BRIEF COMMUNICATION

Mild Lafora disease: Clinical, neurophysiologic,

and genetic findings
*1Edoardo Ferlazzo, 1Laura Canafoglia, Roberto Michelucci, *Antonio Gambardella,
Elena Gennaro, Elena Pasini, Patrizia Riguzzi, Rosaria Plasmati, Lilia Volpi, *Angelo Labate,
*Sara Gasparini, #Flavio Villani, Marina Casazza, **Maurizio Viri, Federico Zara,
Berge A. Minassian, Julie Turnbull, Jose M. Serratosa, Rosa Guerrero-L
opez,
Silvana Franceschetti, and *Umberto Aguglia
Epilepsia, 55(12):e129e133, 2014
doi: 10.1111/epi.12806

SUMMARY

Laura Canafoglia is a
neurophysiologist
skilled in multimodal
assessment of
myoclonic syndromes
and rare epilepsies.

We report clinical, neurophysiologic, and genetic features of an Italian series of

patients with Lafora disease (LD) to identify distinguishing features of those with a
slowly progressive course. Twenty-three patients with LD (17 female; 6 male) were
recruited. Mean age ( SD) at the disease onset was 14.5  3.9 years and mean followup duration was 13.2  8.0 years. NHLRC1 mutations were detected in 18 patients;
EPM2A mutations were identified in 5. Patients who maintained >10 years gait autonomy were labeled as mild and were compared with the remaining LD patients with a
typical course. Six of 23 patients were mild and presented significantly delay in the age
at onset, lower neurologic disability score at 4 years after the onset, less severe seizure
phenotype, lower probability of showing both photoparoxysmal response on electroencephalography (EEG) and giant somatosensory evoked potentials, as compared to
patients with typical LD. However, in both mild and typical LD patients, EEG showed
disorganization of background activity and frequent epileptiform abnormalities. Mild
LD patients had NHLRC1 mutations and five of six carried homozygous or compound
heterozygous D146N mutation. This mutation was found in none of the patients with
typical LD. The occurrence of specific NHLRC1 mutations in patients with mild LD
should be taken into account in clinical practice for appropriate management and
counseling.
KEY WORDS: Progressive myoclonus epilepsy, Mild, Slowly progressive, EEG,
Dementia.

Dr. Edoardo Ferlazzo

is Assistant Professor
of Neurology at Magna
Graecia University of
Catanzaro, Italy.

Lafora disease (LD; MIM#254780) is an autosomal

recessive progressive myoclonus epilepsy (PME) typically
starting during adolescence. Most patients with LD have

mutations of the EPM2A gene encoding laforin or

NHLRC1/EPM2B encoding malin.1,2 LD is clinically characterized by refractory generalized (mainly tonicclonic) or

e129

e130
E. Ferlazzo et al.
visual seizures and spontaneous and reflex myoclonus, usually followed by rapidly progressive dementia and neurologic deteriorations, typically leading to a vegetative
state and death within less than one decade from the beginning.36 Age at onset before age 6 or after age 20 years,
evolution over more than one decade and the absence of
cognitive decline, were traditionally considered as exclusion diagnostic criteria for LD.3,7 Gomez-Abad et al.8
showed that patients with NHLRC1 mutations could have a
slightly longer course of disease as compared to EPM2Amutated subjects. Franceschetti et al.1 and Lesca et al.9
indicated a great variability of the clinical phenotype associated with NHLRC1 mutations including patients with
mild or severe outcome. Baykan et al.10 reported a Turkish
LD family with a slowly progressive course (follow-up
over 10 years in three of four subjects) carrying a homozygous D146N mutation of NHLRC1 gene. The same mutation
was found by Franceschetti et al.1 in three unrelated
patients with mild myoclonus and absent or mild cognitive decline at 4-year follow-up, as well as by Lanoiselee
et al.11 in a Turkish patient with late onset and preserved
gait at 4-year follow-up. Gene variants of protein targeting
to glycogen (PTG, a protein modulating glycogen synthesis), were believed to contribute to milder phenotype in
LD.12
The aim of this study is to report clinical, neurophysiologic, and genetic features of an Italian series of LD patients
to identify distinguishing features of those with a slowly
progressive course.

