Metachromatic leukodystrophy manifesting as a schizophrenic disorder: Computed tomographic correlation

Finelli, Pasquale F.

doi:10.1002/ana.410180117

Cited by 41 publications

(22 citation statements)

References 7 publications

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“…Although a higher residual activity has been found in adult forms in comparison with infantile and juvenile MLD [2], some of the values reported in the literature are extremely low. In most of the cases de scribed in which the precise values have been expressed, the range is between 5 and 10% of control values [12,16,22,25]; this is also the case in our own experience. In some cases, values of 20% have been found [18].…”

Section: Biochemical Diagnosismentioning

confidence: 77%

Adult Forms of Metachromatic Leukodystrophy: Clinical and Biochemical Approach

et al. 1991

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The clinical and biochemical characteristics of metachromatic leukodystrophy (MLD), true adult forms and late juvenile forms which are still living at adulthood, are reviewed as they both are observed in adult Neurology and Psychiatry departments. Mental deterioration is often the first symptom, evolving progressively; and dementia finally occurs. The latency before the appearance of neurological objective symptoms may be long and extend for several years. In many cases, the behavioral abnormalities are the first symptoms. Some of these forms have been diagnosed as schizophrenia. Very seldom, neurological symptoms, especially ataxia, occur without cognitive or psychiatric disturbances. Most of these cases have pyramidal and cerebellar symptoms, at diverse degrees. Seizures can also occur which in some cases can be early symptoms associated to mental deterioration. The association of central and peripheral neurological symptoms is very characteristic of MLD. The peripheral neuropathy is not generally clinically evidenced, but is rarely-missing electrophysiologically. Arylsulfatase A determination should be performed for diagnosis as a first step, and confirmed by the accumulation of sulfatide, either by quantitative determinations in urine or by the sulfatide loading test. It is as yet not clear why certain forms have a rather rapid evolution in 5 years, and others have a very protracted course during decades.

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Section: Biochemical Diagnosismentioning

confidence: 77%

Adult Forms of Metachromatic Leukodystrophy: Clinical and Biochemical Approach

et al. 1991

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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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“…1,2 Depression, hypomania or psychosis is common, and in adult MLD, the disease may present as a schizophrenic disorder. 3 The disease has a variable, often slow but progressive course with a mean survival of 12 years after onset of the initial symptoms. 4 After treatment with allogeneic hematopoietic SCT (HSCT), transplanted macrophages migrate through the blood-brain barrier and then differentiate into microglia, which replace ARSA-deficient microglia 5 and also support them with functional ARSA through cross-correction of the enzyme.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic SCT: a useful treatment for late metachromatic leukodystrophy

Solders

Martin

Andersson

et al. 2014

Bone Marrow Transplant

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In metachromatic leukodystrophy (MLD), the deficiency of the lysosomal enzyme arylsulfatase A (ARSA) leads to demyelination in the central and peripheral nervous system and ultimately to death. Allogeneic hematopoietic SCT (HSCT) is currently the only treatment for adult and late-onset juvenile MLD, although it is still in question because of insufficient follow-up. We wanted to determine whether HSCT could halt the progression of adult and late-onset juvenile MLD. Four treated unrelated patients and three untreated siblings were included in the study, and followed regularly for up to 18 years after transplantation. The patients were assessed from clinical examination, ARSA enzyme levels, magnetic resonance imaging of the brain and neuropsychological and neurophysiological tests. In the treated patients, ARSA levels were normal up to 18 years after transplantation. The parameters evaluated stabilized and remained stable after a latency period of 12-24 months. Two patients live normal lives, partially in a protected environment. The other two patients stabilized at a low cognitive and functional level. One of the controls is demented, one is in a vegetative state and one died. We conclude that, in comparison with their untreated siblings, HSCT halted the progression of the disease in our treated patients.

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Metachromatic leukodystrophy manifesting as a schizophrenic disorder: Computed tomographic correlation

Cited by 41 publications

References 7 publications

Adult Forms of Metachromatic Leukodystrophy: Clinical and Biochemical Approach

Adult Forms of Metachromatic Leukodystrophy: Clinical and Biochemical Approach

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

Hematopoietic SCT: a useful treatment for late metachromatic leukodystrophy

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