Alternative titles; symbols
SNOMEDCT: 1173997008; ORPHA: 477749;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q34 | Microangiopathy and leukoencephalopathy, pontine, autosomal dominant | 618564 | Autosomal dominant | 3 | COL4A1 | 120130 |
A number sign (#) is used with this entry because of evidence that autosomal dominant pontine microangiopathy and leukoencephalopathy (PADMAL) is caused by heterozygous mutation in the COL4A1 gene (120130) on chromosome 13q34.
Autosomal dominant pontine microangiopathy and leukoencephalopathy (PADMAL) is a form of cerebral small vessel disease (CSVD) resulting in the onset of recurrent ischemic strokes in the thirties or forties. Affected individuals develop progressive, but variable, cognitive and motor impairment, consistent with progressive multi-infarct dementia. Brain imaging shows lacunar infarcts, often with a pontine predilection, as well as diffuse leukoencephalopathy affecting various brain regions. Although there are overlapping clinical features, the disorder is genetically and pathologically distinct from CADASIL (125310) (summary by Verdura et al., 2016).
Sourander and Walinder (1977) reported a 3-generation Swedish family with onset of recurrent ischemic neurologic episodes between 29 and 38 years of age. Affected individuals had a progressive neuropsychiatric disease with pyramidal, bulbar, and cerebellar symptoms, and gradually developed multi-infarct dementia. None of the patients had hypertension. Neuropathologic examination of 3 patients showed cerebral atrophy and cystic infarctions due to an occlusive disease of small intracerebral and leptomeningeal arteries and arterioles. Cerebral vessels showed concentric thickening of the vascular wall and narrowing of the vascular lumen associated with subendothelial fibrous proliferation, hyaline degeneration of the intima and media, and fragmentation of the elastic lamina. In a follow-up of the family reported by Sourander and Walinder (1977), Low et al. (2007) excluded a diagnosis of CADASIL (125310) by genetic analysis. Furthermore, Low et al. (2007) noted that the clinical and pathologic features in the Swedish family indicated were distinct from CADASIL, suggesting a novel small vessel disease.
Hagel et al. (2004) reported a large multigenerational German family with progressive neurologic symptoms associated with recurrent cerebral lacunar infarcts. Most patients had onset after 30 years of age, but 1 patient had onset at age 12. Features included gait disturbances, ataxia, dysarthria, cognitive decline, and psychiatric abnormalities. Neuropathologic examination of 5 patients showed alterations of the small cerebral arteries and arterioles, such as concentric intimal thickening, hyperelastosis, atrophy of the vascular smooth muscle cells, and fibro-hyalinosis or fibrosis. Collagen IV was detected in the fibrotic regions with immunostaining. The basal ganglia, thalami, pons, and pyramidal tracts were predominantly affected. PAS-positive granular material as described in CADASIL was not observed. Ding et al. (2010) reported detailed brain imaging results of affected members of the family reported by Hagel et al. (2004). Common features included lacunar infarcts in the pons and subcortical and periventricular white matter lesions, consistent with leukoencephalopathy. Lesions in the temporal lobe were rare. None had atherosclerotic changes. Ding et al. (2010) suggested the acronym PADMAL for 'pontine autosomal dominant microangiopathy and leukoencephalopathy' to describe the disorder.
Verdura et al. (2016) reported a large French family (F1) in which 4 individuals presented with recurrent ischemic strokes associated with CSVD between 37 and 43 years of age. Initial features included sudden onset of anesthesia of the limbs, facial palsy, diplopia, or loss of balance, followed by subtle cognitive decline, mood disturbances, and progressive motor impairment with gait instability. Cognitive dysfunction included symptoms of dementia and dysexecutive function. The mother of the proband had a history of recurrent ischemic strokes leading to a bedridden state and death at 67 years of age. Brain imaging in the 4 clinically symptomatic individuals showed microvascular lesions in the pons and subcortical hemispheric area as well as white matter hyperintensities that correlated with age. Two additional clinically asymptomatic family members in a younger generation showed punctiform white matter hyperintensities in the centrum semiovale; these patients carried the mutation. Subsequently, 5 additional families with a similar disorder were identified, including the large German family (F2) previously reported by Hagel et al. (2004) and Ding et al. (2010). Families F4, F5, and F6 contained 1 proband, each of whom had a deceased parent with a similar phenotype. F3 was a multigenerational family with at least 8 affected individuals. All patients had recurrent ischemic strokes with onset between 35 and 45 years of age that resulted in progressive but variable impairments of motor and cognitive skills leading to disability in some cases. Neuroimaging studies showed multiple ischemic lacunae with a pontine predilection and variable leukoencephalopathy in the cerebral hemispheres with frequent involvement of the temporal lobe. Electron microscopic analysis of skin biopsies of 3 patients from family 3 showed duplications and focal disruptions of the basement membrane in most vessels and abnormal accumulation of extracellular matrix proteins in the subendothelial spaces between vascular smooth muscle cells. There was a thickened and poorly dense lamina densa, disconnection and degeneration of vascular smooth muscle cells, and increased fibrosis of the walls of small venules. Granular osmiophilic material, a specific biomarker of CADASIL, was absent.
