MRI Features of Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy (PADMAL)

Ding, Xiao‐Qi; Hagel, Christian; Ringelstein, E. B.; Buchheit, Stefan; Zeumer, H.; Kuhlenbäumer, Gregor; Appenzeller, Silke; Fiehler, Jens

doi:10.1111/j.1552-6569.2008.00336.x

Cited by 40 publications

(32 citation statements)

References 31 publications

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“…This family showed similar early onset of SVD‐type dementia, but, like the Swedes, was not linked to the NOTCH3 gene and lacking the hallmark features of CADASIL pathology including granular osmiophilic material (GOM) in vessel walls . The family was described to exhibit pontine infarcts and their condition was termed pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) . Any genetic abnormalities involved in both the Swedish and German familial disorders remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Vascular Pathology and Phenotyping Familial and Sporadic Cerebral Small Vessel Diseases

et al. 2013

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We quantified vascular changes in the frontal lobe and basal ganglia of four inherited small vessel diseases (SVDs) including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), hereditary multi-infarct dementia of Swedish type (Swedish hMID), and hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Vascular pathology was most severe in CADASIL, and varied with marginally greater severity in the basal ganglia compared to the frontal lobe. The overall sclerotic index values in frontal lobe were in the order CADASIL ≥ HERNS > PADMAL > Swedish hMID > sporadic SVD, and in basal ganglia CADASIL > HERNS > Swedish hMID > PADMAL> sporadic SVD. The subcortical white matter was almost always more affected than any gray matter. We observed glucose transporter-1 (GLUT-1) protein immunoreactivities were most affected in the white matter indicating capillary degeneration whereas collagen IV (COL4) immunostaining was increased in PADMAL cases in all regions and tissue types. Overall, GLUT-1 : COL4 ratios were higher in the basal ganglia indicating modifications in capillary density compared to the frontal lobe. Our study shows that the extent of microvascular degeneration varies in these genetic disorders exhibiting common end-stage pathologies but is the most aggressive in CADASIL.

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Section: Introductionmentioning

confidence: 99%

Quantitative Vascular Pathology and Phenotyping Familial and Sporadic Cerebral Small Vessel Diseases

et al. 2013

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“…Upon rigorous scrutiny of the clinical, genetic and morphological features it is identified to be a novel SVD whose genetic identity still remains unknown [28]. In the case of the encephalopathy described in the large German family [25] it is now appreciated that these individuals also exhibit lacunar infarcts in the pons strikingly different from CADASIL so that SAE has been aptly described as pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL [29].…”

Section: Introductionmentioning

confidence: 99%

Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain

Yamamoto

Craggs

Baumann

et al. 2011

Neuropathology Appl Neurobio

121

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Advances in molecular genetics have enabled identification of several monogenic conditions involving small vessels predisposing to ischaemic and haemorrhagic strokes and diffuse white matter disease. With emphasis on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we review the molecular pathogenesis of recently characterized disorders including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and the Collagen type IV, alpha 1 (COL4A1)-related disorders. CADASIL remains the most common hereditary small vessel disease (SVD) caused by >190 different mutations in the NOTCH3 gene, which encodes a cell-signalling receptor. Mutant NOTCH3 instigates degeneration of vascular smooth muscle cells in small arteries and arterioles leading to recurrent lacunar infarcts. Mutations in the serine protease HTRA1 gene are associated with CARASIL. Aberrant HTRA1 activity results in increased transforming growth factor-β signalling provoking multiple actions including vascular fibrosis and extracellular matrix synthesis. The RVCL disorders characterized by profound retinopathy are associated with mutations in TREX1, which encodes an abundant 3'-5' DNA-specific exonuclease. TREX1 mutations lead to detrimental gain-of-function or insufficient quantities of enzyme. The COL4A1-related disorders are highly variable comprising four major phenotypes with overlapping systemic and central nervous system features including SVD with cerebral haemorrhages in children and adults. Mutant COL4A1 likely disrupts the extracellular matrix resulting in fragile vessel walls. The hereditary SVDs albeit with variable phenotypes demonstrate how effects of different defective genes converge to produce the characteristic arteriopathy and microvascular disintegration leading to vascular cognitive impairment.

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“…In addition to well known associations with cardiovascular risk factors, [25][26][27]29,30 familial forms of SVD as well as a possible genetic connection have been questioned in the pathogenesis. 29,31 Underlying chemical inflammation facilitating atherosclerotic changes may play a role. 32 Biochemical markers have been implicated.…”

Section: Discussionmentioning

confidence: 99%

T2 Hyperintensity of Medial Lemniscus: Higher Threshold Application to ROI Measurements is More Accurate in Predicting Small Vessel Disease

Hakky

Erbay²,

Brewer³

et al. 2013

Journal of Neuroimaging

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MRI Features of Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy (PADMAL)

Cited by 40 publications

References 31 publications

Quantitative Vascular Pathology and Phenotyping Familial and Sporadic Cerebral Small Vessel Diseases

Quantitative Vascular Pathology and Phenotyping Familial and Sporadic Cerebral Small Vessel Diseases

Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain

T2 Hyperintensity of Medial Lemniscus: Higher Threshold Application to ROI Measurements is More Accurate in Predicting Small Vessel Disease

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