CLINICAL GENETICS ISSN 0009-9163

A new autosomal recessive syndrome of 4 . pachygyria

Straussberg R, Gross S, Amir J, Gadoth N. A new autosomal recessive syndrome of pachygyria. Clin Genet 1996: 50: 498-501. 0 Munksgaard, 1996

Pachygyria is a rare development disorder resulting from impaired neur- onal migration. Usually, it is a sporadic phenomenon, but rare dominant or autosomal recessive syndromes are known. This report describes a fam- ily in which the parents are first cousins and three of the siblings suffer from moderate mental retardation, pachygyria and strabismus. It is sug- gested that this is a distinct type of autosomal recessive pachygyria.

The lissencephaly-pachygyria complex is one of the neuronal migration disorders. While Iissence- phaly (agyria) refers to total absence of cortical sulci (Barkovich et al. 1991), pachygyria refers to a less pronounced abnormality with a few broad, flat gyri separated by shallow sulci. Usually, type I lissencephaly occurs sporadically and is then referred to as Isolated Lissencephaly Sequence (ILS) (Dobyns et al. 1984, Rijk-van Andel et al. 1990, Aicardi 1992, Dobyns et al. 1992). Two main syndromes with type I lissencephaly are designated Miller-Dieker and Norman-Roberts syndromes (Dobyns et al. 1984). Miller-Dieker syndrome is always inherited and is due to chro- mosomal deletion or heterezygous mutation (Do- byns et al. 1991). The Norman-Roberts syn- drome is autosomal recessive (Dobyns et al. 1984). Both are associated with microcephaly, characteristic dysmorphic features and severe mental retardation.

In the present report we describe three siblings with pachygyria, strabismus and moderate men- tal retardation, but without dysmorphic features. This form of familial pachygyria may represent a new autosomal recessive syndrome.

R. Straumberg’, S. Gross‘, J. A m i f and N. Gadothj ‘Child Developmental Center, %hild Day Care Center, Hasharon Hospital - Gold Medical Center, 3Department of Neurology, Beilinson Medical Center, Petah-Tiqva, and the Sackler School of Medicine, Tel-Aviv University, Israel

Key words: autosomal recessive - lissencephaly - pachygyria

Dr R.Straussberg, Department of Pediatrics C, Schneider Children’s Medical Center Israel. Petah-Tiqva, Israel. Tel: 972-3-939-3700.

Received in revised version 27 July, accepted for publication 7 August 1996

Fa: 972-3-939-3801

Case reports

The patients are three siblings born to Israeli- Arab parents who are first cousins. A 10-year- old sister is healthy. The propositus (Patient B, Fig. 1) is an 8-year-old girl born after an un- eventful pregnancy and delivery who was being followed up because of gross psychomotor delay. Currently, she is functioning in the range of moderate mental retardation. Neurological examination showed left esotropia, increased muscle tone, brisk deep tendon reflexes with sus- tained ankle clonus and bilateral upturned toes. Mild truncal ataxia and finger dysmetria were present. At the age of 5 , the patient experienced a few generalized tonic-clonic and absence seiz- ures which subsequently became more frequent and refractory to drug administration.

Patient C (Fig. 1). a 3-year-old sister of the pro- positus, was born after an uneventful pregnancy and delivery. She was brought to the Child Devel- opment Center because of gross development delay in both motor and cognitive functions. The patient was unable to talk except for the word “mamma”, was not toilet trained and walked clumsily with a

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Autosomal recessive syndrome of pachygyria

Table 1. Clinical and laboratory data of the patients

Patient 1 Patient 2 Patient 3

Mental retardation Epilepsy Febrile convulsions Head circumference Esotropia Dysmorphic features Pyramidal signs Cerebellar signs Eye fundus examination CK level Karyotype EEG

Moderate Yes No

Normal Yes No Yes Yes

Normal Normal Normal

Abnormal

Moderate No Yes

Normal Yes No Yes Yes

Normal Normal Normal

Abnormal

Moderate No Yes

Normal Yes No Yes Yes

Normal Normal Normal

Abnormal

wide-based gait, holding her mother’s hand. The girl had esotropia, pyramidal and cerebellar in- volvement similar to that observed in her sister. In the past, when she was 2 years old, she experienced a single febrile convulsion.

Patient D (Fig. l ) , a 1.5-year-old brother of pa- tients B and C, was also brought to the Child De-

Fig. 1. The four siblings. Note the healthy child in the left up- permost picture, while those affected have convergent stra- bismus.

velopmental Center because of marked develop- mental delay. At that age he could not talk at all and did not have any elemental jargon. He crawled on all fours and rolled over from prone to supine position. At the age of 11 months he experienced a single febrile convulsion. On physical examin- ation, his muscle tone was increased, he had brisk (4+) deep tendon reflexes and sustained ankle clo- nus. The boy had esotropia similar to that of his elder sisters.

