Seizure: European Journal of Epilepsy 71 (2019) 247–257

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Seizure: European Journal of Epilepsy

journal homepage: www.elsevier.com/locate/seizure

Review

The best evidence for progressive myoclonic epilepsy: A pathway to T

precision therapy
⁎
Alessandro Orsinia, Angelo Valettob, Veronica Bertinib, Mariagrazia Espositoa, Niccolò Carlia, ,
Berge A. Minassianc, Alice Bonuccellia, Diego Peronia, Roberto Micheluccid, Pasquale Strianoe,f
a
Pediatric Neurology, Pediatric University Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Italy
b
Citogenetic Unit, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy
c
Pediatric Neurology, University of Texas Southwestern and Dallas Children's Medical Center, Dallas, TX, USA
d
IRCCS-Istituto delle Scienze Neurologiche di Bologna, Unit of Neurology, Bellaria Hospital, Bologna, Italy
e
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto 'G. Gaslini', Italy
f
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy

A B S T R A C T

Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized
epilepsy, and neurological deterioration, including dementia and ataxia. PMEs may have infancy, childhood, juvenile or adult onset, but usually present in late
childhood or adolescence, at variance from epileptic encephalopathies, which start with polymorphic seizures in early infancy. Neurophysiologic recordings are
suited to describe faithfully the time course of the shock-like muscle contractions which characterize myoclonus. A combination of positive and negative myoclonus is
typical of PMEs. The gene defects for most PMEs (Unverricht-Lundborg disease, Lafora disease, several forms of neuronal ceroid lipofuscinoses, myoclonus epilepsy
with ragged-red fibers [MERRF], and type 1 and 2 sialidoses) have been identified. PMEs are uncommon disorders, difficult to diagnose in the absence of extensive
experience. Thus, aetiology is undetermined in many patients, despite the advance in molecular medicine. Treatment of PMEs remains essentially symptomaticof
seizures and myoclonus, together with palliative, supportive, and rehabilitative measures. The response to therapy may initially be relatively favourable, afterwards
however, seizures may become more frequent, and progressive neurologic decline occurs. The prognosis of a PME depends on the specific disease. The history of
PMEs revealed that the international collaboration and sharing experience is the right way to proceed. This emerging picture and biological insights will allow us to
find ways to provide the patients with meaningful treatment.

1. Definition and history of progressive myoclonus epilepsies potential pathways for a targeted, personalized approach for their
treatment.
The Progressive Myoclonus Epilepsies (PMEs) are a group of un-
common clinically and genetically heterogeneous disorders (mainly 2. Unverricht-Lundborg disease (ULD) (OMIM #254800)
autosomal recessive), characterised by myoclonus, generalized epi-
lepsy, and progressive neurological deterioration, including dementia ULD is the purest type of PMEs, with only few symptoms associated
and ataxia [1]. PMEs are disorders with debilitating evolution, re- with epileptic seizures and myoclonus [4]. It is the most common, less
sistance to treatment and poor prognosis, and it is estimated that these severe form of PME, with an autosomal recessive inheritance and it
diseases are responsible for up to 1% of epileptic syndromes in children occurs in late childhood or adolescence. Sex distribution is equal. Al-
and adolescents around the world. The rarity and complexity of the though it occurs worldwide, its prevalence is higher in some geographic
disorders that cause PMEs have resulted in a confusing literature since areas (Finland, Mediterranean region, Reunion Island) and in areas
the first description, a century ago (Table 1) (Table 2). The recent with a high rate of consanguinity [1,5]. Its worldwide prevalence is
history of PMEs begins in 1989 with a consensus statement published in unknown; in Finland, approximately 4 in 100,000 people are affected.
the wake of the Marseille PME workshop. The consensus helped to ULD has been related to mutations in the CTSB (cystatin B) gene,
define the various types of PMEs known at that time and set the agenda located in 21q22.3. Cystatin B protects the cell from endogenous pro-
for a new era of genetic research, which soon led to the discovery of teases and its deficiency causes hyperexcitability and impaired neu-
many PME genes [2,3]. ronal function of cortical networks. An unstable minisatellite repeat
Here, we review the main advances in the field and also address the expansion of a dodecamer (CCCCGCCCCGCG) in the 5-prime

⁎
Corresponding author.
E-mail address: [email protected] (N. Carli).

https://doi.org/10.1016/j.seizure.2019.08.012
Received 16 July 2019; Received in revised form 21 August 2019; Accepted 23 August 2019
1059-1311/ © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
A. Orsini, et al. Seizure: European Journal of Epilepsy 71 (2019) 247–257

Abbreviations: ULD Unverricht-Lundborg disease; MERRF myoclonic epilepsy with ragged red fibers; NCL neuronal ceroid lipofuscinosis; AR autosomal recessive; AD autosomal dominant; EEG electroencephalography.
untranslated region of the gene (601145.0003) could be the most likely

Normal or progressive cerebral

cerebral atrophy (late stage)

source of the disorder [6].

hypometabolism in early
In addition to the expanded repeat mutation and the 2 or 3 repeats

Cerebellar, pontine and

Cerebral and cerebellar
found in alleles considered to be normal, alleles with 12–17 repeats,

Possible posterior
NEUROIMAGING

Usually normal termed 'premutational', were identified and shown to be transmitted

unstably to the offspring. These 'premutational' alleles were not con-
nected with a clinical phenotype [7].

atrophy

atrophy
stages
Point mutations identified in EPM1 patients were found as com-
pound heterozygous with the 12-bp repeat expansion allele, or some-
times homozygous. All EPM1 patients had residual gene activity; pa-

Mutation in TPP1, CLN3 and

Neuraminidase deficiency in
Lafora bodies in skin biopsy

Ragged red fibers in muscle

tients with null point mutations in homozygous state were not found,
biopsy or MTTK mutation

fibroblasts or leucocytes
Typical inclusions or probably because they are not viable [7].
DIAGNOSTIC CLUES

CSTB gene mutation

or EPM2A mutation

CSTB belongs to the family 1 of the protease inhibitor superfamily.

Human CSTB (also known as stefin 1, stefin B, or neutral cysteine
protease), inhibits in vitro several cathepsins (B, H, L and S), by tight
reversible binding. The main function of cathepsins is non-selective
CLN5

degradation of intracellular proteins to peptides and amino acids, but

they also participate in antigen procession and apoptosis. In lympho-
blastoid cells of EPM1 patients, decreased inhibitory activity of CSTB
generalized spike and wave of
Focal discharges and bursts of
Diffuse spike and wave 6–12

has been shown to correlate with enhanced activity of cathepsins B, L

Trains of positive spikes

and S, providing in vivo evidence for cathepsin regulation by CSTB. The

Focal and generalized
Diffuse epileptiform

physiological functions of CSTB, however, are likely not limited to ca-

EEG FEATURES

thepsin binding. Cystatin B has also been shown to inhibit apoptosis in

cerebellar cells. Data obtained in mice suggest that EPM1 should be
discharges

discharges

associated

classified as a primary neurodegenerative disorder, with CSTB having

2–5 Hz

an endogenous neuroprotective role in different neuronal populations.

