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PubMed2007

The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence.

Recent studies have made great strides towards identifying putative genetic events underlying the evolution of the human brain and its emergent cognitive capacities. One of the most intriguing findings is the recurrent identification of adaptive evolution in genes associated with primary microcephaly, a developmental disorder characterized by severe reduction in brain size and intelligence, reminiscent of the early hominid condition. This has led to the hypothesis that the adaptive evolution of these genes has contributed to the emergence of modern human cognition. As with other candidate loci, however, this hypothesis remains speculative due to the current lack of methodologies for characterizing the evolutionary function of these genes in humans. Two primary microcephaly genes, ASPM and Microcephalin, have been implicated not only in the adaptive evolution of the lineage leading to humans, but in ongoing selective sweeps in modern humans as well. The presence of both the putatively adaptive and neutral alleles at these loci provides a unique opportunity for using normal trait variation within humans to test the hypothesis that the recent selective sweeps are driven by an advantage in cognitive abilities. Here, we report a large-scale association study between the adaptive alleles of these genes and normal variation in several measures of IQ. Five independent samples were used, totaling 2393 subjects, including both family-based and population-based datasets. Our overall findings do not support a detectable association between the recent adaptive evolution of either ASPM or Microcephalin and changes in IQ. As we enter the post-genomic era, with the number of candidate loci underlying human evolution growing rapidly, our findings highlight the importance of direct experimental validation in elucidating their evolutionary role in shaping the human phenotype.

Adolescent↗

PubMed1975

Ring chromosome 13 syndrome.

A girl in whom a ring chromosome 13 was found, presented with microcephaly, mental retardation and multiple minor malformations. She was born after a full term pregnancy, small for date and with a small head circumference. She underwent craniotomy at the age of 18 months because of premature closure of the metopic sutures. At age 4 1/2 years, she presented with mental retardation, microcephaly, asymmetrical mongoloid slanting of narrow palpebral fissures, bilateral epicanthic folds, broad and prominent nasal bridge, normal sized ears and open mouth. She had somewhat short second and fifth fingers, with a single crease on the right fifth finger and normal thumbs. This case supports previous reports that a clinically recognizable ring chromosome 13 syndrome can be defined.

Abnormalities, Multiple↗

PubMed1994

Multiple coagulation defects and the Cohen syndrome.

A 13-year-old male presented with new onset seizures, sagittal sinus thrombosis with cerebral hemorrhage, and extensive venous thrombosis of the lower limbs. Laboratory investigation demonstrated combined deficiency of protein C, protein S, and antithrombin III. He and his 17-year-old sister had a mental retardation-multiple anomaly syndrome associated with microcephaly, unusual facies, and lax connective tissue. Their dysmorphology included elongated faces with narrow forehead, arched eyebrows, large mouth with down-turned corners, malformed teeth, and furrowed tongue. Both had Marfanoid habitus with lax joints, pectus excavatum, kyphoscoliosis, and flat narrow feet. The most likely diagnosis for these siblings is the autosomal recessive Cohen syndrome of mental retardation, congenital hypotonia with Marfanoid habitus, microcephaly, pleasant affect, micrognathia, and open mouth with prominent incisors. The sagittal sinus thrombosis, left frontal intracranial hemorrhage, carotid aneurysm, tortuous descending aorta, and deep venous thrombosis suffered by the male sibling adds the Cohen syndrome to genetic vasculopathies that may be associated with stroke.

Adolescent↗

PubMed1981

Abnormal head circumference in learning-disabled children.

The head circumferences of 73 learning-disabled children were compared with those of a matched control population of 71 children. Macrocephaly was noted in eight learning-disabled children but in only three controls, and microcephaly was present in seven learning-disabled children but in none of the controls. Abnormal head circumferences were noted in nine learning-disabled males but in only three control males. Since this study revealed an increased prevalence of both macrocephaly and microcephaly in children with learning disabilities, future studies of such children should include accurate measurements of head circumference. It may be found that abnormal head circumference, when accompanied by other signs, can be used to identify preschool children potentially at risk for learning disabilities.

Cephalometry↗

PubMed1999

Familial epilepsy with unilateral and bilateral malformations of cortical development.

