Review

Progressive myoclonic epilepsies: a review of genetic and

therapeutic aspects
Amre Shahwan, Michael Farrell, Norman Delanty Lancet Neurol 2005; 4: 239–48
Department of Neurology and
The progressive myoclonic epilepsies (PMEs) are a group of symptomatic generalised epilepsies caused by rare Neuroscience (A Shahwan
MRCPCH, N Delanty FRCPI); and
disorders, most of which have a genetic component, a debilitating course, and a poor outcome. Challenges with PME Department of Pathology
arise from difficulty with diagnosis, especially in the early stages of the illness, and further problems of management (Neurology), Beaumont
and drug treatment. Recent advances in molecular genetics have helped achieve better understanding of the different Hospital, Dublin, Ireland
disorders that cause PME. We review the PMEs with emphasis on updated genetics, diagnosis, and therapeutic options. (Prof M Farrell FRCPath)
Correspondence to:
Dr Norman Delanty, Department
Progressive myoclonic epilepsies (PMEs) are and mild dementia is typically a late feature. However,
of Neurology, Beaumont
characterised by myoclonic seizures, tonic-clonic seizures, this is not constant and progress in the genetic basis of Hospital, Dublin 9, Ireland
and progressive neurological deterioration, typically with the disorder has led to finding atypical evolutions even normandelanty@eircom.net
cerebellar signs and dementia. In different disease within the same family, with some affected individuals
entities, various types of seizures and neurological displaying severe cognitive involvement. With advances
symptoms also occur, which may guide the clinician to in antiepileptic drug development and their use, the
the most likely cause. Myoclonus in PME is typically prognosis of the disease has improved significantly and
fragmentary and multifocal, and is often precipitated by patients now live into their sixties.7
posture, action, or external stimuli such as light, sound, or The EEG background may be normal during the first
touch. It is particularly apparent in musculature of the years of the disease. EEG features may mimic completely
face and distal extremities. Bilateral massive myoclonic that of idiopathic generalised epilepsy at the beginning of
jerks that tend to involve muscles of proximal limbs may the disease. With progress of the illness, it becomes
also occur.1 With the disabling myoclonus there is the risk abnormal with diffuse slow background activity and
of injury and impairment of activities of daily living. The generalised high-voltage spike and wave, and polyspike
age of onset, presenting symptoms, predominance of and wave paroxysms, ranging from a slow frequency of
symptoms as seizures, or myoclonus over cerebellar signs 2–3 Hz to faster frequencies of 4–6 Hz,8,9 which reach a
and dementia vary substantially across the different maximum anteriorly. Photosensitivity is typical.10 MRI of
disorders. There are five main causes of PME that have the brain may be normal or can show reduced bulk of the
been more accurately defined with recent advances in basis pontis, medulla, and cerebellar hemispheres, and
genetic studies (panel 1). less often, cerebral atrophy.11

Unverricht-Lundborg disease Genetics and diagnosis

Unverricht-Lundborg disease (ULD), or epilepsy ULD is linked to chromosome 21q22.3.12 Further linkage
progressive myoclonus type 1, is an autosomal-recessive disequilibrium and historical recombination breakpoint
disorder that was described by Unverricht2 in 1891, and mapping placed the associated gene, CSTB (formerly
by Lundborg3 in 1903. It is the most common PME. It
was initially recognised as a geographic cluster in
Finland, where the prevalence is one in 20 000 births.4 Panel 1: Definite diagnosis of specific types of PME
Clusters of a phenotypically and sometimes genetically
Unverricht-Lundborg disease
identical disorder occur in southern Europe and north
CSTB gene mutation
Africa,5 and sporadically worldwide.
Lafora disease
Clinical picture and investigations Lafora bodies in skin biopsy or EPM2A mutation
The age of symptom onset in ULD is 6–15 years.6
Myoclonic epilepsy with ragged red fibres
Symptoms progress insidiously. Stimulus-sensitive
Ragged red fibres in muscle biopsy or MTTK mutation
myoclonic jerks are an essential feature for the diagnosis
of the disease and are the first symptom in at least half of Neuronal ceroid lipofuscinosis
patients.7 The myoclonus is generally quite severe and Typical intracellular inclusions or mutation in TPP1, CLN3, and
shares the common characteristics of myoclonus in CLN5
other PMEs. Generalised tonic-clonic seizures are the
Sialidoses
presenting feature in many patients,8 but in rare cases
Neuraminidase deficiency in leucocytes or fibroblasts
these may not occur. Absence seizures may also be
observed. Neurological examination is initially normal, Dentatorubral-pallidoluysian atrophy
but patients later develop ataxia, incoordination, Abnormal CAG repeats
intention tremor, and dysarthria. Progression to ataxia

