Familial Infantile Myoclonic Epilepsy: Clinical Features in a Large Kindred with Autosomal Recessive Inheritance

Familial Infantile Myoclonic Epilepsy: Clinical Features in aLarge Kindred with Autosomal Recessive Inheritance

*Fabrizio A. de Falco, *Luigi Majello, *Roberto Santangelo, †Mariano Stabile,‡Franca Dagna Bricarelli, and ‡Federico Zara

*Department of Neurological Sciences, Loreto Mare Hospital, and †Medical Genetics Service, A. Cardarelli Hospital, Naples;and ‡Human Genetics Laboratory, Galliera Hospital, Genoa, Italy

Summary: Purpose: To describe the clinical features of alarge kindred with familial infantile myoclonic epilepsy(FIME) with autosomal recessive inheritance, and to discussthe nosology of the early infantile myoclonic epilepsies (IMEs).

Methods: The family descends from the intermarriage of twocouples of siblings. In a previous study, we mapped the geneticlocus to chromosome 16p13.We analyzed results of family re-cords and personal history, psychomotor development, neuro-logic examination, epilepsy features, and EEG recordings foreach subject.

Results: FIME has a strong penetrance (eight affected of 14subjects) and a homogeneous clinical picture. Like the benignform of infantile myoclonic epilepsy (BIME), FIME is a trueidiopathic IME with unremarkable history, no neurologic or

mental impairment, good response to treatment, and normalinterictal EEG pattern. Conversely, onset with generalized epi-leptic seizures without fever (four patients) or with fever (onepatient), frequency and duration of the myoclonic seizures, oc-currence of generalized tonic–clonic seizures (GTCSs) in allpatients and persistence of seizures into adulthood are charac-teristics of the severe infantile myoclonic epilepsy (SIME).

Conclusions: Clinical overlap probably exists among themyoclonic epilepsies of infancy. FIME differs from other formsof IME in its phenotypic features. The peculiar mode of in-heritance is explained by the genetic background of the fami-ly. Genetic studies suggest linkage to chromosome 16 infamilial cases of true IME. Key Words: Myoclonic epilepsy—Infancy—Nosology—Genetics.

The nosologic classification of infancy and earlychildhood epilepsies characterized by myoclonic sei-zures has always been difficult (1–8). Excludingprogressive myoclonic epilepsies and syndromes withpseudomyoclonic seizures (6), such as the West and Len-nox–Gastaut syndromes, true myoclonic epilepsies of in-fancy and childhood are characterized primarily by ageat onset, absence of structural brain damage, lack of neu-rologic signs or symptoms preceding the onset of epilep-tic symptoms, and by the presence of myoclonic seizuresas a characteristic clinical feature. Among the myoclonicepilepsies occurring within the first year of life, the Com-mission on Classification of Epilepsies and EpilepticSyndromes of the International League Against Epilepsy(9) classifies benign infantile myoclonic epilepsy(BIME) (10) among the generalized idiopathic epilepsiesand severe infantile myoclonic epilepsy (SIME) (3) inthe group of the “epilepsies and syndromes undeter-mined whether focal or generalized.” The idiopathic,

symptomatic, or cryptogenic etiology remains undefinedin the latter form. Although both syndromes have distin-guishing features for clinical course, association withother types of epileptic seizures, appearance of psycho-motor retardation or neurologic signs, and response totreatment, they also share such features as age at onset,characteristic myoclonic seizures, presence of febrileconvulsions that are sometimes the first manifestations,and family history of epilepsy or febrile convulsions.

Many forms of idiopathic epilepsies are probably ge-netically determined, although the variability of clinicalphenotypes and the frequent occurrence of a “complex”pattern of inheritance make identification of the geneticdefect difficult. Here we describe a large Italian kindredwith a familial infantile myoclonic epilepsy (FIME) in-herited as an autosomal recessive trait. The clinical fea-tures are benign because they are not associated with anyneurologic or psychomotor deterioration and are easilycontrolled by appropriate treatment. However, myoclon-ic seizures are associated with generalized tonic–clonicseizures (GTCSs) and persist into adulthood. Genetic as-pects are peculiar in this family, because the foundinggrandparents were siblings married to siblings from an-

Accepted September 19, 2001.Address corresponding and reprint requests to Dr. F. A. de Falco at

Via dei Mille, 59, 80121 Napoli, Italy. E-mail: [email protected]

Epilepsia, 42(12):1541–1548, 2001Blackwell Science, Inc.© International League Against Epilepsy

1541

other family. Thus the two branches of offspring share allfour grandparents, although the parents are not consan-guineous. With DNA analysis, we mapped the geneticlocus to chromosome 16p13, and this was reported in aprevious article in 2000 (11). The aim of this study wasto describe the clinical features of this inherited form oftrue myoclonic epilepsy and to discuss its nosologic clas-sification.

