RESUMO
Cisplatin is a common chemotherapy drug with a nearly universal side effect of ototoxicity. The cellular mechanisms underlying cisplatin ototoxicity are poorly understood. Efforts in drug development to prevent or reverse cisplatin ototoxicity have largely focused on pathways of oxidative stress and apoptosis. An effective treatment for cisplatin ototoxicity, sodium thiosulfate, is associated with reduced survival in disseminated hepatoblastoma, highlighting the need for more specific drugs. The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways have been shown to be involved in the pathogenesis of noise-induced hearing loss and cochlear synaptopathy in vivo , and these pathways have been implicated broadly in cisplatin cytotoxicity. This study sought to determine whether the UPR can be targeted to prevent cisplatin ototoxicity. Neonatal cochlear cultures and HEK cells were exposed to cisplatin and UPR-modulating drugs, and UPR marker gene expression and cell death measured. Treatment with ISRIB, a drug that activates eif2B and downregulates the pro-apoptotic PERK/CHOP pathway of the UPR, was tested in an in vivo mouse model of cisplatin ototoxicity and well as a head and neck squamous cell carcinoma (HNSCC) cell-based assay of cisplatin cytotoxicity. Cisplatin exhibited a biphasic, non-linear dose-response of cell death and apoptosis that correlated with different patterns of UPR marker gene expression in HEK cells and cochlear cultures. ISRIB treatment protected against cisplatin-induced hearing loss and hair-cell death, but did not impact cisplatin's cytotoxic effects on HNSCC cell viability. These findings demonstrate that targeting the pro-apoptotic PERK/CHOP pathway with ISRIB can mitigate cisplatin ototoxicity without reducing anti-cancer cell effects, suggesting that this may be a viable strategy for drug development.
RESUMO
RNA molecules rely on proteins across their life cycle. DDX3X encodes an X-linked DEAD-box RNA helicase with a Y-linked paralog, DDX3Y. DDX3X is central to the RNA life cycle and is implicated in many conditions, including cancer and the neurodevelopmental disorder DDX3X syndrome. DDX3X-linked conditions often exhibit sex differences, possibly due to differences between expression or function of the X- and Y-linked paralogs DDX3X and DDX3Y. DDX3X-related diseases have different mutational landscapes, indicating different roles of DDX3X. Understanding the role of DDX3X in normal and disease states will inform the understanding of DDX3X in disease. We review the function of DDX3X and DDX3Y, discuss how mutation type and sex bias contribute to human diseases involving DDX3X, and review possible DDX3X-targeting treatments.
Assuntos
Neoplasias , Transtornos do Neurodesenvolvimento , Humanos , Masculino , Feminino , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Transtornos do Neurodesenvolvimento/genética , Mutação , RNA/metabolismo , Neoplasias/genética , Antígenos de Histocompatibilidade MenorRESUMO
BACKGROUND: GLI3 encodes a zinc finger transcription factor that plays a role in the sonic hedgehog pathway. Germline pathogenic GLI3 variants are associated with Greig cephalopolysyndactyly and Pallister-Hall syndromes, two syndromes involving brain malformation and polydactyly. METHODS: We identified patients with pathogenic GLI3 variants and brain malformations in the absence of polydactyly or other skeletal malformation. RESULTS: Two patients were identified. Patient #1 is a 4-year-old boy with hypotonia and global developmental delay. Brain MRI showed a focal cortical dysplasia, but he had no history of seizures. Genetic testing identified a de novo likely pathogenic GLI3 variant: c.4453A>T, p.Asn1485Tyr. Patient #2 is a 4-year-old boy with hypotonia, macrocephaly, and global developmental delay. His brain MRI showed partial agenesis of the corpus callosum, dilatation of the right lateral ventricle, and absent hippocampal commissure. Genetic testing identified a de novo pathogenic GLI3 variant: c.4236_4237del, p.Gln1414AspfsTer21. Neither patient had polydactyly or any apparent skeletal abnormality. CONCLUSIONS: These patients widen the spectrum of clinical features that may be associated with GLI3 pathogenic variants to include hypotonia, focal cortical dysplasia, and other brain malformations, in the absence of apparent skeletal malformation. Further study is needed to determine if GLI3 pathogenic variants are a more common cause of focal cortical dysplasia or corpus callosum agenesis than presently recognized.