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 Review
known as EPM1), between regions D21S2040 and
D21S1259.13 CSTB encodes cystatin B, a cysteine
protease inhibitor.14 The main mutation in CSTB, even
among patients of different ethnic origins, is an unstable
expansion of a dodecamer repeat (CCCCGCCCCGCG)
in the 5´ untranslated promoter region.15 The range of
normal alleles (repeats) is two to three copies, but
expanded alleles associated with the disease phenotype
contain at least 30 copies. Five other mutations that
affect one or two nucleotides in CSTB cause the disease
in a few patients.16 Affected individuals may have
expansion of the dodecamer on both alleles, expansion
on one and point mutation on the other, or, rarely, a
point mutation on both alleles. Cystatin B inhibits the
papain family of cysteine proteases, which are involved
in the initiation of apoptosis. The exact pathophysiology
of the disease remains unknown. Presumably, with
mutations in cystatin B and loss of its inhibition of
cysteine proteases, apoptosis proceeds abnormally and
neurodegeneration results.17 A multiprotein complex has
been identified to interact with cystatin B in vitro.18
Immunofluorescent confocal microscopy showed that
the same proteins are present in the granule cells of the
developing cerebellum and the purkinje cells of adult rat
cerebellum, which raises the possibility that a cystatin B
multiprotein complex may have a specific cerebellar
function.18 For diagnosis, clinical suspicion is
paramount. Detection of the mutation in the cystatin B
gene can be used to confirm the diagnosis (panel 1).
Treatment
There is no specific treatment for ULD, and palliative and
rehabilitative management is therefore the mainstay of
patient care. For seizure and myoclonus control, valproic
acid has traditionally been the drug of choice, especially if
started early in the course of the disease.19 Clonazepam
may also help as an add-on therapy.19 High-dose
piracetam also helps in many patients.20 Levetiracetam
had a substantial beneficial effect on a female patient
with ULD. She was able to walk assisted and write her
name, after being wheelchair bound with severe
stimulus-evoked and action-induced multifocal
myoclonus.9 The antimyoclonic effect of levetiracetam in
13 patients with ULD was most effective when started
early in the course of the disease.21 Zonisamide has been
used with success.22 Phenytoin may significantly worsen
myoclonus and precipitate cerebellar signs and cerebellar
atrophy.23 Myoclonus in a patient treated with vagus-
nerve stimulation also improved.24
Lafora’s disease
First described by Lafora and Gluelkin in 1911, Lafora’s
disease is characterised by epilepsy, myoclonus,
dementia, and Lafora bodies, which are periodic-
acid–Schiff-positive intracellular polyglucosan inclusion
bodies found in neurons, heart, skeletal muscle, liver,
and sweat-gland duct cells.25
240
Clinical picture and investigations
In most patients, the onset of progressively worsening
seizures occurs age 12–17 years. Before that, physical
and mental development is within normal limits.26 Many
patients experience isolated febrile and non-febrile
convulsions earlier in childhood.27 At onset it may be
difficult to distinguish Lafora’s disease clinically from
typical idiopathic generalised epilepsy with no evidence
of cognitive decline, particularly juvenile myoclonic
epilepsy. Seizure types in Lafora’s disease include
myoclonus, occipital seizures with transient blindness
and visual hallucinations, atypical absences, and atonic
and complex partial seizures. As the disease progresses,
seizures become more intractable and status epilepticus
of any seizure type is not unusual.28,29 Cognitive decline,
dysarthria, and ataxia appear early. Emotional
disturbance is common early in the disease and
dementia develops gradually. Later, patients are disabled
with continuous myoclonus.30 Most patients die within
10 years of onset.31 Early in Lafora’s disease, the EEG has
a well-organised background with multiple spike-and-
wave discharges, and photosensitivity is common;
however, induced epileptiform discharges may occur
only at low frequency (1–6 Hz) of photic stimulation.32
Erratic myoclonus may be seen without EEG correlation.
Spike-and-wave discharges are not accentuated during
sleep. During the next few months to years, the
background deteriorates and sleep features are lost.
Multifocal epileptiform abnormalities, mainly occipital
in location, appear in addition to generalised bursts.33 In
longitudinal EEG studies, the spike-and-wave pattern
changes from a frequency of 3 Hz in the early stages to
faster frequencies of 6–12 Hz as the disease progresses.34
Lafora bodies, are present in neurons, but can be seen in
many other tissues such as skin, liver, and muscle,
although diagnosis is most conveniently made by
examination of the eccrine ducts of the sweat glands in a
skin biopsy specimen.35 Lafora bodies may range in size
from a barely visible 1 m dot to a large, rounded
intracytoplasmic basophilic structure (figure 1).
Genetics and diagnosis
Lafora’s disease is an autosomal recessive disorder. Up
to 80% of patients with the disorder have a mutation in
the EPM2A gene on chromosome 6q at locus 24.36 The
gene encodes laforin, a dual-specificity protein tyrosine
phosphatase, primarily associated with ribosomes. The
function of laforin is largely unknown but involvement
in translational regulation and protein folding may
underlie the molecular basis of the disease.37 Laforin
may also cause glycogen synthase hyperfunction,
contributing to the endoplasmic-reticulum-associated
polyglucosan depositions seen in the disease.30 More
recently, a new Lafora’s disease locus, NHLRC1
(formerly EPM2B), has been mapped to a 2·2 Mbp
region at 6p22, a region that codes for several proteins,
including kinesins, which play a major part in axonal
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 Review