Extensive clinical and laboratory examinations carried out on all three siblings failed to disclose any abnormalities characteristic of the common CNS-degenerative diseases of childhood. The karyotypes were normal. Specifically, serum CK levels were normal and a complete and meticulous eye fundus examination showed normal results for all siblings (Table 1). The EEG tracings of the pa- tients were similar and showed well-formed sym- metrical sleep spindles. However, pseudoperiodic bilateral synchronous slow- and sharp-wave reg- ular discharges were seen every 5-10 s, increasing during early sleep. This pattern was more promi- nent in the older girl.

The radiological findings were similar in all three siblings. Brain CT disclosed typical pachygyria. Axial and coronal MRI images using T1-weighted (TR: 600 ms/TE: 27 ms) and/or T2-weighted (TR: 3000 ms/TE 27-30 ms) images disclosed pachygyr- ia, more prominent in the frontal area. The main findings were a broad and thick “rolling” cortical surface with shallow sulci and a Sylvian fissure. The ventricular system was somewhat enlarged (Fig. 2A, 2B).

Abnormally high intensity signals on Tz- weighted images from the periventricular region indicated areas of prominent dysmyelination (Fig. 2C). The chanzes were identical in all patients re- gardless of the variability in neurological impair- ment or the presence of epilepsy. “Band hetero- topia” was not seen.

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Discussion

This family seems to be affected by a new auto- soma1 recessive disorder. The three children de- scribed have a normal mental pre- and perinatal history. However, they show a significant delay in developmental milestones during the first year of life, without arrested head growth and without dysmorphic features. Left esotropia is present in all three. They show pyramidal and cerebellar im-

Fig. 2. A. Sagittal spin echo (TR-600rTE-27) image shows a broad thick cortical surface with shallow sulci especially an- terior to the Sylvian fissure. B. Axial spin echo (TRdOO/TE- 27) image shows that the cortex is pachygyric in the frontal lobes and less so in the occipital region. C. Axial spin echo (TR-3000rTE-90) image. Areas of prolonged T2 relaxation are seen in the region of the external capsules, compatible with dysmyelination (arrow).

pairment together with moderate mental retar- dation. Although intractable epilepsy was present in one patient only, the pseudoperiodic EEG re- corded from the other siblings without convulsions may predict the appearance of epilepsy in the fu- ture. The neuroradiological features in all three pa- tients are identical and compatible with pachygyria according to Barkovich et al. (1991).

Usually, pachygyria is a sporadic phenomenon. Familial pachygyria is present in association with

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and those reported by Aicardi (1991) and Kuz- niecky (1994). is segregating as an autosomal re- cessive syndrome.

Zellweger syndrome (Volpe & Adams 1972), cer- tain types of congenital nephrosis (Robain & De- onna 1983) and sudanophilic leukodystrophy (Norman et al. 1962). Recently, two brothers who both suffered from mental retardation, atypical ab- sence, atonic and generalized tonic-clonic seizures, were described (Kuzniecky 1994). MRI was char- acterized as diffuse cortical dysplasia that prob- ably represents pachygyria primarily over the par- ietal regions bilaterally in both patients. Two brothers with pachygyria-lissencephaly, agenesis of corpus callosum and microcephaly were described by Bhatt et al. (1994). A family with three small siblings with pachygyria, cerebellar hypoplasia and congenital lymphedema was also reported (Hourihane et al. 1993). Our syndrome should be differentiated from muscle-eye-brain disease (San- tavuori et al. 1989) because of normal CK levels and normal ophthalmologic examinations, al- though strikingly bright areas of white matter were seen in MRI in both syndromes (Fig. 2C). Re- cently, Ferrie et al. (1995) described brothers of Greek origin from a small village, who were fol- lowed up because of global developmental retar- dation, particularly in the cognitive and language functions. There were no dysmorphic features, and strabismus was noted in the older brother. Intrac- table seizures were noted in both of them during the second year of life. EEG and video-EEG showed diffuse, slow backgrounds with bursts of fast and slow activity. MRI examination was com- patible with agyria-pachygyria of the posterior portion of the brain with an area of polymicrogyr- ia in the parietal cortex.

Some MRI cases of agyria-pachygyria may be reclassified as internal polymicrogyria, if the path- ological information is known (Ferrie et al. 1995). In our patients the subtle, uneven appearance of the surface and the white matter abnormalities (Fig. 2C) give rise to the possibility that the path- ological abnormality is in fact polymicrogyria. Thus, when agyria-pachygyria is inherited together with polymicrogyria they may have been caused by the same genetic defect. Aicardi reported a boy and a girl, the product of a consanguineous mar- riage, in whom diffuse pachygyria, EEG abnor- malities and moderate mental retardation were present, but without dysmorphic features (Aicardi 1989, Aicardi 1991). The description of these children resembles that of our patients. However, esotropia was not mentioned. It seems that pachy- gyria without dysmorphic features, as in our cases

Acknowledgements

We wish to thank Dr. Goren from the Department of Radi- ology, Beilinson Medical Center, for his assistance in inter- preting the X-ray and MRI findings.

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