Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153640 (Cerebellum)
 1,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sustained levels of methylmalonate comparable to those of human methylmalonic acidemia were achieved in the blood of young rats from the 5th till the 25th day of life by injecting them subcutaneously with buffered methylmalonic acid (MMA) twice a day at 8-h intervals. A matched group of rats (controls) was treated with saline. The animals were weighed and killed by decapitation at 25 days of age. Cerebellum and cerebrum were weighed and their contents of protein, DNA and ganglioside N-acetylneuraminic acid (G-NeuAc), as well as the protein/DNA ratio determined. Body weight, cerebral and cerebellar weight did not differ in both groups. The concentrations of protein, DNA and the protein/DNA ratio were also similar in the experimental and control groups. The results indicate that MMA per se does not interfere with the appetite of the animals and does not affect cellular proliferation and growth in cerebrum and cerebellum. We also found that G-NeuAc concentration is significantly reduced in the cerebellum. Therefore, since a deficit of an important component of brain closely related to the dendritic surface (synaptogenesis) occurs in MMA-treated rats, it is tempting to speculate whether this alteration may be associated or even partly responsible for the mental retardation in patients affected by methylmalonic acidemia.
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PMID:Diminished concentrations of ganglioside N-acetylneuraminic acid (G-NeuAc) in cerebellum of young rats receiving chronic administration of methylmalonic acid. 338 36

Cerebellum malformations are frequently diagnosed since the advent of the neuroradiological studies (computed tomography, magnetic resonance imaging and ultrasonography). Cerebellar hypoplasia is found in association with a wide variety of neurologic and systemic disorders. Clinical picture in newborn may be different than in other periods of life. Two characteristics are interesting in neonatal period: their relation with abnormal respiratory control and mental retardation. The pathophysiology of cerebellar hypoplasia is uncertain, however experimental studies suggest than an abnormality of the Bergman glia may lead to the observed granulle cell layer deficiency in this malformation. It is tempting to speculate that a similar migrational abnormality in the cerebrum accounts for the intellectual impairment seen in some affected patients. Respiration is a complex neural function requiring precise coordination of numerous neural circuits. Cerebellar hypoplasia may be important in the pathogenetic mechanism of abnormal respiratory control due to cerebellar respiratory control disturbance. Also diaphragmatic dysfunction may occur in association with cerebellar atrophy. We report two newborns with cerebellar hypoplasia (vermis and hemispheres) associated with central respiratory and neurological dysfunction, and mental retardation.
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PMID:[Cerebellar hypoplasia in the newborn: association with respiratory control disorders and mental retardation]. 855 88

Spinocerebellar ataxia 13 is a slowly progressive and relatively pure autosomal dominant cerebellar ataxia with childhood onset and mental deficiency. The responsible gene has been assigned to a 5.2 Mbases interval on chromosome 19q in a single French family.
Cerebellum 2005
PMID:Spinocerebellar ataxia with mental retardation (SCA13). 1589 58

The devastating nature and lack of effective treatments associated with neurodegenerative diseases have stimulated a world-wide search for the elucidation of their molecular basis to which mouse models have made a major contribution. In combination with transgenic and knockout technologies, large-scale mouse mutagenesis is a powerful approach for the identification of new genes and associated signalling pathways controlling neuronal cell death and survival. Here we review the characterization of the robotic mouse, a novel model of autosomal dominant cerebellar ataxia isolated from an ENU-mutagenesis programme, which develops adult-onset region-specific Purkinje cell loss and cataracts, and displays defects in early T-cell maturation and general growth retardation. The mutated protein, Af4, is a member of the AF4/LAF4/FMR2 (ALF) family of putative transcription factors previously implicated in childhood leukaemia and FRAXE mental retardation. The mutation, which lies in a highly conserved region among the ALF family members, significantly reduces the binding affinity of Af4 to the E3 ubiquitin-ligase Siah-1a, isolated with Siah-2 as interacting proteins in the brain. This leads to a markedly slower turnover of mutant Af4 by the ubiquitin-proteasome pathway and consequently to its abnormal accumulation in the robotic mouse. Importantly, the conservation of the Siah-binding domain of Af4 in all other family members reveals that Siah-mediated proteasomal degradation is a common regulatory mechanism that controls the levels, and thereby the function, of the ALF family. The robotic mouse represents a unique model in which to study the newly revealed role of Af4 in the maintenance of vital functions of Purkinje cells in the cerebellum and further the understanding of its implication in lymphopoeisis.
Cerebellum 2005
PMID:The robotic mouse: unravelling the function of AF4 in the cerebellum. 1632 81

