Received: 24 April 2023

| Accepted: 19 August 2023

DOI: 10.1002/epd2.20152

REVIEW ARTICLE

ILAE Genetics Literacy series: Progressive myoclonus

epilepsies

Jillian M. Cameron1 | Colin A. Ellis2 | Samuel F. Berkovic1 |

for the ILAE Genetics Commission* | the ILAE Genetic Literacy Task Force*

1
Epilepsy Research Centre, Department
of Medicine, University of Melbourne, Abstract
Austin Health, Melbourne, Victoria, Progressive Myoclonus Epilepsy (PME) is a rare epilepsy syndrome characterized
Australia
2
by the development of progressively worsening myoclonus, ataxia, and seizures.
Department of Neurology, University
of Pennsylvania Perelman School of
A molecular diagnosis can now be established in approximately 80% of individu-
Medicine, Philadelphia, Pennsylvania, als with PME. Almost fifty genetic causes of PME have now been established,
USA although some remain extremely rare. Herein, we provide a review of clinical
Correspondence phenotypes and genotypes of the more commonly encountered PMEs. Using
Samuel F. Berkovic, Epilepsy Research an illustrative case example, we describe appropriate clinical investigation and
Centre, 245 Burgundy St., Heidelberg
therapeutic strategies to guide the management of this often relentlessly progres-
3084, VIC, Australia.
Email: s.berkovic@unimelb.edu.au sive and devastating epilepsy syndrome. This manuscript in the Genetic Literacy
series maps to Learning Objective 1.2 of the ILAE Curriculum for Epileptology
Funding information
(Epileptic Disord. 2019;21:129).
American Academy of Neurology
Susan S. Spencer Clinical Research
Training Scholarship; Mirowski Family KEYWORD
Foundation; National Health and progressive myoclonus epilepsies
Medical Research Council, Grant/
Award Number: APP1196637; National
Institute of Neurological Disorders
and Stroke, Grant/Award Number:
K23NS121520

1 | P RO G RE SSIVE M YOCLON US is often in later childhood or adolescence and patients

EPILEPSY
Progressive Myoclonus Epilepsy (PME) is a rare general-
ized epilepsy syndrome, clinically characterized by the de-
velopment of progressively worsening myoclonus, ataxia,
and tonic–­clonic seizures,1 with variable associated cog-
nitive decline and neuropsychiatric disturbance.2,3 Onset
typically become extremely functionally impaired by
their symptoms. As the name suggests, myoclonus is core
to the PME phenotype. Stimulus-­sensitive myoclonus
(also referred to as reflex myoclonus, that is myoclonus
induced or exacerbated by a variety of stimuli including
light, sound, touch, and action) is a key manifestation.
Action-­induced myoclonus is a characteristic feature and

*The ILAE Genetics Commission and The ILAE Genetic Literacy Task Force members are listed in Appendix 1.
This report was written by experts selected by the International League Against Epilepsy (ILAE) and was approved for publication by the ILAE.
Opinions expressed by the authors, however, do not necessarily represent the policy or position of the ILAE.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2023 The Authors. Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

670 | wileyonlinelibrary.com/journal/epd2
 Epileptic Disorders. 2023;25:670–680.

