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In 2018, Dobyns et al reported de novo MACF1 variants in eight children with a complex brain malformation[1]: diffuse pachygyria with more severe posterior involvement; flat ventral brainstem with - incosistently - a tiny bump on the ventral surface; pontine clefts, and wiede and flat medulla with visible pyramids on the ventral surface. This pattern appeared likely pathognomonic. Clinical features were severe developmental delay, spasticity, and seizures within the first year. We found this imaging pattern (>[Fig. 1]) while reviewing unsolved brainstem malformations in an infant presenting in 2006 with infantile spams and microcephaly. On follow-up, this girl had treatment-resistant epilepsy, severe cognitive impairment, no speech, pronounced spastic cerebral palsy resulting in scoliosis, hip dislocation, and multiple contractures, requiring orthopedic interventions. Swallowing was not impaired. Targeted genetic testing confirmed a pathogenic de novo MACF1 variant [c.15682G>T p.(Asp5228Tyr)]. This observation confirms the value of careful pattern recognition[2] and supports the view that this pattern is likely pathognomonic.

We report a new patient who presented with dysmorphic features and congenital heart disease. In addition, her brain magnetic resonance imaging revealed leukoencephalopathy, cavum septum pellucidum, perisylvian polymicrogyria, and focal occipital pachygyria. Her regular karyotype showed 46,XX add 6 (p25) due to malsegregation of a maternal balanced translocation 46,XX,t(6;7)(p25;q33) while the array-comparative genomic hybridization identified a 3.307 Mb heterozygous deletion at 6p25.3-p25.2 and 23.95 Mb duplication at 7q33-q36.3. A previous patient with the same developmental brain malformations and leukoencephalopathy with 6p25 deletion including TUBB2A and TUBB2B genes had been reported. Thus, confirming that these specific developmental brain malformations are due to TUBB2A and TUBB2B haploinsufficiency. Our report is the first to present the developmental brain malformations associated with whole gene deletions of the two tubulin genes and provide further insights into the etiology of developmental brain malformations and white matter abnormalities associated with 6p25 deletions.

Microcephalic osteodysplastic primordial dwarfism (MOPD) is defined as a syndrome presenting with intrauterine and postnatal growth retardation, typical facial appearance, skeletal dysplasia and brain abnormalities. Autosomal-recessive inheritance is suspected. Sharing clinical manifestations, the former type III has been accepted to be the same entity as type I. We present the case of a male infant with MOPD I and micrencephaly with simplified gyral pattern to a degree defining it as microlissencephaly (MLIS). The brain abnormalities in MOPD I have not yet been classified. Reviewing the literature, we conclude that microlissencephaly appears to be the distinct developmental brain abnormality in MOPD I. Conversely, osteodysplastic changes have to be taken into consideration in the differential diagnosis of microlissencephaly. In addition, our patient suffered from acute lymphatic leukaemia which has not previously been described in association with MOPD I.

Improvements in neuroimaging techniques have highlighted the role of cerebral dysplasia in developmental disorders and in epilepsy. The current classification is founded on the presumed timing of the first insult as deduced from the imaging appearances. Although clinical neurophysiological findings are often non-specific, several unusual patterns have been reported in association with certain types of malformation. These include the high amplitude rhythmic activities of lissencephaly, and focal rhythmic spikes. In this general review, we describe the electroence-phalographic and evoked potential findings in a wide range of cerebral dysplasias, including our personal experience of rare conditions such as Ramer-Lin syndrome. We focus on their role in assessment and on potential insights into pathophysiology.