PATIENTS AND METHODS

Figure 1 shows the pedigree of the family. Bothbranches descend from nonconsanguineous founders(generation I), but from the same geographic area (theprovince of Napoli, Italy). Two sib pairs who intermar-ried represent the members of the second generation.Therefore, the two branches of offspring cousins (seven+ seven individuals) belonging to the third generationhave nonconsanguineous parents, but share grandparentsand thus have a common genetic descent. In the firstoffspring (III-1 to III-7), comprising three men and fourwomen aged between 24 and 43 years, five are affected(two men, three women). In the second branch of off-spring (III-8 to III-14), composed of six men and onewoman aged between 36 and 47 years, three men areaffected. Three members of generation II (II-1, II-2, andII-4) and 11 from generation III (III-1 to III-7 and III-9to III-12) were given physical examinations and EEGrecordings. Five subjects had a cranial computed tomog-raphy (CT) scan or magnetic resonance imaging (MRI).All subjects in generation II and 11 of 14 from genera-tion III (III-1 to III-7 and III-9 to III-12), seven of whomare affected, agreed to undergo DNA analysis (11). Twosubjects from generation IV (IV-7, IV-22) also weregiven physical examinations, EEGs, and CT scans orMRIs. Because all the subjects were examined duringadulthood, extended clinical histories were taken frompatients and parents. For each subject, we investigatedthe following information: (a) familial and personal his-

tory; (b) psychomotor development; (c) neurologic ex-amination; (d) epilepsy features (onset, type of seizures,pharmacologic treatment, course, and outcome); and (e)neuroradiologic examination. EEG recordings were per-formed on a 16-channel electroencephalograph. Elec-trodes were placed according to the international 10-20system. Intermittent photic stimulation (IPS) was per-formed with trains of ∼8 s at a progressively increasingfrequency, separated by 5-s intervals, with closed andopened eyes, according to our laboratory’s routine prac-tice (12,13). A prolonged IPS also was performed withgreen light. Many subjects had previous EEG recordings,but none had EEG examination performed in childhood.

RESULTS

Clinical findingsIn a previous study, published in the 2000 (11), the

genetic locus was mapped on chromosome 16p13 in acritical region of 3.4-cM, between D16S3024 andD16S423 (Fig. 2). This family may be the first exampleof idiopathic epilepsy inherited as an autosomal reces-sive trait. None of the parents (the two couples of sib-lings from the generation II) developed epilepsy,although the woman II-2 showed minor paroxysmal EEGabnormalities over the temporal regions (Fig. 3). Con-versely, in generation III, the disease penetrance appearsto be high, with eight of 14 subjects affected. Of the 30subjects in generation IV, only two (IV-7 and IV-22) hadepilepsy, but they had no myoclonic seizures.

The affected individuals of generation III had homo-geneous clinical characteristics (Table 1):

• Clinical onset: The symptoms began with afebrilegeneralized epileptic seizures between ages 4 and 7months in subjects III-2, III-3, III-4, and III-5, withfebrile convulsions at age 3 years in III-6 and withmyoclonic seizures between ages 12 and 18 monthsin patients III-8, III-9, and III-10.

FIG. 1. Pedigree of the Italian family with familial infantile myoclonic epilepsy: branches I and II come from the intermarriage of two sibpairs. Solid symbols, affected subjects. Subject IV-7 had idiopathic generalized epilepsy, and subject IV-22 had febrile convulsions ofinfancy. *Neurologic examination; +EEG examination; °DNA analysis.

F. A. DE FALCO ET AL.1542

Epilepsia, Vol. 42, No. 12, 2001

• Clinical features: All affected individuals had nor-mal psychomotor development and had no signs ofcognitive deterioration. The neurologic examinationwas normal in all subjects, and the neuroradiologicinvestigations (cranial CT and/or MRI) carried outon five patients were unremarkable. All were mar-ried with children.

• Febrile convulsions (FCs): These occurred in fiveaffected individuals from the first offspring (III-2 toIII-6), at ages between 5 and 36 months.