PURPOSE: To describe a family in whom two sisters with epilepsy, mental retardation, and microcephaly had different malformations of cortical development detected by magnetic resonance imaging (MRI). METHODS: Clinical investigation of the patients and their family. High-resolution MRI, cognitive testing, and repeated EEG recording in both patients. RESULTS: In one patient, the malformation was bilateral and diffuse but much more pronounced in the parietal and occipital regions, with MRI characteristics indicating pachygyria-polymicrogyria. In the other patient, the abnormality involved the right hemisphere, predominating around the perisylvian region, with MRI more clearly indicative of polymicrogyria. A brother also had severe epilepsy, diffuse EEG abnormalities, mental retardation, and microcephaly, but could not be studied neuroradiologically. CONCLUSIONS: Lack of MRI studies in the parents and brother does not allow a precise hypothesis on the mode of transmission. However, findings from this family indicate that unilateral malformations of cortical development detected during investigations after seizure onset may be genetically based, suggesting that a single genetic abnormality could be responsible for bilateral or unilateral malformations.

Adult↗

PubMed1997

Growth factor properties of VIP during early brain development. Whole embryo culture and in vivo studies.

Vasoactive intestinal peptide (VIP), a 28 amino acid neuropeptide widely distributed in the mammalian nervous system, has potent growth-related actions that influence cell division, neuronal survival, and neurodifferentiation. To address the potential effects of VIP on embryonic growth, whole postimplantation embryo cultures were used. After a 4-hour incubation, VIP stimulated growth as assessed by the following increases from control: embryonic volume (63%), DNA (103%), and protein content (63%), as well as the number of cells in S-phase (490%). No apparent histological abnormalities are produced by VIP. To assess the in vivo function of VIP in early CNS growth, a VIP antagonist (VA) was injected i.p. between E9 and E11. VA induced a dose reduction of the DNA (84% of controls) and protein (80% of controls) contents of the E11 head and a decrease of E17 brain weight (87% of controls). In contrast, body growth was less affected by the antagonist. injections of VA for a longer period (E9 to E17) did not increase the severity of the microcephaly. By ex vivo autoradiography, GTP-sensitive VIP binding sites were detected in the germinative neuroepithelium between E9 and E11, but not between E13 and E15, during neuronal migration. These data demonstrate that VIP regulates mitogenic activity in the premigratory neuroepithelium. Although this effect is limited to a short ontogenic period, blockade of VIP by a specific antagonist induces a severe microcephaly.

Amino Acid Sequence↗

PubMed2001

Fetal brain disruption sequence in a newborn infant with a history of cordocentesis at 21 weeks gestation.

The case is reported of a full term infant with severe microcephaly, overlapping sutures, prominence of the occipital bone, and scalp rugae. No other associated malformations were observed. The only obstetric history of interest was the performance of cordocentesis at 21 weeks gestational age because of low maternal alpha fetoprotein levels. Ultrasound scans performed until then were normal. Cranial growth retardation was detected on ultrasound scanning at 25 weeks and intrauterine growth retardation as well as severe microcephaly at 34 weeks. Neuroimaging studies performed on the newborn infant showed intense cerebral atrophy in both hemispheres. Other complementary investigations gave negative results. A relation is proposed between the cordocentesis and the development of vascular disruption, which could have caused the fetal brain disruption sequence in this case.

Brain↗

PubMed1993

Holoprosencephaly: a family showing dominant inheritance and variable expression.

A family with probable dominant holoprosencephaly is presented with five affected subjects in two sibships, the offspring of healthy sisters who are presumed gene carriers. Of the affected children, three had cebocephaly and died shortly after birth. One had left choanal atresia, retinal coloboma, a single central maxillary incisor, microcephaly, short stature, and learning problems. Another had only a single central maxillary incisor. The occurrence of hypotelorism, microcephaly, and unilateral cleft lip and palate as minor manifestations of the gene in possible and probable gene carriers is discussed.

Abnormalities, Multiple↗

PubMed2005

[Aicardi-Goutières syndrome: report of two new cases].