Assuntos
Malformações do Desenvolvimento Cortical , Polidactilia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Pré-Escolar , Proteínas Hedgehog/genética , Humanos , Masculino , Malformações do Desenvolvimento Cortical/complicações , Hipotonia Muscular/complicações , Hipotonia Muscular/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Polidactilia/complicações , Polidactilia/diagnóstico por imagem , Polidactilia/genética , Síndrome , Proteína Gli3 com Dedos de Zinco/genéticaRESUMO
BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands' primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands' fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development.
Assuntos
Mutação com Perda de Função , Perda de Heterozigosidade , Proteínas de Neoplasias/genética , Transtornos do Neurodesenvolvimento/etiologia , Adolescente , Adulto , Animais , Movimento Celular , Criança , Pré-Escolar , Drosophila , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Lactente , Masculino , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Proteoma/análise , Adulto JovemRESUMO
The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). Deleted in colorectal carcinoma (DCC) and netrin 1 (NTN1) are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in Dcc and Ntn1 knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with DCC mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.
Assuntos
Astrócitos/metabolismo , Corpo Caloso/metabolismo , Receptor DCC/metabolismo , Telencéfalo/metabolismo , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/metabolismo , Agenesia do Corpo Caloso/patologia , Animais , Células COS , Linhagem Celular Tumoral , Movimento Celular , Forma Celular , Chlorocebus aethiops , Corpo Caloso/embriologia , Receptor DCC/genética , Regulação da Expressão Gênica no Desenvolvimento , Genótipo , Idade Gestacional , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfogênese , Mutação , Netrina-1/genética , Netrina-1/metabolismo , Fenótipo , Transdução de Sinais , Telencéfalo/embriologiaRESUMO
The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Genes DCC , Estudos de Associação Genética , Mutação , Fenótipo , Agenesia do Corpo Caloso , Sequência de Aminoácidos , Sítios de Ligação , Sequência Conservada , Bases de Dados Genéticas , Humanos , Imageamento por Ressonância Magnética , Modelos Moleculares , Netrina-1/química , Netrina-1/metabolismo , Ligação Proteica , Conformação Proteica , Domínios Proteicos/genética , SíndromeAssuntos
Demência Frontotemporal/genética , Mutação , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Tuberosa/metabolismo , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/metabolismoRESUMO
Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.
Assuntos
Agenesia do Corpo Caloso/genética , Deficiências do Desenvolvimento/genética , Mutação/genética , Receptores de Superfície Celular/genética , Proteínas Supressoras de Tumor/genética , Anormalidades Múltiplas/genética , Encéfalo/patologia , Corpo Caloso/patologia , Receptor DCC , Família , Feminino , Humanos , Masculino , Malformações do Sistema Nervoso/genética , Células-Tronco Neurais/patologia , Penetrância , FenótipoRESUMO
Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.
Assuntos
Doenças de Pequenos Vasos Cerebrais/genética , Leucoencefalopatias/genética , Mutação , RNA Nucleolar Pequeno/genética , Adolescente , Adulto , Calcinose/genética , Calcinose/patologia , Linhagem Celular , Doenças de Pequenos Vasos Cerebrais/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 17 , Estudos de Coortes , Cistos/genética , Cistos/patologia , Exoma , Feminino , Ligação Genética , Genoma Humano , Humanos , Lactente , Leucoencefalopatias/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Adulto JovemRESUMO
OBJECTIVE: To determine the molecular basis of a severe neurologic disorder in a large consanguineous family with complete agenesis of the corpus callosum (ACC), pontocerebellar hypoplasia (PCH), and peripheral axonal neuropathy. METHODS: Assessment included clinical evaluation, neuroimaging, and nerve conduction studies (NCSs). Linkage analysis used genotypes from 7 family members, and the exome of 3 affected siblings was sequenced. Molecular analyses used Sanger sequencing to perform segregation studies and cohort analysis and Western blot of patient-derived cells. RESULTS: Affected family members presented with postnatal microcephaly and profound developmental delay, with early death in 3. Neuroimaging, including a fetal MRI at 30 weeks, showed complete ACC and PCH. Clinical evaluation showed areflexia, and NCSs revealed a severe axonal neuropathy in the 2 individuals available for electrophysiologic study. A novel homozygous stopgain mutation in adenosine monophosphate deaminase 2 (AMPD2) was identified within the linkage region on chromosome 1. Molecular analyses confirmed that the mutation segregated with disease and resulted in the loss of AMPD2. Subsequent screening of a cohort of 42 unrelated individuals with related imaging phenotypes did not reveal additional AMPD2 mutations. CONCLUSIONS: We describe a family with a novel stopgain mutation in AMPD2. We expand the phenotype recently described as PCH type 9 to include progressive postnatal microcephaly, complete ACC, and peripheral axonal neuropathy. Screening of additional individuals with related imaging phenotypes failed to identify mutations in AMPD2, suggesting that AMPD2 mutations are not a common cause of combined callosal and pontocerebellar defects.