• Myoclonic seizures (MSs): Myoclonic seizures ap-peared between ages 5 and 36 months and persisted

to adulthood in all patients. Their clinical featuresare similar in all the affected subjects from bothbranches of offspring and varied with age. In child-hood, MSs were spontaneous and could be erratic,bilateral, or massive. They occurred isolated or inclusters, several times a day, and could last formany hours (sporadic myoclonic status epilepticus),with preserved consciousness. They sometimes pre-ceded a convulsive seizure. During adolescence,MSs occurred several times a week, sometimes last-ing 30 min or longer. These persisted until the ap-pearance of GTCSs, which marked the end of the

FIG. 3. Subject II-2, a 62-year-old nonaffected woman. The EEG examination showed mild and not well-localized paroxysmal abnor-malities, prevailing over posterior and temporal regions.

FIG. 2. Pedigree and chromosome 16p13haplotypes in the examined subjects. Solidsymbols, affected subjects.

FAMILIAL INFANTILE MYOCLONIC EPILEPSY 1543


myoclonic status. During youth, the myoclonic at-tacks more often had a localized pattern. They werespontaneous and facilitated by fatigue or drowsi-ness, or induced by intense and persistent stimula-tion (acoustic stimuli or variations in light intensity)or by repetitive movements. For example, MSscould have onset from the hands while peeling po-tatoes or from the legs after long walks or againfrom the eyes after persistent light stimulus: in par-ticular, patients complained of involuntary rapideyelid and eyeball movements; almost none of thesubjects tolerated intense green and could not take awalk through the woods. One subject reported theonset of myoclonic jerks in the legs culminating ina GTCS after standing up in the back of a truckwhile riding over rough terrain during military ser-vice. The trigger stimuli in our patients were unlikethose of the reflex myoclonic epilepsy of infancydescribed by Ricci et al., in 1995 (14), in which,regardless of the type of stimulus used, surprise ap-peared fundamental in triggering attacks. In alltypes of reflex epilepsy, the unexpected nature ofthe stimulus is the main factor in precipitation (15),whereas in our family, the MS was induced by per-sisting trigger stimuli. All the subjects had learnedto avoid situations triggering myoclonic jerks andrecognized those attacks that preceded a generalizedseizure.

• GTCSs: All affected subjects had GTCSs that werespontaneous or followed a prolonged myoclonic sta-tus, with onset in early infancy in patients III-2 toIII-6 and between 4 and 8 years in patients III-8 toIII-10. GTCSs were more frequent in infancy and inadolescence, but persisted even into adulthood, ex-cept for patient III-4 (his last GTCS was at age 19years). Patient III-6 had repeated GTCSs at deliveryand a true status convulsivus after appendectomy.

• Clinical course and therapy: The symptoms werecharacterized by a high incidence of myoclonic at-tacks between the ages of 4 and 12 years and by

GTCSs between 12 and 16 years. During adulthoodthere was a decline in the number of GTCSs andMSs. Drug treatment has been effective on GTCSsin subjects III-3, III-4, III-5, and III-6, but drugsuspension is followed by new attacks. Patient III-2began treatment with valproate (VPA) in 1997, aftera further GTCS, and achieved total control of sei-zures. In these patients, MSs are reduced but stillpersist with therapy. Three patients are receiving notherapy and still have MSs provoked by repetitivemovements or fatigue and sporadic GTCSs, every 2to 3 years.

Two subjects of generation IV had epilepsy butthey had no MSs. Subject IV-7 (a woman of 20years), had two GTCSs when she was 18 years old.She had no epileptic manifestations during infancyor childhood. The cranial CT scan was normal, butthe MRI revealed a minor finding of nodular peri-ventricular heterotopia. Psychomotor development,neurologic examination, and EEG recordings wereunremarkable, and she had no further episodes aftertreatment with VPA began. Subject IV-22 (a 12-year-old girl) had FCs when she was aged 7 monthsand 3 years. She was given VPA until age 5 years,had no further seizures, and is currently well. Herneurologic examination, EEG, and cranial CT werenormal.

EEG findingsIn generation II, only subject II-2 (a 61-year-old

woman) showed mild paroxysmal abnormalities on theEEG examination (Fig. 3). She was normal, without epi-leptic symptoms. Seven of the eight affected patients ofgeneration III were examined, and many of them hadpreviously performed EEGs. We obtained no ictal EEGrecordings in any of these patients. The interictal exami-nation was normal in subjects III-2, III-4, III-5, and III-6.Patient III-9 showed mild left temporal abnormalitiesthat were not specific for epilepsy. Patients III-3 (a 40-year-old woman, first branch of the pedigree) showed a

TABLE 1. Clinical features of eight patients with familial myoclonic epilepsy of infancy (generation III) and of two patientswith different epileptic syndromes (generation IV)