INTRODUCTION: Aicardi-Goutières syndrome is an early onset autosomal recessive progressive encephalopathy, clinically characterized by acquired microcephaly, severe psychomotor delay and involvement of pyramidal and extrapyramidal tracts. Intracranial calcifications, especially at the level of the basal ganglia, white matter abnormalities, lymphocytosis and raised interferon (IFN)-alpha in blood and cerebrospinal fluid (CSF) form part of this syndrome. CASES REPORTS: We describe two unrelated infants (a 3-month-old boy and an 11-month-old girl) who both presented with hypotonia, microcephaly, and psychomotor delay. Mild choreic and dystonic movements, as well as progressive spasticity, were also observed in the girl. Extensive investigations revealed intracranial calcifications, mild CSF lymphocytosis in the boy, and raised IFN-a in blood and CSF in both patients. COMMENTS: Aicardi-Goutières syndrome should be kept in mind when investigating microcephalic and retarded patients with cerebral calcifications initially suggestive of TORCH infection. Appropriate genetic counseling should be provided.

Brain Diseases↗

PubMed2002

Pontocerebellar hypoplasia type 2 and Reye-like syndrome.

Pontocerebellar hypoplasia is an autosomal recessive syndrome with onset during the fetal period. Two subtypes of pontocerebellar hypoplasia have been described on the basis of clinical and neuropathologic criteria. Pontocerebellar hypoplasia type 2 is characterized by progressive microcephaly, early onset of extrapyramidal dyskinesia, and near absence of motor and cognitive development, without signs of either spinal or peripheral involvement. We report a clinical observation of a patient with pontocerebellar hypoplasia type 2, a 3-year-old girl with progressive microcephaly, dystonic limb movements, and absence of motor and cognitive development. Cranial magnetic resonance imaging revealed pontocerebellar hypoplasia. At the age of 2 years, she suffered a Reye-like syndrome that worsened her condition. Differential diagnosis was established with intrauterine injuries, other malformative syndromes, and neurodegenerative or neurometabolic disorders, which can be associated with cerebellar hypoplasia.

Brain↗

PubMed2003

Autopsy case of multiple anomalies with hypoplastic cerebrum, eyes, and endocrine organs, mimicking Micro syndrome.

We report an autopsy case of multiple anomalies with severe micrencephaly, bilateral microphthalmos, and hypoplastic endocrine organs. We examined expressions of calcium-binding proteins and hypothalamic and pituitary hormones. A female proband presented with microcephaly, microphthalmia, and psychomotor development delay. At the age of 23 years, she died of cardiorespiratory failure. The endocrine organs demonstrated severe underdevelopment, and the hypoplastic eyeballs had remnant lens, vitreous hemorrhage, and retinal detachment. The brain weighed 260 g; the cerebrum, cerebellum, and brain stem were extremely small; and the tertiary sulci were absent in the cerebral surface. The cross-sectional area of cerebral cortex was reduced to about one third of those in the control, although six-layered lamination, density of pyramidal neurons, and expressions of calcium-binding proteins were comparatively preserved in the cerebral cortex. The third ventricle was hypoplastic, and the bilateral thalami appeared to be fused and the hippocampus was unrolled, whereas the corpus callosum was preserved. In the hypothalamus, the paraventricular nucleus was only identified, and the adenohypophysial somatotrophs were reduced. This may be the first autopsy report of Micro syndrome, which is characterized by microcephaly, brain malformations, optic atrophy, and hypogenitalism, although the case lacked agenesis of the corpus callosum.

Abnormalities, Multiple↗

PubMed2006

A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor.