Coffin-Lowry syndrome (CLS) is a rare form of X-linked mental retardation caused by mutations of the RSK2 gene, associated with cognitive impairment and skeletal malformations. We conducted the first morphometric study of CLS brain morphology by comparing brain volumes from two CLS families with healthy controls. Individuals with CLS consistently showed markedly reduced total brain volume. Cerebellum and hippocampus volumes were particularly impacted by CLS and may be associated with specific interfamilial RSK2 mutations. We provide preliminary evidence that the magnitude of hippocampus volume deviation from that of controls may predict general cognitive outcome in CLS.
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PMID:Altered neurodevelopment associated with mutations of RSK2: a morphometric MRI study of Coffin-Lowry syndrome. 1731 37

"Unertan syndrome" consists of two main symptoms: quadrupedal gait and primitive cognitive abilities including language and conscious experience. To assess the central mechanisms involved in this syndrome, the authors performed MRI and PET scans on affected and unaffected individuals from both families. All affected individuals were also subjected to neurological examination. To assess the integrity of the peripheral and central vestibular system, Barany's caloric test was applied to the affected individuals. Brain MRI and PET scans were performed on normal subjects (n = 7) and patients (n = 7). Right- and left-cerebral and cerebellar areas, including the vermial and callosal areas, were measured on the MRI scans using a computer cursor. Quadrupedal gait, mental retardation, dysartric speech, nystagmus, severe truncal ataxia, hyperreflexia, astasia, and abasia were observed in the affected individuals from both families. Cerebellum and vermis were atrophic in the MRI and PET scans of the first family. In contrast, the brain MRI seemed to be normal in the MRI and PET scans of affected individuals from the second family. The caloric test revealed central vestibular damage in patients from the first family and peripheral vestibular damage in patients from the second family. The results suggest that "Unertan syndrome," discovered in two unrelated families, may be caused by peripheral or central vestibular damage resulting from different genetic defects. Cerebellar hypoplasia may not be a prerequisite for the emergence of this syndrome. Primitive mental abilities may be explained by damage within the vestibulo-cerebellar system, whereas the quadrupedal gait may be due to a genetic defect within the higher brain centers that suppress the atavistic brain networks controlling quadrupedal gait and helped in the emergence of the habitual bipedal gait during human evolution. This retarded development of human locomotion - devolution - may illuminate the brain mechanisms responsible for the transition from quadrupedality to bipedality in human evolution.
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PMID:"Unertan syndrome" in two Turkish families in relation to devolution and emergence of Homo erectus: neurological examination, MRI, and PET scans. 1830 5

Thyroid hormone plays an essential role in proper mammalian development of the central nervous system and peripheral tissues. Lack of sufficient thyroid hormone results in abnormal development of virtually all organ systems, a syndrome termed cretinism. In particular, hypothyroidism in the neonatal period causes serious damage to neural cells and leads to mental retardation. Although thyroxine is the major product secreted by the thyroid follicular cells, the action of thyroid hormone is mediated mainly through the deiodination of T(4) to the biologically active form 3,3', 5-triiodo-L-thyronine, followed by the binding of T(3) to a specific nuclear receptor. Before reaching the intracellular targets, thyroid hormone must cross the plasma membrane. Because of the lipophilic nature of thyroid hormone, it was thought that they traversed the plasma membrane by simple diffusion. However, in the past decade, a membrane transport system for thyroid hormone has been postulated to exist in various tissues. Several classes of transporters, organic anion transporter polypeptide (oatp) family, Na(+)/Taurocholate cotransporting polypeptide (ntcp) and amino acid transporters have been reported to transport thyroid hormones. Monocarboxylate transporter8 (MCT8) has recently been identified as an active and specific thyroid hormone transporter. Mutations in MCT8 are associated with severe X-linked psycomotor retardation and strongly elevated serum T3 levels in young male patients. Several other molecules should be contributed to exert the role of thyroid hormone in the central nervous system.
Cerebellum 2008
PMID:Thyroid hormone transporters in the brain. 1841 73