Hz

Despite this progress, the molecular pathogenesis of EPM1 as well as

the normal physiological function of CSTB still remains to be elucidated
retinitis pigmentosa, optic

[8]. Oxidative stress is correlated with many neurological conditions

except in Kuf’s disease
Macular degeneration,
Retinal dystrophy and

and several case reports have suggested that antioxidant therapies, in-
cluding N-acetylcysteine, may alleviate symptoms in ULD patients [9].
Cherry-red spot
FUNDOSCOPY

Glial activation and particularly microglial activation may also con-

tribute to the pathogenesis of the disease. The observed microglial ac-
atrophy
Normal

Normal

tivation precedes the onset of myoclonus and is followed by gliosis and

neuronal loss [10].
Myoclonus is present since the early stages, with diffuse myoclonic
Mild/late or absent; psychosis

jerks at awakening. Myoclonus is typically distal, triggered by action,

Type II: learning disability

sensory stimulation or surprise. Over months or few years, myoclonus

becomes movement-related and increases with stress, causing major
(visual and auditory

disability [4]. Generalized tonic-clonic seizures (GTCSs) are usually

Rapid progression

grounds for an initial referral but in general they are a less prominent
hallucinations)
Early/severe

source of disability than myoclonus and in most patients become a

DEMENTIA

Variable

relatively minor feature over time [11]. GTCS typically occur at awa-
kening or during sleep. With disease progression, they may evolve into
cascade seizures, characterized by increasingly intense and violent
myoclonic jerks, culminating into a GTCS. GTCS usually decrease
spontaneously with advancing age. Other kind of seizures are rare.
CEREBELLAR

Progressive

Ataxia, impaired walking and instability upon standing are associated

Mild/late

Variable

Variable

with myoclonus and they usually decrease when myoclonus is fully

SIGNS

Early

controlled.
Cognitive impairment may be from mild to moderate [4,5]. In some
studies, it has been demonstrated a loss of attention, short-term
Myoclonic and

memory and executive functions [5].

Myoclonic

Myoclonic

Myoclonic
SEIZURES

Psychiatric comorbidities are frequent in ULD patients. A variety of

occipital

Variable

neuropsychological disorders have been documented in ULD patients in

Summary of PMEs clinical features.

various combinations [11,12].

The most typical EEG findings in ULD patients are represented by
normal or moderately slow background activity, generalized fast spike
(YEARS)

Variable

Variable

Variable
AGE AT

or polyspike and wave discharges at 3–5 Hz, both spontaneous and

ONSET

12–17
6–15

induced by intermittent photic stimulation (IPS), mainly between 10

and 15 flashes/s. Focal EEG abnormalities prevalent over the central
Lafora’s disease

and the posterior regions may be detected [13], particularly during

REM sleep with evidence of typical vertex and central fast spikes [14].
Sialidosis
DISEASE

MERRF

EEG abnormalities, tend to decrease over time after an average of 15

Table 1

ULD

NCL

years of disease.
Photosensitivity is a nearly constant feature of ULD (from 88% to

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Table 2
Molecular genetics of PME.
DISEASE INHERITANCE CHROMOSOME LOCUS GENE PROTEIN FUNCTION

ULD AR Ch21q22.3 CSTB Cystatin B Cysteine protease inhibitor

LD AR Ch6q24 Ch6p22 EPM2A EPM2B Laforin Malin Dual specificity protein tyrosine phosphatase
MERRF Maternal Mitochondrial DNA MTTK tRNALys Mitochondrial function and metabolism
NCL Classical late infantile AR Ch11p15 TPP1 Tripeptidyl peptidase 1 –
Juvenile AR Ch6p CLN3 – –
Adult (Kufs disease) AR/AD – – – –
Finnish-variant late infantile AR Ch13q21-q32 CLN5 – –
Variant late infantile AR Ch15q21-23 CLN6 – –
Sialidosis Type I AR Ch6p21.3 NEU1 Sialidase 1 –
Type II AR Ch20 NEU1 Sialidase 1 –