Detailed classification of brain malformations such as lissencephaly has led to the positional cloning of genes required for normal neuronal migration and the identification of unique molecular pathways governing brain structure. While classical magnetic resonance imaging (MRI) patterns of lissencephaly involve primarily the cerebral cortex, malformations in this spectrum can be associated with significant cerebellar underdevelopment and have recently been referred to as lissencephaly with cerebellar hypoplasia (LCH). The phenotypic features of 34 children were found to define 6 subtypes of LCH. Two of these (LCHa and LCHb) were associated with mutation in the LIS1, DCX and RELN genes, respectively. Gene mutations that exemplify four additional classes (LCHc, d, e and f) remained to be determined. Phenotypic features included small head circumference, cortical malformation ranging from agyria to simplification of the gyral pattern and from near normal cortical thickness to marked thickening of the cortical gray matter. Cerebellar manifestations ranged from midline hypoplasia to diffuse volume reduction and disturbed foliation. We conclude that LCH is within the spectrum of DCX and LIS1 mutations, that LCH associated with RELN mutation is distinguished by the severity of cerebellar and hippocampal involvement, and that several distinctive patterns indicate additional genetic mutations that can produce LCH.

Isolated Lissencephaly Sequence (ILS) and Double-Cortex Syndrome (DC) are neuronal heterotopias caused by developmental defects in neuronal precursor cell migration. We report on the clinical and genetic assessment of a German pedigree with DCIILS. Affected males showed clinical symptoms typical of lissencephaly, i.e. seizures, severe mental retardation and extensive physical disability starting in the early postnatal period. Females, however, displayed a milder phenotype with epileptic seizures being the only clinical symptom of note. The MR imaging of a male ILS patient showed a smooth cortex with pachygyria, hydrocephalus and a diffuse, broad distribution of grey matter throughout the brain. In the affected female, a double cortex syndrome in the form of a subcortical bilateral band of grey matter was evident by MR imaging. The molecular and genetic basis of DC/ILS is associated with mutations in the X-linked doublecortin gene (DCX). The genetic assessment of the family revealed a novel missense mutation 211 G-->T in DCX exon 2 in affected family members. This mutation cosegregated with the clinical symptoms and resulted in a non-conservative amino acid substitution A71S. DCX is a microtubule-associated phosphoprotein and mutations in DCX might affect cytoskeletal dynamics and the regulation of cell migration.

MR imaging, clinical data and underlying pathogenesis of subcortical laminar heterotopia (SCLH), also known as band heterotopia, in two sisters and their mother are presented.On MR imaging a different degree of SCLH was found in all three affected family-members. The inversion recovery sequence was considered most useful in the demonstration of the heterotopic band of gray matter and the assessment of cortical thickness.The younger sister presented with epileptic seizures at the age of five months and a delayed achievement of developmental milestones. The older sister of seven years had epileptic seizures since the age of one year, and developmental delay. Their mother has only had one seizure-like episode at the age of 39. Her psychomotor development had been normal.Investigation of DNA samples of the three female family-members revealed a mutation in the X-linked doublecortin gene. Within families with band heterotopia, this gene has also been related to male family members with lissencephaly.

MR imaging, clinical data and underlying pathogenesis of subcortical laminar heterotopia (SCLH), also known as band heterotopia, in two sisters and their mother are presented. On MR imaging a different degree of SCLH was found in all three affected family-members. The inversion recovery sequence was considered most useful in the demonstration of the heterotopic band of gray matter and the assessment of cortical thickness. The younger sister presented with epileptic seizures at the age of five months and a delayed achievement of developmental milestones. The older sister of seven years had epileptic seizures since the age of one year, and developmental delay. Their mother has only had one seizure-like episode at the age of 39. Her psychomotor development had been normal. Investigation of DNA samples of the three female family-members revealed a mutation in the X-linked doublecortin gene. Within families with band heterotopia, this gene has also been related to male family members with lissencephaly.