and dendritic transport in neurons (table 1).38 Evidence

for a third locus for Lafora’s disease, yet to be identified,
has been recently reported.39
The narrow age of onset, progressive dementia, rapid
and relentless progression to death, and frequent
occipital seizures are clinical clues to diagnosis.
Diagnosis is confirmed by detecting Lafora bodies in
skin biopsy specimens, but this is likely to be superseded
by analysis of the EPM2A gene, yielding a known
mutation in 80% of patients with Lafora’s disease.

Treatment
Treatment for Lafora’s disease remains palliative.
Advances in gene, protein, or stem-cell therapies may
allow replacement of the defective protein in the future.
Knockout mouse and natural canine models of the
disease may yield new insights into pathogenesis, and
may facilitate the testing of new therapeutic approaches.
Meanwhile, on the basis of the knowledge that Lafora
bodies are carbohydrate compounds, an international
collaborative clinical trial based at the US National
Institutes of Health has been begun to test whether
carbohydrate restriction will diminish Lafora-body
formation and disease progression.30
Myoclonic epilepsy with ragged red fibres
Myoclonic epilepsy with ragged red fibres (MERRF) is one
of the common causes of PME. It may be sporadic or
familial. Mitochondrial diseases can be both maternally
and paternally inherited, but typical MERRF, and the
syndrome of mitochondrial encephalomyopathy, lactic
acidosis, and stroke-like episodes (known as MELAS), are
maternally inherited.40
Clinical picture and investigations
The syndrome of MERRF is characterised by myoclonus,
generalised epilepsy, ataxia, and ragged red fibres in
muscle biopsy (figure 2). The clinical spectrum can vary,
and the syndrome exhibits intrafamilial variation in age
Figure 1: Basophilic neuronal intracytoplasmic spherical Lafora bodies
These may vary in size and degree of basophilia, and are distributed through the cortex, substantia nigra, thalamus,
and cerebellar cortex. Muscle, liver, and skin appendages can also contain Lafora bodies.
of onset and clinical severity.41 Common clinical
manifestations include myopathy, neuropathy, hearing
loss, dementia, short stature, and optic atrophy. Less
commonly, cardiomyopathy, pigmentary retinopathy,
pyramidal signs, ophthalmoparesis, multiple lipomas,
and diabetes mellitus can occur.42 There is an overlap
with the syndrome of MELAS, but MERRF usually has a
longer course and is associated with milder behavioural
and cognitive deficits.43
In patients with MERRF, the EEG shows generalised
spike-and-wave discharges at 2–5 Hz, with background
slowing that progresses as the disease advances. Focal
epileptiform discharges can also be seen.44 Muscle
biopsy shows ragged red fibres in over 90% of patients.45
Biochemical studies of respiratory-chain enzymes in
muscle extracts usually show decreased activity.46 Brain