The morphogenetic factor Sonic hedgehog (SHH) has been discovered as one of the masterplayers in cerebellar patterning and was subjected to intensive investigation during the last decade. During early postnatal development, this continuously secreted cholesterol-modified protein drives the expansion of the largest neuronal population of the brain, the granular cells. Moreover, it acts on Bergmann glia differentiation and would potentially affect Purkinje cells homeostasis at adult age. The cerebellar cortex constituted an ideal developmental model to dissect out the upstream mechanisms and downstream targets of this complex pathway. Its deep understanding discloses some of the mechanistic disorders underlying pediatric tumorigenesis, congenital ataxia, and mental retardation. Therapeutical use of its regulators has been consolidated on murine transgenic models and is now considered as a realistic human clinical application. Here, we will review the most recent advances made in the comprehensive understanding of SHH involvement in cerebellar development and pathology.
Cerebellum 2009 Sep
PMID:SHH pathway and cerebellar development. 1922 9

We report the results of a retrospective analysis of radiological and clinical findings in 45 cases of midbrain-hindbrain anomalies and review recent advances in embryology and molecular neurogenetics. Among 45 patients with midbrain-hindbrain malformations, 16 cases of molar tooth malformation, 12 of cerebellar hypoplasia, ten of posterior fossa cyst and cerebellar vermian hypoplasia, three of rhombencephalosynapsis, two of Fukuyama congenital muscular dystrophy and two cases of isolated cerebellar dysplasia were identified. Twenty-six patients presented with motor-mental retardation, which was the most common clinical finding. Eleven patients were born to consanguineous parents. The correct diagnosis of cerebellar malformation is important for determining prognosis, the risk of recurrence and the need for genetic counselling. Integrated classification of malformations based on morphology, embryology and molecular neurogenetics may be useful.
Cerebellum 2009 Sep
PMID:Malformations of the midbrain and hindbrain: a retrospective study and review of the literature. 1933 79

Neurological disorders represent a large share of the disease burden worldwide, and the incidence of age-related forms will continue to rise with life expectancy. Gene targeting has been and will remain a valuable approach to the generation of clinically relevant mouse models from which to elucidate the underlying molecular basis. However, as the aetiology of the majority of these conditions is still unknown, a reverse approach based on large-scale random chemical mutagenesis is now being used in an attempt to identify new genes and associated signalling pathways that control neuronal cell death and survival. Here, we review the characterisation of a novel model of autosomal dominant cerebellar ataxia which shows general growth retardation and develops adult-onset region-specific Purkinje cell loss as well as cataracts and defects in early T-cell maturation. We have previously established that the mutated protein Af4, which is a member of the AF4/LAF4/FMR2 (ALF) family of transcription cofactors frequently translocated in childhood leukaemia, undergoes slower proteasomal turnover through the ubiquitin pathway and abnormally accumulates in Purkinje cells of the cerebellum. We have also shown that Af4 functions as part of a large multiprotein complex that stimulates RNA polymerase II elongation and mediates chromatin remodelling during transcription. With the forthcoming identification of the gene targets that trigger Purkinje cell death in the robotic cerebellum, and the functional conservation among the ALF proteins, the robotic mouse promises to deliver important insights into the pathogenesis of human ataxia, but also of mental retardation to which FMR2 and LAF4 have been linked.
Cerebellum 2009 Sep
PMID:The robotic mouse: understanding the role of AF4, a cofactor of transcriptional elongation and chromatin remodelling, in purkinje cell function. 1934 Apr 90


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