POS Sex Age (yr) PM DEV FC Clinical onset (age) MS (age) GTCS EEG

III-2 F 44 Normal Yes GTCS apyr (4 mo) Yes (5 mo) Yes NormalIII-3 F 42 Normal Yes GTCS apyr (7 mo) Yes (9 mo) Yes Polyspikes in IPSIII-4 M 40 Normal Yes GTCS apyr (5 mo) Yes (7 mo) Yes NormalIII-5 M 37 Normal Yes GTCS apyr (5 mo) Yes (8 mo) Yes NormalIII-6 F 33 Normal Yes FC (3 yr) Yes (3 yr) Yes NormalIII-8 M 49 Normal No MS (16 mo) Yes (16 mo) Yes NormalIII-9 M 48 Normal No MS (12 mo) Yes (12 mo) Yes Left temporal abnormalitiesIII-10 M 46 Normal No MS (12 mo) Yes (12 mo) Yes Polyspikes in IPS

IV-7 F 20 Normal No GTCS apyr (18 yr) No Yes NormalIV-22 F 12 Normal Yes FC (7 mo) No No Normal

apyr, apyrexia; FC, febrile convulsion; GTCS, generalized tonic–clonic seizures; IPS, intermittent photic stimulation; MS, myoclonic seizures; PMDEV, psychomotor development.



diffuse abnormal background activity, with slow and ir-regular occipital alpha rhythm mixed with diffuse thetaactivity and sporadic isolated bilateral sharp waves overthe occipital regions (Fig. 4a). In this patient, IPS in-duced moderate-voltage irregular spike-and-slow wavecomplexes and paroxysmal bursts of high-voltage poly-spikes more evident over the occipital region (Fig. 4b, c).Patient III-10 (a 44-year-old man, second branch) had anormal background activity, but prolonged IPS first in-duced a normal driving response (Fig. 5a), then a syn-chronous eyelid myoclonias (Fig. 5b), and finally a burstof high-voltage polyspike-and-slow wave complexeswith maximal expression over the occipital regions (Fig.5c): the patient asked to stop the examination because“he felt the seizure coming.” In the EEG laboratory, itwas impossible to precipitate MSs by repetitive move-ments in any patient, also because many of them weretaking antiepileptic drugs (AEDs).

DISCUSSION

The cases of FIME described here show a hereditarypattern of an autosomal recessive mendelian transmis-sion with high penetrance (eight affected of 14 subjects)and remarkably homogeneous clinical expression. Theclinical characteristics of FIME are interesting for dis-cussing the nosology of myoclonic epilepsies of infancy.In the International Classification of ILAE, the benignand the severe forms of myoclonic epilepsy of infancyare grouped separately; the first one among the general-

ized idiopathic epilepsies and the second among the un-determined, whether focal or generalized group.Occurrence of other types of seizures, appearance of psy-chomotor retardation, usually severe, development ofneurological signs and persistence of seizures in adult-hood with resistance to antiepileptic drugs distinguishSIME from BIME. Nevertheless, the two forms shareage at onset, myoclonic seizures as the characteristicclinical expression, presence of febrile convulsions thatare sometimes the initial clinical feature, and a familyhistory of epilepsy or febrile convulsions. In BIME, onemay see the association with mild mental retardation orwith sporadic GTCSs, before or after the onset of MSs,sometimes after discontinuation of treatment (10,16–19).Usually complete control of seizures is never achieved inSIME, although some children classified as SIME weredescribed as achieving good seizure control (20,21). Inhis classification of “myoclonic epilepsies of infancy andchildhood,” Aicardi and Chevrie (1) included BIME andSIME under the same heading as cryptogenic myoclonicepilepsy, among the true myoclonic epilepsies of infancyand early childhood. He considered that “although bothbenign and severe forms of cryptogenic myoclonic epi-lepsy undoubtedly exist, such a sharp distinction is notalways possible and intermediate types between benignand malignant forms are also encountered.” Discussingthe myoclonic epilepsies of infancy, and particularlyBIME and SIME, Lombroso (22) emphasized that thetwo forms cannot be clearly separated on the basis of

FIG. 4. Subject III-3, a 42-year-old affected woman. The EEG examination showed diffuse abnormal background activity, with sporadicisolated bilateral sharp waves over the occipital regions (a). Intermittent photic stimulation induced the appearance of moderate-voltageirregular spike-and-slow wave complexes and paroxysmal bursts of high-voltage polyspikes with maximal expression over the occipitalregions (b, c).