Disease Inheritance Chromosome locus Gene Protein Function Mutation

ULD AR Ch21q22.3 CSTB Cystatin B Cysteine protease inhibitor Unstable expansion of dodecamer repeat or point
mutations
Lafora’s disease AR Ch6q24 EPM2A Laforin Dual specificity protein tyrosine phosphatase More than 20 mutations
Ch6p22 NHLRC1 ··
MERRF Maternal Mitochondrial DNA MTTK tRNALys Mitochondrial function and metabolism Point mutations
NCL
Classical late infantile AR Ch11p15 TPP1 Tripeptidyl peptidase 1 ·· Multiple
Juvenile AR Ch6p CLN3 ·· ·· 1·02 kbp deletion
Adult (Kufs disease) AR/AD ·· ·· ·· ·· ··
Finnish-variant late infantile AR Ch13q21-q32 CLN5 ·· ·· CLN5 Finnish major
Variant late infantile AR Ch15q21-23 CLN6 ·· ·· Multiple
Sialidoses
Type I AR Ch6p21.3 NEU1 Sialidase 1 ·· Multiple
Type II AR Ch20 NEU1 Sialidase 1 ·· Multiple
DRPLA AD Ch12p13.31 DRPLA Atrophin 1 ·· Unstable expansion of CAG repeats

MERRF=myoclonic epilepsy with ragged red fibres; NCL=neuronal ceroid lipofuscinoses; DRPLA=dentatorubral-pallidoluysian atrophy; AR=autosomal recessive; AD=autosomal dominant; ··= unknown.

Table 1: Molecular genetics of PME

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 Review
Figure 2: Ragged red fibres in the skeletal muscle fibre of a patient with MERRF
MRI may show brain atrophy and basal ganglia
calcifications.43 Grey-matter signal changes on
T2-weighted images are sometimes seen, with deep
cerebral nuclei being more involved than the cerebral
cortex. When signal changes are seen in the white
matter, the peripheral white matter is the earliest to be
involved.47
Genetics and diagnosis
The most common molecular defect is an adenosine to
guanine substitution at nucleotide pair 8344 (8344A→G)
in the tRNALys gene (MTTK) of mitochondrial DNA, and
is present in 90% of typical MERRF patients.48 Another
rare identified molecular cause of MERRF is a tyrosine
to cytosine substitution (8356T→C) in the same gene,49
and another is a guanine to adenosine substitution
(8363G→A).50 However, in some individuals, a mutation
has not been identified. Clinical clues to the presence of
MERRF include deafness, optic atrophy, myopathy,
lipomas, intrafamilial variation in age of onset, and
maternal transmission. Ragged red fibres and mutations
in germline DNA (eg, peripheral blood) can be used to
confirm the diagnosis.51
Treatment
There is no specific therapy for MERRF, but, as in many
mitochondrial disorders, many patients are empirically
treated with combinations of antioxidant vitamins and
cofactors including coenzyme Q10 and L-carnitine.52
Valproic acid causes inhibition of carnitine uptake, so
must be used with caution and combined with
L-carnitine supplementation.53
In most patients, mutant and wildtype mitochondrial
DNA molecules coexist (heteroplasmy), and there is a
threshold amount of mutant mitochondrial DNA
necessary for the disease to be expressed clinically.
242
Antigenomic peptide nucleic acids that specifically
inhibit replication of mutant but not wildtype
mitochondrial DNA templates in vitro have been
developed and expressed in cultured human myoblasts.54
Furthermore, mutant mitochondrial DNA predominates
in mature myofibres, but is rare or undetectable in
skeletal muscle satellite cells, a pattern that is thought to
result from positive selection for the mutant
mitochondrial DNA in postmitotic myofibres and loss of
the mutant by genetic drift in satellite cells. This finding
lends itself to new approaches for treatment, for
example, by increasing the incorporation of satellite cells
through regeneration after injury to myofibres by
resistance exercise training,55 or by bupivacaine
hydrochloride injection.56
Neuronal ceroid lipofuscinoses
The neuronal ceroid lipofuscinoses (NCLs) are
characterised by the accumulation of abnormal amounts
of lipopigment in lysosomes (figure 3). There are five
types of NCL that may cause PME: classic late infantile
NCL (type 2) or Jansky-Bielschowsky disease; juvenile
NCL (type 3), Spielmeyer-Vogt-Sjogren disease, or Batten
disease; adult NCL (type 4), Kuf’s disease, or Parry
disease; late infantile Finnish variant NCL (type 5); and
late infantile variant NCL (type 6). Each form of the
disease is genetically distinct, with an autosomal recessive
inheritance in all except for the adult form, which may
have autosomal dominant inheritance.57
Classic late infantile NCL
Classic late infantile NCL usually has an onset between
2·5 and 4 years. Myoclonic, tonic-clonic, atonic, and
atypical absence seizures are typically the first
manifestation of the disease. Within a few months from
onset, ataxia and psychomotor regression appear,
whereas visual failure develops later. Optic fundi show
attenuated retinal vessels and macular degeneration
(table 2). Epilepsy is intractable and dementia and
spasticity are relentlessly progressive, with death
occurring about 5 years after onset.25
EEG shows background slowing and disorganisation
with generalised epileptiform discharges. Specific
electrophysiological features are posterior spikes in
response to low-frequency photic stimulation in EEG
studies, and the giant visual evoked potentials elicited
only with flash stimulation.58 The gene for this disease
(TPP1) has been mapped to chromosome 11p15.59 This
gene encodes the protein tripeptidyl peptidase 1 (TPP1).
Multiple mutations that include missense, nonsense,
deletion, insertion, and splicing mutations have been
detected.60 TPP1 removes tripeptides from the
N-terminal of proteins undergoing degradation in
lysosomes. The specificity and substrate range of TPP1
is still not clear. Reduced or undetectable TPP1 enzyme
activity in fibroblasts or leucocytes can be used to
confirm the diagnosis.58
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Late infantile Finnish variant NCL

