Clinical Genetics 199 I : 40: 467-470 Short Communication

An autosomal familial

recessive form of benign neonatal seizures

RAPHAEL SCHIFFMANN', YEHUDA SHAPIRA' AND STEPHEN G. RYAS\" 'Pediatric Neurology Unit, Department of Pediatrics, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel and 'Section of Neurology, Department of Pediatrics, University of Texas Health

Science Center, San Antonio, Texas

We present a consanguineous sibship with benign familial neonatal seizures. The mode of transmission of the disorder in this family seems to be autosomal recessive, which is contrary to the usual autosomal dominant type. Linkage analysis failed to show tight linkage between the disease locus and the autosomal dominant locus assigned to chromosome ZOq. We thus conclude that benign familial neonatal seizures is a genetically heterogeneous type of epilepsy.

Received 16 JUIJ 1990, revised 23 MUJ accepted for publication 7 June 1991

Key words: autosomal recessive; benign; epilepsy; familial convulsions; neonatal seizures

Benign familial neonatal seizures (BFNS) is a distinct type of epilepsy (McKusick 1988 No- I2 120). It is characterized clinically by onset of generalized convulsions within the first few days of life. The seizures frequently recur during subsequent weeks and resolve by I year of age (Shevell et al. 1986). The infants are always normal except for oc- casional but transient hypertonia. No meta- bolic abnormality has been found to cause this disorder (Zonana et al. 1984). About 15% of patients are said to develop epilepsy as adults. The only mode of transmission described thus far is autosomal dominant with a high degree of penetrance (McKusick 1988). Recently, this trait was linked to gen- etic markers on chromosome 20 (Leppert et al. 1989).

Clinical History

We identified a sibship of Iranian Jews with BFNS. There were four affected children in the same generation (Fig. 1). There was no

history of neonatal seizures in any member of the extended family; the paternal grand- parents were personally interviewed by one of the authors (R.S.), and they denied any kind of seizures in their two sons (individ- uals 111-2 and 111-3 - Fig. 1).

All four infants were born after normal pregnancy and delivery, and manifested generalized tonic clonic seizures between 6 and 36 h of age. These seizures did not respond to pyridoxin and responded poorly to phenobarbital. Neurological examination uniformly showed only marked hypertonia. Both the seizures and the hypertonia re- solved by 4 months of age. All children remained seizure-free (on a follow-up of 18 months to 16 years) with normal motor and cognitive development. Interictal EEG was normal in all but one infant who had gen- eralized 3Hz spike and wave discharges on one occasion with subsequent normal EEGs. During the neonatal period, serum electrolytes, glucose, ammonia, lactate, ami- no acid as well as urine organic acid analysis

468 S C H I F F M A N N E T A L .

I %-

I I r

Fig. 1. Pedigree of family. Symbols: Neonatal seizures

I First-cousin marriage

were normal in all four patients, as was routine cerebrospinal fluid (CSF) analysis. Glycine level in CSF was normal in one patient. All four patients had normal cranial CT scans.

Linkage Analysis

Methods Genomic DNA was prepared by phenol/ chloroform extraction of lysed peripheral blood lymphocytes. The samples were di- gested with the restriction enzyme TaqI (New England Biolabs, Beverly, Massachu- setts) and the resulting fragments were size- fractionated by 0.7% agarose gel electro- phoresis and transferred by capillary action to nylon membranes (Hybond N +, Amer- sham, Arlington Heights, Illinois) according to protocols supplied by the manufacturer. Hybridization with the radiolabelled (Fein- berg & Vogelstein 1984) markers D20S19 and D20S20 (purchased from the American Type Culture Collection, Camden, N. J.) and subsequent stringency washes were per- formed as described by Budowle & Baechtel (1990). Autoradiograms of the membranes were then prepared and marker genotypes assigned to each individual.