CONTEXT: The type 1 IGF-I receptor (IGF1R) mediates the biological functions of IGF-I. Binding of IGF-I to the IGF1R results in autophosphorylation of the intracellular beta-subunit and activation of intracellular signaling. OBJECTIVE: The objective of this study was to evaluate the functional characteristics of a novel IGF1R mutation and describe the phenotypic features of two patients with this mutation. DESIGN: The study was performed in a university hospital. PATIENTS: We describe a 35-yr-old female with mild intrauterine growth failure, progressive postnatal growth retardation, severe failure to thrive, and microcephaly. Her daughter was born with severe intrauterine growth retardation and also showed postnatal failure to thrive and microcephaly. RESULTS: We found a heterozygous G3148-->A nucleotide substitution in the IGF1R gene, changing a negatively charged glutamic acid at position 1050 into a positively charged lysine residue (E1050K). E1050 is a conserved residue in the intracellular kinase domain. Dermal fibroblasts of the mother showed normal binding of iodinated IGF-I, but autophosphorylation and activation of downstream signaling cascades upon challenging with IGF-I was markedly reduced. Consequently, the maximal [(3)H]thymidine incorporation upon challenge with a dose range of IGF-I was reduced compared with a panel of control cells (3.65 +/- 1.79-fold vs. 6.75 +/- 4.7-fold stimulation; P < 0.01). These data suggest that the mutation results in the inactivation of one copy of the IGF1R gene. CONCLUSIONS: These two patients support the key role for IGF-I in intrauterine and postnatal growth. The different phenotypes of these and earlier described patients may be associated with variability in IGF-I signaling. The degree of intrauterine growth retardation may be partially determined by the presence or absence of maternal IGF-I resistance.

Adult↗

PubMed2003

A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21.

OBJECTIVE: To describe a novel form of pontocerebellar hypoplasia (PCH) and map its genetic locus. BACKGROUND: PCH is a heterogeneous group of disorders that are characterized by abnormally small cerebellum and brainstem. Autosomal recessive inheritance has been implied in many cases, but no genetic loci have been mapped to date. METHODS: The authors studied a consanguineous family from the Sultanate of Oman with three siblings with a novel form of PCH. The authors performed clinical studies and linkage analysis of this pedigree. RESULTS: The clinical features of the affected children include developmental delay, progressive microcephaly with brachycephaly, seizures during the first year of life, hypotonia with hyperreflexia, short stature, and optic atrophy. Imaging studies showed a small pons and cerebellum, prominent sulci and lateral ventricles, and decreased cerebral white matter volume. A lack of dyskinesias distinguishes this pedigree from PCH type 2. Genetic studies of this family revealed evidence of significant linkage to chromosome 7q11-21 (maximum multipoint lod score 3.23). CONCLUSIONS: This pedigree represents a novel form of autosomal recessive PCH, which the authors propose to call cerebellar atrophy with progressive microcephaly (CLAM). This disorder maps to chromosome 7q11-21, and this locus was named CLAM. This report represents the first identification of a genetic locus for PCH.

Abnormalities, Multiple↗

PubMed1999

Filippi syndrome: report of three additional cases.

Filippi syndrome is an autosomal recessive condition characterized by variable soft tissue syndactyly of the fingers and toes, microcephaly, pre- and postnatal growth retardation, mildly abnormal craniofacial appearance, and mental retardation. We report on three unrelated individuals with Filippi syndrome. All have microcephaly, minor facial anomalies, variable syndactyly of digits, growth impairment, and developmental delay. One patient also has polydactyly, which has not been reported previously in the Filippi syndrome.

Abnormalities, Multiple↗

PubMedDate not supplied

Clinical features of 21 patients with lissencephaly type I (agyria-pachygyria).

Lissencephaly (agyria-pachygyria) is the most severe neuronal migration disorder, characterized by total or partial absence of gyri. In this study, 21 patients with lissencephaly type I (9 girls, 12 boys) with a mean age of 19 +/- 21 months (2 weeks-8 years) were evaluated clinically and graded according to neuroradiological findings (19 patients by magnetic resonance imaging MRI and 2 by computed tomography CT). Three patients were classified as lissencephaly grade 2 and 18 patients as grade 3 or 4. Clinically, 12 patients (57%) had microcephaly, and eight (38%) had facial dysmorphism. All the patients had prominent psychomotor retardation, moderate to severe; the most frequent neurological findings were spastic guadriplegia (36.4%) and hypotonia with exaggerated tendon reflexes (27.3%). Seventy-eight percent of the patients had epileptic seizures resistant to conventional treatment. Lissencephaly is a cerebral cortical malformation that should be considered in children with developmental delay with or without microcephaly and facial dysmorphism. In addition, it should be investigated in the etiology of early-onset childhood epilepsy.

Abnormalities, Multiple↗

PubMed2001

Brain dysmorphology in individuals with severe prenatal alcohol exposure.