RESUMO
Homozygous recessive mutations in the PRICKLE1 gene were originally reported in three consanguineous families with myoclonic epilepsy. Subsequently, several studies have identified neurological abnormalities in animal models with both heterozygous and homozygous mutations in PRICKLE1 orthologues, including epilepsy in flies and in mice with heterozygous PRICKLE1 mutations. We describe a fetus with a novel de novo mutation in PRICKLE1 associated with agenesis of the corpus callosum.
Assuntos
Agenesia do Corpo Caloso/complicações , Agenesia do Corpo Caloso/genética , Proteínas com Domínio LIM/genética , Mutação/genética , Polimicrogiria/complicações , Polimicrogiria/genética , Proteínas Supressoras de Tumor/genética , Adulto , Consanguinidade , Análise Mutacional de DNA , Epilepsia/etiologia , Epilepsia/genética , Feminino , Humanos , NeuroimagemRESUMO
KBG syndrome is a rare, autosomal dominant disorder caused by mutations or deletions leading to haploinsufficiency for the Ankrin Repeating Domain-Containing protein 11 (ANKRD11) at chromosome 16q24.3. Kabuki syndrome is caused by mutations or deletions of lysine (K)-specific methyltransferase 2D (KMT2D) and lysine-specific methylase 6A (KDM6A). We report on a male with developmental delays, cleft palate, craniofacial dysmorphism, hypotonia, and central nervous system anomalies including diminished white matter with thinning of the corpus callosum. Exome sequencing revealed a de novo mutation in ANKRD11, c.2606_2608delAGA, predicting p.Lys869del and an additional, de novo mutation, c.2353T>C, predicting p.Tyr785His in KDM1A, a gene not previously associated with a human phenotype. We describe this child as the first report of a deleterious sequence variant in KDM1A and hypothesize that his phenotype resulted from the combined effect of both mutations.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Face/anormalidades , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/genética , Histona Desmetilases/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Mutação , Fenótipo , Proteínas Repressoras/genética , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/genética , Encéfalo/patologia , Fácies , Humanos , Lactente , MasculinoRESUMO
Agenesis of the corpus callosum (ACC), cerebellar hypoplasia (CBLH), and polymicrogyria (PMG) are severe congenital brain malformations with largely undiscovered causes. We conducted a large-scale chromosomal copy number variation (CNV) discovery effort in 255 ACC, 220 CBLH, and 147 PMG patients, and 2,349 controls. Compared to controls, significantly more ACC, but unexpectedly not CBLH or PMG patients, had rare genic CNVs over one megabase (pâ=â1.48×10⻳; odds ratio [OR]â=â3.19; 95% confidence interval [CI]â=â1.89-5.39). Rare genic CNVs were those that impacted at least one gene in less than 1% of the combined population of patients and controls. Compared to controls, significantly more ACC but not CBLH or PMG patients had rare CNVs impacting over 20 genes (pâ=â0.01; ORâ=â2.95; 95% CIâ=â1.69-5.18). Independent qPCR confirmation showed that 9.4% of ACC patients had de novo CNVs. These, in comparison to inherited CNVs, preferentially overlapped de novo CNVs previously observed in patients with autism spectrum disorders (pâ=â3.06×10â»4; ORâ=â7.55; 95% CIâ=â2.40-23.72). Interestingly, numerous reports have shown a reduced corpus callosum area in autistic patients, and diminished social and executive function in many ACC patients. We also confirmed and refined previously known CNVs, including significantly narrowing the 8p23.1-p11.1 duplication present in 2% of our current ACC cohort. We found six novel CNVs, each in a single patient, that are likely deleterious: deletions of 1p31.3-p31.1, 1q31.2-q31.3, 5q23.1, and 15q11.2-q13.1; and duplications of 2q11.2-q13 and 11p14.3-p14.2. One ACC patient with microcephaly had a paternally inherited deletion of 16p13.11 that included NDE1. Exome sequencing identified a recessive maternally inherited nonsense mutation in the non-deleted allele of NDE1, revealing the complexity of ACC genetics. This is the first systematic study of CNVs in congenital brain malformations, and shows a much higher prevalence of large gene-rich CNVs in ACC than in CBLH and PMG.