CAMERON et al.
is typically fragmentary and multifocal. Myoclonus tends
to be refractory to treatment and cause the most function-
ally significant impairment.4
There are many forms of PME, with now almost fifty
established genetic causes, although some are extremely
rare (see Table S15). The most common cause of PME
worldwide is Unverricht-­Lundborg Disease (ULD),6 with
highest reported prevalence in Finland (1.9/100 000).7
Other important causes of PME include Lafora Disease
(LD, prevalence 1–­9/106,8), the Neuronal Ceroid Lipofus-
cinoses (NCL), and Myoclonic epilepsy with ragged red fi-
bers (MERRF). Geographical distribution varies for some
forms of PME, particularly those with recessive inheri-
tance, dependent on the frequency of consanguinity and
local founder effects.
2 | ET I O LOGY AN D G E N ET ICS OF
PME
A molecular diagnosis can now be established in approxi-
mately 80% of patients with PME.9,10 Clinical phenotypes
and genotypes associated with some of the more common
forms of PME are outlined below.
2.1 | Unverricht-­Lundborg disease
ULD is an autosomal recessive condition due to ho-
mozygous or compound heterozygous pathogenic
variants in CSTB.6 The most common type of genetic
variant, seen in 90% of disease alleles worldwide, is an
unstable expansion of a 12-­nucleotide dodecamer repeat
(5′-­CCCCGCCCCGCG-­3′).11 ULD-­associated alleles
typically contain at least 30 repeat copies.12 Although
initial small studies did not show a correlation between
the expansion size and clinical features, a larger study
suggested that the size of the CSTB expansion is likely
to have a modulating effect on age of disease onset, se-
verity of myoclonus, and neurophysiological markers.13
Anticipation (that is increase in expansion from parent
to child) has not been identified. Missense pathogenic
variants in CSTB account for a minority of causative
variants.14 Individuals who are compound heterozy-
gotes, with one missense and one repeat expansion vari-
ant, have been reported to have a more severe disease
phenotype.15,16
Typical onset of ULD is in late childhood to adolescence
(peak 12–­13 years of age). Myoclonus is the predominant
feature at onset, progressing over months to years before
plateauing in middle life (17). Medication refractory reflex
myoclonus, particularly action myoclonus, is common
and the main cause of functional disability. Other than
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   671
Key points
• In the evaluation of PME, certain clinical and
EEG findings can help narrow the list of differ-
ential diagnoses to specific diseases.
• Important PMEs include Unverricht-­Lundborg
Disease, Lafora Disease, Neuronal Ceroid
Lipofuscinoses, and Myoclonic Epilepsy with
Ragged Red Fibers.
• A molecular diagnosis can now be established
in approximately 80% of patients with PME.
While PME gene panels are currently useful,
exome or genome sequencing will likely sup-
plant these in the future.
• Treatment mainly symptomatic.
myoclonus, generalized tonic–­clonic seizures (GTCS)
are the most common seizure type, with absence and
focal seizures with impaired awareness reported rarely.4
GTCS typically respond to antiseizure medication, but
also independently decrease in frequency as the disease
progresses.17 The most commonly associated neurological
manifestation is ataxia. Cognition is relatively preserved,
although subtle impaired processing and executive func-
tion have been reported.18,19 Psychiatric co-­morbidities are
common, with high rates of depression and suicidal be-
haviour.18 Reduced life expectancy is seen, with a median
age at death of 53.9 years.7
2.2 | Lafora disease
Lafora Disease is an autosomal recessive condition due
to loss-­of-­function variants in EPM2A (65%–­70% of cases)
or NHLRC1/EPM2B.20 No definitive genotype–­phenotype
correlations have been established, though a longer life
expectancy and milder disease course have been described
with some NHLRC1 variants, particularly the recurrent
missense variant p.Asp146Asn.21,22
EPM2A encodes laforin23 and NHLRC1 encodes
malin.24 Whilst their roles are incompletely understood,
both proteins are involved in glycogen metabolism. Evi-
dence suggests they act as a complex to prevent the accu-
mulation of insoluble glycogen.25–­27 LD is associated with
the pathognomonic finding of Lafora bodies (diastase-­
resistant periodic acid–­Schiff (PAS-­D)-­positive aggregates
of abnormally branched, insoluble polyglucosans), which
are found in the brain, liver, skeletal and cardiac myocytes
and sweat glands. It is thought a deficiency of functional
laforin or malin results in normally soluble glycogen
 |
672   
containing abnormally long chains and precipitating and
aggregating as Lafora bodies.28
Typical onset of LD is in late childhood or early ad-
olescence (8–­19 years, peak at 14–­16 years). Focal oc-
cipital seizures are a characteristic feature particularly