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

100% in different studies). Unlike other PMEs but similar to patients aspect and it may be precipitated by voluntary movements, the thought
with idiopathic generalized epilepsies and PPR, photosensitivity in ULD of movement, passive joint movements, light, touch or sound stimuli.
tends to disappear over the years, its prevalence decreasing to ∼30% Leg tremors and generalized seizures may also occur. A few vacuolated
after 15 years of disease [15]. lymphocytes and histiocytes may be present in peripheral blood and
Outcome in adults ranges from independent active life with minimal bone marrow (BM) smears, respectively. At the ultrastructural level,
impairment to severe disability and wheelchair-bound or even bed- swollen lysosome are visible in BM cells and in Kupffer cells of the liver
ridden patients. [18].
Sialidosis type II may present dysmorphic features (coarse facial
3. Sialidosis (OMIM# 256550) features, short trunk, barrel chest, spinal deformity and skeletal dys-
plasia) and sometimes it is associated with hepatomegaly, corneal
Sialidosis is an autosomal recessive lysosomal storage disorder due clouding and hearing loss[HYPERLINK \l "Ref21″ \o "[21] S.
to isolated neuraminidase (sialidase) deficiency leading to a defect in Franceschetti and L. Canafoglia, Sialidoses, (in eng), Epileptic Disord,
the degradation of glyco-proteins and accumulation of sialic-acid-con- vol. 18, no. S2, pp. 89–93, Sep 2016, doi: 10.1684/epd.2016.0845.″ \h
taining oligosaccharides and glycol-peptides. It was first reported as 21]. Type II sialidosis is further classified in three subtypes: congenital
‘cherry-red spot-myoclonus syndrome’ because of the characteristic or hydropic with onset in utero, infantile with onset between birth and
aspect of the fundus oculi, resulting from storage material in perifoveal 12 months, and juvenile with onset past 2 years of age [18]. Patients
ganglionic cells [16]. with the congenital form show severe non-immune hydrops fetalis and
Sialidosis is caused by mutations in the gene encoding neur- ascites. The clinical presentation at birth includes facial oedema, in-
aminidase, NEU1. It is classified on the basis of the patients’ phenotype guinal hernias and hepatosplenomegaly. All patients have major dys-
and onset age [17]. NEU1 is localized in 6p21.33 and encodes lyso- morphism, including coarse face, vertebral deformities, visceromegaly
somal neuraminidase. To date, > 40 NEU1 disease-causing mutations with enlargement of spleen and liver, dysostosis multiplex, and severe
have been identified. Most of these are missense mutations that do not mental retardation. Renal involvement has also been described. Both
affect NEU1 mRNA synthesis or stability [18]. Besides point mutations, the infantile patients with longer survival and the juvenile cases de-
also small deletions can be causative: an 11-kb deletion encompassing velop macular cherry-red spots and myoclonus and may also have
the entire coding and promoter regions of the NEU1 gene was identified hearing loss and angiokeratoma.
in 2 patients with sialidosis [19]. The penetrance and degree of severity of the symptoms in these
Two types of sialidosis can be distinguished: type I and type II sia- patients correlate closely with the type of NEU1 mutations involved
lidosis. Severe type II is caused by inactivate sialidase, while in the and, in turn, the levels of residual enzyme activity [18].The typical
milder form there is some residual activity [17]. macular change (red-cherry-spots) depends on ganglionic degeneration
Sialidase is part of a multienzyme complex containing other lyso- and may lead to late visual failure; however it can be clinically un-
somal enzymes such as: cathepsine A, b-galactosidase and N-acetyl- detectable for many years and may disappear in the late stages of the
galactosamine-6-solfate sulfatase. Sialidase removes terminal sialic acid disease. Two distinct forms of myoclonic activity, namely massive
molecules from oligosaccharides and glycoproteins, and its deficiency myoclonic jerks and facial myoclonus, are recognizable. Action myo-
causes macromolecular storage and urinary sialy-oligosaccharides ex- clonus is the main characteristic of “late” type I sialidosis, but may also
ertion [20]. The accumulation of the sialic acid-rich substrates con- occur in patients with type II sialidosis [21]. The second form of
tributes to the pathogenesis, and light and electron microscopy reveals myoclonic activity is restricted to the lower face and mouth and in-
vacuolations in the neurons and in the perineuronal and interfascicular terferes with speech. It is intermittent and often asymmetrical. This
oligodendroglia, but also in the endothelial cells. Diffuse neuronal in- facial myoclonus occurs independently of the massive myoclonic jerks.
tracytoplasmic storage of lipofuscin-like pigment is detectable in the MRI findings are normal in the early stages, while in the late stages
neocortex, thalamus, brainstem and spinal cord, as well in extra-ner- cerebellar, pontine and cerebral atrophy can appear [21].
vous organs [21]. Diagnosis is usually supported by increased urinary bound sialic
Sialidosis type I (also known as cherry-red spot myoclonus syn- acid excretion and confirmed by the genetic analysis or by the neur-
drome) presents with the typical clinical features of the PMEs, a slowly aminidases deficiency in cultured fibroblast. Sialidosis type II should be
progressive syndrome characterized by late-onset, decreased visual differentiated from other storage disease sharing similar features and
acuity associated with bilateral macular cherry-red spot (that may fade sialidosis type I should be differentiated from other types of PME.
later in the course of the disease) in childhood or juvenile age, nys-
tagmus, cerebellar ataxia, action myoclonus and generalized tonic- 4. Neuronal ceroid lipofuscinosis (NCLs)
clonic seizures. The onset of the disease is typically with gait abnorm-
alities, decreased visual acuity, or both. Young onset cataract formation The neuronal ceroid lipofuscinoses (NCLs) are the most common
has also been detected [21]. Myoclonus is the most prominent clinical cause of dementia in children. They are a group of genetically-

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Table 3
Genetic classification of NCLs.
LOCUS NAME GENE SYMBOL LOCUS PROTEIN NAME PHENOTYPIC SPECTRUM CAUSING DEFECT

CLN1 PPT1 1p34.2 Palmitoyl protein thioesterase 1 I, LI, J, A lysosomal enzymes

CLN2 TPP1 11p15.4 Tripeptidyl peptidase 1 LI, J, P lysosomal enzymes
CLN3 CLN3 16p11.2 CLN3 J, P transmembrane proteins
CLN4 DNAJC5 20q13.33 DnaJ homolog A (Parry disease) subfamily C member 5 –
CLN5 CLN5 13q22.3 CLN5 LI, J, P, A –
CLN6 CLN6 15q23 CLN6 LI, P, A (Kufs type A) transmembrane proteins
CLN7 MFSD8 4q28.2 Major facilitator superfamily LI, J domain-containing protein 8 transmembrane proteins
CLN8 CLN8 8p23.3 CLN8 LI, P transmembrane proteins
CLN9 n/a unknown Unknown unknown –
CLN10 CTSD 11p15.5 Cathepsin D C, LI, J, A lysosomal enzymes
CLN11 GRN 17q21.31 Granulins A –
CLN12 ATP13A2 1p36.13 Probable cation-transporting J ATPase 13A2 –
CLN13 CTSF 11q13.2 Cathepsin F A (Kufs type B) lysosomal enzymes
CLN14 KCTD7 7q11.21 BTB/POZ domain-containing I protein KCTD7 –

Abbreviations: Aadult; C congenital; I infantile; J juvenile; LI late-infantile; P protracted; – unknown.

