Psychiatric Disturbances in Metachromatic Leukodystrophy

Hyde, Thomas M.; Ziegler, James; Weinberger, Daniel R.

doi:10.1001/archneur.1992.00530280095028

Cited by 270 publications

(137 citation statements)

References 73 publications

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“…The abnormal interactions between neuronal populations will clearly have infrastructural correlates, but these are likely to be expressed at the level of synaptic specialisations, cellular morphology and cytoarchitectonics. Any misconception that the disconnection hypothesis pertains to the extrinsic connections themselves is understandable given that evidence, cited in support of the disconnection hypothesis, refers explicitly to interruptions of cortico-cortical connections (e.g., psychotic symptoms in metachromatic leukodystrophy; Hyde et al, 1992). However, it is important to remember that this sort of evidence is being used as a 'lesion deficit' model of a functional disconnection.…”

Section: What Sort Of Disconnection Syndrome?mentioning

confidence: 99%

“…However, the evidence for white matter pathology in schizophrenia is not remarkable. Having said this, white matter disorders such as metachromatic leukodystrophy do provide compelling models of schizophrenia, particularly where the pathophysiology may involve an anatomical deafferentation of the prefrontal cortex (Hyde et al, 1992). See also Bruton et al (1994).…”

Section: Anatomical Disconnectionsmentioning

confidence: 99%

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The disconnection hypothesis

Friston

1998

Schizophrenia Research

790

469

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This article reviews the disconnection hypothesis of schizophrenia and presents a mechanistic account of how dysfunctional integration among neuronal systems might arise. This neurobiological account is based on the central role played by neuronal plasticity in shaping the connections and the ensuing dynamics that underlie brain function. The particular hypothesis put forward here is that the pathophysiology of schizophrenia is expressed at the level of modulation of associative changes in synaptic efficacy; specifically the modulation of plasticity in those brain systems responsible for emotional learning and memory, in the post-natal period. This modulation is mediated by ascending neurotransmitter systems that: (i) have been implicated in schizophrenia; and (ii) are known to be involved in consolidating synaptic connections during learning. The proposed pathophysiology would translate, in functional terms, into a disruption of the reinforcement of adaptive behaviour that is consistent with the disintegrative aspects of schizophrenic neuropsychology.

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Section: What Sort Of Disconnection Syndrome?mentioning

confidence: 99%

Section: Anatomical Disconnectionsmentioning

confidence: 99%

The disconnection hypothesis

Friston

1998

Schizophrenia Research

790

469

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“…40,41 It is also noteworthy that a large subset of patients with the rare lateonset form of metachromatic leukodystrophy, a severe demyelinating CNS disorder, display psychotic symptoms. 42,43 Interestingly, the atypical antipsychotic clozapine seems to have enhanced therapeutic efficacy as compared to typical drugs (eg haloperidol and chlorpromazine) in treatment-refractory schizophrenia. 23 The concentrations of haloperidol (10 mM) and clozapine (30 mM) that gave comparable SREBP activation in the glioma cell cultures were approximately 400 and 15-fold higher than the upper therapeutically relevant serum concentrations of these drugs.…”

Section: Antipsychotic-induced Lipogenesis In Glioma Cellsmentioning

confidence: 99%

Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action?

et al. 2005

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Several studies have reported on structural abnormalities, decreased myelination and oligodendrocyte dysfunction in post-mortem brains from schizophrenic patients. Glia-derived cholesterol is essential for both myelination and synaptogenesis in the CNS. Lipogenesis and myelin synthesis are thus interesting etiological candidate targets in schizophrenia. Using a microarray approach, we here demonstrate that the antipsychotic drugs clozapine and haloperidol upregulate several genes involved in cholesterol and fatty acid biosynthesis in cultured human glioma cells, including HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase-1), FASN (fatty acid synthase) and SCD (stearoyl-CoA desaturase). The changes in gene expression were followed by enhanced HMGCR-enzyme activity and elevated cellular levels of cholesterol and triglycerides. The upregulated genes are all known to be controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We show that clozapine and haloperidol both activate the SREBP system. The antipsychotic-induced SREBP-mediated increase in glial cell lipogenesis could represent a novel mechanism of action, and may also be relevant for the metabolic side effects of antipsychotics. 2 Heritability has been demonstrated to play an important role in the etiology, but numerous genetic linkage and association studies have yielded conflicting results, although there are now several promising candidate susceptibility genes. 3 Brain imaging studies of schizophrenic patients have shown various structural and functional abnormalities, including enlargement of the ventricles and volume reductions in specific brain regions, 4,5 even in first episode and drug-naïve subjects. [6][7][8] On the other hand, degenerative histopathological findings are strikingly absent. These observations hint at a neurodevelopmental origin of the disorder (for a review, see Harrison and Lewis 9 and Liddle and Pantelis 10 ).

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“…Moreover, in patients with metachromatic leukodystrophy, psychosis only occurs if the cortical white matter is affected in early adulthood. Lesions developing before this are not associated with psychosis 24 .…”

Section: Figure (A) Midsagittal View Demonstrating Complete Agenesismentioning

confidence: 96%

Total agenesis of the corpus callosum in a patient with childhood-onset schizophrenia

Dursun¹,

Hallak²,

Crippa³

et al. 2003

Schizophrenia Research

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-The hypothesis that schizophrenia involves aberrant inter-hemispheric communication has a long pedigree, however its precise role remains unclear. We therefore report the case of a total agenesis of the corpus callosum in a 21-year-old man with childhood-onset schizophrenia. The presence of schizophrenia with very early onset on absence of corpus callosum offers an opportunity to examine neurodevelopmental model and theories regarding to interhemispheric communication in the pathogenesis of psychosis.KEY WORDS: schizophrenia, corpus callosum, agenesis. Agenesia completa de corpo caloso em um paciente com esquizofrenia de início na infânciaRESUMO -A hipótese que a esquizofrenia envolve comunicação inter-hemisférica aberrante possui longa tradição, entretanto seu papel permanece incerto. Nós relatamos um caso de agenesia total do corpo caloso em um homem de 21 anos portador de esquizofrenia de início na infância. A associação de esquizofrenia de início precoce na ausência de corpo caloso oferece uma oportunidade para exame do modelo neurodesenvolvimental e de teorias que envolvem a comunicação interemisférica na patogênese da psicose. PALAVRAS-CHAVE: esquizofrenia, corpo caloso, agenesia.

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Psychiatric Disturbances in Metachromatic Leukodystrophy

Cited by 270 publications

References 73 publications

The disconnection hypothesis

The disconnection hypothesis

Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action?

Total agenesis of the corpus callosum in a patient with childhood-onset schizophrenia

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