Neurology India, Vol. 55, No. 1, January-March, 2007, pp. 57-60
A new autosomal recessive disorder of bilateral frontotemporal pachygyria without microcephaly: Report of a case and review of literature
Phadke ShubhaR, Girisha KM, Phadke RajendraV
Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014
Date of Acceptance: 14-Aug-2006
Code Number: ni07016
Pachygyria is a disorder of neuronal migration. We report an Indian family with four siblings with developmental delay, infrequent seizures, normal head size and mild to moderate mental retardation. Two of them had bilaterally symmetrical frontotemporal pachygyria. Dysmorphism and neurological signs were absent in the affected subjects. Affected male and female siblings with normal parents suggests autosomal recessive mode of inheritance. We believe these cases represent a new autosomal recessive disorder of neuronal migration. Other similar cases of lissencephaly are reviewed.
Keywords: Developmental delay, magnetic resonance imaging, mental retardation, microcephaly, pachygyria
Malformations due to abnormality of neuronal migration include the spectrum of lissencephaly. In general, the disorders of neuronal migrations are known to be associated with developmental delay, mental retardation of severe degree, microcephaly and intractable seizures.
In this report, we describe four siblings with developmental delay, mild mental retardation and normal head circumference without facial dysmorphism and focal neurological signs. Bilateral frontotemporal pachygyria was documented in two of them. These features make the family represent a distinct disorder of neuronal migration hitherto unreported in the literature. We review the cases that share a few common features.
The family was referred to the genetic clinic for evaluation of developmental delay. The Brahmin family from Uttar Pradesh of India had no previous mentally retarded individuals. The parents had a nonconsanguineous marriage and had all the four children affected with global developmental delay [Figure - 1].
The proband (II-2) was born following an uneventful pregnancy and delivery. Birth weight was 3.5 kg. Neonatal course was uneventful. Milestones recollected by parents were: Social smile at two to three months, head holding at three to four months, rolling over at nine to ten months, sitting without support at three years and walking by three to three and a half years. At the age of five years, when she presented to our clinic she had not attained bowel and bladder control. She had speech delay with ability to use only bisyllables. She was able to comprehend her parents' communication. Parents admitted that she was gradually acquiring newer skills. In the seventh month of life, she had two episodes of generalized tonic clonic convulsions that did not recur. On physical examination, her height at five years of age was 105 cm (25th percentile); head circumference was 48.5 cm (mean = 50.5 cm; -2SD = 48 cm). There was no dysmorphism. Muscle tone, power and deep tendon reflexes were normal. She did not have any abnormal neurological signs. Hearing and vision were normal. No other malformations were seen. There were no cerebellar signs and abnormal primitive reflexes. Formal assessment of intelligence could not be made as the girl was inattentive and mildly hyperactive. Her G-banded karyotype was normal. Magnetic resonance imaging of brain showed generalized pachygyria [Figure - 2],[Figure - 3],[Figure - 4]. The gyral pattern of the frontal and temporal lobes consisted of a few broad gyri. Gray matter thickness was in the range of 6 mm to 9 mm. Parietal and occipital regions were much less involved. Corpus callosum was well formed. There was no evidence of gray matter heterotopia. Posterior fossa structures were normal. Ventricles were also normal. Fifteen months later she was evaluated again. At that point of time, she had attained bowel and bladder control. Her speech had improved and she had a vocabulary of five to six common words. She did not have seizures in the intervening period.
Clinical details of other siblings were also noted. II-1 also had global developmental delay. She had started walking at two years of age. She had attained control over her bowel and bladder. At seven and a half years she was able to recognize English alphabets, but was not able to write. She spoke sentences of three to four words with meaning. Seguin form board test showed mild retardation in development (score of 60%). She had six to seven episodes of generalized tonic clonic seizures starting at nine months of age. There was good response to antiepileptic drug. Her electroencephalogram did not show any abnormalities. Her examination revealed normal head circumference (50 cm, 50th percentile) and absence of dysmorphism or neurological signs. Her magnetic resonance imaging also showed findings similar to those of II-2 [Figure - 5]. She also had pachygyria mainly involving the frontal and temporal lobes without heterotopia. Corpus callosum and cerebellum were normal.