Assuntos
Agenesia do Corpo Caloso/genética , Cerebelo/anormalidades , Variações do Número de Cópias de DNA , Malformações do Desenvolvimento Cortical/genética , Malformações do Sistema Nervoso/genética , Adolescente , Adulto , Agenesia do Corpo Caloso/patologia , Cerebelo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Masculino , Malformações do Desenvolvimento Cortical/patologia , Pessoa de Meia-Idade , Malformações do Sistema Nervoso/patologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Mucopolysaccharidosis type IIIA, or Sanfilippo syndrome type A, is a lysosomal storage disorder caused by deficiency of heparan N-sulfamidase, resulting in defective degradation and subsequent storage of heparan sulfate. It is characterized by progressive nervous system involvement. Cribriform changes in the corpus callosum, basal ganglia, and white matter, diffuse high-intensity signal in the white matter, and cerebral atrophy have been described in patients with this disorder. This case report describes a child with Sanfilippo syndrome type A who exhibited fairly mild clinical findings but an unusual magnetic resonance imaging pattern that included multiple moderate-sized cysts (probably enlarged perivascular spaces) within the corpus callosum and an abnormal appearance of the clivus and cervical vertebrae. This case calls attention to the variety of appearances possible with magnetic resonance imaging in Sanfilippo syndrome type A.
Assuntos
Ventrículos Cerebrais/patologia , Mucopolissacaridose III/patologia , Criança , Corpo Caloso/patologia , Espaço Epidural/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Mucopolissacaridose III/diagnóstico por imagem , RadiografiaRESUMO
Deletions of chromosome 1q42-q44 have been reported in a variety of developmental abnormalities of the brain, including microcephaly (MIC) and agenesis of the corpus callosum (ACC). Here, we describe detailed mapping studies of patients with unbalanced structural rearrangements of distal 1q4. These define a 3.5-Mb critical region extending from RP11-80B9 to RP11-241M7 that we hypothesize contains one or more genes that lead to MIC and ACC when present in only one functional copy. Next, mapping of a balanced reciprocal t(1;13)(q44;q32) translocation in a patient with postnatal MIC and ACC demonstrated a breakpoint within this region that is situated 20 kb upstream of AKT3, a serine-threonine kinase. The murine orthologue Akt3 is required for the developmental regulation of normal brain size and callosal development. Whereas sequencing of AKT3 in a panel of 45 patients with ACC did not demonstrate any pathogenic variations, whole-mount in situ hybridization confirmed expression of Akt3 in the developing central nervous system during mouse embryogenesis. AKT3 represents an excellent candidate for developmental human MIC and ACC, and we suggest that haploinsufficiency causes both postnatal MIC and ACC.
Assuntos
Agenesia do Corpo Caloso , Quebra Cromossômica , Deleção Cromossômica , Cromossomos Humanos Par 1 , Microcefalia/genética , Proteínas Proto-Oncogênicas c-akt/genética , Translocação Genética , Adolescente , Animais , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Humanos , Lactente , Masculino , CamundongosRESUMO
Joubert syndrome-related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions that share a midbrain-hindbrain malformation, the molar tooth sign (MTS) visible on brain imaging, with variable neurological, ocular, and renal manifestations. Mutations in the CEP290 gene were recently identified in families with the MTS-related neurological features, many of which showed oculo-renal involvement typical of Senior-Loken syndrome (JSRD-SLS phenotype). Here, we performed comprehensive CEP290-mutation analysis on two nonoverlapping cohorts of JSRD-affected patients with a proven MTS. We identified mutations in 19 of 44 patients with JSRD-SLS. The second cohort consisted of 84 patients representing the spectrum of other JSRD subtypes, with mutations identified in only two patients. The data suggest that CEP290 mutations are frequently encountered and are largely specific to the JSRD-SLS subtype. One patient with mutation displayed complete situs inversus, confirming the clinical and genetic overlap between JSRDs and other ciliopathies.
