- Balanced translocations and abnormal phenotypes : what is the relationship ?
It is possible to classify the known genetic causes of cortical malformations according to several criteria. We arbitrarily choosed to present here the known genes based on the simplified classification of the neuronal migration disorders that is presented in this other page. The genetic defect (most often a mutation) can cause a proliferation defect, a migration defect or a defect in cortical patterning. These defects are sometimes found together in a given patient. The malformations caused by a metabolic disease or associated with a chromosomal rearrangement are also presented below.
This gene is homologous to the drosophila "abnormal-spindle" gene, necessary for the proper organization of the mitotic spindle of embryonic neuroblasts. The human gene is located in 1q31. It is highly expressed in the primary sites of cortical neurogenesis in the mouse embryo. All the known mutations are truncating mutations. A complete description of all mutations identified in the ASPM gene can be found here. All patients present severe primary microcephaly with head circumference at -5 to -7 standard deviations (Bond et al. 2002). They are mildly retarded but show no dysmorphic feature or other clinical characteristics.
This gene, located in 20q13, encodes the ADP-ribosylation factor guanine nucleotide-exchange factor-2. This protein is important for vesicular trafficking and its dysfunction has deleterious effects on the neuronal proliferation and migration. Only two mutations are currently known in this gene, both identified in consanguineous turkish families (Sheen et al. 2004). Other than the microcephaly, these patients are also presenting with periventricular nodular heterotopia.
This gene is located in 17p13, a region commonly deleted in Miller-Dieker syndrome (Reiner et al. 1993). The LIS1 protein binds cytoplasmic dynein and is involved in nucleokinesis processes, especially in the developping nervous system. In addition to the complete gene deletions found in Miller-Dieker syndrome, point mutations are also found in the LIS1 gene. Rare somatic mutations can be responsible for the formation of a "band" of heterotopic grey matter inside the white matter. This phenotype is called "double cortex" and is similar to what is seen in female carrier of a DCX mutation.
This gene is located in Xq28 (Fox et al. 1998). It encodes a protein that can bind the actin cytosqueleton and regulate its organization through association with several cytoplasmic molecules. The inheritance pattern is X-linked dominant. Only women are affected by the classical bilateral periventricular nodular heterotopia (BPNH) phenotype, the only associated clinical sign being epilepsy (rare male cases do exist but they are presenting additional malformations).
This gene is located in Xq22 ( Gleeson et al. 1998 ; des Portes et al. 1998). It encodes "doublecortin", a protein binding microtubules. This associatiion stabilizes the microtubule network, facilitating cellular migration (especially neuronal migration). The inheritance pattern is X-linked. Affected males have a severe form of lissencephaly (severe mental retardation, epilepsy). Carrier females generally display a band of heterotopic neurons inside the white matter (the "double cortex").
The reelin gene is located in 7q22 in humans (Hong et al. 2000). This gene is one of the best known because of the reeler mouse that allowed the molecular cloning of the mouse homologous gene in 1995. The reelin protein is highly expressed by Cajal-Retzius cells. It is essential for proper lamination of the cerebral cortex. The very rare patients described with a mutation in this gene have moderate lissencephaly and major cerebellar hypoplasia.
This gene is located in Xp22 (Stromme et al. 2002). It is the homolog of the aristaless homeotic gene of drosophila. In mouse, ARX is highly expressed in the cerebral cortex and it could be important for the specification of several neuronal subtypes and for axonal navigation. Mutations in this gene cause a specific type of lissencephaly associated with abnormal genitalia (XLAG), West syndrome, Partington syndrome and certain types of X-linked mental retardation.
This gene, located in 12q13 (Keays et al. 2007), encode alpha-1 tubulin. The gene is important for the formation of tubulin heterodimers. When abnormal, it causes important defects of cellular proliferation and migration. Besides an abnormal cerebral cortex, the patients carrying a mutation in the TUBA1A gene also present with defects in cerebellum, hippocampus, corpus callosum and the brainstem (Poirier et al. 2007).
This gene is located in 10q26 (Brunelli et al. 1996). It is the ortholog of the empty-spiracles drosophila homeotic gene. Together with PAX6, EMX2 is involved in the regionalization of the neocortex. All the mutations in this gene were identified by the same group.
This gene is located in 16q13 (Piao et al. 2004). It is a G-protein coupled receptor highly expressed by neuronal progenitor cells. All the mutations known in this gene cause frontoparietal polymicrogyria.
Peroxysomes are involved in a large number of biochemical reactions (fatty acid oxydation, peroxyde metabolism). They are abnormal in several genetic diseases in humans. This is the case of Zellweger syndrome. This syndrome can be caused by a mutation in many different PEX genes (PEX1, PEX3, PEX12, PEX14, PEX26). Zellweger syndrome patients have polymicrogyria but this malformation is not isolated (pour revue voir Brosius et Gartner, 2002). The patients are also presenting neonatal hypotonia, facial dysmorphism, kidney and liver disease. Polymicrogyria is thus secondary to the generalized metabolic failure.
This syndrome is associated with a peculiar form of lissencephaly called "cobblestone lissencéphalie" following the aspect of the cortical surface. It is also called HARD +/- E because of the phenotype of the patients : hydrocephaly, agyria, retinal dysplasia, with or without encephalocele. Most patients have a muscular dystrophy and shortened lifespan. A review can be found here van Reeuwijk et al. 2005.
This disease is essentially a muscular dystrophy (Chiyonobu et al. 2005). All the patients have mental retardation and more than 80% of them have cerebral malformations, especially polymicrogyria. Some forms of Walker-Warburg syndrome can be confused with FMD. This gene is located in 9q31.
MELAS est un acronyme pour myopathie mitochondriale, encéphalopathie, acidose lactique et pseudo-crises d'apoplexie. MELAS stands for mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. This syndrome is almost always caused by a recurrent mutation in a mitochondrial gene encoding Leucine tRNA (Keng et al. 2003). Other tRNA can also be involed. Polymicrogyria was documented in a patient presenting a typical mutation. This association has currently not been reported by other groups.
A male patient presenting a severe neonatal encephalopathy was reported with a mutation in the MeCP2 gene and bilateral perisylvian polymicrogyria (Geerdink et al. 2002). This association has currently not been reported in other patients.
A large number of chromosomal rearrangements were reported in patients having a cortical malformation. These rearrangements are often complex and unbalanced, thus decreasing their interest to clone new genes. Nonetheless, several association are more often described and they are detaile below. Regarding polymicrogyria, an excellent review has recently been published (Jansen and Andermann 2005).
Several patients with the 22q11 deletion and polymicrogyria were described (Sztriha et al. 2004). This association is rare but not exceptional. Several types of polymicrogyria were documented depending on their topography and localization (uni or bilateral).
This famous chromosomal rearrangement is causing Miller-Dieker syndrome. The LIS1 gene is located inside the deleted interval and it is responsible for the lissencephaly phenotype of the patients (see above and Cardoso et al. 2003).
Two patients presenting a trisomy of the 5p15 region were reported in 2003 (Sheen et al. 2003). Both are suffering from periventricular nodular heterotopia. This region of chromosome 5 thus potentially contain a new locus for this type of cortical malformation.