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PubMedDate not supplied

An Italian family affected by autosomal dominant microcephaly with chorioretinal degeneration.

PURPOSE: We studied an Italian family affected by the autosomal dominant form of microcephaly and chorioretinal degeneration that was characterized by various degrees of clinical expression. METHODS: An ophthalmologic examination, including visual acuity, visual field testing, an electroretinogram, and fundus photography, and a neurologic examination, including neurodevelopmental status and neuroimaging studies, were performed for all subjects. Skeletal radiography, chromosome studies, and serologic investigations were also performed. RESULTS: In this family, only two of the six affected members had an association of microcephaly, myopia, and chorioretinal degeneration. The other family members showed microcephaly, slight mental retardation, and short stature, but not chorioretinopathy. CONCLUSIONS: The significant finding in members from this dominant pedigree of microcephaly was the association of short stature and high myopia, heretofore seen only in families with recessive microcephaly. These findings could be useful for genetic counseling in the apparently isolated forms of microcephaly with chorioretinopathy.

Adult↗

PubMed2006

Microcephalin: a causal link between impaired damage response signalling and microcephaly.

Seckel Syndrome (SS) and Primary Microcephaly (MCPH) are disorders exhibiting marked microcephaly with a head circumference less than three standard deviations below the mean. ATR-Seckel Syndrome is conferred by mutations in ataxia and telangiectasia and Rad3 related (ATR), a kinase that activates a DNA damage signalling response. Cell lines from additional SS patients, who are normal for ATR, show defective ATR signalling, suggesting that they carry mutations in other components of the ATR pathway. Primary Microcephaly is distinct from SS since patients display solely microcephaly without accompanying marked growth delay. MCPH1, the first Primary Microcephaly causative gene identified, encodes three BRCT domains, similar to other damage response proteins. Recent studies employing MCPH1 siRNA or exploiting cell lines from MCPH1 patients have shown that MCPH1 functions in the ATR-dependent DNA damage response pathway. Additionally, MCPH1 has a function in the regulation of mitotic entry that is ATR-independent and confers a characteristic phenotype of premature chromosome condensation. Recent studies will be reviewed and their relationship to the aetiology of microcephaly discussed.

Ataxia Telangiectasia Mutated Proteins↗

PubMed1984

Is a gene for microcephaly located on chromosome 1?

A 3-month-old boy with true microcephaly showed the same balanced reciprocal translocation 1q4p as his carrier mother. This reciprocal translocation had been transmitted for at least four generations. Different banding techniques allowed one to describe the rearrangement as: rcp t(1;4) (1pter----1q31::4p161----4pter; 4qter----4p153::1q321----1qter). On the other hand, the proband's father seemed to be a border-line mentally retarded and one of his relatives suffered from mental retardation of unknown origin. Taking into account all these results together with the current literature, it was concluded that the microcephaly appearing in our case could be due to the following two facts: (a) the father was an heterozygote for the gene for microcephaly, and (b) damage or a minute deletion on chromosome 1 between 1q31 and 1q321 bands could occur in the mother's family resulting in a mutation for microcephaly. If this was so, the gene for microcephaly should be located on chromosome 1 at the level of the 1q31-1q321 junction.

Adult↗

PubMed2004

A critical role of Pax6 in alcohol-induced fetal microcephaly.