early in disease.29 Myoclonus manifests early and es-
calates rapidly over months to years to intractable ac-
tion-­ and stimulus-­sensitive myoclonus. Various other
seizure types (GTCS, absence, atonic) rapidly develop.
LD is associated with a rapidly progressive dementia
with significant apraxia, visual loss, and neuropsychi-
atric disturbance. The prognosis is poor. Early studies
suggested death occurred within 10 years of disease
onset,28,30 but more recent data suggests the prognosis
may be less grim, with a median survival of 11 years.31
Late onset (>18 years) appears to be related to longer
disease duration and slower progression.31
2.3 | Neuronal ceroid lipofuscinoses
(NCL)
The NCLs, also known as Batten Disease, are a group
of monogenic neurodegenerative conditions grouped
together due to a shared histopathological signature,
namely abnormal intracellular lysosomal lipopigment
storage material with various characteristic forms on
ultrastructural examination of brain and peripheral tis-
sues such as skin or lymphocytes. To date, 13 different
NCL-­related genes have been identified. Although some
clinical heterogeneity is seen, broadly the clinical phe-
notype includes a combination of seizures, visual failure,
dementia, and decline in motor function. Most forms of
NCL have onset in infancy or early childhood. Important
childhood forms of NCL that can present with a PME
phenotype include CLN2 disease, CLN5 disease, and the
late-­infantile form of CLN6 disease. CLN2 disease, due
to pathogenic variants in TPP1, is associated with visual
loss and significant language delay. 32 It is the only form
of PME for which there is disease-­modifying treatment,
hence prompt recognition and diagnosis is of critical im-
portance (see treatment section below). KCTD7 patho-
genic variants have been described in individuals with a
PME phenotype both with and without histopathologi-
cal evidence of abnormal lysosomal storage material on
biopsy.33,34
A PME phenotype can also be associated with the re-
cessive adult-­onset NCLs (also referred to as Kufs disease),
particularly CLN6 disease. Vision is typically preserved in
the adult-­onset NCLs. CLN4 disease, due to pathogenic
variants in DNAJC5, is the only autosomal dominant form
of NCL described, and also presents with an adult-­onset
PME phenotype.
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CAMERON et al.
2.4 | Myoclonic epilepsy and ataxia due
to KCNC1 mutation (MEAK)
MEAK is a form of PME caused by a recurrent het-
erozygous missense variant, p.Arg320His in KCNC1.
Most cases are sporadic due to de novo variants but a
few families with autosomal dominant inheritance
are reported.35 KCNC1 encodes Kv3.1, a subunit of the
Kv3 subfamily of voltage-­gated tetrameric potassium
channels.35 The p.Arg320His variant has a dominant-­
negative loss-­of-­function effect in vitro.35 Kv3.1 expres-
sion is largely restricted to the central nervous system,
with predominant expression in GABAergic interneu-
rons.36 Thus, disinhibition due to impaired activity of
these inhibitory interneurons is a plausible pathogenic
mechanism.35
The clinical phenotype is characterized by the onset of
myoclonus between 6 and 14 years of age.8 Myoclonus is
the most prominent clinical feature, typically becoming
very severe during adolescence and impacting mobility.
Infrequent GTCS are seen, and cognition is largely pre-
served. Early death has not been observed.
2.5 | Myoclonic epilepsy associated with
ragged red fibers (MERRF)
MERRF is one of many mitochondrial disorders due to
pathogenic variants in mitochondrial DNA. Mitochon-
drial DNA encodes polypeptides involved in the mito-
chondrial respiratory chain. Almost all reported MERRF
pathogenic variants affect the gene for tRNA lysine MT-­
TK, with the m.8344A>G variant identified in 80%–­90%
of patients.37
MERRF is characterized by myoclonus, generalized
seizures, myopathy, and progressive ataxia. Onset is
typically in childhood, although adult onset is seen. As
is typical of mitochondrial disorders, the phenotype is
extremely variable, and multisystem involvement (par-
ticularly affecting tissues with high metabolic demand)
is seen.38 Common associated features include hearing
impairment, sensorimotor peripheral neuropathy, cog-
nitive impairment, short stature, and optic atrophy.
Less common features include cardiomyopathy, diabe-
tes mellitus, pyramidal signs, retinitis pigmentosa, and
ophthalmoplegia. Multiple lipomas, ranging from small
subcutaneous nodules to large masses, can be seen, typi-
cally on the neck or trunk.38,39 There is some phenotypic
overlap with other mitochondrial disorders, particularly
Mitochondrial Encephalopathy, Lactic Acidosis, and
Stroke-­like episodes (MELAS). Although acute episodes
of neurological impairment are the most common neu-
rological presentation associated with MELAS, a broad