II-3 had one episode of seizure at 18 months of age. She had started walking at an earlier age (18 months) compared to her siblings. On evaluation at three and a half years of age she had mild but definite delay in development. Her head circumference was also normal for her age (49 cm, 50th percentile).
II-4 was born of an uneventful pregnancy and delivery. At the age of 13 months, he was sitting with support. He was approaching and transferring objects with hands. But he was unable to sit without support. He had just started babbling. He had a generalized tonic clonic seizure associated with fever at the age of nine months. His head circumference was 47 cm (50th percentile) and length was 78 cm (50th percentile). There were no focal neurological signs. During the follow-up 15 months later, he had started to stand with support and say bisyllables. There was mild to moderate developmental delay. Neuroimaging of II-3 and II-4 were not done in view of financial constraints.
The family described here has a disorder of neuronal migration with normal head circumference. Though there was no consanguinity, affection of four siblings of either sex with unaffected parents strongly supports the autosomal recessive pattern of inheritance.
All the children had mild to moderate developmental delay. None had dysmorphism. Neurological examination was unremarkable. Other organ systems were not involved. Though magnetic resonance imaging is available only in two children, the clinical history, physical findings are suggestive of existence of the same disorder in all the offspring of the couple. Magnetic resonance imaging (MRI) done in two of the cases showed pachygyria predominantly involving the frontotemporal regions and normal cerebellar hemispheres.
Barkovich et al have classified abnormalities of neuronal migration into three groups, namely lissencephaly/subcortical band heterotopia spectrum, Cobble-stone ® cobblestone complex and other heterotopias. The first group of lissencephaly/subcortical band heterotopia spectrum has classical lissencephaly which was conspicuously absent in the present family. The other types of lissencephalies are associated with agenesis of corpus callosum or cerebellar hypoplasia. Both these findings were not seen in the magnetic resonance imaging of the two cases of the family in this case report. Cobblestone lissencephaly is associated with eye and muscle disorders or may exist as an isolated anomaly. Absence of cobblestone appearance in the MRI of these cases rules out the possibility of this variety of neuronal migration anomaly in these cases.
Some genes for central nervous system malformations are known and have been included in the classification of central nervous system malformations by Sarnat and Sarnat. The genes causing lissencephaly include autosomal genes like LIS1, fukutin, RELN, DAB1 and X-linked genes, namely L1-NCAM and doublecortin. The clinical features of disorders caused by L1-NCAM and doublecortin are distinct from the present cases. X-linked mode of inheritance is unlikely in the present family due to involvement of males and females with similar severity. The distribution of pachygyria in our subjects is distinct from these entities.
The cases reported by Ramirez et al have normal head size and predominant frontotemporal pachygyria similar to our cases. But these cases differ from our subjects by the presence of telecanthus, esotropia, hypertelorism and slightly decreased neuromuscular tone and deep tendon reflexes. In addition to Ramirez et al , Hong et al and Kuzniecky have reported cases of lissencephaly with normal head circumference., These cases are compared in [Table - 1]. All these cases had mental subnormality of variable severity and most of the cases had seizures. Cases described by Hong et al are caused by mutations in the RELN gene and are characterized by cerebellar hypoplasia and cerebellar signs. Cases reported by Kuzniecky have pachygyria predominantly involving the parietal region. None of these cases had aplasia of corpus callosum. All these cases and our cases show family history consistent with autosomal recessive mode of inheritance. The pachygyria predominantly involving some lobes of the cerebrum in these cases with normal head circumference is characteristic. Kurul et al have described magnetic resonance imaging findings of cases with localized pachygyria. Five of their cases had bilateral fronto-temporo-parietal agyria-pachygyria and six cases had bilateral frontoparietal agyria-pachygyria. The clinical features of individual subjects have not been described. It will be interesting to separately look into the clinical details of these cases.
At the clinical level, the phenotype of the cases in the present report appears to be different from the previously reported cases of pachygyria without microcephaly and this may represent a new entity. Our cases and the previously reported cases of pachygyria with normal head circumference appear to be a distinct entity and need to be added to the classification of the lissencephaly/pachygyria spectrum. Sub-grouping of this group of pachygyria with normocephaly depending on the predominant lobe of involvement and associated neurological and nonneurological features may need to await further reports of similar cases.
Copyright 2007 - Neurology India
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