Microcephalia vera and microcephaly with simplified gyral pattern

Key-words Disease name and synonyms Definition/Diagnosis criteria Excluded diseases Differential diagnosis Etiology Clinical description Genetics Diagnostic methods Frequency Genetic counseling Antenatal diagnosis Management including treatment Unresolved questions References Abstract Microcephaly is defined by an occipitofrontal circumference (OFC) below -2 standard deviation (SD) for age and sex. Severe microcephaly refers to an OFC < -3SD. Microcephalia vera (MV) and microcephaly with simplified gyral pattern (MSG) are genetic forms of isolated congenital microcephaly (< -3 SD at birth), with no extracerebral malformation. Their incidence has been estimated between 1/25 000 and 1/50 000 births. In MV, the brain is abnormally small because of a reduced number of neurons, but is keeping (sub) normal gyral pattern and has no other gross pathological abnormality. Mental retardation is usually moderate and in most cases, patients have no systematized neurological defects or seizures. Brain weight typically is < 500 g (1/3 normal) and OFC is between 24 and 29 cm at birth (normal OFC being higher than 32 cm). MSG has been misdiagnosed as MV or lissencephalies in the past. This disorder is defined by congenital severe microcephaly, reduced number and shallow appearance of gyri, and normal to thin cortex. Five types of MSG have been delineated on the basis of MRI and neurodevelopmental findings, but MV and MSG are likely to represent a continuous phenotype. Mental retardation ranges from mild and moderate (type 1) to severe (types 2 to 5). Pyramidal signs may be observed. Some forms (types 2 to 5) are associated with early-onset seizures and a poor prognosis. MV and MSG are due to abnormal neuronal and glial proliferation. In both types, the cortex is of normal (2.5 mm to 4 mm) or reduced thickness and has normal cytoarchitectonic appearance, with 6 layers of neurons, which contrasts with microlissencephalies or lissencephalies with microcephalies, characterized by an abnormal cortical thickness and an anarchic cytoarchitectony. MV and MSG are inherited in an autosomal recessive pattern. To date, no locus has been associated with MSG. Eight loci have been associated with MV and among those, three genes have been identified, MCPH1, ASPM, SLC25A19.There is no specific treatment for MV and MSG.Microcephaly is defined by an occipitofrontal circumference (OFC) below -2 standard deviation (SD) for age and sex. Severe microcephaly refers to an OFC < -3SD. Microcephalia vera (MV) and microcephaly with simplified gyral pattern (MSG) are genetic forms of isolated congenital microcephaly (< -3 SD at birth), with no extracerebral malformation. Their incidence has been estimated between 1/25 000 and 1/50 000 births. In MV, the brain is abnormally small because of a reduced number of neurons, but is keeping (sub) normal gyral pattern and has no other gross pathological abnormality. Mental retardation is usually moderate and in most cases, patients have no systematized neurological defects or seizures. Brain weight typically is < 500 g (1/3 normal) and OFC is between 24 and 29 cm at birth (normal OFC being higher than 32 cm). MSG has been misdiagnosed as MV or lissencephalies in the past. This disorder is defined by congenital severe microcephaly, reduced number and shallow appearance of gyri, and normal to thin cortex. Five types of MSG have been delineated on the basis of MRI and neurodevelopmental findings, but MV and MSG are likely to represent a continuous phenotype. Mental retardation ranges from mild and moderate (type 1) to severe (types 2 to 5). Pyramidal signs may be observed. Some forms (types 2 to 5) are associated with early-onset seizures and a poor prognosis. MV and MSG are due to abnormal neuronal and glial proliferation. In both types, the cortex is of normal (2.5 mm to 4 mm) or reduced thickness and has normal cytoarchitectonic appearance, with 6 layers of neurons, which contrasts with microlissencephalies or lissencephalies with microcephalies, characterized by an abnormal cortical thickness and an anarchic cytoarchitectony. MV and MSG are inherited in an autosomal recessive pattern. To date, no locus has been associated with MSG. Eight loci have been associated with MV and among those, three genes have been identified, MCPH1, ASPM, SLC25A19.There is no specific treatment for MV and MSG. Verloes A. Microcephalia vera and