Primary microcephaly refers to the clinical finding of a head circumference less than 3 standard deviations (SD) below the age- and sex-related mean, present at birth. Primary microcephaly is a static developmental anomaly, distinguished from secondary microcephaly, which ... Primary microcephaly refers to the clinical finding of a head circumference less than 3 standard deviations (SD) below the age- and sex-related mean, present at birth. Primary microcephaly is a static developmental anomaly, distinguished from secondary microcephaly, which refers to a progressive neurodegenerative condition. Microcephaly is a disorder of fetal brain growth; individuals with microcephaly have small brains and almost always have mental retardation, although rare individuals with mild microcephaly (-3 SD) and normal intelligence have been reported. Additional clinical features may include short stature or mild seizures. MCPH is associated with a simplification of the cerebral cortical gyral pattern and a slight reduction in the volume of the white matter, consistent with the small size of the brain, but the architecture of the brain in general is normal, with no evidence of a neuronal migration defect (review by Woods et al., 2005). Most cases of primary microcephaly show an autosomal recessive mode of inheritance. Because MCPH directly affects neurogenesis, or neurogenic mitosis, rather than growth of the skull, some prefer the term 'micrencephaly' (Hofman, 1984). MCPH1 in particular is associated with premature chromosome condensation in cell studies (Darvish et al., 2010). - Genetic Heterogeneity of Primary Microcephaly Primary microcephaly is a genetically heterogeneous disorder. MCPH2 with or without cortical malformations (604317) is caused by mutation in the WDR62 gene (613583) on chromosome 19q13.12; MCPH3 (604804) is caused by mutation in the CDK5RAP2 gene (608201) on chromosome 9q34; MCPH4 (604321) is caused by mutation in the CASC5 gene (609173) on chromosome 15q14; MCPH5 (608716) is caused by mutation in the ASPM gene (605481) on chromosome 1q; MCPH6 (608393) is caused by mutation in the CENPJ gene (609279) on chromosome 13q12.2; MCPH7 (612703) is caused by mutation in the STIL gene (181590) on chromosome 1p32; and MCPH8 (614673) is caused by mutation in the CEP135 gene (611423) on chromosome 4q; MCPH9 (614852) is caused by mutation in the CEP152 gene (613529) on chromosome 15q21; MCPH10 (615095) is caused by mutation in the ZNF335 gene (610827) on chromosome 20q13; and MCPH11 (615414) is caused by mutation in the PHC1 gene (602978) on chromosome 12p13.
Primary or true microcephaly is different from microcephaly secondary to degenerative brain disorder (Cowie, 1960). In true microcephaly, there is no neurologic defect, other than mental deficiency, and no skeletal or other malformation. The differentiation of primary and ... Primary or true microcephaly is different from microcephaly secondary to degenerative brain disorder (Cowie, 1960). In true microcephaly, there is no neurologic defect, other than mental deficiency, and no skeletal or other malformation. The differentiation of primary and secondary microcephaly was investigated by Qazi and Reed (1973). In a biometric analysis of brain size of micrencephalics compared to normal controls, Hofman (1984) found that micrencephalics have a significantly lower brain weight in adolescence than in early childhood, and that this cerebral dystrophy continues throughout adulthood, leading to death in more than 85% of males and 78% of females before age 30 years. Since this decline in brain weight is not accompanied by a similar reduction in head circumference, the brains of elderly micrencephalic individuals no longer occupy the entire cranial cavity. Hofman (1984) concluded that head circumference is an unsuitable parameter for estimating brain size in micrencephaly. Mikati et al. (1985) reported microcephaly associated with short stature and mental retardation in 3 brothers and a sister out of 9 children of first-cousin parents. Hypergonadotropic hypogonadism and a variety of minor anomalies were also present. Tolmie et al. (1987) described the clinical and genetic findings of a series of microcephalic patients referred to the Genetic Counselling Service for the West of Scotland. There were 29 isolated cases and 9 families with recurrent microcephaly. The sib recurrence risk of 19% was taken to reflect the high incidence of autosomal recessive microcephaly. In this series, there appeared to be several varieties of recessive microcephaly. The most frequent, affecting 5 sib pairs, was associated with spastic quadriplegia, seizures, and profound mental handicap. In 15 families with 1 microcephalic child, prenatal diagnosis by serial ultrasound scans was undertaken in 21 subsequent pregnancies. Four recurrences were detected in the third trimester and 1 recurrence was missed because no scan was performed after 24 weeks gestation when the ultrasound