Microcephaly and lissencephaly. Developmental disorders of cerebral cortex (lissencephaly Microcephaly Malformations of cortical and development.) - Genes involved.

The development of cerebral cortex is a coordinated process that involves the development of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetrical and asymmetrical mitosis, followed by migration of postmitotic neurons to their proper place in the cerebral cortex, where they will be established in six highly ordered and functionally specialized layers.

The developmental malformations of the brain cortex (MCD: Malformations of Cortical Development) are a group of structural alterations of the brain that reflect neuronal developmental disorders of neural progenitors, cell proliferation, migration of neurons or organization .

Abnormalities of neurogenesis

In this group of alterations microcephaly, the hemimegalencephaly and cortical focal dysplasia are included.

Primary microcephaly (microcephaly vera) is an autosomal recessive disorder characterized by reduced brain size than normal, accompanied by mental retardation. This process is caused by heterozygous mutations in ASPM, CDK5RAP2, CENPJ or MCPH1 genes. The cerebral cortex presents pachygyria previous dominance. In this process there are anomalies dividing neural progenitor cells are crucial in its pathogenesis. This microcephaly is characterized by congenital, manifest at birth, microcephaly is at least three standard deviations from the average size with a brain preserved architecture and absence of other neurological disorders or growth or related central nervous system manifestations, with mental retardation of varying degrees. Epileptic seizures are rare, although cases have been reported with them.

The characteristics of each of the processes, due to anomalies neurogenesis, may be summarized as follows:


    • ASPM gene - Mental retardation, with previous pachygyria generally not associated with epilepsy, autosomal recessive inheritance.
    • Gene CDK5RAP2 - Mental retardation, microcephaly associated with type 3 (MCPH3), with relatively well preserved gyrus without abnormalities of brain structure. No other alterations syndromic. Autosomal recessive inheritance.
    • Gen CENPJ. Mental retardation, microcephaly associated with type 6 (MCPH6), with relatively well preserved gyrus without abnormalities of brain structure. No other alterations syndromic. Autosomal recessive inheritance.


    • Unknown genes - Mental retardation, early - onset seizures (epilepsy often untreatable), with or without accompanying mucocutaneous syndrome.

Focal cortical dysplasia:

    • Unknown genes - focal and generalized seizures.

Abnormalities neuronal migration

There are three types of processes in this group: periventricular heterotopia, subcortical heterotopia and lissencephaly band.

Lissencephaly is altered neuronal migration generating grooves and abnormal gyri. Affected children have microcephaly, developmental delay and early - onset epileptic seizures. The main cause are de novo mutations (new, not inherited) in TUBA1A gene (?-tubulin 1A). Mutations in this gene result in a group of rare brain malformations, sharing the fact abnormalities in the cerebral convolutions, characterized by simplification or absence of folds associated with abnormal organization of cortical layers, as a result of defects neuronal migration during embryogenesis. Children with lissencephaly have problems feeding and swallowing, abnormalities of muscle tone (hypotonia hypertonia initial then limb), seizures (infantile spasms), and pronounced psychomotor retardation. They have been described many forms of lissencephaly and ranking is based on the associated malformations and the underlying etiology. They described two groups: classical lissencephaly (type I) and its variants, and lissencephaly pebbles (cobblestones) (formerly known as Type II). The latter is due to the abnormal stop neuronal migration.

In Type I, the brain is apparently smooth absence or substantial reduction of the convolutions (gyri) normal cerebral cortex thickened with four layers more or less organized instead of six normal layers. In type I variants exist extracorticales anomalies (total or subtotal agenesis of corpus callosum and / or cerebellar hypoplasia), allowing subdivided into several subgroups can be distinguished according to their genetic etiology.

There are several genes that may be involved: LIS1, DCX, ARX, TUBA1A and WDR62, among others. These genes are related to the formation and microtubule function required for neuronal migration in the developing cerebral cortex. LIS1 gene mutations are causing lissencephaly boxes isolated or syndrome Miller-Dieker. Mutations in the gene give rise ARX also to agenesis of corpus callosum (X-LAG syndrome, X-linked lisencephalia With the corpus callosum agenesis of). De novo mutations (new, not inherited) in TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders. In lissencephaly related TUBA1A may exist perisylvian pachygyria in milder forms, posterior predominant pachygyria in the most severe forms associated dysgenesis limbus internal and moderate to severe cerebellar hypoplasia capsule. The pachygyria is characterized by a brain area with an abnormally smooth surface, creased and minor grooves, unlike lissencephaly which is similar but affecting all brain surface.

