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Genes Identified Joubert Syndrome Russell Ferland, in collaboration with Wafaa Eyaid in Saudi Arabia as well as other clinicians in Saudi Arabia and Turkey, recently identified a gene that causes Joubert syndrome. Individuals affected with Joubert syndrome typically show weakness, abnormal breathing and eye movements, clumsiness, developmental delay and autism. MRI findings include absence of the cerebellar vermis and the “molar tooth sign” formed by an abnormal configuration of the superior cerebellar peduncles that connect the cerebellum to the midbrain and thalamus. Homozygous mutations in the Abelson helper integration site gene (AHI1) were found in individuals with Joubert syndrome in three of the five consanguineous families studied (Ferland et al., Nature Genetics 36(9): 1008-13, 2004). Bilateral Frontoparietal Polymicrogyria Xianhua Piao in our laboratory along with Lina Basel-Vanagaite at the Rabin Medical Center in Israel originally mapped Bilateral Frontoparietal Polymicrogyria (BFPP) to 16q12.2-21 (Piao et al., Am J Hum Genet 70: 1028-1033, 2002). After this publication, we enrolled several additional families with BFPP and published the clinical and radiological features of 10 affected families (Chang et al., Ann Neurol 53(5): 596-606, 2003). We have recently discovered that the GPR56 gene is responsible for BFPP (Piao et al., Science 303(5666): 2033-6, 2004). In BFPP, the polymicrogyria is concentrated in the frontal lobes, with milder involvement of the parietal and posterior parts of the cortex. The majority of patients with BFPP demonstrate developmental delay, gait difficulty, language impairment, dysconjugate gaze, and seizures. Periventricular Nodular Heterotopia Several years ago, our laboratory identified the gene responsible for X-linked periventricular nodular heterotopia (PH), the filamin 1 (FLNA) gene (Fox et al., Neuron 21(6): 1315-25, 1998). Periventricular heterotopia is most often a disorder diagnosed in females as male pregnancies affected with X-linked PH are likely to miscarry. Females typically have seizures and show a spectrum of learning difficulties (Chang et al., Neurology 8;64(5):799-803, 2005). In PH, the neurons of the brain do not migrate during brain development to their expected location. Instead, some of them form clumps deep beneath the cerebral cortex, lining the ventricles of the brain. These heterotopia may be seen by MRI scanning as pea-sized bumps on the edges of the ventricles. PH appears to be genetically heterogeneous and we continue to look for other genes involved. Volney Sheen reported two cases of PH localizing to chromosome 5p, suggesting a new PH locus along the telomeric end of chromosome 5p (Sheen et al., Neurology 60(6): 1033-6, 2003). Microcephaly with Periventricular Heterotopia Volney Sheen originally reported two consanguineous pedigrees with PH that were suggestive of autosomal recessive inheritance (Sheen et al., Neurology 60: 1108-1112, 2003). Subsequent linkage analysis and candidate gene testing identified the causal gene as ARFGEF2 in two Turkish families (Sheen et al., Nature Genetics 36(1): 69-76, 2004). The clinical presentation of these two families differs from those with X-linked PH in that affected individuals have microcephaly, developmental delay and recurrent infections. Pontocerebellar Hypoplasia Ganeshwaran Mochida in our laboratory mapped a novel form of pontocerebellar hypoplasia to 7q11-21. Anna Rajab at the Ministry of Health in the Sultanate of Oman described this syndrome clinically and was joint first author on the publication (Rajab et al., Neurology 60: 1664-1667, 2003). Individuals with this type of pontocerebellar hypoplasia show developmental delay, progressive microcephaly with brachycephaly, seizures, hypotonia with hyperreflexia, short stature and optic atrophy. Autosomal Recessive Primary Microcephaly Researchers at the University of Leeds in the UK, in collaboration with Ganeshwaran Mochida in our laboratory, identified a gene involved in autosomal recessive primary microcephaly (MCPH) called the ASPM gene (Bond et al., Nature Genetics 32(2): 316-20, 2002). Two new genes have recently been identified by this collaborative group, CDK5RAP2 (MCPH3) and CENPJ (MCPH6) (Bond et al., Nature Genetics 37(4): 353-5, 2005). Autosomal recessive primary microcephaly is characterized by microcephaly present at birth and nonprogressive mental retardation. Lissencephaly with Cerebellar Hypoplasia Autosomal recessive lissencephaly with cerebellar hypoplasia was found to be associated with reelin (RELN) mutations by Susan Hong in our laboratory (Hong et al., Nature Genetics 26(1): 93-96, 2001). The children reported with this condition showed significant cognitive and motor delay, myopia, nystagmus, hypotonia and seizures. X-linked Mental Retardation In collaboration with Kristina Allen in our laboratory, researchers at the Institut National de la Sante et de la Recherche Medicale in France determined that mutations in the PAK3 gene can cause X-linked nonspecific mental retardation (Bienvenu et al., Am J Med Genet 93(4): 294-8, 2000). Double Cortex Syndrome/X-linked lissencephaly Joe Gleeson, Kristina Allen and Jeremy Fox identified the doublecortin (DCX) gene, which is responsible for Double Cortex syndrome/X-linked Lissencephaly (Gleeson et al., Cell 92(1): 63-72, 1998). The term “double cortex” is based on the appearance of an extra layer of neurons under the normal gray matter of brain cortex. Double Cortex syndrome occurs primarily in girls and presents commonly with seizures and developmental delay. Males with mutations in the doublecortin gene typically have lissencephaly identified on MRI with clinical features of seizures and cognitive and motor delay. |
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