Methods
We describe 23 patients with LD followed in three
Italian epilepsy centers. Clinical, genetic, and neurophysiologic features were retrospectively evaluated. We
collected data from each patient including age at onset,
mortality, follow-up duration, onset symptoms, and type
and number of drugs used. To assess the progression of
the disease, we used a simplified disability scale based
on the residual motor and mental functions, daily living
and social abilities at 4 years from disease onset, with
scores ranging from 1 to 5 (modified by Franceschetti

et al.1): (1) mild cognitive and motor impairment, preserved daily living activities, and social interaction; (2)
moderate mental decline, limitations in motor activities,
and limited social interaction; (3) severe mental and
motor impairment, needing help in walking and regular
assistance in daily living activity, and poor social interaction; (4) patient wheelchair-bound or bedridden, and no
significant daily living activities or social interaction; (5)
exitus due to LD. Neuropsychological examination was
performed by clinical interview; formal testing was performed in a few patients. We assessed the presence of
spontaneous generalized epileptiform activities as well as
photoparoxysmal response (PPR) in EEG recordings performed during the course of the disease. We evaluated
somatosensory evoked potentials (SEPs) in 21 of 23
patients using standard methods. SEPs were defined as
giant, provided that they exceeded the mean value +3
SD of the normative laboratory values (peak-to-peak
amplitude of N20-P25: 5.2  2.4 lV). Brain magnetic
resonance imaging (MRI) was performed in 22 of 23
patients in different stages of disease.
EPM2A and NHLRC1 genes were investigated in all
patients. The genetic findings of 12 patients have been
reported previously.1,12
To highlight peculiarities of patients with a slowly
progressive LD, we compared subjects who maintained
>10 years gait autonomy (labeled as mild LD) with the
remaining LD patients with a typical course. PTG variants were analyzed in all patients with mild LD and one
subject with a typical LD course (patient 5), according to
Guerrero et al.12 Statistical analysis to assess differences
between mild and typical LD was performed with chisquare test (for dichotomous variables), Mann-Whitney
U-test (for ordinal categorical variables), and t-test (for
continuous variables). Survival analysis was performed to
analyze the cumulative time-dependent chance of losing
gait autonomy. Survival curves were generated according
to the Kaplan-Meier method and compared with the logrank test. Differences were considered statistically significant at p < 0.05. The coordinating ethical committee
(Bianchi-Melacrino-Morelli Hospital, Reggio Calabria,
Italy) approved the study.

Accepted August 19, 2014; Early View publication September 30, 2014.
*Magna Grcia University of Catanzaro, Catanzaro, Italy; Regional Epilepsy Center, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria,
Italy; Neurophysiopathology and Epilepsy Center, IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy; IRCCS - Institute of
Neurological Sciences of Bologna, Unit of Neurology, Bellaria Hospital, Bologna, Italy; Laboratory of Human Genetics, Galliera Hospital, Genova,
Italy; #Division of Clinical Epileptology, IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy; **Epilepsy Center, Fatebenefratelli and
Ophthalmic Hospital, Milan, Italy; Laboratory of Neurogenetics, Department of Neuroscience, Institute G. Gaslini, Genova, Italy; Department of
Pediatrics (Neurology), Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;and Department of Neurology, Biomedical
Network Research Center on Rare Diseases (CIBERER), IIS-Jimenez Daz Foundation, Madrid, Spain
1
These authors contributed equally to the manuscript.
Address correspondence to Umberto Aguglia, Regional Epilepsy Centre, Bianchi-Melacrino-Morelli Hospital, Magna Graecia University of Catanzaro,
Via Melacrino, 89100 Reggio Calabria, Italy. E-mail: u.aguglia@unicz.it
Wiley Periodicals, Inc.
2014 International League Against Epilepsy
Epilepsia, 55(12):e129e133, 2014
doi: 10.1111/epi.12806