Case Report: Within the last 3 year we saw seven inpatients with double cortex syndrome at our Department in Kork. Five out of seven girls had a history of visual auras which were accompanied by panic attacks in two. We report of a girl with impressive transient MRI findings supporting the hypothesis of visual auras. The 15-year old girl with mild to moderate cognitive impairment presented with a typical double cortex syndrome in MRI. There were no other affected relatives and her development was primarily retarded. At the age 4 years a first generalized tonic-clonic seizure occurred. In the following year she suffered from repetitive grand-mal and by the age of 7 years increasing and more dyscognitive seizures with staring and cyanosis appeared. Attacks with complete loss of vision for several minutes were reported. However, no prophylaxis with anticonvulsive drugs was started and seizures were treated with acute benzodiazepine administration. At age 13/8 years she had a day with several seizures with confusion and repetitive eye deviation. Because of panic attacks she was hospitalized for the first time. Prolonged dyscognitive seizures (atypical absences), headaches, vertigo, and eye deviations to the left were recognized. MRI 5 days after admission showed a marked edema on T2 images in the right parieto-occipital region. Control after 8 days revealed a complete recovery in MRI. After 6 months she was again admitted to hospital with an episode of several days with repetitive visual auras, with suspected amaurosis and vertigo. An acute MRI demonstrated again an edema in the identical right parieto-occipital area. Conclusion: Auras are a common seizure manifestation in lissencephaly. To our experience, visual auras are frequent. They may lead to panic attacks that can be falsely interpreted as behavioral problems, especially in mentally handicapped patients.

We report on two sisters of first degree cousin parents who were born with severe hypotonia, arthrogryposis multiplex congenita (AMC) and dysmorphic features consistent with the fetal akinesia/hypokinesia sequence. They needed assisted ventilation and each died at the age of 5 months. Both had type II lissencephaly (cobblestone lissencephaly) which was visualized by magnetic resonance imaging (MRI) in the proband. Ophthalmic evaluation revealed no ocular malformations in either of them. Brain auditory evoked potentials (BAEP) revealed bilateral severe sensorineural hearing loss in the proband, whereas an MRI-guided open muscle biopsy of the sartorius muscle (the only remaining thigh muscle) showed features of muscular dystrophy. Immunohistochemistry revealed normal dystrophin, dystrophin-associated glycoproteins (DAG) and merosin. Certain clinical and pathological features distinguish the disease seen in these sisters from reported isolated cases where lethal AMC was associated with brain dysplasia and from the main syndromes of congenital muscular dystrophy/cobblestone lissencephaly. Differences from the Walker-Warburg syndrome, which simulates it in severity, included the absence of severe hydrocephalus, normal creatine kinase (for age) and minimal (mainly periventricular) white matter abnormalities. The findings suggest either an independent entity, in the studied family, or an allelic variation of the cobblestone lissencephaly (type II lissencephaly) syndrome.

A newborn with a rare type of lissencephaly is reported, characterized by extreme cerebral and cerebellar hypoplasia. The diagnosis was made by postmortem magnetic resonance imaging, indicating the value of such studies to evaluate neuronal migration disorders in patients in whom autopsy cannot be performed. Two earlier described microlissencephaly syndromes, the "Barth" and "McComb" type, are reviewed.

Cobblestone lissencephaly is the characteristic brain malformation observed in Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and Walker-Warburg syndrome (WWS). The diagnostic criteria for all three require the presence of congenital muscular dystrophy, and criteria for MEB and WWS require retinal abnormalities. We report three patients from two consanguineous families of Middle Eastern origin with cobblestone lissencephaly but no abnormalities of the eyes or muscle. Based on the current diagnostic criteria for the cobblestone lissencephaly syndromes, this disorder must be classified separately from the others, but it may well be allelic to MEB and WWS. Linkage studies have excluded the gene for this disorder from the region of the FCMD gene on chromosome 9q31-32.