history, genetic background, or clinical-EEG character-istics at the onset. Therefore, he grouped them togetherin a syndrome of early myoclonic epilepsies, termed“infantile myoclonic epilepsy following febrile convul-sions.” Some of Lombroso’s cases had clinical charac-teristics similar to those of ours, like the presence ofprolonged myoclonic attacks (true myoclonic status epi-lepticus), lasting even hours, sometimes preceding aGTCS. This has also been reported by other authors inchildren with the severe form (23,24) and in a “benign”form of myoclonic epilepsy in children, described in1990 by Dulac et al. (25). In his extensive discussion ofmyoclonus and epilepsy in children, Fejerman (7) in-cluded BIME among the true idiopathic myoclonic epi-lepsies and SIME among the cryptogenic epilepsies.From descriptions by previous authors (1,2,26,27), in thelatter group he included a cryptogenetic myoclonic epi-lepsy with clinical aspects that would place it somewherebetween BIME and SIME and could overlap withDoose’s myoclonic–astatic epilepsy (28). This cryptoge-netic myoclonic epilepsy closely resembles the earlychildhood myoclonic epilepsy (ECME), as defined byDelgado-Escueta et al. (29). Fejerman concluded his pro-posal of classification by underlining the difficulty stillpersisting in correctly classifying all the epilepsies withMSs.

The clinical features of FIME place it in the broadspectrum of the myoclonic epilepsies of infancy. FIME isan early infantile true myoclonic epilepsy that sharesmany aspects with BIME. It appears to be a generalized

idiopathic epilepsy of infancy, with negative personalhistory, absence of psychomotor or neurologic impair-ment, and good response to treatment. As in BIME (16),the interictal EEG was normal or had mild abnormalities,but frequently with paroxysmal features on IPS. Con-versely, the onset with afebrile generalized epileptic sei-zures (in four patients) or febrile (in one patient), thepresence of GTCS in all patients, the frequency and du-ration of the MSs, sometimes continuous, particularlypreceding a convulsive seizure, and the persistence ofseizures in adulthood resemble SIME (23), although inFIME, consciousness was always preserved, even inmyoclonic status epilepticus.

The pattern of autosomal recessive inheritance is pe-culiar to FIME and is likely to be explained by the par-ticular descent of affected individuals from siblings inone family intermarrying with siblings from anotherfamily. A high frequency of family history of epilepsyalso was found in the benign and severe myoclonic epi-lepsies (19,20,30–34), such as in the myoclonic crypto-genic epilepsy reported by Fejerman (7) and in earlychildhood myoclonic epilepsy (ECME) (29). One pair ofsiblings (23) and two pairs of twins (35,36) were de-scribed in SIME. Of the 14 cases of myoclonic epilepsyof infancy described by Lombroso (22), including thebenign and severe forms, 57% had a family history ofepilepsy, and among these, there were a couple of twins.These findings support the importance of the geneticfactor in determining such forms of epilepsy. It is knownthat genetic factors play an important role in the etiology

FIG. 5. Subject III-10, a 46-year-old affected man. The EEG examination showed normal background activity with a normal drivingresponse to intermittent photic stimulation (IPS) (a). Prolonged IPS induced synchronous eyelid myoclonias (b) and finally a burst ofhigh-voltage polyspike-and-slow wave complexes over the occipital regions (c).



of generalized idiopathic epilepsies (37–40), and in thelast few years, many chromosomal loci for myoclonicepilepsies have been identified. Among the idiopathicgeneralized myoclonic epilepsies with complex inheri-tance, two loci predisposing to juvenile myoclonic epi-lepsy (JME), in chromosome 6p (41–43) and 15q (44)were described, suggesting that different genetic loci candetermine this epilepsy phenotype. In childhood absenceepilepsy evolving to JME (or JME with absence), a pre-disposing gene may exist on chromosome 1p (45,46).Moreover, Delgado-Escueta et al. (29) hypothesized asingle-locus etiology in 6p for JME and for at least someof the childhood absence seizures, epilepsy with grandmal seizures, and ECME, because they found these dif-ferent phenotypes in members of the same JME family.The gene for benign adult familial myoclonic epilepsy(BAFME) was recently identified on chromosome 8q(47,48), an autosomal dominant myoclonic epilepsy firstdescribed by Inazuki et al. (49) and by Yasuda (50) inJapanese families. Among the myoclonic epilepsies ofinfancy, BIME and SIME have a strong genetic back-ground and could have a complex genetic transmissionor a heterogeneity of loci (45). In SIME, the absence ofetiologic factors, the high rate of family history for epi-lepsy and for FC (51), and the frequent photosensitivityindicate a genetic predisposition (23). Recently it washypothesized that SIME could be included in the broadspectrum of the generalized epilepsy with febrile sei-zures plus (GEFS+) (52,53), a genetic disorder with het-erogeneous clinical phenotypes (54,55). A mutation in�1 (SCN1B) (56) and �1 (SCN1A) (57,58) subunitgenes of neuronal sodium channel have been associatedwith GEFS+ types 1 and 2, respectively, and just re-cently, de novo mutations of SCN1A were identified inseven patients with SIME (59). Both GEFS+ and FIMEinvolve fever-associated seizures, but GEFS+ has an au-tosomal dominant pattern of inheritance and a heteroge-neous phenotypic expression, whereas FIME is recessiveand has homogeneous clinical features.