e131
Mild Lafora Disease

Results
The 23 LD patients (17 female) belonged to 22 families.
The average age (SD) at the disease onset was 14.5 
3.9 years, the mean follow-up duration was 13.2  8.0 years,
and the average age at last observation was 28.1 
10.2 years. NHLRC1 mutations were detected in 18 patients,
whereas EPM2A mutations were identified in 5 (Table 1).
Among 23 patients with LD , 6 (5 female) could be labeled
as mild (Table 1; patients 1823), whereas the remaining 17
had a typical course (Table 1; patients 117). Ten of 17
patients with typical LD had died at last follow-up (mean age
at death 22.6 years; range 2028; mean disease duration
8.25 years, range 411) (Table 1); in all these subjects, gait
autonomy was lost from 1 to 7 years before death. The
remaining 7 of 17 patients with typical LD had a mean age
of 23.6 years (range 1540) and mean disease duration of
11.9 years (range 523) at last follow-up.

All patients with mild LD were alive at last follow-up

(mean age 42.1 years, range 4047; mean disease duration
24.1 years, range 1929).
Seizures (tonicclonic or absences) were the presenting
symptom in 12 patients (3 of 6 patients with mild LD and 9
of 17 patients with typical LD). During follow-up, all
patients with typical LD had frequent (from daily to weekly)
visual, clonic, or generalized tonicclonic seizures (GTCS).
On the contrary, among patients with mild LD, patient 21
never had seizures, patient 20 had only two GTCS during
19 years of disease history, patients 19 and 22 had sporadic
GTCS at yearly frequency, patient 18 had monthly GTCS,
and patient 23 had weekly clonic or GTCS seizures.
Notably, none of the patients with mild LD reported visual
or other focal seizures.
At last observation, cognitive decline was absent or mild
in two of six (patients 21 and 22), moderate in three of six
(patients 1820), and severe in one of six (patient 23)

Table 1. Main clinical and genetic findings in our LD series

Patients/
gender

Age at
onset

Years of follow-up
(age at last follow-up)

1/F
2/Fa
3/Fa

13
8.5
12.5

4/M

Score at
4 years

Score at last
follow-up

p.Asp82Arg fsX7
Unknown
p.Gly279Ser
Unknown
p.Arg108Cys p.Ser158X

2
2
3

4
3
5

p.Arg241X p.Gly279Ser

p.Glu67X p.Gly331fsX3

p.Gly158Argfs17 p.Pro69Ala

p.Val221Asnfs2
p.Gly158Argfs17
p.Gly331Glufs3
p.Pro69Ala p.Glu280Lys

4
4
3
4

5
5
4
5

p.Pro69Ala p.Glu280Lys

p.Glu280Lys
p.Gly121Ser p.Glu67X

4
3

5
5

p.Pro69Ala p.Ala277AspfsX23

p.Pro69Ala
p.Phe204LeufsX28
p.Asp146Asn
p.Asp146Asn
p.Asp146Asn
p.Asp146Val
p.Ser339Ilefs13
p.Asp146Val p.Ser339Ilefs13

3
1
2
2
2
1

5
4
2
2
2
1

p.Leu87Pro

Gene

Mutation

Protein (mutation)

8 (21)
9 (17.5)
11 (23.5)

EPM2A
EPM2A
EPM2A

17

11 (28)

EPM2A

5/F

17

23 (40)

EPM2A

6/F

12

10 (22)

NHLRC1

7/Fa

18 (27)