We describe two cases of oculocerebrocutaneous syndrome (OCCS) or Delleman syndrome, characterized by congenital anomalies that involve the skin, orbit, and central nervous system (CNS). Complete MRI studies of the orbit, CNS and the entire spinal region must be performed in these cases. New MRI techniques can show cortical malformations, such as polymicrogyria, lissencephaly, or abnormal disposition of cortical sulci and gyri. Lesions can be bilateral or unilateral, as occurred in our patients. In one case, the ocular, skin, cerebral, and cerebellar lesions involved mainly the same side, whereas in the second case, all anomalies were generalized and the patient also showed skin hypopigmented lesions distributed bilaterally. Both patients show severe encephalopathy and Dandy-Walker malformation. One case is blind and shows generalized hydrocephalus, and the other one has vision through an eye, and has complete agenesis of the corpus callosum and severe disorder of neuronal migration and cortical organization with polymicrogyria and abnormal cortical sulci and gyri in a cerebral hemisphere. Our second case shows arachnoid cysts in both temporal, retrocerebellar, and spinal (D(8)-D(11)) regions, and lipoma in the pontomedullary and spinal (D(4)-D(7)) regions. The latter features correspond more to ECCL than to OCCS. The overlap between the two syndromes is unquestionable and it is possible that they constitute different manifestations of the same disorder.

Mutations in the Aristaless-related homeobox (ARX) gene are associated with a broad spectrum of disorders including X-linked lissencephaly with abnormal genitalia (XLAG) and absent corpus callosum. Here, we describe a family with two male infants suffering from agenesis of the corpus callosum (ACC), intractable epilepsy, and abnormal genitalia. The phenotype of both affected patients differed in severity of the cerebral malformation with one showing no obvious evidence for lissencephaly. Both infants lacked any psychomotor development and died at the age of 17 weeks and 18 months, respectively. Genetic analysis of the ARX gene revealed a novel frameshift mutation in exon 4 (nt1419_1420insAC) leading to a shortened protein lacking the aristaless domain. In summary, analysis of the ARX gene should not only be considered in male patients with typical features of XLAG but also in those presenting with early onset epilepsy, ACC, and abnormal genitalia without obvious neuroradiological features of lissencephaly.

X-linked lissencephaly with abnormal genitalia (XLAG) is a rare disorder caused by mutations in the aristaless-related homeobox (ARX) gene. We report on the clinical data of a boy with a 1-bp deletion (790 delC) resulting in a frame shift in the ARX gene and prolonged survival until age 18 months. Similar to other patients, the boy showed postnatal microcephaly, hypothalamic dysfunction, intractable neonatal seizures, and chronic diarrhoea. In addition, he suffered from exocrine pancreatic insufficiency and renal phosphate wasting became apparent from age 5 months, both of which have not been described previously in XLAG. This allows us to speculate that the phenotype of XLAG is more complex than hitherto known and may include renal phosphate wasting which might not have been observed in other patients due to early death.

Baraitser-Winter syndrome is a rare autosomal recessive disorder characterized by developmental delay, dysmorphic features, and multiple malformations also involving the brain. We report a further case and provide updated information about an unrelated girl reported in the original paper by Baraitser and Winter. Both of them presented with pachygyria and the latter case was recently found to have subcortical band heterotopia on high resolution brain MRI imaging. These two patients and a review of the previously reported cases indicate that a specific pattern of brain anomalies falling in the agyria-pachygyria-band spectrum is associated with this dysmorphic syndrome, which may be considered another example of syndromic neuronal migration defect.

The clinical courses, neuroimaging and muscle biopsy findings of two infants born to an inbred Arab family are described. They had a syndrome of micrencephaly with simplified gyral pattern, abnormal myelin formation and arthrogryposis. Increased variation of fiber size was seen in the muscle biopsy, creatine kinase, however was normal. Large areas of muscle were replaced by adipofibrous tissue. The infants had dysmorphic features consistent with the fetal akinesia/hypokinesia sequence. The abnormalities were suggestive of microlissencephaly probably associated with a dysgenetic process in the muscles. The syndrome showed an autosomal recessive inheritance.