determined neurodegenerative conditions linked by the characteristic NCL have a recognizable phenotype that correlates with the pro-
accumulation of abnormal storage material (NCL-specific lipopigments gressive grey matter neurodegenerative process involving the cortex,
[22] in neurons and other cell types, and a degenerative disease course deep grey nuclei, cerebellum, and retina. The age at disease onset can
[23]. NCLs are characterized by a progressive decline of cognitive and range from birth to adulthood. The main alerting symptoms are the
motor capacities, retinopathy evolving into blindness, variable cere- combination of two or more among dementia, visual loss, epilepsy, and
bellar atrophy, and myoclonic epilepsy, leading to significantly de- motor deterioration. The order in which symptoms occur is variable
creased life expectancy [24]. The characteristics of these symptoms can and depends both on age at onset and on genetic form. In a young child,
vary and the age at disease onset ranges from birth to young adulthood first symptoms are developmental slowing followed by standstill, then
[23]. The incidence in USA and Scandinavian countries is 1:12.500 later regression of psychomotor development, or epilepsy. In a school
while the world-wide incidence is 1:100.000 [25]. child, first symptoms are usually visual loss and behaviour change,
More than a dozen genes containing nearly 400 mutations related to followed by dementia [23].
underlying human NCLs have been identified. These genes belong to The first approach to diagnosis should consider age at onset and
the neuronal ceroid lipofuscinosis (CLN) family Table 3. type of clinical presentation [23]. Suggestive situations can be divided
Traditionally, NCL diseases were classified according to the age at in four typical groups: (1) very young infants, including new-borns with
disease onset (congenital, infantile, late infantile, juvenile, adult) and congenital epilepsy and microcephaly, (2) young children with devel-
sometimes also according to the respective authors [23]. An inter- opmental standstill or regression and severe epilepsy, (3) school chil-
nationally developed new NCL nomenclature clearly identifies each dren with visual loss, followed by dementia and epilepsy, and (4) young
NCL disease both genetically and clinically [23].Very recently, a new adults with non-specific mental, motor or behavioural abnormalities. In
nomenclature has been discussed and subsequently proposed which is each of these groups, a characteristic set of NCL types can be expected,
gene-based and specific to phenotypic variation arising from different caused by variable mutations in the known NCL genes Table 4.
mutations. This is an axial diagnostic classification system that includes
seven axes: affected gene (CLN gene symbol), mutation diagnosis,
biochemical and clinical phenotype, ultrastructural features, level of 5. Neuroserpinosis (PME associated with neuroserpin inclusion
functional impairment and other remarks (additional genetic, en- bodies) (OMIM #604218)
vironmental, or clinical features). NCL classification according to the
affected gene, combined with the age at onset, is sufficient for general Familial encephalopathy with neuroserpin inclusion bodies (FENIB)
use [24]. is a conformational proteinopathy, characterised by neuronal inclusion
The unifying finding in NCL patients is the accumulation, in neurons bodies composed of neuroserpin, a serine protease inhibitor (SERPIN).
and other cell types, of autofluorescent storage material (lipopigment FENIB is responsible for progressive myoclonic epilepsy and/or pre-
accumulations) revealed upon electron microscopy (EM), despite senile dementia. FENIB should be considered in cases of progressive
having diverse underlying biochemical aetiologies [26]. NCLs are myoclonic epilepsy and dementia particularly where there is family
considered as lysosomal storage diseases (LSDs), however many distinct history of neuropsychiatric diseases [28].
characteristics are observed. In fact, the accumulating material in NCLs FENIB is due to mutations in SERPINI1 gene, located on chromo-
is not a disease specific substrate and the main storage material is the some 3q26, which encodes for a serine protease inhibitor, neuroserpin
subunit C of mitochondrial ATP synthase or sphingolipid activator (NS). Genotype-phenotype correlations are remarkably strong with
proteins A and D. The precise function of the NCL proteins as well as the clinical features increasing in severity (S49 P, S52R, L47 P, H338R,
disease mechanisms is largely unknown[HYPERLINK \l "Ref27″ \o " G392E to G392R, from the less to the most severe). Clinical severity
[27] A. Jalanko and T. Braulke, Neuronal ceroid lipofuscinoses, (in refers to an earlier onset of the symptoms and an increasing contribu-
eng), Biochim Biophys Acta, vol. 1793, no. 4, pp. 697–709, Apr 2009, tion of the epileptic component of the syndrome [28].
doi: 10.1016/j.bbamcr.2008.11.004.″ \h 27]. Under the electron mi- The Serine protease inhibitors (serpins) are a super-family of pro-
croscope, the accumulated material takes different forms: granular os- teins that inhibits a wide range of proteases. Mutations may render
miophilic deposits (GRODs), curvilinear profiles (CLP), fingerprint serpins prone to aggregation and direct toxicity is a consequence of the
profiles (FPP), as well as rectilinear complex (RLC) or so called ‘con- intracellular accumulation of serpin aggregates (polymers) and may
densed forms’. The ultrastructural findings do not absolutely correlate result in death of the synthetic cell. There may also be associated loss-
with clinical presentation, and the same NCL may contain more than of-function effects caused by the deregulated hyperactivity of the target
one pattern of inclusion. Furthermore, the appearance of the patholo- proteases and this may underpin the development of epilepsy.
gical inclusions can depend on the tissue examined [24]. Cytotoxicity is seen exclusively in neurons of the central nervous system
and this aggregation causes gain-of-function neuronal dysfunction. NS

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Table 4
Diagnostic algorithm for NCL diseases.
CLINICAL PRESENTATION NECESSARY DIAGNOSTIC POSSIBLY AFFECTED GENES

Newborn with epilepsy and microcephaly. Enzyme testing for cathepsin D If pisitive for CTSD deficiency: CLN10
(CtsD) (leucocytes or fibroblasts).
If negative: further enzyme
testing for PPT1 and TTP1.
Young child (> 6 months) with developmental standstill or Enzyme testing for PPT1 and TPP1 (dry blood spots or leucocytes or
regression and/or newly occurring severe epilepsy of fibroblasts).
unknown cause. PPT1 deficient: CLN1
TPP1 deficient: CLN2
If PPT1 and TPP1 enzyme activities are normal: Electron microscopic
examination (skin biopsy or lymphocytes).
If storage material is present: genetic testing. CLN5, CLN6, CLN7, CLN8, CLN14
School child with visual loss and/or dementia and Search for lymphocyte vacuoles (light microscopy of blood smear).
epilepsybetween ages 4 and 7. If lymphocyte vacuoles are present: CLN3
If no lymphocyte vacuoles, enzyme testing for PPT1, TPP1 and CtsD.
PPT1 deficient: CLN1
TPP1 deficient: CLN2
CTSD deficient: CLN10
If PPT1 and TPP1 enzyme activities are normal: Electron microscopic
examination (skin biopsy or lymphocytes).
If storage material is present: CLN5, CLN6, CLN7, CLN8, CLN12
Young adult with non-specific mental, motor or behavioral Enzyme testing for PPT1, TPP1 and CtsD.
abnormalities. PPT1 deficient: CLN1
TPP1 deficient: CLN2
CTSD deficient: CLN10
CTSF deficient: CLN13
If enzyme activities are normal: Electron microscopic examination (skin
biopsy or lymphocytes).
If storage material is present: genetic testing (eventually in special cases If autosomal dominant: CLN4. If
even without detection of storage material), consider possible mode of autosomal recessive: CLN6, CLN11,
inheritance. CLN13