NHLRC1

c.243_246del
c.302-?_c.476+? (del exon2)
c.835G>A
c.302-?_c.476+? (del exon 2)
c.322C>T
c.473C>G
c.721C>T
c.835G>A
c.199G>T
c.992del
c.468-469del
c.205C>G
c.661-692del
c.468-469del
c.992del
c.205C>G
c.838G>A
c.205C>G
c.838G>A
c.838G>A
c.361G>A
c.199G>T
c.205C>G
c.826-829dup
c.205C>G
c.612del
c.436G>A
c.436G>A
c.436G>A
c.437A>T
c.1014_1015insATCT
c.437A>T
c.1014_1015insATCT
c.260T>C

8/Ma
9/Fa
10/F
11/Ma

18.5
16.5
13
13

4 (22.5)
4 (20.5)
5 (18)
8 (21)

NHLRC1
NHLRC1
NHLRC1
NHLRC1

12/Ma

14

8 (22)

NHLRC1

13/Fa
14/M

16
12

9.5 (25.5)
8 (20)

NHLRC1
NHLRC1

15/F

10

5 (15)

NHLRC1

16/F
17/Fa
18/Fa
19/Fa
20/F
21/Mb

12
12
15
13
22
23

9 (21)
15 (27)
25 (40)
29 (42)
20 (42)
19 (42)

NHLRC1
NHLRC1
NHLRC1
NHLRC1
NHLRC1
NHLRC1

22/Fb

22

25 (47)

NHLRC1

23/Fa

13

27 (40)

NHLRC1

Patient included in the series published by Franceschetti et al.

Siblings.

Epilepsia, 55(12):e129e133, 2014

doi: 10.1111/epi.12806

e132
E. Ferlazzo et al.
A

Figure 1.
Cumulative time-dependent
probability of maintaining gait
autonomy in the entire sample (A)
and by clinical forms of LD (B).
Epilepsia ILAE

patients with mild LD. In all 17 patients with typical LD,

cognitive decline varied from moderate to severe.
Patients with mild LD had a significantly later age at
disease onset compared with patients with typical LD
(18.0  4.8 vs. 12.8  4.0 years; p = 0.02). Five of six
patients with mild LD carried either a homozygous or compound heterozygous D146N mutation of the NHLRC1 gene
and walked without support at last follow-up (Table 1,
patient 1822). The remaining mild LD patient carried a
different NHLRC1 mutation (Table 1, patient 23) and lost
her gait autonomy 24 years after disease onset (at age 37).
Finally, patients with typical LD, carrying various EPM2A
or NHLRC1 gene mutations, lost gait ability after 5.9 
2.5 years after disease onset. Survival curves for gait ability, for the whole sample and separately for the two groups,
are shown in Figure 1. At last follow-up, patients with mild
LD showed a significantly lower severity score as compared to patients with typical LD (median 2, range 14 vs.
median 5, range 35; Mann-Whitney U = 4.00,
p < 0.001). Of interest, the severity score at 4 years of disease duration already showed a statistically significant less
severe impairment in patients with mild LD compared with
patients with typical LD (median 2, range 12 vs. median
3, range 14; Mann-Whitney U = 13.1, p = 0.0062).
At last follow-up, all patients were on valproate, associated with one or more drugs (including levetiracetam, zonisamide, lamotrigine, barbiturates and benzodiazepines, in
different combinations).
At the moment of our earliest observation and during the
follow-up, we did not detect obvious differences in the EEG
pattern between patients with mild and patients with typical
LD. At last evaluation, all patients with LD had EEG with
slow background activity and very active spontaneous generalized epileptiform discharges, whereas PPR was present
in 2 of 6 patients with mild LD and in 15 of 17 patients with
typical LD (p = 0.008). Amplitude of SEPs was repeatedly
normal in all patients with mild LD, whereas it was consistently giant in all typical LD patients who underwent SEP
recordings (n = 15; p < 0.0001). MRI showed mild brain
atrophy in 6 of 17 patients with typical LD and in 2 of 5
Epilepsia, 55(12):e129e133, 2014
doi: 10.1111/epi.12806