In conclusion, FIME does not seem to correspondto any already known epilepsy type and could be anisolated syndrome explained by the unique genetic back-ground of the family. Without a more precise under-standing of the etiology, debate about how overlappingclinical forms are classified will continue. It is probablethat in this group, there are genetic and cryptogeneticforms with very similar features. Progress in understand-ing the genetic etiology of epilepsies, the identificationof responsible genes, and the protein products will con-tribute to our understanding of the molecular pathwaysof epileptogenesis and provide neurobiologic criteria forthe classification of epilepsies, beyond the different phe-notypic expression. The clinical and genetic study oflarge families affected by epileptic syndromes with ho-mogeneous phenotypes could lead to identification of

susceptible chromosomal loci and to understanding ofthe neurobiologic basis. Our previous study showed thata gene associated with myoclonic epilepsies of infancy islocated on chromosome 16. The homogeneous pheno-type and the genetic characterization of FIME entail im-portant information on the nosologic classification of thisgroup of diseases and suggest the investigation of chro-mosome 16 in familial cases of true myoclonic epilepsyof infancy.

REFERENCES

1. Aicardi J, Chevrie JJ. Myoclonic epilepsies of childhood. Neuro-paediatrie 1971;3:177–90.

2. Jeavons PM. Nosological problems of myoclonic epilepsies inchildhood and adolescence Dev Med Child Neurol 1977;19:3–8.

3. Dravet C, Roger J, Bureau M, et al. Myoclonic epilepsies in child-hood. In: Akimoto H, Kazamatsuri H, Seino M, et al., eds. Ad-vances in epileptology: XIIIth epilepsy international symposium.New York: Raven Press, 1982:135–40.

4. Lombroso CT, Erba G. Myoclonic seizures: considerations in tax-onomy. In: Akimoto H, Kazamatsuri H, Seino M, et al., eds. Ad-vances in epileptology: XIIIth epilepsy international symposium.New York: Raven Press, 1982:129–34.

5. Roger J, Dravet C, Bureau M, et al., eds. Epileptic syndromes ininfancy, childhood and adolescence. London: John Libbey, 1992.

6. Aicardi J. Myoclonic epilepsies of infancy and childhood. AdvNeurol 1986;43:11–31.

7. Fejerman N. Myoclonies et epilepsies chez l’enfant. Rev Neurol(Paris) 1991;147:78–97.

8. Aicardi J. Myoclonic epilepsies of infancy and early childhood. In:Aicardi J, ed. Epilepsy in children. 2nd ed. New York: RavenPress, 1994:67–79.

9. Commission on Classification and Terminology of the Interna-tional League Against Epilepsy. Proposal for revised classificationof epilepsies and epileptic syndromes. Epilepsia 1989;30:389–99.

10. Dravet C, Bureau M. L’epilepsy myoclonique benigne du nourris-son. Rev Electroencephalogr Clin Neurophysiol 1981;11:438–44.

11. Zara F, Gennaro E, Stabile M, et al. Mapping of a locus for afamilial autosomal recessive idiopathic myoclonic epilepsy of in-fancy to chromosome 16p13. Am J Hum Genet 2000;66:1552–7.

12. Kasteleijn-Nolst Trenite DGA. Photosensitivity in epilepsy: elec-trophysiological and clinical correlates. Acta Neurol Scand 1989;80(suppl 125):1–149.

13. De Falco FA, Roberti R, Florio C, et al. Photoparoxysmal responseon eye closure in photosensitive patients. Acta Neurol 1992;14:290–6.

14. Ricci S, Cusmai R, Fusco L, et al. Reflex myoclonic epilepsy ininfancy: a new age-dependent idiopathic epileptic syndrome re-lated to startle reaction. Epilepsia 1995;36:341–8.

15. Deonna T. Reflex seizures with somatosensory precipitation: clini-cal and electroencephalographic patterns and differential diagno-sis, with emphasis on reflex myoclonic epilepsy of infancy. In:Zifkin BG, Andermann F, Beaumanoir A, et al., eds. Advances inneurology. Vol 75: reflex epilepsies and reflex seizures. 1998;193–206.

16. Dravet C, Bureau M, Genton P. Benign myoclonic epilepsy ofinfancy: electroclinical symptomatology and differential diagnosisfrom the other types of generalized epilepsies of infancy. EpilepsyRes Suppl. 1992;6:131–5.