Assuntos
Anormalidades Múltiplas/genética , Antígenos de Neoplasias/genética , Encéfalo/anormalidades , Nefropatias/genética , Dente Molar/anormalidades , Proteínas de Neoplasias/genética , Transtornos da Motilidade Ocular/genética , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Proteínas de Ciclo Celular , Criança , Pré-Escolar , Estudos de Coortes , Proteínas do Citoesqueleto , Análise Mutacional de DNA , Feminino , Humanos , Nefropatias/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Mutação , Transtornos da Motilidade Ocular/diagnóstico , Fenótipo , SíndromeRESUMO
OBJECTIVE: We sought to categorize the structural brain anomalies associated with abnormalities of the corpus callosum and anterior and hippocampal commissures in a large cohort. MATERIALS AND METHODS: Brain MR images of adult and pediatric patients from our institution and from a national support organization (the ACC Network) were retrospectively evaluated for the type and severity of commissural anomalies and the presence and type of other structural abnormalities. RESULTS: Of 142 cases that were reviewed, 82 patients had agenesis of the corpus callosum (ACC), while 60 had hypogenesis of the corpus callosum (HCC). Of the overall cohort, almost all had reduced white matter volume outside the commissures, the majority had malformations of cortical development (most commonly heterotopia or abnormal sulcation), many had noncallosal midline anomalies (including abnormal anterior or hippocampal commissures and interhemispheric cysts and lipomas), and several patients had abnormalities of the cerebellum or brainstem. Sixty-six patients had Probst bundles, which were more common in patients with ACC than in those with HCC. Probst bundles were present in all four patients who had ACC or HCC but no other midline, cortical, or posterior fossa anomalies. CONCLUSION: Isolated commissural anomalies were rare in the populations of patients examined. Most cases of ACC and HCC were associated with complex telencephalic, diencephalic, or rhombencephalic malformations. Reduced cerebral hemispheric white matter volume and malformations of cortical development were seen in more than half of the patients, suggesting that many commissural anomalies are part of an overall cerebral dysgenesis. ACC and HCC appear to lie along a dysgenetic spectrum, as opposed to representing distinct disorders.
Assuntos
Agenesia do Corpo Caloso , Imageamento por Ressonância Magnética , Adolescente , Adulto , Córtex Cerebral/anormalidades , Criança , Pré-Escolar , Feminino , Hipocampo/anormalidades , Humanos , MasculinoRESUMO
PURPOSE OF REVIEW: Infantile spasms, mental retardation, autism, and dystonia represent disabling diseases for which little etiologic information is available. Mutations in the Aristaless related homeobox gene (ARX) have been found in patients with these conditions. This discovery provides important genetic information and may ultimately offer treatment options for these patients. RECENT FINDINGS: Recent work has demonstrated that mutations in ARX cause X-linked West syndrome, X-linked myoclonic epilepsy with spasticity and intellectual disability, Partington syndrome (mental retardation, ataxia, and dystonia), as well as nonsyndromic forms of mental retardation. Patients with these aforementioned diseases and ARX mutations were not reported to have brain imaging abnormalities. In contrast, mutations in ARX mutations have also been found in X-linked lissencephaly with abnormal genitalia, which typically includes severe brain malformations (lissencephaly, agenesis of the corpus callosum, and midbrain malformations), intractable seizures, and a severely shortened lifespan. ARX knockout mice manifest defects in overall neuroblast proliferation as well as selective abnormalities in gamma-aminobutyric acid-ergic interneuron migration. Consistent with these findings in mice, phenotype/genotype studies in humans suggest that truncating mutations cause X-linked lissencephaly with abnormal genitalia, and insertion/missense mutations result in epilepsy and mental retardation without cortical dysplasia. SUMMARY: Mutations in the homeobox gene, ARX, cause a diverse spectrum of disease that includes cognitive impairment, epilepsy, and in another group of patients severe cortical malformations. Although the precise prevalence of ARX mutations is unclear, ARX may rival Fragile X as a cause of mental retardation and epilepsy in males.