CAMERON et al.
range of neurological manifestations including PME are
well-­recognized.
2.6 | Sialidosis
Sialidosis is an autosomal recessive lysosomal storage
disorder due to pathogenic variants in NEU1, resulting
in sialidase deficiency and abnormal accumulation of
sialic acid-­rich substrates in the CNS and other organ
systems.40 There are two forms of sialidosis, type I (nor-
momorphic) and II (dysmorphic). Patients with type I
sialidosis have some residual sialidase activity, and ex-
hibit a PME phenotype characterized by progressively
worsening multifocal myoclonus with seizures and
ataxia. Typical age of onset is between 10 and 20 years.
A characteristic macular “cherry-­red spot” can be de-
tected, due to storage material in perifoveal ganglionic
cells, and can result in visual impairment.41 Early in the
disease, the cherry-­red spot may be clinically undetect-
able, and it may also disappear in the later stages of the
disease.42
3 | F URT HE R FOR M S OF PM E
Other well-­described forms of PME include Action
Myoclonus Renal Failure Syndrome (AMRF, SCARB2),
GOSR2 “North Sea” PME, and Spinomuscular Atrophy-­
PME (SMA-­PME, ASAH1) amongst others. The most
distinguishing (but not universal) feature of AMRF is
renal involvement, initially presenting as proteinuria
and then progressing to nephrotic syndrome and end-­
stage renal failure. “North-­Sea” PME is so-­called as all
described cases have birthplaces clustered around the
North Sea, a result of a founder effect. A persistently
raised CK in the context of a normal muscle biopsy is
typical, and associated clinical features include scoliosis
and peripheral neuropathy. SMA-­PME is a rare condi-
tion characterized by the presence of both lower motor
neuron degeneration and classical PME features; either
can occur first.43 Furthermore, a PME phenotype can
also be seen as part of a wider neurological spectrum
of disease in various conditions including Dentatorubral
pallidoluysian atrophy (DRPLA), Gaucher's Disease,
and Juvenile Huntington's Disease.
4 | R A RE A N D E ME RG IN G FORMS
With now almost fifty genes associated with PME,
many forms remain extremely rare. The biochemical
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   673
pathways involved are diverse and constantly expanding,
as highlighted by the recent novel association of dolichol-­
dependent glycosylation with the PME phenotype due
to pathogenic variants impacting NUS1, DHDDS, and
ALG10.9 There are increasing descriptions of cases of PME
due to pathogenic variants in genes associated with other
neurodevelopmental conditions, broadening the spectrum
of clinical phenotypes associated with these genes. This
includes but is not limited to the developmental and epi-
leptic encephalopathies (for example, TBC1D24, DHDDS,
CHD2, and CACNA2D2).
5 | THE UNSOLVED RESIDUUM
Despite the rapidly evolving understanding of the genetic
architecture of PME, 20% of individuals remain without a
molecular diagnosis. This unsolved residuum will likely
be a collection of ultra-­rare causes in novel genes, or due
to pathogenic variants, which are more challenging to
identify and interpret with current available technologies,
such as repeat expansion mutations, or variants in non-
coding regions affecting mechanisms such as transcrip-
tional regulation or epigenetic modification. Nongenetic
etiologies, including autoimmune, may warrant consider-
ation, as highlighted by the association of coeliac disease
with various neurological manifestations including myo-
clonus and ataxia.44,45
Of note, the Progressive Myoclonic Ataxias (PMAs)
are defined as conditions generally presenting first with
prominent ataxia, before subsequently developing my-
oclonus and in some cases epilepsy.46 There is clearly a
significant clinical phenotypic overlap between PME and
PMA, and several conditions are described under both cat-
egories in the literature. An awareness of this when con-
sidering differential diagnoses and potential underlying
etiologies in those who remain without a genetic diagno-
sis is important.
6 | INV ESTIGATION STRATEGIE S
6.1 | History and examination
PME should be considered in patients with myoclonus
(especially if refractory to medication), progressive motor
impairment, cognitive deterioration, sensory, and cerebel-
lar signs. Because most genetic causes are recessive, fam-
ily history may be unrevealing, or may include affected
siblings only. Inquiring about consanguinity is essential.
Some features of history and examination may suggest
specific PME syndromes (Table 1).
 |