also inhibits tPA and plays physiological roles in the development of the loss of self-sufficiency and dementia [32]. People with the S52R, L47 P
central nervous system [29], in learning, in memory and also in such and H338R variants have larger and more numerous intraneuronal in-
pathological events as stroke [30]and epilepsy [31]. NS is also thought clusions associated with progressively earlier onset of symptoms,
to regulate the sensitivity of neurons to glutamatergic excitatory neu- during early adulthood (S52R, L47 P) and adolescence (H338R) [36].
rotransmission at the NMDA (N-methyl-D-aspartate) receptor. The epi- Neuro-histology is dominated by eosinophilic, PAS-positive in-
leptic component of FENIB may be due to dysfunction of the NS/tPA traneuronal inclusions in the brain [32]. The French family described
pathway [28].The rate of aggregation of the least clinically-aggressive by Gourfinkel-An et al. [35] with S52R mutation showed progressive
NS mutant, S49 P, is more than 10 times higher than that of the wild myoclonic epilepsy associated with a frontal syndrome starting from
type protein, whereas the association rate constant for tPA is essentially the age of 18 with severe myoclonus, generalized tonic-clonic seizures,
unchanged [32]. The next most severe mutation, S52R, results in a and absences. The EEG of one of the patients showed diffuse slow
further tenfold increase in the polymerization rate and the loss of ef- waves, spikes, and spike-wave discharges superimposed on a slow
fective tPA inhibition [33]. NS polymers gradually become entangled in background, with photic sensitivity at around 1 Hz. Cerebral MRI re-
the neuronal endoplasmic reticulum (ER) and form inclusions, known vealed cortico-subcortical atrophy. Additionally, cerebellar symptoms
as Collins bodies. and pyramidal signs were also present. Cognitive deterioration was
To date, only a few families and exceptionally rare non-familial severe [35]. L47 P mutation resulting in a proline to leucine amino acid
cases of progressive myoclonic epilepsy linked to the SERPINI1gene substitution was recently reported by (Hagen et al., 2011) [36], in a
have been described. patient with progressive myoclonus epilepsy and declining mental
Belorgey et al. reported 2 unrelated Caucasian families, carrying 2 status starting in adulthood [36]. Generalized seizures occurred early
different heterozygous mutations (S49 P and S52R) [32]; he also de- with myoclonus and progressive gait disturbances. Neuroimaging re-
scribed a small family with 2 affected siblings with S49 P mutation. vealed mild atrophy and multiple periventricular white matter lesions,
Davis et al. reported two patients with the disorder, a 23-year-old consistent with demyelination [36].In the most severe cases, caused by
man with an 8-year history of progressive myoclonic epilepsy, de- the most polymerogenic mutations, namely G392R and G392E, the
mentia, tremor, and dysarthria, and a 13-year-old girl with progressive patients exhibit the earliest onset of symptoms, with rapidly-pro-
myoclonus epilepsy, intractable seizures, myoclonus, and dementia gressive symptomatology consisting in profound intellectual decline
who died at the age of 19 during status epilepticus [34]; Gourfinkel-An during childhood associated with severe, uncontrolled epilepsy, ag-
et al. subsequently described a small French family with a heterozygous gressive behaviour, intellectual decline, psychic seizures, and subtle
S52R missense mutation at position 273 in exon 2, the same as in the seizures with eyelid myoclonus [28].
two families from the United States [35]; S49 P mutation have diffuse
small intraneuronal inclusions of neuroserpin with an onset of dementia
6. Spinal muscolar atrophy associated with progressive
between the ages of 45 and 60 [34]. Patients show cognitive decline,
myoclonus epilepsy (SMA-PME) OMIM #613468
deficits in attention and concentration, response regulation difficulties,
and impaired visuospatial skills. Memory is also impaired. In adult-
SMA-PME is a rare syndrome characterized by lower motor neuron
hood, generalized seizures and, later on, status epilepticus are frequent.
disease associated with progressive myoclonic epilepsy caused by mu-
Slow speech, diplopia, nystagmus, dysarthria, and myoclonus in the
tations in ASAH1 (N-Acylsphingosine Amidohydrolase), which encodes
extremities were also described. At last stages of the disease there are
an acid ceramidase [37]. It has been described in childhood and is