17. Giovanardi Rossi P, Parmeggiani A, Posar A, et al. Benign myo-clonic epilepsy: long-term follow-up of 11 new cases. Brain Dev1997;19:473–9.

18. Rossi PG, Parmeggiani A, Posar A, et al. Benign myoclonic epi-lepsy: long-term follow-up in 11 new cases. Brain Dev 1997;19:473–9.

19. Lin Y, Itomi K, Takada H, et al. Benign myoclonic epilepsy in



infants: video-EEG features and long-term follow-up. Neuropedi-atrics 1998;29:268–71.

20. Hurst DL. Severe myoclonic epilepsy of infancy. Pediatr Neurol1987;3:269–72.

21. Fernandez-Jaen A, Leon MC, Martinez-Granero MA, et al. Diag-nosis in severe myoclonic epilepsy in childhood: study of 13 cases.Rev Neurol 1998;26:759–62.

22. Lombroso CT. Early myoclonic encephalopathy, early infantileepileptic encephalopathy, and benign and severe infantile myo-clonic epilepsies: a critical review and personal contribution. J ClinNeurophysiol 1990;7:380–408.

23. Dravet C, Bureau M, Roger J. Severe myoclonic epilepsy in in-fants. In: Roger J, Dravet C, Bureau M, et al., eds. Epileptic syn-dromes in infancy, childhood and adolescence. London: JohnLibbey, 1985:7, 58–67.

24. Yakoub M, Doulac O, Jambaque I, et al. Early diagnosis of severemyoclonic epilepsy in infancy. Brain Dev 1992;14:299–303.

25. Dulac O, Plouin P, Chiron C. “Benign” form of myoclonic epi-lepsy in children. Neurophysiol Clin 1990;20:115–29.

26. Loiseau P, Legroux M, Grimond P, et al. Taxometric classificationof myoclonic epilepsies. Epilepsia 1974;15:1–11.

27. Dalla Bernardina B, Capovilla G, Chiamenti C, Trevisan E, Cola-maria V, Fontana E. Cryptogenic myoclonic epilepsies of infancyand early childhood: nosological and prognostic approach. In:Wolf P, Dam M, Janz D, et al., eds. Advances in epileptology. NewYork: Raven Press, 1987;16:175–9.

28. Doose H. L’epilepsie myoclono-astatique du jeune enfant. In:Roger J, Dravet C, Bureau M, et al., eds. Les syndromes epilep-tiques de l’enfant et de l’adolescent. London : John Libbey Euro-text, 1984:77–8.

29. Delgado-Escueta AV, Greenberg D, Weissbecker K, et al. Genemapping in the idiopathic generalized epilepsies: juvenile myo-clonic epilepsy, childhood absence epilepsy, epilepsy with grandmal seizures, and early childhood myoclonic epilepsy. Epilepsia1990;31:S19–29.

30. Dalla Bernardina B, Capovilla G, Gattoni MB, et al. Epilepsiemyoclonique grave de la premiere anne. Rev ElectroencephalogrNeurophysiol Clin 1982;12:21–5.

31. Dulac O, Arthuis M. L’epilepsie myoclonique severe de l’enfant.In: Journees Parisiennes de pediatrie. 1982;1:259–68.

32. Dalla Bernardina B, Colamaria V, Capovilla G, et al. Nosologicalclassification of epilepsies in the first three years of life. In: NisticòG, Di Perri R, Meinardi H, eds. Epilepsy: an update on researchand therapy. New York: Alan Liss, 1983:165–83.

33. Dravet C, Bureau M, Guerrini R, et al. Severe myoclonic epilepsyin infancy. In: Roger J, Bureau M, Dravet C, et al., eds. Epilepticsyndromes in infancy, childhood and adolescence. 2nd ed. London:John Libbey, 1992:75–88.

34. Nieto-Barrera M, Lillo MM, Rodriguez-Collado C, et al. Severemyoclonic epilepsy in childhood: epidemiologic analytical study.Rev Neurol 2000;30:620–4.

35. Fugjiwara T, Nakamura H, Watenabe M, et al. Clinicoelectro-graphic concordance between monozygotic twins with severe myo-clonic epilepsy in infancy. Epilepsia 1990;31:281–6.

36. Ohki T, Watanabe K, Negoro T, et al. Severe myoclonic epilepsyin infancy: evolution of seizures. Seizure 1997;6:219–24.

37. Delgado-Escueta AV, Serratosa JM, Liu A, et al. Progress in map-ping human epilepsy genes. Epilepsia 1994;35(suppl 1);S29–40.