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674    CAMERON et al.

T A B L E 1 History and examination features suggestive of

specific PME syndromes.

Finding Associated syndrome

Visual seizures (history) Lafora disease
Occipital seizures (EEG)
Vision loss, retinopathy NCLs (but rarely in adult-­onset
cases)
Sialidosis
Cherry-­red spot in macula Sialidosis (also Niemann–­Pick
disease, Gaucher disease)
Myopathy MERRF
Hearing loss
Cutaneous lipomas
Stroke-­like attacks MELAS
Hepatosplenomegaly Gaucher disease
Peripheral neuropathy Multiple PME syndromes,
Ataxia nonspecific
Optic atrophy
FIGURE 1 Diagnostic approach to suspected PME.
Photosensitivity (at low
flash rate)
Psychiatric symptoms
targeted single-­gene testing based on phenotype. Gene
panels for PME or comprehensive epilepsy panels are
6.2 | EEG and imaging available from most commercial laboratories. Exome or
genome sequencing have additional advantages and are
EEG should be performed in all patients. It is important replacing gene panels as first-­line genetic tests because
to recognize that there can be considerable variabil- they can detect findings not detected by a gene panel and
ity in EEG characteristics between the various PMEs. enable future reanalysis for undiagnosed cases. Many di-
In most, but not all, forms of PME, the background is agnostic laboratories now offer a gene panel off an exome
typically normal early in the disease course, progressing or genome backbone, which allows for reanalysis with an
to irregular diffuse slowing as the disease progresses. updated gene list after 18 months–­2 years.
Epileptiform discharges are typically generalized spike-­ Clinicians should be aware of several pitfalls in genetic
and-­wave or polyspike-­and-­wave, but focal or multifocal testing for PMEs. Repeat expansions (as seen in ULD
epileptiform activity has also been reported in several and DRPLA) are typically not captured well by current
different PME subtypes.47,48 Occipital discharges and/ sequencing-­based tests (including gene panels and exome
or seizures are often seen in PME, particularly in La- sequencing) and may require specialized PCR testing or
fora disease.28 Photosensitivity is common in many of Southern blot, or specific bioinformatics added to genome
the PMEs.49 In particular, photosensitivity at low flash sequencing to detect expansion variants. Thus the ability
frequencies (<6 Hz) should raise suspicion for a PME, of a test to cover these expansion variants should be dis-
although it is not entirely specific for PME nor for an cussed with the diagnostic laboratory. An additional pit-
individual PME subtype.50,51 Neuroimaging in patients fall of gene panel or exome sequencing is that sequencing
with PME is typically normal or shows nonspecific of mitochondrial DNA is not standard. It is important that
atrophy.52 clinicians are aware of this, though typically mitochon-
drial DNA testing is only appropriate to include as a first-­
line genetic test if there are specific clinical features, which
6.3 | Genetic testing suggest an underlying mitochondrial pathology. Whole
genome sequencing has the advantage of being able to
Genetic testing should now be the first-­line diagnostic test cover both expansion variants and mitochondrial variants,
whenever PME is suspected (Figure 1), and should be per- as well as complex structural and noncoding variants, and
formed early given the profound prognostic implications so is likely to become the test of choice for PME as costs of
of the diagnosis and emerging targeted therapies. Genetic WGS come down and availability increases.
testing for PME is now widely available, noninvasive, and Many PMEs are autosomal recessive. This is import-
high-­yield. The long and growing list of causative genes ant when interpreting the results of genetic testing. For
(Table S1) warrants a broad testing strategy, rather than recessive disorders, a single heterozygous pathogenic