measurements indicated satisfactory head growth. The main reason for late diagnosis was that head growth did not slow appreciably until the last trimester. Although Qazi and Reed (1975) stated that carriers of primary microcephaly have diminished intelligence, Pattison et al. (2000) noted that this had not been seen in any of the families in with linkage to specific MCPH loci had been reported. Bond et al. (2005) emphasized that MCPH is evident at birth, with head circumference ranging between 4 and 12 standard deviations below the mean and thereafter remaining proportionately small with age. Cognitive functions are reduced, but epilepsy and other neurologic disorders or decline are rarely reported, and motor skills are preserved. It is hypothesized that neuronal precursor cells in the neuroepithelium are affected, resulting in reduced production of functional neurons during fetal life. Darvish et al. (2010) reported 8 unrelated consanguineous families from Iran with primary microcephaly-1. Head circumference of affected individuals ranged from -3 to -11 SD, and mental retardation ranged from mild to severe. Karyotype analysis of 1 affected individual from each family showed curly chromosomes with a high level of breakage. There were also increased numbers of prophase looking cells (80%), compared to control (13%). The features were consistent with premature chromosome condensation. Tommerup et al. (1993) reported a Danish girl, born of consanguineous parents, with microcephaly, craniosynostosis, ptosis, bird-like facies with micrognathia, and moderate mental retardation, associated with a highly increased frequency of spontaneous chromosome breakage. In addition, unique cellular features included endomitosis and hypersensitivity to clastogenic agents as observed in phytohemagglutinin-stimulated peripheral lymphocytes. Both the alkyating agent Trenimon and the radiomimetic drug bleomycin produced an abnormal frequency of changes. Abnormal chromosomal spiralization and some aspects of abnormal cellular division were also observed. In the patient reported by Tommerup et al. (1993), Farooq et al. (2010) identified a homozygous truncating mutation in the MCPH1 gene (S101X; 607117.0007), thus widening the phenotypic spectrum of MCPH1-related diseases.
In 2 families with primary microcephaly sharing an ancestral 8p23 haplotype, Jackson et al. (2002) identified a homozygous mutation in the microcephalin gene (S25X; 607117.0001). All 7 affected individuals were homozygous for the mutation, and their 8 unaffected ... In 2 families with primary microcephaly sharing an ancestral 8p23 haplotype, Jackson et al. (2002) identified a homozygous mutation in the microcephalin gene (S25X; 607117.0001). All 7 affected individuals were homozygous for the mutation, and their 8 unaffected parents were heterozygous for the mutation. In the 2 sibs from the family with microcephaly and premature chromosome condensation originally reported by Neitzel et al. (2002), Trimborn et al. (2004) identified a homozygous 1-bp insertion, 427insA, in the MCPH1 gene (607117.0002). The mutation was present in heterozygous state in the parents and was not present in 220 control alleles. In 6 affected members of a consanguineous Iranian family with mental retardation, mild microcephaly, and premature chromosome condensation in at least 10 to 15% of cells, Garshasbi et al. (2006) identified a homozygous deletion in the MCPH1 gene (607117.0003). Short stature was also a feature in the 2 affected females. Darvish et al. (2010) identified 8 different homozygous mutations in the MCPH1 gene (see, e.g., 607117.0004-607117.0006) in 8 (8.7%) of 112 Iranian families with primary microcephaly, mental retardation, and premature chromosome condensation. Six of the mutations were predicted to result in a truncated protein. One of the families and the corresponding mutation had been reported by Garshasbi et al. (2006).
In the Netherlands, the frequency of true microcephaly was placed at about 1 in 250,000 by Van den Bosch (1959).
Scala et al. (2010) found no mutations in the MCPH1 gene in a large cohort of ... In the Netherlands, the frequency of true microcephaly was placed at about 1 in 250,000 by Van den Bosch (1959). Scala et al. (2010) found no mutations in the MCPH1 gene in a large cohort of nonconsanguineous patients with microcephaly who did not have mutations in the ASPM gene (605481). The cohort included 81 unrelated patients (78% Caucasian, 16% Arab, 6% other). Thirty-four patients met the strict MCPH criteria of congenital microcephaly at least -4 SD, mental retardation, and no brain malformations; 47 patients met the expanded criteria of microcephaly -2 to -3 SD, possible brain malformations, and borderline-to-normal intellectual function. In each group, about 19% had borderline mental retardation and about 23% had seizures. The findings indicated that MCPH1 mutations are not common in populations with a low prevalence of consanguinity.