Two-point linkage analysis was per- formed with the program LIPED (Ott 1985)

on an IBM-AT compatible personal com- puter (multipoint analysis was unnecessary because the marker D20S20 was uninforma- tive). Linkage analysis was performed separ- ately for autosomal recessive and autosomal dominant modes of inheritance. Penetrance for the latter model was assumed to be 90% (Leppert et al. 1989).

Results

Only the marker D20S19 was informative in this pedigree. Lod scores for autosomal recessive and dominant modes of inherit- ance are given in Table 1.

Discussion

The four patients described here have an epileptic syndrome phenotypically very similar to the already well-described auto- soma1 dominant BFNS. In the families pre- viously described, this disorder manifested itself in nearly every generation. Zonana et al. (1984), in reviewing the literature, could find only one possible case of non-pen- etrance among 116 affected individuals be- longing to 16 families. That patient had fe- brile seizures as an infant (Petit & Fenichel 1980). In order to postulate an autosomal dominant mode of transmission of the dis-

Table 1

Disease locus vs. locus D20S19

Lod score Sex-averaged recombination Autosomal Autosomal fraction recessive dominant

0.5000 0.4000 0.3000 0.2000 0.1500 0.1000 0.0500 0.0010 0.0000

O.Oo0 - 0.065 - 0.298 - 0.821 - 1.281 -2.008 - 3.371

-11.649 cc -

O.Oo0 - 0.064 - 0.272 - 0.690 - 1.031 - 1.540 - 2.428 - 8.541

cc -

A U T O S O M A L R E C E S S I V E F A M I L I A L E P I L E P S Y 469

order in this family, one would have to as- sume non-penetrance of the BFNS gene in all four subjects of generation 111 (Fig. I). Although a theoretical possibility, this is un- likely. The prevalence of abnormal EEG in our symptomatic patients with BFNS is very low and therefore cannot be used to identify asymptomatic carriers of the non- penetrance gene.

The high degree of consanguinity and the absence of neonatal seizures in previous generations in this sibship make an auto- somal recessive mode of transmission of this type of BFNS most likely.

The results of the linkage analysis under both autosomal dominant and autosomal recessive models militate against tight link- age between the disease locus and BFNS locus assigned to chromosome 20q by Lep- pert et al. For example, with dominant in- heritance at 10% recombination, the lod score of - I .540 corresponds to a 36: I odds ratio favoring non-linkage over linkage be- tween the disease and marker loci. Although it apppears unlikely that a mutation very close to the marker locus is responsible for the disease phenotype in our pedigree, somewhat looser linkage (> 10% recombi- nation for recessive and >7”h recombi- nation for dominant inheritance) cannot be reliably excluded.

Ryan et al. (1990) have demonstrated the existence of an autosomal dominant BFNS locus distinct from the one assigned to chro- mosome 20q by Leppert by detecting signifi- cantly negative lod scores for D2OS19 and D20S20 versus the disease locus in a large pedigree from San Antonio. Because the chromosomal location of this BFNS variant has not yet been determined, it is not poss- ible to assess by linkage analysis its rel- evance to the pedigree described herein.

The presence of a transient metabolic ab- normality causing neonatal seizures in these patients must also be considered. Transient hypoglycemia, hypocalcemia, hypomagne-

semia. hypo- or hypernatremia, hyperam- monemia as well as narcotic withdrawal can each cause transient neonatal seizures (Vol- pe 1987).

Recently, transient nonketotic hypergly- cinemia was added to that list (Schiffmann et al. 1989). Our investigation did not reveal any such abnormality.

In conclusion, it seems that BFNS is a genetically heterogeneous type of epilepsy. In addition to the more common autosomal dominant form, we presented a rarer auto- somal recessive form.

Note Added in Proof

Subject IV-I recently developed, at age 9 years, brief complex partial seizures that re- sponded well to Carbamazepine. She other- wise continues to do well.

Acknowledgment

We wish to thank Sara Berger for her sec- retarial assistance.

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