CAMERON et al.
variant is not sufficient to cause disease; such a patient
is an unaffected carrier. On the other hand, when a par-
ticular syndrome is strongly suspected but only a single
heterozygous pathogenic variant is detected, an occult
second pathogenic variant may exist, but not yet have
been detected by the testing which has been ordered to
date.53 This means that broadening the testing, for ex-
ample, to whole genome sequencing, which can detect a
wider variety of genomic mechanisms, may be appropri-
ate, and discussion with a clinical genetics team can be
helpful to discuss the next best steps. When two different
pathogenic variants are identified in the same gene (com-
pound heterozygous), it is necessary to confirm that the
two variants are on different alleles (“in trans”), that is
one inherited from each parent, rather than on the same
allele (“in cis”). This can be checked by segregating the
variants in both parents, with the anticipation that each
will carry one of the two variants found in the patient,
although very occasionally one variant may be de novo
and not inherited. Finally, variants of uncertain signif-
icance (VUS) must be interpreted with caution, and in
most cases should not be considered diagnostic nor used
to guide management. Discussion with a genetics team
can be helpful to consider if further options, such as func-
tional studies, may be possible to help further investigate
VUS. Reanalysis after time with updated knowledge and
gene lists is also helpful for families without a confirmed
molecular diagnosis.
6.4 | Ancillary tests
In the past, the evaluation of suspected PME often in-
cluded an assortment of specialized tests, such as enzyme
assays and tissue biopsies. In the modern genetic era, these
should be considered ancillary, and may not be necessary
If genetic testing is diagnostic. Ancillary testing still plays
a role when an orthogonal test may be helpful to support a
genetic diagnosis, for example, to help determine the sig-
nificance of a VUS.
6.4.1 | Laboratory tests
Some common laboratory tests may suggest particular
PME syndromes. Renal impairment is often a feature of
AMRF.54 Elevated CK has been associated with North-­Sea
PME, despite normal muscle biopsies.55 Elevated lactate
may suggest a mitochondrial disorder, but is neither sensi-
tive nor specific.
Enzyme assays have been developed for several of the
NCLs caused by lysosomal enzyme deficiencies.56–­58 Urine
sialo-­oligosaccharides are elevated in sialidosis. These
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   675
assays are ordered and performed individually, and sys-
tematic approaches to the selection of tests are limited.58
6.4.2 | Neurophysiology
Giant evoked potentials in response to both visual and
somatosensory stimulation have been reported in several
PMEs.48,59,60 Although the diagnostic utility of this finding
has not been studied systematically, this is an accessible
and noninvasive test, which can be used to demonstrate
cortical hyperexcitability in individuals with PME. Nerve
conduction and EMG studies may be indicated to evalu-
ate specific comorbid features such as neuropathy or
myopathy.
6.4.3 | Tissue biopsies
Before the era of readily available molecular testing, tissue-­
based diagnosis was a standard part of the diagnostic evalu-
ation of PME.57,61 Today, biopsies are not necessary in cases
with a clear genetic diagnosis and compatible phenotype.
Biopsies may be useful in selected patients with nondiag-
nostic genetic testing. Tissue diagnosis pertains mostly to
LD and the NCLs. The pathognomonic Lafora bodies seen
in LD can be identified on axillary skin biopsy, though the
sensitivity and specificity are not known, and are likely to
vary across institutions based on local experience.
Similarly, the sensitivity and specificity of biopsy for
NCL are unknown. In adult-­onset NCL, intracellular stor-
age material may be absent in peripheral tissues (false
negatives), while normal accumulation of age-­related
lipofuscin may be misinterpreted as pathological (false
positives).62 When a mitochondrial disorder is suspected,
muscle biopsy may show ragged red fibers. Again, the
sensitivity and specificity of this test are unknown, and
muscle biopsy is now primarily reserved for patients with
nondiagnostic genetic testing.
7 | TREATMENT STRATEGIES IN
PME
Management of patients with PME presents several chal-
lenges. For most types of PME, there are no available
disease-­modifying therapies and treatment strategies are
symptomatic, aimed at seizure control and suppression of
myoclonus. The rarity of the condition means evidence-­
based efficacy data is minimal, and is largely in small pop-
ulations of ULD or LD if at all.
Antiseizure medications (ASMs) are the current main-
stay of treatment. Valproate was the initial ASM shown to
 |
676   
be effective in convulsive seizure and myoclonus control
in ULD.63 Benzodiazepines, including clonazepam and
clobazam, have well-­established efficacy for the manage-
ment of myoclonus, and are typically used as an add-­on
therapy. More recently several ASMs including levetirace-
tam, topiramate, zonisamide, and brivaracetam have been
reported to be effective in PME. Piracetam is a useful an-
timyoclonic agent,64 and perampanel has been associated
with a beneficial effect on action myoclonus, disability,
and seizures in PME.40
7.1 | Adjunctive therapies
Even when used in combination, ASMs typically fail to
adequately control the complex and progressive symp-
tomatology experienced by patients with PME, and
consideration needs to be given to adjunctive thera-
pies. There is limited data exploring dietary therapeutic
strategies in PME, with only small case series of the ke-
togenic diet and modified Atkins diet in LD and North
Sea PME, respectively, showing some improvement in
myoclonus.65,66 Similarly, limited case reports and case
series of neuromodulatory therapies including VNS,
DBS and rTMS have variable results, and all warrant
further exploration. With the increasing appreciation
of the role of neuroinflammation in neurodegenerative
disorders, immunomodulatory medications may also
have a therapeutic role, though this is yet to be estab-
lished.67,68 Animal data suggests that metformin may
have a disease-­modifying role in Lafora disease,69,70
though the very limited clinical data that is currently
available suggests that its use is not associated with clin-
ically meaningful benefit.71 Further data is required to
clarify this.
7.2 | Enzyme replacement therapies
Enzyme replacement is currently available for treatment