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inherited as an autosomal recessive trait [38]. Distal muscle weakness 8. Action myoclonus renal-failure syndrome (AMRF) (OMIM
was defined in patients with PME; however, Jankovic and Rivera were #254900)
the first to report the association of hereditary myoclonus and pro-
gressive distal muscle atrophy as a separate clinical entity in 1979 [39]. AMRF is an autosomal recessive syndrome characterized by pro-
Functional studies in cultured fibroblasts showed that acid cer- gressive myoclonus epilepsy sometimes associated with renal dysfunc-
amidase was reduced in both overall amount and enzymatic activity. tion. AMRF is caused by the loss of function of the gene SCARB2
Ceramide level was doubled in the patient’s fibroblasts. Ceramides are (Scavenger Receptor Class B, Member 2) (* 602257), which encodes
the precursors to complex sphingolipids, which are important for LIMP2 (lysosomal integral membrane protein type 2).
normal functioning of both the developing and mature brain. LIMP2 is a ubiquitously expressed [49] glyco-protein located in
A total of 11 affected individuals have been reported thus far, lysosomal membranes. Overexpression of LIMP-2 causes an enlarge-
leading to a relatively precise phenotypic characterization [37,40]. The ment of early and late endosomes/lysosomes, impairs the endocytic
onset of the disorder occurs between 1 and 6 years of age with lower membrane traffic. These findings support the idea that LIMP-2 plays a
motor neuron disease leading to progressive muscle weakness and soon role in the biogenesis and maintenance of the endolysosomal system
followed by the occurrence of clinical and EEG characteristics of [49]. Moreover, LIMP-2 appears to display a role as a multifunctional
myoclonus epilepsies. SMA-PME has an inevitable progressive course. receptor at the plasma membrane for the lysosomal delivery of acid
The epileptic pattern is characterized by brief myoclonic seizures hydrolase-glucocerebrosidase (GC) [50].
without loss of consciousness, generalized epileptic seizures and myo- The predominant clinical manifestations of AMRF are progressive
clonic jerks, absences with head drop or postural lapses in the upper myoclonus epilepsy and renal failure [51–53]. Age of onset ranges
limbs, atonic seizures. Electromyography (EMG) shows evidence of between the late teens and early twenties. One of the most important
motor neuron disease despite only mild proximal muscle weakness, and neurological symptoms is the tremor, which starts in the fingers and
a chronic denervation process while muscle biopsy shows neurogenic hands, and it is exacerbated by fine motor activities. The patients later
atrophy. The EEG shows subcortical myoclonic epileptiform abnorm- develop involuntary spontaneous action-activated myoclonic jerks and
alities which are sensitive to hyperventilation, paroxysmal activity involuntary spontaneous myoclonic jerks at rest. Generalized tonic-
consisting of frequent, diffuse bursts of sharp waves and polyspike and clonic seizures occur in the majority of patients [49]. Other common
wave complexes. Brain MRI is most often normal or displays mild su- features include ataxia, dysarthria due to cerebellar dysfunction, au-
pratentorial and subtentorial cortical atrophy. Myoclonic seizures are ditory defects [52] and a rare demyelinating peripheral neuropathy
most often refractory to antiepileptic drugs. Variable degrees of cog- [54]. Cognitive function is preserved or only slightly affected until the
nitive impairment (usually mild) occur [41].Taking into account on- final stages of the disease. Renal involvement is heralded by the ap-
going therapeutic research for Farber disease, a disease allelic to SMA- pearance of proteinuria that can progress to a nephrotic syndrome and
PME, screening for ASAH1or acid ceramidase activity should be pro- end-stage renal disease.
posed for the diagnosis and future treatment of patients with PME or Death occurs usually within 7–15 years after disease onset. The
SMA. absence of renal involvement in PME associated with SCARB2 muta-
tions has also been described, particularly in Italian patients showing an
invariably fatal course [55–57].
7. MEAK: PME-Ataxia due to potassium channel mutation (OMIM EEG shows generalized epileptiform abnormalities [53,56], and
#616187) background activity slows progressively over the years. Intermittent
photic stimulation can trigger bursts of generalized spike-polyspike-
This is the most recently described subtype of PME and is caused by wave discharges, often associated with massive myoclonic jerks. Brain
a recurrent de novo heterozygous mutation in the KCNC1 (Potassium imaging studies are usually unremarkable or show diffuse cerebral
Channel, Voltage-Gated, Shaw-Related Subfamily, Member 1) gene, atrophy and cerebellar atrophy. Widespread deposition of abnormal,
which encodes for the Kv3.1 protein (a subunit of the Kv3 subfamily of extraneuronal brown pigment in the brain, with no neuronal loss or
voltage-gated potassium channels) [42]. MEAK was first described in significant gliosis, has been reported [53]. It has been suggested that
2015, when a cohort of 84 unconfirmed, unrelated PME patients was the pigment consists of lipofuscin-like oxidized lipid or proteolipid
extensively investigated and mutations in the KCNC1gene [43] were [53]. The patients without renal involvement showed different neuro-
identified. degenerative changes, such as neuronal loss and gliosis in the brain
KCNC1encodes the highly conserved potassium ion channel subunit [55].
of the Kv3 subfamily of voltage-gated tetrameric potassium ion chan-
nels [44]·.Previous studies have shown that loss of Kv3 function dis- 9. Myoclonic epilepsy with ragged red fibers (OMIM #545000)
rupts the firing properties of fast-spiking neurons [45,46], affects neu- and Alpers-Huttenlocher syndrome (OMIM #203700)
rotransmitter release [47], and induces cell death [48]. In MAEK the
most affected neurons include inhibitory GABAergic interneurons [46] The two most common mitochondrial epilepsies are MERRF (myo-
and cerebellar neurons. clonic epilepsy with ragged red fibers) and AHS (Alpers-Huttenlocher
MEAK patients generally have a normal early development. The first syndrome, also known as hepatopathic poliodistrophy) [58].
symptom is usually myoclonus, with an onset ranging from the age of MERRF is a maternally inherited mitochondrial disease and re-
6–14 years. Myoclonus tends to progressively worsen with time causing presents a phenotype that can be produced by mutation in more than 1
gait disturbances. Learning difficulties before seizure onset are not mitochondrial gene, e.g., MTTK (590060), MTTL1 (590050), MTTH
common, while some patients develop mild cognitive impairment fol- (590040), MTTS1 (590080), MTTS2 (590085), MTTF (590070).
lowing seizure onset. Typical electroencephalographic features com- Features of the MERRF syndrome have also been associated with mu-
prise generalized epileptiform discharges and, in some cases, photo- tation in the MTND5 gene (516005).The A-to-G mutation at nucleotide
sensitivity. Brain imaging is either normal or shows cerebellar atrophy 8344 accounts for 80–90% of MERRF cases [59]. MERRF is a multi-
[42].The early clinical presentation and evolution of MEAK resembles systemic disorder with onset occurring during childhood after a period
that of Unverricht-Lundborg disease (ULD). MEAK might be clearly completely normal development, characterized bymyoclonus, episodes
distinguished from ULD, as patients with MEAK usually suffer a more of generalized epilepsy, progressive ataxia, and ragged-red fibers (RRF)
severe course. with partial deficiency of cytochrome c oxidase [58]. Other clinical
manifestations include hearing loss, peripheral neuropathy, cognitive
decay, short stature, exercise intolerance, and optic atrophy and ataxia.