A variant of late infantile NCL has been found in Finland
(NCL type 5). This variant differs from classic late
infantile NCL (type 2) in that onset is later, at around age
5 years, and includes symptoms of clumsiness and
hypotonia. This is followed by visual impairment at age
5–7 years, and then ataxia at 7–10 years. Myoclonic and
tonic-clonic seizures usually appear at around 8 years of
age. Progression is slower than in NLC type 2. EEG is
similar to that in NCL type 2, but the substantial
response to photic stimulation develops later, at age
7–8 years.61
The gene associated with the disease, CLN5, is found
almost exclusively in Finland and has been mapped to
chromosome 13q21–q32.62 The most common mutation
(Finnish major mutation or CLN5 Fin major) occurs in
94% of Finnish patients and is a 2 bp deletion in exon 4.
The CLN5 gene encodes for a putative transmembrane
protein of 407 amino acid residues, the function of
which is unknown.58 Figure 3: Section of cortex examined under fluorescent light to show yellow intracytoplasmic autofluorescence
typical of the accumulated lipofuscin in Kuf’s disease
Late infantile variant NCL
A variant of late infantile NCL, sometimes called early reveals optic atrophy, macular degeneration, and
juvenile NCL, Gypsy-Indian late infantile NCL, or NCL attenuated vessels. Death occurs about 8 years after
type 6, features an intermediate onset of symptoms at disease onset.64
age 5–7 years and a course that leads to death in the mid EEG shows a slow background with generalised spike
twenties. The associated gene, CLN6, has been mapped and wave. Epileptiform abnormalities are accentuated
to chromosome 15q21–23. The encoded protein and during sleep but not with photic stimulation.65 The gene
function are unknown.59 There is no major founder associated with this disease, CLN3, is located on the
mutation for this disease; 18 mutations have been short arm of chromosome 16.66,67 The CLN3 gene
reported, including missense, nonsense, small deletions encodes a protein of 438 amino-acid residues, the
or insertions, and splice-site mutations. Cases reported function of which is unknown. The most common
in Costa Rica, Venezuela, Pakistan, and the Czech mutation of more than 25 mutations identified is a
Republic show that families from the same country do 1·02 kbp deletion that removes exons 7 and 8, resulting
not all share the same mutation.63 in production of a truncated protein containing the
original 153 N-terminal residues followed by 28 new
Juvenile NCL amino acid residues.68
Juvenile-onset NCL, also known as Batten disease or
NCL type 3, starts at age 4–10 years with visual failure. Adult NCL
Dementia and extrapyramidal features develop Adult NCL (Kuf’s disease, or NCL type 4), may have its
gradually, and seizures are not a prominent onset in childhood or adolescence, despite its
manifestation of the disease. Most patients are blind by denomination. Myoclonus can first occur as late as age
their second decade. The most common seizure type is 30 years. Dementia, ataxia, and extrapyramidal signs
generalised tonic-clonic; myoclonus is usually subtle. may develop first. There are no ophthalmological
Behavioural and psychiatric problems, including abnormalities or visual failure.69 EEG shows generalised
psychosis and hallucinations are common. Fundoscopy fast spike-and-wave discharges with photosensitivity.70

Disease Age at onset (years) Prominent seizures Cerebellar signs Dementia Fundi Dysmorphism
ULD 6–15 Myoclonus ++++ Mild and late Mild and late or absent Normal No
Lafora’s disease 12–17 Myoclonus and occipital seizures Early Early and relentless Normal No
MERRF Any age Myoclonus ++ Variable Variable With or without optic atrophy or retinopathy With or without
NCL Variable Variable Variable Rapidly progressive Macular degeneration and visual failure, except No
Kuf’s disease
Sialidoses Variable Myoclonus +++ Gradual Absent in type I; learning difficulty in type II Cherry-red spot type II ++