Maternal alcohol abuse during pregnancy is one of the leading causes of birth defects in humans. Despite extensive studies, the molecular basis is still not clear. Here we transiently exposed Xenopus embryos to alcohol and showed that alcohol dose-dependently produced microcephaly and growth retardation. Moreover, it reduced the expression of several key neural genes (xPax6, xOtx2, xSox3, xSox2, and xNCAM), of which xPax6 was most vulnerable. An alcohol concentration as low as 0.3% could produce more than 90% reduction of xPax6 expression. Consistently, microinjection of xPax6 expression plasmid to Xenopus embryos dose-dependently rescued alcohol-induced microcephaly and restored the expression of xOtx2, xSox3, xSox2, and xNCAM. To test whether reactive oxygen species (ROS) is the upstream signal for alcohol-induced microcephaly and xPax6 suppression, we overexpressed catalase in Xenopus embryos and found that catalase not only decreased alcohol-induced H(2)O(2) formation, but also fully restored Pax6 expression and reversed microcephaly. In contrast, xPax6 and catalase could only provide partial protection against growth retardation. Results from this study illustrate for the first time the critical role of H(2)O(2)-mediated Pax6 suppression in alcohol-induced microcephaly and suggest the presence of additional mechanisms for alcohol-induced fetal growth retardation.

Animals↗

PubMed1992

Autosomal recessive microcephaly with severe psychomotor retardation.

Autosomal recessive microcephaly has long been recognized in association with normal early motor development and mild to severe mental retardation. We report three sibling pairs with microcephaly and severe neurological impairment. These cases and other sibling pairs reported in the literature illustrate that microcephaly with spasticity and severe mental retardation may also have autosomal recessive inheritance. Furthermore this severely affected group of patients forms a significant proportion of cases of genetic microcephaly. We looked for specific morphological features to identify these forms of genetic microcephaly for genetic counselling, but failed to find characteristic abnormalities among our group of patients.

Adolescent↗

PubMed1999

Acquired microcephaly after low Apgar score in Zimbabwe.

Serial head circumference measurements were made on 165 African babies born with a 5 min Apgar score of 5 or less. Measurements were taken at birth and at 4, 9, and 12 months of age. In the majority of infants the onset of microcephaly could be diagnosed as early as 4 months of age. Twenty-five of the 142 infants were microcephalic at 1 year. Neurological development was impaired in 19 of the 25 (76 per cent) microcephalic infants and in 18 of the 117 (15 per cent) normocephalic infants. Fourteen of the 16 (88 per cent) infants with severe quadriplegia developed microcephaly before the age of 4 months. A decreased rate of head growth during the first 4 months of life in African infants born with a low Apgar score correlates closely with the development of microcephaly. Infants with an acquired microcephaly have a high probability of developing neurologic impairment by the age of 1 year. Serial head circumference measurement in low Apgar score babies in developing countries is an easy, simple, and inexpensive method to detect microcephaly.

Analysis of Variance↗

PubMed2000

A case-control etiologic study of microcephaly.

We studied the possible environmental factors in the origin of microcephaly by comparing the exposures of 109 infants with isolated microcephaly with those of two matched population controls, in addition to those of 812 patient controls (that is, infants with Down syndrome). Cases and patient controls were selected from the large population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities registered between 1980 and 1996, whereas matched population controls were selected from the national birth registry. We found that there were more females than males among cases with isolated microcephaly. Evaluation of birth weight and gestational age indicated intrauterine growth retardation among microcephalic patients. The use of clotrimazole was higher among mothers in the matched population control group than among mothers of cases. Maternal use of a large dose (about 6 mg per day) of folic acid and more than 50 mg per day of iron during pregnancy was associated with a 40-50% decrease in microcephaly. Thus, the pharmacological doses of folic acid and iron may have some preventive effect against isolated primary microcephaly.

Case-Control Studies↗

PubMed2001

Molecular genetics of human microcephaly.

Human microcephaly comprises a heterogeneous group of conditions that are characterized by a failure of normal brain growth. Microcephaly can be caused by many injurious or degenerative conditions, or by developmental malformations in which the growth of the brain is impaired as a result of defects in pattern formation, cell proliferation, cell survival, cell differentiation, or cell growth. These latter forms of congenital microcephaly are frequently inherited, usually as recessive traits, and are associated with mental retardation and sometimes epilepsy. Some of the genes that cause congenital microcephaly are likely to control crucial aspects of neural development, and may also be involved in the evolutionary explosion of cortical size that characterizes primates. There has recently been a rapid advance in the use of genetic mapping techniques to identify genetic loci responsible for microcephaly. Although several loci have been mapped, the condition is clearly genetically and clinically heterogeneous.