of CLN2 disease, caused by pathogenic variants in the
gene TPP1, leading to a deficiency in the lysosomal en-
zyme tripeptidyl peptidase 1. Enzyme replacement ther-
apy via intraventricular infusion of recombinant human
tripeptidyl peptidase 1 (cerliponase alfa) results in less
decline in motor and language function that in historical
controls.57 This is the first disease-­modifying treatment
for a type of PME and holds the promise that similar ap-
proaches may be successful in other forms of PME. Sev-
eral PME-­causing pathogenic variants result in enzyme
deficiencies (including Sialidosis, SMA-­PME, and Gau-
cher's disease), and may be good targets for enzyme re-
placement therapies.
19506945, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/epd2.20152, Wiley Online Library on [02/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CAMERON et al.
7.3 | Gene therapies
Gene and nucleotide-­based therapies are not yet clinically
available for any of the PMEs. In mouse models of CLN6
disease, bilateral intracerebroventricular injections of
adeno-­associated viral 6 carrying functional copies of CLN6
have been shown to increase lifespan and reduce neuro-
pathological features.72 Antisense oligonucleotide (ASO)
therapy has been shown both in vitro and in vivo to have
beneficial impacts. Patient-­derived fibroblasts from an in-
dividual with ULD homozygous for the c.66G>A CSTB
pathogenic variant expressed normal CSTB protein levels
when treated with a specific locked nucleic acid ASO target-
ing the cryptic donor splice site in intron 1 of CSTB.73 Such
precision medicine therapeutic strategies are clearly still in
their initial stages but hold promise that future improved
targeted therapies will be feasible for patients with PME.
ACKNOWLEDGMENTS
CAE is supported by the National Institute of Neurologi-
cal Disorders and Stroke award number K23NS121520;
the American Academy of Neurology Susan S. Spencer
Clinical Research Training Scholarship and the Mirowski
Family Foundation. SFB is supported by an NHMRC In-
vestigator Grant (APP1196637). Open access publishing
facilitated by The University of Melbourne, as part of the
Wiley -­ The University of Melbourne agreement via the
Council of Australian University Librarians.
ORCID
Colin A. Ellis https://orcid.org/0000-0003-2152-8106
Samuel F. Berkovic https://orcid.
org/0000-0003-4580-841X
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SUPPORTING INFORMATION
Additional supporting information can be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Cameron JM, Ellis CA,
Berkovic SF. ILAE Genetics Literacy series:
Progressive myoclonus epilepsies. Epileptic Disord.
2023;25:670–680. https://doi.org/10.1002/epd2.20152
APPENDIX 1
Full list of ILAE Genetics Commission
members
Piero Perucca, Bladin-­Berkovic Comprehensive
Epilepsy Program, Austin Health, Australia, and
Department of Medicine (Austin Health), Melbourne
Medical School, The University of Melbourne, Australia;
J. Helen Cross, UCL-­Institute of Child Health, Great
Ormond Street Hospital for Children, London & Young
Epilepsy, Lingfield, UK; Holger Lerche, Department of
Neurology and Epileptology, Hertie Institute for Clinical
Brain Research, University of Tuebingen, Tuebingen,
Germany; Alina I. Esterhuizen, UCT/MRC Genomic
and Precision Medicine Research Unit, Division of
Human Genetics, Department of Pathology, Institute
of Infectious Disease and Molecular Medicine, Faculty
of Health Sciences, University of Cape Town, Cape
Town, South Africa; Iscia Lopes-­Cendes, Department
of Translational Medicine, University of Campinas,
Campinas, Brazil; Meng-­Han Tsai, Department of
Neurology, Kaohsiung Chang Gung Memorial Hospital
and Chang Gung University College of Medicine,
Kaohsiung, Taiwan; Daniel H. Lowenstein, Department
of Neurology, University of California, San Francisco,
USA; Nigel C. K. Tan, Department of Neurology,
National Neuroscience Institute, Singapore, Singapore;
Ingo Helbig, Division of Neurology, The Children's
Hospital of Philadelphia, Philadelphia, USA; Heather
C. Mefford, Center for Pediatric Neurological Disease
Research, St. Jude Children's Research Hospital,
|
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   679
Memphis, USA; Andreas Brunklaus, Institute of Health
and Wellbeing, University of Glasgow, UK; Gaetan
Lesca, Department of Genetics, Hospices Civils de
Lyon, Bron, France.
Full list of ILAE Genetic Literacy Task
Force members
Elizabeth Emma Palmer, Centre of Clinical Genetics.
Sydney Children's Hospitals Network, and University
of New South Wales, Randwick, NSW, Australia;
Amy McTague, Developmental Neurosciences, UCL
Great Ormond Street Institute of Child Health, and
Department of Neurology, Great Ormond Street Hospital
for Children, London, UK; Faiza Fakhfakh, Laboratory
of molecular and functional genetics, Faculty of sci-
ence, Sfax University of Sfax, Tunisia; Norman Delanty,
Department of Neurology, Beaumont Hospital, Dublin,
and FutureNeuro Research Centre, RCSI, Dublin; Daniel
H. Lowenstein, Department of Neurology, University
of California, San Francisco, USA; Nigel C. K. Tan,
Department of Neurology, National Neuroscience
Institute, Singapore, Singapore; Ingo Helbig, Division
of Neurology, The Children's Hospital of Philadelphia,
Philadelphia, USA; Alina I. Esterhuizen, UCT/MRC
Genomic and Precision Medicine Research Unit, Division
of Human Genetics, Department of Pathology, Institute
of Infectious Disease and Molecular Medicine, Faculty of
Health Sciences, University of Cape Town, Cape Town,
South Africa.
APPENDIX 2
Case study
A 12-­year-­old female was referred to neurology out-
patients with a six-­month history of increasing upper
and lower limb jerks, which were starting to impact
her ability to complete schoolwork. She had a history
of three generalized tonic–­clonic seizures over a two-­
year period, on the background of unremarkable birth
and developmental milestones. There was no signifi-
cant family history. Examination revealed some subtle
difficulty with tandem gait, with no other focal neuro-
logical deficit. The remainder of her general physical
examination was unremarkable. EEG revealed normal
background rhythm, with rare generalized spike–­wave
discharges and a grade IV photoparoxysmal response.
A diagnosis of Juvenile Myoclonic Epilepsy was made,
and the patient was commenced on 500 mg bd lev-
etiracetam. Over the subsequent 12 months, she had
no further convulsive seizures, though she had in-
creasingly severe and frequent upper and lower limb
jerks, was quite clumsy, and had several falls despite
 |