ULD=Unverricht-Lundborg disease; MERRF=myoclonic epilepsy with ragged red fibres; NCL=neuronal ceroid lipofuscinoses; +=prominent feature

Table 2: Some differentiating clinical characteristics of PME

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 Review
The disease is sometimes observed as a sporadic case,
or as familial disease with autosomal recessive
inheritance (most commonly), or with autosomal
dominant inheritance (least commonly), suggesting
genetic heterogeneity of the disease.57
Diagnosis and treatment of NCL
Diagnosis of NCL is typically suspected clinically
(table 2) and supported by electrophysiological studies.
Visual and ophthalmological abnormalities point to NCL
forms other than type 4. MRI findings in NCL include
cerebral and cerebellar atrophy, T2-hyperintensity of the
lobar white matter, and thinning of the cerebral cortex.71
Definitive diagnosis currently relies on finding typical
intracellular inclusions by electron microscopy,72 which
can be located in eccrine secretory cells and also in
conjuctival or muscle biopsy. Suction biopsy of rectal
mucosa is also a reliable method to show the
inclusions.73 The inclusions have different morphologies
that point to individual types of NCL, being curvilinear
in late infantile NCL and fingerprint figure in juvenile
and adult NCL (figure 4).74–76
There is no specific treatment and like most other
causes of PME the mainstay of treatment is supportive
and palliative care. Antioxidant treatment in patients
with juvenile NCL, with vitamins E and C and
methionine, has been tried in one study but a definite
benefit has not been confirmed.77 Gene therapy is still
experimental. Treatment options for the future include
delivering active TPP1 to CNS and retinal cells in a
sufficient quantity and time to prevent cell loss.
Theoretically, this can be achieved by enzyme
augmentation therapy, allogenic stem-cell
transplantation, and other forms of gene therapy.78
Figure 4: Fingerprint intraneuronal inclusion typical of Kuf’s disease (electron micrograph)
Reproduced with permission from Dustri Verlag.76
244
These strategies are based on the concept that the pro-
TPP1 protein is taken up via mannose-6-phosphate
receptors on both the producer and the neighbouring
cells.79,80 Recently, virus-mediated gene transfer of TPP1
to the CNS of mice has been reported as a potential
therapy for late infantile NCL.81
Sialidoses
Two sialidoses are rare causes of PME. Sialidoses type I
(cherry-red spot myoclonus syndrome) is caused by
deficiency of  neuraminidase. It has a juvenile or adult
onset and produces a rather pure intention and action
myoclonus. Slow progression and absence of mental
deterioration or dysmorphism are characteristic of the
syndrome. There is gradual visual failure, tonic-clonic
seizures, ataxia, and a characteristic cherry-red spot in
the fundus.82
Sialidoses type II is caused by a deficiency of both
N-acetyl neuraminidase and -galactosialidase, and is
therefore also called galactosialidoses. The time of onset
varies from the neonatal period to the second decade of
life. Clinical features include coarse facial features,
corneal clouding, hepatomegaly, skeletal dysplasia, and
learning disability in addition to the myoclonus. EEG
background shows low-voltage fast activity, but slowing
can be seen in patients with dementia. Massive
myoclonus is associated with trains of 10–20 Hz, small,
vertex-positive spikes preceding the electromyographic
artefact.83 MRI findings in sialidoses range from normal
in the early stages to cerebellar, pontine, and cerebral
atrophy as the disease progresses.84
The sialidoses are autosomal recessive disorders. The
human sialidase gene (NEU1) is located inside the locus
of the MHC on chromosome 6p21.3.85 Sialidase is
targeted to the endosomal-lysosomal compartment as an
integral membrane protein by vesicular transport, which
involves association of the adapter proteins with a
tyrosine-containing internalisation signal at the
C-terminus of the enzyme.86 There are no major founder
mutations for the sialidoses. Several mutations
including five novel mutations have been described; the
mutated protein may prevent substrate binding or
impair the folding of the sialidase enzyme.87 More than
39 mutations in NEU1 have been described,87,88
including splice-site mutations, insertions and deletions,
nonsense, and missense mutations. The most common
of these are the missense mutations, which cause almost
complete loss of enzyme activity. The analysis of these
mutations reveals substantial molecular heterogeneity,
reflecting the diversity of clinical phenotypes. Patients
with a combination of a mild and a severe mutation have
a clinically milder form of the disease, suggesting that a
small percentage of normal sialidase activity may protect