Brain↗

PubMed1975

A possible major contribution to mental retardation in the general population by the gene for microcephaly.

In a study of 13 families with genetic microcephaly, it was found that 11 of 24 parents (two fathers not ascertained) and 11 of 33 non-microcephalic siblings were of subnormal intelligence. In a rare autosomal recessive condition, all parents and two-thirds of unaffected siblings are presumed carriers of the gene. It so, nearly 50% of all presumed heterozygotes in the present study were mentally retarded. The proportion agrees well with the other major study of microcephaly in North America, but differs from the Dutch study. On the basis of pooled data from the three studies and the estimated incidence of 1:40000 for genetic microcephaly, it is postulated that (1) about 0.34% of the general population is mentally retarded because it is carrying the gene for microcephaly and (2) about one of nine mentally retarded individuals is heterozygous for the gene for microcephaly.

Adolescent↗

PubMed1994

Early prediction of the development of microcephaly after hypoxic-ischemic encephalopathy in the full-term newborn.

The development of microcephaly after significant hypoxic-ischemic cerebral injury in the full-term newborn has major prognostic significance. However, the onset of microcephaly in this context may be delayed more than 12 months. OBJECTIVES. To determine whether serial head circumference measurements and decreased rate of head growth in asphyxiated full-term newborns during the first few months of life may predict the development of eventual microcephaly. METHODOLOGY. Serial head circumference measurements at 4, 8, and 18 months of age were obtained in 54 full-term newborns who had acute, hypoxic-ischemic encephalopathy. The rate of head growth was determined on the basis of changes in head circumference ratios which are calculated as follows: actual head circumference/mean head circumference for age x 100%. Head circumference ratios were correlated with severity of newborn encephalopathy and outcome at 18 months. RESULTS. A decrease in head circumference ratios of > 3.1% between birth and 4 months of age was highly predictive of the eventual development of microcephaly before 18 months (sensitivity 90%, specificity 85%). CONCLUSIONS. These data demonstrate that serial head circumference measurements during the first 4 months of life and calculation of decreased rate of head growth in full-term newborns with hypoxic-ischemic encephalopathy may predict microcephaly before its actual occurrence.

Brain Ischemia↗

PubMed1996

Segregation analysis of microcephaly.

Microcephaly is a heterogeneous disorder with genetic and environmental causes. However, there is little information on what proportion of cases are caused by inherited susceptibility, or the mode of inheritance in familial cases. To address these questions, we have performed classical and complex segregation analyses for microcephaly on 2 sets of family data collected from genetic counseling clinics in Vancouver and Jerusalem. These samples consisted of 143 affected individuals in 127 families ascertained from Vancouver, and 101 affected individuals in 59 families ascertained from Jerusalem. The results of the segregation analyses for the Vancouver sample indicated that approximately half of all microcephaly cases were due to highly penetrant recessive mutant alleles, with the remainder being sporadic. Although a recessive model allowing for the occurrence of sporadic cases fit the data from Vancouver best, a dominant model could not be statistically rejected. The classical segregation analysis on the Jerusalem sample suggested that both a dominant model with 29% of the cases being sporadic and a purely recessive model provided adequate fit to the data. Although the complex segregation analysis of this sample indicated that a dominant model provided a more parsimonious explanation for the observed familial variation, a recessive model was only marginally rejected. It should be noted that in the Jerusalem sample, families tended to be ascertained in the genetic counseling clinic only after the birth of a second affected child. This could be a potential bias which could inflate the segregation ratio, thus giving the impression of dominant inheritance. Our analyses, while confirming the complex nature of the cause of microcephaly, indicate that it may be necessary to await the results of genetic linkage analysis before a definitive mode of inheritance can be determined.

Alleles↗

PubMed1987

Autosomal recessive nonsyndromal microcephaly with normal intelligence.

