sialidosis (sialidase 1 and beta-galactosidase) and in some types of neuronal ceroid lipofuscinosis (palmitoyl protein thioesterase 1, tripeptidyl-peptidase 1, and cathepsin D).

Neuroimaging. Structural brain MR is usually normal or shows diffuse atrophy in later stages. An MRI and MR spectroscopy study in patients with Unverricht-Lundborg disease showed loss of the bulk of the basis pontis, medulla, and cerebellar hemispheres as well as spectroscopy abnormalities in the pons, suggesting that brainstem involvement could play a role in the pathophysiology of the disease (47). In Lafora disease, abnormalities in spectroscopy, mainly in the frontal cortex, cerebellum, and basal ganglia, have been described (82). Cerebellar atrophy may also be noted in MEAK (56).

Pathological studies. Lafora disease can be reliably diagnosed by examining eccrine sweat gland duct cells with periodic acid-Schiff (13). In cases of neuronal ceroid lipofuscinosis not confirmed by enzyme analysis, identification of typical inclusions with electron microscopy examination of peripheral white blood cells or skin will confirm the diagnosis. These inclusions are detectable in many cell types in the late-infantile form of the disease. However, diagnostic inclusions may be limited to eccrine secretory cells in the juvenile and adult varieties (53). False-negative skin biopsies in Lafora disease and in late-infantile and juvenile neuronal ceroid lipofuscinosis are mostly attributed to failure to examine the appropriate cell type properly (07).

Study of muscle biopsy specimens with modified Gomori trichome and oxidative enzyme reactions may demonstrate ragged red fibers in MERRF (33). Abnormal mitochondria may be identified in muscle or skin using electron microscopy studies. Normal light and electron microscopic studies of muscle do not rule out the diagnosis of MERRF.

Targeted genetic testing will confirm the diagnosis in most cases of progressive myoclonus epilepsy, where the clinical phenotype is classical. In other cases, next generation sequencing may be needed. However, it must be accepted that some cases will not be classified even after careful clinical and genetic studies (25).

Management

Management of these disorders may be distressingly difficult. Overall, treatment of progressive myoclonus epilepsies remains limited to symptomatic management of seizures, myoclonus, and intercurrent complications. There is no specific treatment yet for most genetic disorders underlying the progressive myoclonus epilepsy syndrome although new therapies may soon be available. Going beyond a palliative treatment approach of progressive myoclonus epilepsies requires a fine understanding of biological processes. Once the diagnosis is confirmed, informed genetic counseling should be provided, together with psychological support, to parents, patients, and siblings, especially in those diseases with the worst prognosis. Treatment strategies that have shown to offer benefit in the various progressive myoclonus epilepsies syndromes are summarized below.

Pharmacotherapy. Available data on the efficacy of drugs are primarily observational and come from small groups of patients. Traditional antiepileptic drugs useful in the treatment of progressive myoclonus epilepsies are valproate and clonazepam (34). However, valproate inhibits carnitine uptake and should not be used in mitochondrial disorders. Other drugs shown to be effective include piracetam, levetiracetam, and topiramate (24; 45; 04). Two small, open-label studies support a beneficial role of zonisamide in the symptomatic treatment of progressive myoclonus epilepsies (83; 35). Perampanel also has been found to be useful for the treatment of myoclonus in patients with Unverricht-Lundborg disease although psychological and behavioral side effects may limit its use (17). In a case series, perampanel demonstrated a beneficial effect in action myoclonus, disability, and seizures and was well tolerated in people with progressive myoclonus epilepsies, irrespective of the genetic diagnosis (03). A systematic review of studies that analyzed the efficacy of perampanel for treating myoclonic seizures and symptomatic myoclonus suggested its efficacy in both, especially for treating patients who had a failure of response to valproate and levetiracetam (50). Two clinical trials have failed to show the efficacy of brivaracetam in action myoclonus in patients with Unverricht-Lundborg disease (37).

Drugs that may worsen myoclonus, such as phenytoin, vigabatrin, carbamazepine, and gabapentin, should be systematically avoided. Lamotrigine has an unpredictable effect on myoclonus and must be used with caution (29).

Combinations of antioxidant vitamins and cofactors, like coenzyme Q10 and L-carnitine supplementation, can be used in patients with mitochondrial disorders.

Precision therapies. Enzyme replacement therapy- Specific treatment with enzyme replacement and gene therapy are attractive therapeutic options. A multicenter, open-label study evaluated the effect of enzyme-replacement therapy with intraventricular infusion of recombinant human tripeptidyl peptidase 1 (cerliponase alfa) in 24 patients with ceroid lipofuscinosis type 2 (68). The treatment resulted in less decline in motor and language function than in historical controls. Among others, emerging adverse events included pyrexia, vomiting, and hypersensitivity reactions. Infections were also rarely noted in the intraventricular device that was used to administer the infusion. Ceroliponase alfa (Brineura®) is now currently approved precision treatment for CLN2 and is administered via a surgically implanted intraventricular access device, and studies are ongoing to determine its long term efficacy and complications (15).