against severe phenotypes. Hence, enzyme replacement
therapy is a possible approach to treatment in
sialidoses.88 The gene responsible for galactosialidoses is
located on chromosome 20.89 Protective protein
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cathepsin A (PPCA), a lysosomal carboxypeptidase, is
deficient in galactosialidoses.90 Enzyme-replacement
experiments have been done on PPCA-deficient mice,
which display symptoms similar to those of severe
galactosialidoses. These mice received haematopoietic
progenitors transduced with a bicistronic retroviral
vector based on a murine stem-cell virus, which
overexpresses PPCA and a fluorescent protein marker.
Complete correction of the disease phenotype was seen
up to 10 months after transplantation, and PPCA-
positive cells derived from the bone marrow were
detected in all tissue including the brain.91 The cherry-
red spot should be sought when sialidoses is suspected
clinically. Diagnosis is confirmed by the detection of
high urinary sialyloligosaccharides and by confirmation
of the lysosomal enzyme deficiency in leucocytes or
cultured fibroblasts.92
Dentatorubral-pallidoluysian atrophy
Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare
autosomal-dominant neurodegenerative disorder,
characterised by various combinations of cerebellar
ataxia, choreoathetosis, myoclonus, epilepsy, dementia,
and psychiatric symptoms. First described in Japan,
where it is most prevalent, molecular diagnosis has
allowed detection of the disease in other ethnic
groups.93–95 There is substantial heterogeneity in clinical
presentation, even in the same family. There are three
clinical forms: an ataxochoreoathetoid form, a pseudo-
Huntington form, and a PME form. Patients with onset
before age 20 years often present with the phenotype of
PME, characterised by ataxia, seizures, myoclonus, and
progressive intellectual deterioration.96,97
DRPLA is an autosomal-dominant disorder, caused by
unstable expansion of CAG repeats of a gene at
12p13.31.98,99 The discovery of the DRPLA gene has made
it possible to analyse the diverse clinical presentations on
the basis of the size of the expanded CAG repeats. There
is also an inverse correlation between the age at onset
and the size of the expanded CAG repeats. DRPLA is
characterised by prominent anticipation with a mean
acceleration of age at onset of 26·5 years (SD 2·4) in
paternal transmission and 14 years (SD 4) in maternal
transmission. MRI findings include atrophy of mid-
saggital structures of the cerebellum and brain stem,
particularly the pontine tegmentum. There is strong
inverse correlation between the age at diagnosis by MRI
and the areas of atrophy in patients with large expanded
CAG repeats. However, cerebral white-matter
involvement is associated with the duration of the illness
rather than with the size of the CAG repeats.100 Diagnosis
is confirmed by identifying the abnormal CAG repeats.
Other rare causes of PME
The action-myoclonus renal-failure syndrome, an
autosomal recessive disorder, was described in French
Canadians with PME, severe progressive action
http://neurology.thelancet.com Vol 4 April 2005
Review
myoclonus, dysarthria, ataxia, and renal failure.101 A
juvenile form of Huntington’s disease may also cause
PME.102 Familial encephalopathy with neuroserpin
inclusion bodies is a rare autosomal-dominant disease
that causes progressive dementia and, in some cases, a
familial form of PME. It is caused by mutation in the
gene coding for the serine protease inhibitor (serpin) on
chromosome 3q26. Inclusion bodies are distributed
throughout the cerebral cortex and substantia nigra.103
Non-infantile neuronopathic Gaucher’s disease,
atypical inclusion body disease, neuraxonal dystrophy,
coeliac disease, juvenile GM2 gangliosidosis,
Hallervorden-Spatz disease, and Alzheimer’s disease
beginning in the third or fourth decade are other very
rare causes of a PME phenotype.104
Conclusion: diagnosis and treatment of PME
The PMEs are rare disorders, that typically have a
genetic cause. Most PMEs are autosomal-recessive
disorders, except for adult NCL (Kuf’s disease), DRPLA,
juvenile Huntington’s disease, familial encephalopathy
with neuroserpin inclusion bodies, and MERRF. The
mode of inheritance, especially if dominant, can give a
clue to diagnosis.
In the early stages of PME, clinical and EEG features
may mimic idiopathic generalised epilepsy syndromes,
especially juvenile myoclonic epilepsy, but failure of
therapy and progressive neurological and EEG
deterioration point to a diagnosis of PME. Conversely,
the clinical picture of patients with idiopathic
generalised epilepsy may mimic PME, if they are
inappropriately treated and intoxicated with antiepileptic
drugs, with resultant ataxia, impaired cognitive function,