microcephaly with simplified gyral pattern. Orphanet Encyclopedia. February 2004. http://www.orpha.net/data/patho/GB/uk-MVMSG.pdf 1 Key-words Microcephaly, lissencephaly, cortex, mental retardation, microcephalia vera, microlissencephaly with simplified gyral pattern. Disease name and synonyms • Microcephalia vera (MV); • True micrencephaly; • Radial microbrain; • Microcephaly with simplified gyral pattern (MSG); • Microlissencephaly (partim). Definition/Diagnosis criteria Microcephaly is defined by an occipitofrontal circumference (OFC) below -2 standard deviation (SD) for age and sex. Severe microcephaly refers to an OFC < -3SD. MV and MSG are genetic forms of isolated congenital microcephaly (< -3 SD at birth), with no extracerebral malformation. In both types, the mantle is of normal (2.5 mm to 4 mm) or reduced thickness and has normal cytoarchitectonic appearance, with 6 layers of neurons. MV and MSG are likely to represent a continuous phenotype, mild MSG (at least) being seen in some patients from families with typical MV [Roberts et al., 2002]. Clinically, their diagnosis is made by exclusion of other recognizable etiologies of microcephaly: toxic intrauterine exposure (maternal PKU, maternal alcohol consumption), infectious embryofetopathies (TORCHES), chromosomal anomalies. Excluded diseases • Microcephalies associated with multiple congenital anomalies syndromes and chromosomal disorders; • Microlissencephalies (MLIS) (NormanRoberts syndrome, Barth syndrome); • Lissencephalies, classical and variants; • Llissencephalies with cerebellar hypoplasia; • Lissencephalies with agenesis of the corpus callosum (XLAG syndrome); • Seckel syndrome and variants. Differential diagnosis MSG and MLIS share a similar smoothened brain shape, but differ by the ultrastructure of the cortical mantle: whereas in MV and MSG the mantle is of normal or reduced thickness and has normal cytoarchitectonic appearance, with 6 layers of neurons, in MLIS, the cortex is thickened (10 to 20mm) and has an anarchic cytoarchitectony, often with 4 neuronal layers only. Etiology A standard classification of malformations of abnormal cortical development [Barkovich et al., 2001] divides lesions into those due to neuronal and glial proliferation in the germinal zones versus those due to cellular migration. As proliferation and migration occur synchronously, some of these abnormalities have overlapping features. Abnormal neuronal and glial proliferation lead to microcephalia vera (MV), microcephaly with simplified gyral pattern (MSG) [Barkovich et al., 1998, Dobyns and Leventer, 2003] and, when combined with migration defect, these defects result in microlissencephalies (MLIS). Clinical description Clinical aspects of microcephalia vera MV describes genetic conditions in which the brain is abnormally small because of a reduced number of neurons, but is keeping (sub) normal gyral pattern and has no other gross pathological abnormality. Brain weight typically is < 500 g (1/3 normal comparable with that of early hominids). Very few data are available in the medical literature about MV. Moreover, MV and MSG have been mixed in the past, and, in many cases, there is no clinicopathological correlates. To our best knowledge, nothing has been published on cognition, behaviors or functional imaging in this group of patients. Mental retardation is usually moderate and in most cases, patients have no systematized neurological defects or seizures. Clinically, patients present with narrow, sloping forehead, and pointed vertex. Ears appear falsely large and protruding. By definition, there is no intrauterine growth retardation (IUGR), no postnatal growth retardation and no associated anomalies. Life span may be normal. A unique, extremely rare form of severe microcephaly with early lethality and αketoglutaric aciduria has been reported in the Amish community (Kelley et al., 2002). To date, this disorder has not been reported in other populations. Clinical aspects of microcephaly with simplified gyral pattern (MSG) This disorder is defined by congenital severe microcephaly, reduced number and shallow appearance of gyri, and normal to thin cortex. Based on MRI and neurodevelopmental findings, 5 types have been delineated. Verloes A. Microcephalia vera and microcephaly with simplified gyral pattern. Orphanet Encyclopedia. February 2004. http://www.orpha.net/data/patho/GB/uk-MVMSG.pdf 2 Table 1 shows the Barkovich’s classification of