Alternative titles; symbols
ORPHA: 2512; DO: 0070285;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8p23.1 | Microcephaly 1, primary, autosomal recessive | 251200 | Autosomal recessive | 3 | MCPH1 | 607117 |
A number sign (#) is used with this entry because of evidence that primary microcephaly-1 (MCPH1) is caused by homozygous mutation in the gene encoding microcephalin (MCPH1; 607117) on chromosome 8p23.
Primary microcephaly refers to the clinical finding of a head circumference more than 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. See MCPH2 (604317), caused by mutation in the WDR62 gene (613583) on chromosome 19q13; MCPH3 (604804), caused by mutation in the CDK5RAP2 gene (608201) on 9q33; MCPH4 (604321), caused by mutation in the CASC5 gene (609173) on 15q14; MCPH5 (608716), caused by mutation in the ASPM gene (605481) on 1q31; MCPH6 (608393), caused by mutation in the CENPJ gene (609279) on 13q12; MCPH7 (612703), caused by mutation in the STIL gene (181590) on 1p33; MCPH8 (614673), caused by mutation in the CEP135 gene (611423) on 4q12; MCPH9 (614852), caused by mutation in the CEP152 gene (613529) on 15q21; MCPH10 (615095), caused by mutation in the ZNF335 gene (610827) on 20q13; MCPH11 (615414), caused by mutation in the PHC1 gene (602978) on 12p13; MCPH12 (616080), caused by mutation in the CDK6 gene (603368) on 7q21; MCPH13 (616051), caused by mutation in the CENPE gene (117143) on 4q24; MCPH14 (616402), caused by mutation in the SASS6 gene (609321) on 1p21; MCPH15 (616486), caused by mutation in the MFSD2A gene (614397) on 1p34; MCPH16 (616681), caused by mutation in the ANKLE2 gene (616062) on 12q24; MCPH17 (617090), caused by mutation in the CIT gene (605629) on 12q24; MCPH18 (617520), caused by mutation in the WDFY3 gene (617485) on 4q21; MCPH19 (617800), caused by mutation in the COPB2 gene (606990) on 3q23; MCPH20 (617914), caused by mutation in the KIF14 gene (611279) on 1q31; MCPH21 (617983), caused by mutation in the NCAPD2 gene (615638) on 12p13; MCPH22 (617984), caused by mutation in the NCAPD3 gene (609276) on 11q25; MCPH23 (617985), caused by mutation in the NCAPH gene (602332) on 2q11; MCPH24 (618179), caused by mutation in the NUP37 gene (609264) on 12q23; MCPH25 (618351), caused by mutation in the MAP11 gene (618350) on 7q22; MCPH26 (619179), caused by mutation in the LMNB1 gene (150340) on 5q23; MCPH27 (619180), caused by mutation in the LMNB2 gene (150341) on 19p13; MCPH28 (619453), caused by mutation in the RRP7A gene (619449) on 22q13; MCPH29 (620047), caused by mutation in the PDCD6IP gene (608074) on 3p22; and MCPH30 (620183), caused by mutation in the BUB1 gene (602452) on 2q14.
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 alkylating 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.
Neitzel et al. (2002) reported 2 sibs, born of consanguineous parents, with microcephaly, growth retardation, and severe mental retardation. Chromosome analysis showed a high frequency of prophase-like cells (more than 10%) in lymphocytes, fibroblasts, and lymphoblast cell lines, with an otherwise normal karyotype. Pulse-labeling with (3)H-thymidine and autoradiography showed that, 2 hours after the pulse, 28 to 35% of the prophases were labeled, compared with 9 to 11% in healthy control subjects, indicating that the phenomenon is due to premature chromosome condensation in the early G2 phase. Flow cytometry studies showed that the cell cycle was not prolonged and compartment sizes did not differ from controls. There was also no increased reaction of the cells to X irradiation or to the clastogens bleomycin and mitomycin C, in contrast to results in the cell-cycle mutants ataxia-telangiectasia (208900) and Fanconi anemia (FANCA; 227650). The rates of sister chromatid exchanges and the mitotic nondisjunction rates were 'inconspicuous.' Premature entry of cells into mitosis suggested that mutation in a gene involved in cell-cycle regulation. Neitzel et al. (2002) pointed out that in mammals there is only 1 description of an in vitro mutation (in a hamster cell line) that undergoes premature chromosome condensation at a nonpermissive temperature (Kai et al., 1986; Uchida et al., 1990). This mutation is complemented by the human RCC1 gene (179710). On the basis of homozygosity mapping with highly polymorphic microsatellite DNA markers flanking RCC1 on human 1q36.1, Neitzel et al. (2002) excluded RCC1 as a candidate for the premature chromosome condensation in the sibs they studied. A number of other candidate genes were excluded.
Primary microcephaly is usually inherited as an autosomal recessive trait. Kloepfer et al. (1964) reported an extensive pedigree segregating microcephaly in an autosomal recessive pattern.
Jackson et al. (1998) mapped a locus for a form of primary microcephaly, MCPH1, to chromosome 8p23 by homozygosity mapping of 2 consanguineous Pakistani families. Their results indicated that the gene lies within a 13-cM region between markers D8S1824 and D8S1825 (maximum multipoint lod score = 8.1 at D8S277).
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).
Bond et al. (2005) noted that the ASPM, CDK5RAP2, and CENPJ genes, each of which is mutant in a form of MCPH, encode proteins that are centrosomal components during mitosis, which emphasized the key role of the centrosome in each major stage of the development and function of the nervous system.
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.
Microcephaly can result from exposure of the human fetus to x-rays (Plummer, 1952).
Rizzo and Pavone (1995) described a brother and sister with severe microcephaly associated with small ears, markedly protruding midface, curved nose, and pronounced retrognathia. The brother had borderline/normal intelligence, episodic seizures, and clumsiness; the sister had a normal IQ and neither seizures nor behavioral abnormalities. The authors concluded that this condition was separate and distinct from autosomal recessive microcephaly, the so-called microcephalia vera, because of the normal or near-normal intelligence and the striking facial features.
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