and poorly controlled seizures.1 However,
photosensitivity may require photic stimulation at a
lower frequency than that in idiopathic generalised
epilepsy. A full history of the illness, developmental
history in children, comprehensive family history when
possible, and thorough clinical examination are
imperative to obtain clues to diagnosis.
Although laboratory and pathological studies are still
required for some of the PME disorders, the revolution
in molecular genetics has allowed a definitive diagnosis
of some PMEs such as Unverricht-Lundborg disease,
MERRF, DRPLA, and most patients with Lafora’s
disease. Reaching a definite diagnosis has significant
implications for management and genetic counselling.
Treatment of PME disorders remains essentially that
of managing seizures and myoclonus together with
palliative, supportive, and rehabilitative measures.
Treatment of myoclonus and seizures in PME can prove
to be difficult as both tend to be refractory and resistant
to conventional antiepileptic medications. Controlled
clinical studies could be used to assess the antiepileptic
drug efficacy in PME in large groups of patients, but are
not possible because the incidence of these disorders is
rare. Hence, available data on the efficacy of newer
245
 Review
Panel 2: Drugs and PME
Used for treatment
Valproic acid
Benzodiazepines
Phenobarbital
Piracetam
Levetiracetam
Zonisamide
May aggravate myoclonus
Phenytoin
Carbamazepine
Gabapentin
Vigabatrin
Tiagabine
Use with caution
Lamotrigine in all cases
Valproic acid in MERRF
antiepileptic medications in PME are primarily
anecdotal or observational, based on responses of
individuals or very small groups of patients.105
Commonly used antiepileptic drugs for management
of myoclonus (panel 2) include combinations of valproic
acid, benzodiazepines, phenobarbital, and more
recently, piracetam, zonisamide, and levetiracetam.
Vagus-nerve stimulation may also have a role but needs
to be further investigated and can not yet be considered
as a routine treatment. Care must be taken to avoid
antiepileptic medications that clearly worsen
myoclonus. These include vigabatrin, carbamazepine,
phenytoin, and gabapentin. Lamotrogine has an
unpredictable effect on myoclonus and must be used
with caution.106–108
Through recent advances in molecular genetics,
several gene loci, mutations, and proteins involved in the
pathogenesis of PME disorders have been identified.
Future treatments with gene therapy and enzyme
replacement may help to modify and improve the course
of these progressive disorders.
Search strategy and selection criteria
Data for this review were identified by searches of PubMed with
the terms “myoclonus”, “progressive myoclonic epilepsy”,
“Unverricht-Lundborg disease”, “Lafora disease”, “myoclonic
epilepsy with ragged red fibres”, “neuronal ceroid
lipofuscinosis”, “sialidoses”, “dentatorubral-pallidoluysian
atrophy”, “genetics”, “mutations”, and “myoclonus treatment”.
References and textbooks were also identified through
references cited in relevant articles. Only papers published in
English were reviewed. The search covered publications from
January, 1971, to November, 2004, with inclusion of two
historical references from 1891 and 1903.
246
Authors’ contributions
AS designed and wrote the review and collected the data. MF revised the
review and provided the neuropathological figures. ND developed the
initial idea, contributed to the design of the review, and revised the
paper at its different stages of development for important intellectual
content.
Conflicts of interest
ND has received unrestricted educational and research grant support
from the following pharmaceutical companies: UCB Pharma, Elan
Pharma, GlaxoSmithKline, Jannsen Cilag, Pfizer and Novartis. He is or
has also been a member of Elan Advisory Board (Ireland), UCB Pharma
Advisory Board (UK), Eisai Advisory Board (Europe), Irish advisory
boards of Janssen Cilag and GlaxoSmithKline, and the European
advisory board of Pfizer. He has also received speaker’s honoraria from
UCB Pharma and Jannsen Cilag. The decision to write and submit this
review was entirely his, and was not in any way influenced or initiated
by any pharmaceutical company. MF is not employed by any
pharmaceutical companies nor does he receive any funds from
pharmaceutical or other commercial companies, nor does he have
ownership of stocks in such companies. AS is not employed by any
pharmaceutical company nor does he receive any funds from
pharmaceutical or commercial companies, nor does he have ownership
of stocks in such companies.
Role of the funding source
There is no funding allocated for this study and it is entirely the sole
efforts of the participating authors.
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