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Less common clinical signs are cardiomyopathy, pigmentary retino- has been reported in 19 patients from 12 families; these families had
pathy, pyramidal signs, ophthalmoparesis, and the appearance of variable ethnic origin and showed a high rate of consanguinity (5/12).
multiple lipomas, particularly in the neck and upper trunk [58].The The disease is caused by homozygous mutations in KCTD7gene
muscle biopsy shows RRF using modified Gomori trichrome stain [60]. (potassium channel tetramerization domain-containing protein 7) at
The main neuropathological findings are selective neuronal loss, par- 7q11.21. KCTD7is a member of hyperpolarization of the resting mem-
ticularly affecting the dentate nucleus and the inferior olivary nucleus, brane potential and decreases excitability in patch clamp experiments
and widespread gliosis and degeneration of myelinated tracts, including [66]. This is consistent with an epileptogenic effect of a KCTD7 defect
the superior cerebellar peduncles and posterior columns [61]. [66].
AHS is caused by homozygous or compound heterozygous mutation The disease starts in infancy, between five months and three years of
in the nuclear gene encoding mitochondrial DNA polymerase gamma age, after a period of normal or slightly delayed psychomotor devel-
(POLG; 174763) on chromosome 15q26. Few recessive mutations have opment. Patients typically show an initial severe epileptic disorder,
been reported. AHS is characterized by onset in infancy or early with abundant epileptiform discharges on EEG and myoclonic seizures
childhood often with seizures and/or hypotonia, psychomotor re- in the foreground, associated with cognitive regression and ataxia. The
tardation, intractable epilepsy, liver failure, developmental delay and seizures are described as either myoclonic or generalized tonic-clonic
regression, progressive microcephaly and cortical visual impairment seizures, and they can be precipitated by fever. Other types of seizures
with abnormal visual-evoked potentials. Brain MRI may be normal in (atonic seizures and atypical absences) have also been reported.
the initial stage of disease or show progressive cerebral atrophy. Epilepsy is drugs resistant. Progressive ataxia was reported in all but
Usually, patients die before the age of 3. Most patients experience status one patient. Continuous multifocal myoclonus aggravated by action has
epilepticus and the main cause of death are refractory seizures and liver been observed in more than half of the cases [67]. After a few years, the
failure [62]. disease tends to stabilize, and long survival can be expected. It has been
hypothesized that the epileptic disorder may influence the neurological
10. Autosomal recessive PME due to impaired ceramide synthesis regression observed in patients [68]. All patients have cognitive decline
(OMIM #616230) leading to severe dementia. Differential diagnosis may be with the
classic late-infantile form of NCL and the rare presence of associated
Progressive myoclonus epilepsy due to impaired ceramide synthesis opsoclonus can evoke opsoclonus-myoclonus syndrome. Concerning
is an extremely rare condition, so far reported in a single family of complementary examinations, EEGs were described to be abnormal and
Algerian origin. The patients presented an unusual, severe form of the most common findings were very frequent multifocal and/or gen-
progressive myoclonus epilepsy, characterized by myoclonus, general- eralized spike-waves associated with an excess of slow activity. EEG
ized tonic-clonic seizures and moderate to severe cognitive impairment. abnormalities were more prominent in the posterior areas, and inter-
This autosomal recessive condition is caused by a homozygous mittent light stimulation evoked generalized or posterior epileptiform
mutation in CERS1 (Ceramide Synthase 1). This gene encodes ceramide discharges. KCTD7-related epilepsy could be considered as an epileptic
synthase 1, a transmembrane protein of the endoplasmic reticulum encephalopathy, a condition in which epileptic activity may contribute
(ER), that catalyses the biosynthesis of C18-ceramides. The mutation to progressive neurological decline, such that effective antiepileptic
decreases C18-ceramide levels. We cannot exclude that his represents a intervention might improve developmental outcome [69].
private mutation within this family.
13. Gaucher’s disease type III (OMIM # 231000)
11. GOSR2-Related PME/Ataxia (OMIM #614018)
Gaucher's type III involves a storage of glucocerebroside in various
Progressive myoclonic epilepsy-6 (EPM6) is an autosomal recessive organs. It generally onsets in childhood. The disease is due to a muta-
neurologic disorder caused by mutations in GOSR2 (Golgi Snap tion in the GBA (glucosidase beta acid) gene on chromosome 1q21, with
Receptor Complex Member 2) (604027). It is characterized by onset of a L444 P substitution most common in type III [1].The first symptoms
ataxia in the first years of life, followed by action myoclonus and sei- are often saccadic horizontal eye movements and supranuclear gaze
zures later in childhood, and loss of independent ambulation in the paralysis, which can be associated with strabismus, along with gen-
second decade. Cognition is not usually affected, although mild eralized or focal seizures. It is usual to observe, in these patients, ataxia,
memory difficulties may occur in the third decade [63]. moderate intellectual impairment and low oculo-manual dexterity.
All patients with GOSR2-mediated PME so far reported have a Another typical finding is hepatosplenomegaly. The typical PME phe-
homozygous mutation (c.430 G > T, p.Gly144Trp) in GOSR2 [63,64]. notype is present in only a minority of cases. The EEG shows a normal
The clinical presentation is characterized by early-onset ataxia, to slow background activity and bursts of predominantly posterior or
followed by action myoclonus and seizures [65]. Areflexia, scoliosis in multifocal or polyspike waves, with sensitivity to photic stimulation.
adolescence, elevated creatine kinase levels are other clinical features The somatosensory EP are abnormally enlarged with hearing loss. Di-
[1]. Mild cognitive decline in the late stages of the disease, and loss of agnosis is due with biopsy or with genetic test. There are increased
independent ambulation in the second decade and relentless disease levels of chitotriosidase in plasma. A life expectancy of more than 10
course may be observed [65]. All patients exhibited multiple seizure years can usually be predicted [1].
types, including generalized tonic-clonic seizures, absence seizures, and
drop attacks [64]. Patients showed highly photosensitive generalized 14. Lafora disease (LD) (OMIM #254780)
myoclonus that worsened with action or emotional stress [65]. EEG
analysis revealed generalized spike-and-slow-wave discharges with a Lafora disease is an autosomal recessive progressive myoclonus
posterior predominance, often with a slow background. The generalized epilepsy and it was the second of the PMEs to be identified in 1911 by
discharges are highly photosensitive [65]. Nerve conduction studies Gonzalo Lafora, depending on the mutations of two genes: EPM2A
have been reported to be consistent with a mild, predominantly axonal (Epilepsy, progressive myoclonic 2A)(* 607566), located in chromo-
peripheral neuropathy [64]. MRI have displayed essentially normal some 6q24, that encodes for the Laforin dual specificity phosphatase
findings or generalized cerebral and cerebellar atrophy [64]. and EPM2B (NHLRC1, Nhl Repeat-Containing 1 Gene)(*608072) in
chromosome 6p22.3 that encodes the Malin ubiquitin E3 ligase, both
12. KCTD7-Related PME (OMIM #611726) involved in the complex and not yet completely understood glycogen
metabolism leading to the deficiency of Laforin and Malin, respectively.
Progressive myoclonic epilepsy associated with KCTD7 mutations They both seem to contribute equally to the pathogenic variants’