38. Sander T. The genetics of idiopathic generalized epilepsy: impli-cations for the understanding of its aetiology. Mol Med Today1996;2:173–80.

39. Gardiner RM. Impact of our understanding of the genetic aetiologyof epilepsy. J Neurol 2000;247:327–34.

40. Sander T, Schulz H, Saar K, et al. Genome search for susceptibilityloci of common idiopathic generalized epilepsies. Hum Mol Genet2000;9:1465–72.

41. Greenberg DA, Delgado-Escueta AV, Widelitz H, et al. Juvenilemyoclonic epilepsy (JME) may be linked to the BF and HLA locion human chromosome 6. Am J Med Genet 1988;31:185–92.

42. Weissbecker KA, Durner M, Janz D, et al. Confirmation of linkagebetween juvenile myoclonic epilepsy locus and the HLA region onchr 6. Am J Med Genet 1991;38:32–6.

43. Liu AW, Delgado-Escueta AV, Serratosa JM, et al. Juvenile myo-clonic epilepsy in chromosome 6p12-p11: locus heterogeneity andrecombinations. Am J Med Genet 1995;63:1–9.

44. Elmslie FV, Rees M, Williamson MP, et al. Genetic mapping of amajor susceptibility locus for juvenile myoclonic epilepsy on chro-mosome 15q. Hum Mol Genet 1997;6:1329–34.

45. Minassian BA, Sainz J, Delgado-Escueta AV. Genetics of myo-clonic and myoclonus epilepsies. Clin Neurosci 1996;3:223–35.

46. Westling B, Weissbecker KA, Serratosa JM, et al. Evidence forlinkage of juvenile myoclonic epilepsy with absence to chromo-some 1p. Am J Hum Genet 1996;59(suppl):A241.

47. Mikami M, Yasuda T, Terao A, et al. Localization of a gene forbenign adult familial myoclonic epilepsy to chromosome 8q23.3-24.1. Am J Hum Genet 1999;65:745–51.

48. Plaster NM, Uyama E, Uchino M, et al. Genetic localization of thefamilial adult myoclonic epilepsy (FAME) gene to chromosome8q24. Neurology 1999;53:1180–3.

49. Inazuki G, Naito H, Ohama E, et al. A clinical study and neuro-pathological findings of a familial disease with myoclonus andepilepsy: the nosological place of familial essential myoclonus andepilepsy (FEME). Seishin Shinkeigaku Zasshi 1990;92:1–21.

50. Yasuda T. Benign adult familial myoclonic epilepsy (BAFME).Kawasaki Med J 1991;17:1–13.

51. Benlounis A, Nabbout R, Feingold J, et al. Genetic predispositionto severe myoclonic epilepsy of infancy. Epilepsia. 2001;42:204–9.

52. Viggiotti P, Cardinali S, Montalenti E, et al. Generalized epilepsywith febrile seizures plus and severe myoclonic epilepsy in in-fancy: a case report of two Italian families. Epileptic Disord 2001;3:29–32.

53. Singh R, Andermann E, Whitehouse WP, et al. Severe myoclonicepilepsy of infancy: extended spectrum of GEFS+? Epilepsia2001;42:837–44.

54. Scheffer IE, Berkovic SF. Generalized epilepsy with febrile sei-zures plus: a genetic disorder with heterogeneous clinical pheno-types. Brain 1997;120:479–90.

55. Singh R, Scheffer IE, Crossland K, et al. Generalized epilepsy withfebrile seizures plus: a common childhood-onset genetic epilepsysyndrome. Ann Neurol 1999;45:75–81.

56. Wallace RH, Wang DW, Singh R, et al. Febrile seizures and gen-eralized epilepsy associated with a mutation in the Na+-channelbeta 1 subunit gene SCN1B. Nat Genet 1998;19:366–70.

57. Escayg A, MacDonald BT, Meisler MH, et al. Mutation ofSCN1A, encoding a neuronal sodium channel, in two families withGEFS+2. Nat Genet 2000;24:343–5.

58. Escayg A, Heils A, MacDonald BT, et al. A novel SCN1A muta-tion associated with generalized epilepsy with febrile seizures plusand prevalence of variants in patients with epilepsy. Am J HumGenet 2001;68:866–73.

59. Claes L, Del-Favero J, Ceulemans B, et al. Mutations in thesodium-channel gene SCN1A cause severe myoclonic epilepsy ofinfancy. Am J Hum Genet 2001;68:1327–32.



Documents

Familial Infantile Myoclonic Epilepsy: Clinical Features in a Large Kindred with Autosomal Recessive Inheritance