Autosomal recessive microcephaly is usually associated with moderate to severe mental retardation. An apparently new autosomal recessive disorder comprising a characteristic facial appearance associated with microcephaly and normal intelligence, immunodeficiency, and increased risk for lymphoreticular malignancies has been described recently. We report on a large Arab kindred with frequent consanguineous marriages and eight cases in five sibships with microcephaly, peculiar facies, and normal intelligence. Of these cases, two died of an acute lymphoreticular malignancy or bronchopneumonia. Immunological and chromosomal studies carried out for the three affected living sibs were normal. The existence of an autosomal recessive nonsyndromal variant of microcephaly with normal intelligence is proposed and discussed.

Adolescent↗

PubMed2003

Oligoyric microcephaly in a child with Williams syndrome.

We report a 19-month-old boy with microcephaly, growth and developmental delay, facial dysmorphisms, and simplified gyral pattern. Magnetic resonance imaging (MRI) examination demonstrated microcephaly with simplified gyral pattern or oligogyric microcephaly. The facial phenotype was interpreted as suggestive of Williams syndrome (WS). Fluorescence in situ hybridization (FISH) analysis performed with an elastin probe revealed a deletion in the chromosomal band 7q 11.23, confirming the clinical diagnosis. To our knowledge, this represents the first patient with WS and oligogyric microcephaly.

Abnormalities, Multiple↗

PubMed1980

Ultrasound criteria for in utero diagnosis of microcephaly.

Microcephaly (small head) is clinically important only if there is concomitant micrencephaly (small brain). Extensive studies on patients in mental institutions have shown that there is close correlation among microcephaly, micrencephaly, and mental retardation when the head is more than three standard deviations below the norm. If the small head is less than two standard deviations below the norm, no strong correlation exists with eigher small brain or mental retardation. High-resolution ultrasound permits imaging of the fetal head in utero, allowing accurate evaluation of head size and detection of intracranial anomalies. The microcephalics detected in utero over a 2-year period form the basis of this series, showing close correlation with the known clinical data on children with microcephaly. An approach to ultrasound detection and evaluation of fetal microcephaly is proposed.

Female↗

PubMed1984

The diagnosis of fetal microcephaly.

Of 16 fetuses in whom microcephaly was suspected, nine (56.2%) were affected with microcephaly, and seven (43.8%) were unaffected. Subsequently, nomograms with mean and SDs for biparietal diameter, occipitofrontal diameter, head perimeter: bdominal perimeter, biparietal diameter:femur length, and femur length:head perimeter we derived. With the use of the data from 27 sonograms of the 16 fetuses, different thresholds of abnormality were tested. Three standard deviations from the mean for biparietal diameter, occipitofrontal diameter, head perimeter, and femur length:head perimeter were sensitive thresholds for the diagnosis of fetal microcephaly with no false negative diagnoses. Four standard deviations from the mean for occipitofrontal diameter, head perimeter:abdominal perimeter, and femur length:head perimeter were specific tests with no false positive diagnoses. The use of multiple diagnostic tests was necessary to improve accuracy in the diagnosis of fetal microcephaly. Further clinical studies are needed to delineate more clearly optimal tests and thresholds of abnormality.

Anthropometry↗

PubMed2006

Neuronal apoptosis and gray matter heterotopia in microcephaly produced by cytosine arabinoside in mice.