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phenotypes. It is particularly frequent in Mediterranean countries to prevent it from wrapping around a neighbor chain. This would at-
(Spain, Italy, France), Northern Africa, Southern India, Pakistan and tract laforin which would not only bind the phosphoglucan but via
Middles East, found in 250 families and of these 42% are caused by malin would ubiquitinate and inhibit GS. Laforin would then remove
mutations in EPM2A and 58% by mutations in EPM2B. The prevalence the phosphate [79].
seems to be close to 4 cases per million persons. However, the pre-
valence may be higher, because of the missed and undiagnosed pa- 15. Treatment
tients. [70,71].
The most pathogenic variants include the following loss of function At present, PME treatment remains palliative, with the best current
mutations: splice site, missense, nonsense and small intragenic dele- therapies having limited success in the modulation of symptoms. AED
tions and insertions [72].A third gene, PRDM 8 (Pr Domain-Containing are the only options for seizures control [80]. The most used is valproic
Protein 8, *616639), has been reported and it is associated with early acid, that is usually effective in suppressing, momentarily, most GTCS,
childhood onset phenotype [73].The most common EPM2A mutation is the symptoms associated with photic sensitivity, and some of the
the R241X mutation, that has been found in the 17% of the patients myoclonus. Other AEDs used are: lamotrigine (LTG) but it is not very
with EPM2A mutation, and large deletions make up 10–15%. The most advisable in the context of a myoclonic epilepsy; phenobarbital (PB)
common EPM2B mutations are the missense mutation P69A and the and primidone (PRM) are effective, but at high doses they have cog-
frameshift mutation G158fs16. nitive effects that worse those of the condition; and levetiracetam
Clinically, LD is a fairly homogenous disease with onset in adoles- (LEV). Other helpful drugs include topiramate (TPM) and zonisamide
cence (range: 8–19 years; peak: 14–16 years) in otherwise neurologi- (ZNS), which both have marked antimyoclonic effects. Additional relief
cally normal individuals.and neurological decline soon after, but the can be obtained, often transiently, with ethosuximide, felbamate, and
timing and severity of symptoms can be variable, even within the same benzodiazepines (BZD). Finally, there have been two recent single case
families [74]. Genotype-phenotype correlations do not reveal sub- reports of rather dramatic beneficial effects of perampanel [81]. Pir-
stantial differences between patients with EPM2A and EPM2B muta- acetam (PIR), a more specific antimyoclonic agent, can alleviate the
tions, but a few specific EPM2B mutations appear to correlate with a burden of seizures and myoclonus. Specific therapeutic approaches can
late onset and slow progressing [70,71]. In many cases, the disease be discussed in patients with a severe course: vagal nerve stimulation
shows an insidious near-simultaneous, or closely consecutive, appear- [82] and deep brain stimulation has also been used in PME cases;
ance of headaches, difficulties at school, myoclonic jerks, generalized combined subthalamic and thalamic high-frequency stimulation has
seizures, and visual hallucinations [70,71]. EEG shows a slowing brought some relief, especially in the least severely affected cases
background and spike-wave discharges that do not have the regularity [83].There is no evidence that carbamazepine (CBZ), oxcarbazepine
of the JME’s spike and polyspike-waves. Focal spikes localized in the (OXC), phenytoin (PHT), eslicarbazepine, gabapentin, pregabalin, vig-
occipital regions become apparent and represent an hallmark of the abatrin, or lacosamide are of any benefit and a worsening effect may
disease. During the final stages of the disease EEG shows long bursts of observed. However, in some cases status epilepticus responds well to
diffuse spike-waves and fast polyspikes, associated with massive posi- phenytoin, but it should not be kept as maintenance medication. With
tive or negative myoclonic jerks and enhanced by photic stimulation at the progression of the PME, AED treatment progresses to polytherapy,
low frequency, on a low background activity, predominantly in the with a combination of several of the drugs quoted above. The ketogenic
occipital area. Myoclonus becomes continuous, progressive, generalized diet has been tried, but without success, in relatively advanced cases
and difficult to control over time [74].Occipital seizures may present as [84].
transient blindness, simple or complex visual hallucinations, photo
myoclonic, convulsive photo responses or migraine with scintillating 16. Future directions and potential targeted treatments
scotoma. Not all visual hallucinations are epileptic [74].Important
symptoms in the late stages of the disease are progressive dementia, 16.1. ULD
refractory status epilepticus, psychosis, cerebellar ataxia, dysarthria,
mutism and respiratory failure, leading to total disability or death 5–10 Recently an oligonucleotide therapeutic strategy has been used to
years after clinical onset [70,71]. replace the gene effect.
Brain MRI is usually unremarkable at onset, however two reported A specific locked nucleic acid (LNA) antisense oligonucleotide was
cases FDG-PET revealed posterior hypometabolism during the early designed to block a cryptic 5′ss in intron 1. Overall, this approach al-
stages of the disease [75]. lowed the restoration of the normal splicing pattern [85].
The primary morphological change in LD is the deposition of Considering AEDs therapy Perampanel have been recent associated
polyglucosans, which consists of discrete deposits of fibrillary poly- with a good response in seizure control in all type of seizures [86].
saccharides composed of poorly-branched glucose polymers (LBs) [74].
They are typically found in the brain, in the periportal hepatocytes of 16.2. Sialidosis
the liver, skeletal and cardiac myocytes, and in the eccrine duct and
apocrine myoepithelial cells of the sweat glands [76]. The gradual Enzyme replacement therapy is a possible approach to treatment.
overtaking of synaptic cell processes by LB may underlie the epilepto- This treatment has been evaluated on mouse models. In mice, restored
genesis by escalating disturbance of synaptic function. It has also been neuraminidase activity persisted for some days and it led to a sig-
suggested that there is preferential degeneration of inhibitory inter- nificant reduction of lysosomal storage, however the enzyme could not
neurons in LD [77]. cross the blood-brain barrier. Furthermore, the injected recombinant
There are presently two divergent hypotheses of polyglucosan for- protein may have caused sever anaphylactic reactions [87].
mation in LD: one hypothesis states that the GS enzyme may have an
undesirable side reaction, causing the addition to glycogen of phos- 16.3. Neuronal ceroid lipofuscinosis
phates; these phosphates leading to glycogen precipitation and mis-
tructuring through yet to be clarified mechanisms. This hypothesis is In the last days there have been numerous studies on animal models
supported by laforin’s role as a glycogen phosphatase and by evidence to develop new treatments for NCLs. The most promising approach is an
that such a GS phosphate-adding side reaction does occur [78]. The enzyme replacing therapy. In fact, US Food and Drug Administration
other hypothesis considers glycogen phosphorylation as a desirable (FDA) and the European Medicines Agency (EMA) have recently ap-
event. Every once in a while, during glycogen synthesis, a glycogen proved an intracerebroventricularly administered enzyme replacement
chain is overextended by GS and such a chain would be phosphorylated therapy for neuronal ceroid lipofuscinosis type 2 (CLN2).The first gene

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therapy phase 1 clinical trial [88] was done in ten patients with CLN2 outcome for diseases that in the past had been considered quite un-
disease introducing a gene therapy vector designed to express TPP1 into treatable.
the brain but there was no slowing of disease progression. International In particular we believe it was useful for the epileptologist to un-
cooperation is now contributing to the collection of natural history data derstand this kind of disease which, although singularly are extremely
for all NCL types into the DEM-CHILD Database, which will provide rare, all together represent a significant percentage of the most serious
data to use in future clinical trials and increase understanding of the epilepsies syndromes. The future effort of the research must be to
spectrum of each type of NCLs [89]. identify new drugs against specific pathogenic mechanisms, or a spe-
cific action of mutated proteins, up to a gene replacement therapy.
16.4. SMA-PME
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