patients with mild LD (p = 0.74), whereas MRI was normal

in the remaining subjects.
A PTG variant (c.746A>G, N249S) was found in only
one of 6 patients with mild LD (no. 22).
Exemplificative case report of a patient with mild LD
Patient 20: this 42-year-old woman was born at term after
uneventful pregnancy. At age 22 she started presenting rest
and action myoclonus at face and four limbs, at times with
falls. Myoclonus slowly worsened over the years, with moderate interferences in her daily activities. At age 27, during
her second pregnancy, she had two GTCS that never
recurred thereafter. Visual seizures never occurred. Slow
and progressive mental decline was observed from age 32.
In the same epoch she underwent axillar skin biopsy showing Lafora bodies. EEG showed slow background activity
and frequent generalized fast polyspike-wave discharges
during both wakefulness and sleep. No PPR, no giant SEPs,
and no C-reflex were found during the disease course.
Genetic analysis revealed homozygous D146N mutation of
NHLRC1 gene.

Discussion
We herein described clinical, neurophysiologic, and
genetic features of a series of Italian LD subjects and
attempted to disclose distinguishing features of those with
mild LD.
To assess the severity of the phenotype we used a simplified disability scale based on the residual motor and mental
functions. Severity score assessed 4 years after disease
onset was significantly lower in patients with mild LD
compared with patients with typical LD, thus suggesting
that mild LD can be considered a predictor of better prognosis.
Patients with LD usually have a severe seizure phenotype. In our series, patients with mild LD commonly had no
or rare GTCS and no visual seizures, as compared to
patients with typical LD who had frequent focal as well as
generalized seizures.

e133
Mild Lafora Disease
EEG features did not differ between the two groups.
Indeed, in both patients with mild and those with typical
LD, EEG showed marked disorganization of background
activity with very frequent epileptiform abnormalities, as
originally described for the stationary or terminal period of
the disease.7 However, given the retrospective nature of the
study, we were unable to perform a satisfactory quantitative
EEG evaluation. Photosensitivity and giant SEPs were significantly less common in the mild LD group. We can
hypothesize that, in patients with mild LD, sensorimotor
cortex is relatively preserved, in keeping with a better motor
function and gait ability.13
Although brain MRI was not systematically evaluated in
our series, it does not seem to have prognostic relevance,
since it showed mild atrophy in a similar percentage of
patients with typical (35%) and mild (40%) LD.
In our series, various mutations of EPM2A and NHLRC1
genes were found. However, D146N mutation of NHLRC1
gene was found in most (5/6: 83%) of the subjects with mild
LD, whereas it was never identified in patients with typical
LD. This finding is in line with previous reports on individual patients or families,1,10,11 and it should be taken into
account in clinical practice for appropriate management and
counseling. D146N missense mutation lies in the first
NHLRC1 domain and is known to affect ubiquitation of
PTG protein and interaction with laforin.14 However, the
modulating role of PTG variants in conditioning the course
of LD does not seem to be determining, since a significant
variant was found in only one of six of our patients with
mild LD.
Because of clinically atypical features, it cannot be
excluded that some patients with mild LD could escape a
correct diagnosis, since adult patients with mild PME usually do not undergo diagnostic workup for LD, such as skin
biopsy and genetic screening. Therefore, we believe that a
rapid mutation-specific molecular diagnostic test to detect
D146N mutation might be cost-effective and should be considered in the diagnostic workup of slowly progressive
PME, even before invasive and less-sensitive procedures
such as skin biopsy.15

ethical publication and affirm that this report is consistent with those
guidelines.

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Disclosure
None of the authors has any conflict of interest to disclose. We
confirm that we have read the journals position on issues involved in

Epilepsia, 55(12):e129e133, 2014

doi: 10.1111/epi.12806

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