Subsequently, recessive mutations have been described in WDR62 gene (WD Repeat Domain 62), located on the long arm of chromosome 19 (19q13.12) as the cause of a wide range of cortical malformations including microcephaly, pachygyria and hypoplasia of the corpus callosum. Some patients with mutations in the gene have evidence WDR62 additional abnormalities including lissencephaly, Schizencephaly, Polymicrogyria and cerebellar hypoplasia, which traditionally have been considered separate entities. WDR62 gene expression is transient during the embryonic neurogenesis. Unlike other genes microcephaly, not associated with centrosomes and is located in nucleolus.

In addition, there are isolated Lissencephaly no known genetic defect. Lissencephaly with pronounced microcephaly (microlisencefalia), and polimarformativos Lissencephaly associated with syndromes.

Lissencephaly pebbles (cobblestone) (formerly Type II), includes three entities: Walker-Warburg syndrome, lissencephaly of Fukujama syndrome muscle-oculo-brain (MEB: Muscle-Eye-Brain), characterized by overall disorganization brain organogenesis, guijasrros appearance, complete disorganization of the cortex and the absence of distinct layers.

Other syndromes with other extracerebral manifestations:

Norman-Roberts syndrome: microlisencefalia that differs from classical lissencephaly and other variants by the presence of pronounced microcephaly and a malformation syndrome.

Cerebro--facial fronto of Baraitser-Winter, microcephaly characterized by progressive development over time, with cortical malformation characterized by pachygyria gradient intensity occipital front. In addition, dysmorphic facial features with hypertelorism, broad nose with long nose and prominent root, congenital ptosis and arched eyebrows. In many cases it is associated with coloboma of the iris or retina and sensorineural deafness, cleft lip and palate. In some cases there are congenital heart defects and kidney abnormalities. This syndrome is due to mutations in genes ACTG1 or ACTB. The pachygyria occurs in almost all patients with mutations in the gene ACTG1 and in 60% of patients with mutations of ACTB gene.

The characteristics of each of the processes due to abnormal neuronal migration may be summarized as follows:

periventricular heterotopia

      • Gen FLNA - normal intelligence onset seizures in adolescence, X - linked disorder with male lethality.
      • Gen ARFGEF2 - Mental retardation, microcephaly, autosomal recessive inheritance.

Subcortical band heterotopia

      • Gen DCX - subcortical band heterotopia women, mental retardation, epilepsy, X - linked disorder


      • LIS1 gene - Mutations in this gene are the cause of Miller-Dieker syndrome, facial expressions characteristics, and is due to a deletion in this large gene; In addition, small deletions have been linked to cases of isolated lissencephaly. In both cases the mutations are autosomal recessive, or de novo (new, not inherited) inheritance.
      • Gen DCX - lissencephaly in males, linked to chromosome X.
      • Gene TUBA1A - lissencephaly, similar to those caused by the DCX gene LIS1 and generally due to de novo mutations made.
      • ARX gene - Associated with ambiguous genitalia, hypothalamic dysfunction, neonatal epilepsy, X - linked disorder
      • Gen RELN - Associated with cerebellar hypoplasia and epilepsy, and autosomal recessive inheritance.

Abnormal stop neuronal migration

Lissencephaly pebbles (cobblestone)

      • Gen Fukutin - Fukuyama congenital muscular dystrophy.
      • Gen POMGnT1 - Disease muscle-oculo-cerebral.
      • Gen POMT1 - Walker-Warburg syndrome.

Abnormal neural organization


      • GPR56 gene - bilateral frontoparietal Polymicrogyria. Epilepsy.


      • Gen EMX2 - cleft palate.

Tests in IVAMI: in IVAMI perform detection of mutations associated with any of the genes involved in neurogenesis anomalies (microcephaly, hemimegalencephaly, focal cortical dysplasia); abnormalities of migration (periventricular heterotopia, subcortical band heterotopia, lissencephaly); abnormal stop neuronal migration (lissencephaly in -cobblestone- pebbles); abnormal neural organization (Polymicrogyria, Schizencephaly), by complete PCR amplification of the exons of the genes, and subsequent sequencing.


Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).