Our previous studies revealed abnormalities on structural MRI (sMRI) in small groups of children exposed to alcohol prenatally. Microcephaly, disproportionately reduced basal ganglia volume, and abnormalities of the cerebellar vermis and corpus callosum were demonstrated. The present study used sMRI to examine in detail the regional pattern of brain hypoplasia resulting from prenatal exposure to alcohol using a higher resolution imaging protocol and larger sample sizes than reported previously. Fourteen participants (mean 11.4 years; eight females, six males) with fetal alcohol syndrome (FAS) and 12 participants (mean 14.8 years; four females, eight males) with prenatal exposure to alcohol (PEA) but without the facial features of FAS were compared to a group of 41 control participants (mean 12.8 years, 20 females, 21 males). Findings of significant microcephaly and disproportionately reduced basal ganglia volumes in the FAS group were confirmed. Novel findings were that in FAS participants, white matter volumes were more affected than gray matter volumes in the cerebrum, and parietal lobes were more affected than temporal and occipital lobes. Among subcortical structures, in contrast to the disproportionate effects on caudate nucleus, the hippocampus was relatively preserved in FAS participants. Differences between the PEA group and controls were generally non-significant; however, among a few of the structures most affected in FAS participants, there was some evidence for volume reduction in PEA participants as well, specifically in basal ganglia and the parietal lobe. There were no group differences in cerebral volume asymmetries. Severe prenatal alcohol exposure appears to produce a specific pattern of brain hypoplasia.

Adolescent↗

PubMed1997

Cortical fiber distribution in the somatosensory cortex of rats following prenatal exposure to X-irradiation.

Exposure of fetal rats to X-irradiation at a dose of 1.5 Gy on gestational day 15 results in severe microcephaly. In these X-irradiated rats with microcephaly, a possible alteration of local circuits in the somatosensory cortex was examined using a fluorescent dye, DiI. The dye was placed at the superficial part of the transversely sectioned somatosensory cortex just beneath the pial surface of both the control and X-irradiated rats on postnatal day 11. In the controls, DiI-labeled fibers showed a layer-dependent distribution in the somatosensory cortex, whereas in the X-irradiated rats, this layer-dependent distribution of DiI-labeled fibers was distorted. Furthermore, the fasciculus observed beneath cortical layer VI (white matter), which was made of DiI-labeled axons originating from the cortical neurons, was well developed in the controls. On the other hand, in the X-irradiated rats, the fasciculus made of DiI-labeled fibers was split, reduced in number, and irregularly distributed. These observation suggest that prenatal exposure of fetal rats to X-irradiation may affect the development of local circuits in the cerebral cortex, and may also damage the axonal projection of cortical neurons to the thalamus.

Abnormalities, Radiation-Induced↗

PubMedDate not supplied

Aicardi-Goutières syndrome: differential diagnosis and aetiopathogenesis.

Aicardi-Goutières syndrome (AGS) is a progressive encephalopathy with onset in the first year of life and a recessive autosomal pattern of inheritance. The syndrome is characterised by acquired microcephaly, basal ganglia calcifications, white matter abnormalities, chronic cerebrospinal fluid (CSF) lymphocytosis and raised interferon-alpha (INF-alpha) in the CSF. AGS is diagnosed on the basis of a clinical picture characterised by microcephaly and by the onset of encephalopathy associated with severe psychomotor delay, spasticity and extrapyramidal signs. CT is very important in the diagnosis of AGS, demonstrating clearly the presence of calcifications at basal ganglia level: these are often bilateral and symmetrical. CT scan and MRI reveal leukodystrophy and progressive cerebral atrophy. A raised level of INF-alpha in the CSF constitutes a marker of the syndrome: this level, which falls with age, is higher in the CSF than in the serum, suggesting intrathecal synthesis. Differential diagnosis in AGS is carried out to exclude the presence of other neurological and endocrinological pathologies characterised by the presence of intracranial calcification; considering the white matter abnormalities, it is necessary to exclude forms of leukodystrophy associated with metabolic defects, known or otherwise. One fundamental aspect that remains to be clarified is the aetiopathogenetic mechanism underlying AGS: the most well-founded hypotheses are reported. There does not exist, to date, any causal therapy for AGS, although genetic studies, particularly those focusing on interferon-regulating genes, may well provide some therapeutic indications.

Basal Ganglia Diseases↗