19506945, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/epd2.20152, Wiley Online Library on [02/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
680    CAMERON et al.

adjustments to her antiseizure medication including Case resolution

uptitration of levetiracetam. Examination revealed ac-
tion-­ and stimulus-­sensitive myoclonus and appendicu-
lar and truncal ataxia. Further investigations including
MRI Brain and basic biochemical testing provided no
further diagnostic clues. Cognitive function remained
intact. Given the progressive nature of her condition,
the diagnosis of Progressive Myoclonic Epilepsy (PME)
was considered. After appropriate patient and fam-
ily genetic counseling, a targeted PME gene panel was
requested.
The targeted PME gene panel did not reveal any patho-
genic variants for our patient. CSTB repeat expansion test-
ing was subsequently requested, revealing a homozygous
12-­nucleotide dodecamer repeat expansion, thus provid-
ing molecular confirmation of a diagnosis of Unverricht-­
Lundborg Disease. Myoclonus continued to progress over
the next 3 years, despite the addition of sodium valproate,
piracetam, and clonazepam. A wheelchair was required
for mobilization at the age of 30 years due to the severity
of myoclonus.

Test yourself
1. In a 15-­year-­old male with a history of myoclonus and epilepsy, which of the following features might sug-
gest he has a PME?
A. Macular cherry-­red spot
B. Occipital seizures in his EEG
C. Hepatosplenomegaly
D. All of the above
2. The Progressive Myoclonic Epilepsies
A. Are very rarely associated with ataxia
B. Typically present in the 4th and 5th decades of life
C. Present with myoclonus that is fragmentary and multifocal
D. Can be diagnosed using genetic testing in about 25% of cases
Answers may be found in the supporting information.