Magnetic resonance imaging (MRI) has enabled the identification of neuronal migration disorders in living subjects. This represents an important achievement in the diagnosis of patients with these anomalies. At least five affected families with coexistent subcortical laminar heterotopia and lissencephaly have been reported recently. This association suggests an X-linked pattern of inheritance. In the family that we report, the mother suffered from epilepsy and the oldest daughter from epilepsy and mental retardation. Both patients showed subcortical laminar heterotopia on MRI. The youngest son presented a severe encephalopathy with early onset seizures, and was found to show lissencephaly on MRI. The other two siblings, a boy and a girl, had no neurological abnormalities. The severity of these patients' clinical symptoms were clearly related to MRI findings.

We report the neonatal courses, early postnatal development, and neuroimaging findings of 17 patients with marked microcephaly and simplified cerebral gyral patterns, a condition that we call microlissencephaly. Retrospective analyses of the clinicoradiologic features of these patients allowed segregation of the patients into 5 distinct groups with varying outcomes. The apparent discreteness of these groups suggests multiple etiologies of this malformation, although there appears to be a strong genetic component with probable autosomal recessive inheritance. Utilizing the neonatal course and neuroradiologic features of these infants allows classification of specific subsets, which may be useful to predict outcome.

Malformations of the cerebral cortex are being recognized more frequently as a cause of epilepsy, developmental delay, neurological deficits, and mental retardation. Nonetheless, a standard nomenclature and classification system of these malformations, based upon state-of-the art knowledge derived from genetics, embryology, imaging, and pathology, has not been devised. In this manuscript, we propose such a classification system. Moreover, we have constructed the system such that both the framework and the classifications themselves are flexible and can be adapted as our knowledge of the embryology, genetics, imaging, and pathology of these disorders advances. We believe that the use of this classification system will help both clinicians and researchers to understand and think about these disorders and their causes better. In turn, we hope that this improved understanding will lead to further refinements in classification, to advances in our knowledge and, ultimately, to improvements in therapy.

Twenty-one Dutch patients were the subject of an extensive study into lissencephaly type I. One hundred and fourteen EEG's of these patients were studied. The EEG's were compared to 52 EEG's recorded from 21 patients with an atypical cortical dysplasia and to a control group consisting of 882 EEG's recorded from 823 patients for various reasons. The EEG's in the lissencephaly patients showed the following patterns significantly more often: (a) generalized fast activity (8-18/s) with an amplitude higher than 50 microV, (c) sharp- and slow-wave complexes with an amplitude higher than 500 microV, (d) an alternating pattern consisting of bursts of sharp waves alternating with periods of electrocerebral depression. Ninety-five percent of the lissencephaly patients showed pattern (a) or (c) or both compared to only 5% of the patients with an atypical cortical dysplasia and 0.4% in the controls. The SSEP's recorded in ten patients after stimulation of the median nerve were abnormal in all. EEG and evoked potentials appear to be valuable examinations in the (differential) diagnosis of lissencephaly type I.

The authors report a family in whom three members suffered from congenital hydrocephalus and ocular abnormalities. One of these patients showed along with these symptoms congenital muscular dystrophy. In this child, autopsy disclosed severe cerebral malformations consisting of lissencephaly, arhinencephaly, stenosis of aqueduct, Dandy-Walker cyst and cerebellar micropolygyria. The mode of transmission, the eyes abnormalities and the neuropathological findings of this family resemble the clinical and pathological aspects of Warburg syndrome. However, the presence of congenital muscle dystrophy in one of these children suggests some links with Fukuyama's congenital muscular dystrophy and/or with so-called brain-eye-muscle disease of Santavuori. These three syndromes are shortly discussed. The present case and few others reported in the literature obviously represent a severe and lethal form of a congenital disease involving brain, muscle and eyes.

A child with arthrogryposis multiplex congenita and microcephaly is described. Cranial CT-scan and MRI showed abnormalities consistent with type I lissencephaly. The lissencephaly seems to be the primary cause of the congential contractures. Lissencephaly associated with arthrogryposis multiplex congenita has to be considered as a special kind of lissencephaly syndrome.