Primary microcephaly can be accompanied by numerous migration anomalies. This experiment was undertaken to examine the pathogenesis of gray matter heterotopia and microcephaly that is produced after administering cytosine arabinoside (Ara-C) to mice. Pregnant mice were intraperitoneally injected with Ara-C at 30 mg/kg body weight on days 13.5 and 14.5 of gestation, and then their offspring were examined. On embryonic day 15.5, in the ventricular zone of the cingulate cortex, the neuroepithelial cells lacked BrdU immunoreactivity. Nestin-immunoreactive radial glial fibers and calretinin-positive subplate fibers were disrupted. TUNEL reaction was remarkable throughout the cerebral hemisphere. Subcortical heterotopia in the cingulate cortex and subependymal nodular heterotopia in the dorsolateral part of the lateral ventricles became detectable by the first day after birth. Thirty-two days after birth, microcephaly was apparent; subcortical heterotopia was observed to have increased in size while it was still located in the frontal and cingulate cortices. This experiment demonstrated that Ara-C induces neuronal apoptosis throughout the cerebral hemisphere. The immunohistochemical characteristics in the gray matter heterotopia suggest that both the subcortical and the subependymal heterotopias were formed by neurons originally committed to the neocortex. We conclude that the gray matter heterotopia that accompanies the microcephaly was produced by a disturbance of radial, tangential, and interkinetic neuronal migrations due to the toxicity of Ara-C in the immature developing brain.

Animals↗

PubMed2006

What primary microcephaly can tell us about brain growth.

Autosomal recessive primary microcephaly (MCPH) is a neuro-developmental disorder that causes a great reduction in brain growth in utero. MCPH is hypothesized to be a primary disorder of neurogenic mitosis, leading to reduced neuron number. Hence, MCPH proteins are likely to be important components of cellular pathways regulating human brain size. At least six genes can cause this disorder and four of these have recently been identified: autosomal recessive primary microcephaly 1 (MCPH1), abnormal spindle-like, microcephaly associated (ASPM), cyclin-dependent kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) and centromere protein J (CENPJ). Whereas aberration of ASPM is the most common cause of MCPH, MCPH1 patients can be more readily diagnosed by the finding of increased numbers of "prophase-like cells" on routine cytogenetic investigation. Three MCPH proteins are centrosomal components but have apparently diverse roles that affect mitosis. There is accumulating evidence that evolutionary changes to the MCPH genes have contributed to the large brain size seen in primates, particularly humans. The aim of this article is to review what has been learnt about the rare condition primary microcephaly and the information this provides about normal brain growth.

Animals↗

PubMed2004

Nijmegen breakage syndrome in 13% of age-matched Czech children with primary microcephaly.

The Nijmegen breakage syndrome is a rare autosomal recessive chromosomal instability disorder characterized by early growth retardation, congenital microcephaly, immunodeficiency, borderline mental development, and a high tendency to lymphoreticular malignancies. Most Nijmegen breakage syndrome patients are of Slavonic origin, and all of them known so far carry a founder homozygous 5 nucleotide deletion in the NBS1 gene. Microcephaly was present in 100% of Nijmegen breakage syndrome patients in a recent large international cooperative study. The frequency of Nijmegen breakage syndrome among children with primary microcephaly was not known. Early correct diagnosis of the syndrome is crucial for appropriate preventive care and therapy. We tested 67 Czech patients of different ages with simple microcephaly for the presence of the most common mutation in the NBS1 gene. Three new Nijmegen breakage syndrome cases were detected in this cohort, representing 4.5% of the cohort. All these newly diagnosed Nijmegen breakage syndrome patients were younger than 10 months at the time of diagnosis. They were all born within a 2.5-year period. Twenty-three of the 67 children in the cohort were born within this 2.5-year period, representing a 13% incidence of Nijmegen breakage syndrome. Frequency of Nijmegen breakage syndrome heterozygotes among infants in the Czech Republic is 1: 130-158 and the birth rate is 90,000 per year, therefore in the time span of 2.5 years, three new Nijmegen breakage syndrome homozygotes are expected to be born. Therefore we assume that by DNA testing of Czech primary microcephalic children it is possible to detect all Nijmegen breakage syndrome patients to be expected. The age at correct diagnosis was lowered from 7.1 years at the time before DNA testing, to well under 1 year of age. All new Nijmegen breakage syndrome patients could receive appropriate preventive care, which should significantly improve their life expectancy and prognosis.

Adolescent↗