Gene therapies. No gene therapies are currently approved for human use in progressive myoclonus epilepsies, though there has been progress in the in use of intraventricular injections of rAAV vectors to decrease neurodegeneration in mouse and canine models (84; 41).

ASO therapy. Kim and colleagues identified missplicing of exon 6 in the CLN7 gene causing neuronal ceroid lipofuscinoses in a six-year-old patient with advanced disease, and they designed a specific antisense oligonucleotide to directly correct the splicing defect (40). There was a significant (> 50%) reduction in seizure frequency and duration, along with a good safety profile.

Adjunctive therapies.

Dietary therapies. A pilot study on Ketogenic diet in patients with Lafora body disease showed a lack of efficacy (12). Another prospective observational study studied the efficacy of Modified Atkin’s diet in North Sea progressive myoclonus epilepsy in four patients by taking Health Related Quality of Life (HRQL) as the outcome measure. One patient showed a significant improvement after three months of dietary therapy (76).

Vagal nerve stimulation. A series of case reports have emerged to demonstrate efficacy in terms of seizure frequency, cerebellar symptoms, and improving quality of life at follow up, in patients with progressive myoclonus epilepsies (71; 27; 31; 48; 54).

Deep brain stimulation and repetitive transcranial magnetic stimulation. Sporadic case reports have demonstrated some efficacy in both the above techniques (79; 64; 21). Further studies are needed.

Outcomes

Progressive myoclonus epilepsy is a group of genetic disorders, which currently has a uniformly guarded prognosis. Precision medicine should definitely be considered as the most appropriate management strategy for any genetic disease, especially for devastating disorders like progressive myoclonus epilepsies. For precision medicine, exact identification of the physiologic role of affected protein and the consequences of its mutations are crucial. Earlier diagnosis will aid treatment at a presymptomatic stage. However, due to the genotypic heterogeneity of progressive myoclonus epilepsies, this is an uphill endeavor. Another focus should be improving the quality of life of affected children and the caregivers. There is a recent focus on considering all these disorders under the umbrella of childhood dementia (23). Such an approach might help in highlighting the needs of the affected population and further improving the care and the overall outcomes.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

K P Vinayan MD DM

Dr. Vinayan of the Amrita Institute of Medical Sciences has no relevant financial relationships to disclose.
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A S Jyotsna MBBS DNB DM

Dr. Jyotsna of Apollo BGS Hospital has no relevant financial relationships to disclose.
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Editor

Solomon L Moshé MD

Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.
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Former Authors

Jose M Serratosa MD PhD
Beatriz G Giráldez MD
Jerome Engel Jr MD PhD

Patient Profile

Age range of presentation: 0 to 44 years
Sex preponderance: male>female, >1:1
Heredity: heredity typical

autosomal dominant

autosomal recessive

mitochondrial
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none

ICD & OMIM codes

ICD9: Myoclonus: 333.2
ICD10: Epilepsy, epileptic, epilepsia-myoclonus, myoclonic: G40.3
OMIM: Myoclonus epilepsy of Unverricht and Lundborg: #254800

Myoclonic epilepsy of Lafora: #254780

Myoclonic epilepsy associated with ragged-red fibers, MERRF: #545000

Neuraminidase deficiency: #256550

Epilepsy, progressive myoclonic 4, with or without renal failure, EPM4: #254900

Epilepsy, progressive myoclonic 1B, EPM1B: #612437

Epilepsy, progressive myoclonic 3, with or without intracellular inclusions, EPM3: #611726

Epilepsy, progressive myoclonic 6, EPM7: #614018

Epilepsy, progressive myoclonic 7, EPM7: #616187

Epilepsy, progressive myoclonic 8, EPM8: #616230

Epilepsy, progressive myoclonic 9, EPM9: #616540

Epilepsy, progressive myoclonic 10, EPM10: #616640

Spinal Muscular Atrophy with progressive myoclonic epilepsy, SMAPME: #159950

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Progressive myoclonus epilepsies

Differential Diagnosis

idiopathic generalized epilepsy
juvenile myoclonic epilepsy

Also Relevant

Epilepsy
Lafora disease
Myoclonus
Unverricht-Lundborg disease

Progressive myoclonus epilepsies …

Progressive myoclonus epilepsies

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Other Rare Diseases That May Present as a Progressive Myoclonus Epilepsy

Prognosis and complications

Biological basis

Etiology and pathogenesis

Table 2. Most Common Types of Progressive Myoclonus Epilepsy

Table 3. New Forms of Progressive Myoclonus Epilepsy

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

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Acute cerebellar ataxia in children

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Cerebral edema in childhood

Malformations of the brain

Progressive myoclonus epilepsies

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Other Rare Diseases That May Present as a Progressive Myoclonus Epilepsy

Prognosis and complications

Biological basis

Etiology and pathogenesis

Table 2. Most Common Types of Progressive Myoclonus Epilepsy

Table 3. New Forms of Progressive Myoclonus Epilepsy

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Breath-holding spells

Acute cerebellar ataxia in children

Zika virus: neurologic complications

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Epilepsy with auditory features

Cerebral edema in childhood

Malformations of the brain

This is an article preview.
Start a Free Account
to access the full version.