The transmission pattern of PADMAL in the families reported by Verdura et al. (2016) was consistent with autosomal dominant inheritance.
In 6 affected members from a large French family (F1) with PADMAL, Verdura et al. (2016) identified a heterozygous c.*35C-A transversion in the 3-prime UTR of the COL4A1 gene (120130.0025). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Targeted sequencing of this region of the gene in 202 unrelated probands with a similar disorder identified 2 more heterozygous mutations in the same region of the gene (120130.0026-120130.0027) in affected members of 5 additional families with a similar disorder, including a German family previously reported by Hagel et al. (2004). In vitro functional expression studies in HEK293 cells showed that all the mutations interfered with miRNA29 (see 610782) binding and resulted in increased expression of COL4A1 compared to wildtype. Levels of COL4A1 mRNA were increased in patient fibroblasts compared to controls.
In affected members of a large 5-generation Swedish family with PADMAL originally reported by Sourander and Walinder (1977), Siitonen et al. (2017) identified a heterozygous c.*32G-A transition in the 3-prime UTR of the COL4A1 gene (120130.0028). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in HEK293 cells showed that the mutation interfered with miRNA29 binding and resulted in increased expression of COL4A1 compared to wildtype. The findings confirmed the results of Verdura et al. (2016) and defined a specific phenotype caused by perturbations of the cerebrovascular matrisome that results in recurrent lacunar infarcts.
Ding, X.-Q., Hagel, C., Ringelstein, E. B., Buchheit, S., Zeumer, H., Kuhlenbaumer, G., Appenzeller, S., Fiehler, J. MRI features of pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL). J. Neuroimaging 20: 134-140, 2010. [PubMed: 19187480] [Full Text: https://doi.org/10.1111/j.1552-6569.2008.00336.x]
Hagel, C., Groden, C., Niemeyer, R., Stavrou, D., Colmant, H. J. Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL. Acta Neuropath. 108: 231-240, 2004. [PubMed: 15221337] [Full Text: https://doi.org/10.1007/s00401-004-0887-2]
Low, W. C., Junna, M., Borjesson-Hanson, A., Morris, C. M., Moss, T. H., Stevens, D. L., St Clair, D., Mizuno, T., Zhang, W. W., Mykkanen, K., Wahlstrom, J., Andersen, O., Kalimo, H., Viitanen, M., Kalaria, R. N. Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL. Brain 130: 357-367, 2007. [PubMed: 17235124] [Full Text: https://doi.org/10.1093/brain/awl360]
Siitonen, M., Borjesson-Hanson, A., Poyhonen, M., Ora, A., Pasanen, P., Bras, J., Kern, S., Kern, J., Andersen, O., Stanescu, H., Kleta, R., Baumann, M., Kalaria, R., Kalimo, H., Singleton, A., Hardy, J., Viitanen, M., Myllykangas, L., Guerreiro, R. Multi-infarct dementia of Swedish type is caused by a 3-prime UTR mutation of COL4A1. Brain 140: e29, 2017. Note: Electronic Article. [PubMed: 28369186] [Full Text: https://doi.org/10.1093/brain/awx062]
Sourander, P., Walinder, J. Hereditary multi-infarct dementia: morphological and clinical studies of a new disease. Acta Neuropath. 39: 247-254, 1977. [PubMed: 906807] [Full Text: https://doi.org/10.1007/BF00691704]
Verdura, E., Herve, D., Bergametti, F., Jacquet, C., Morvan, T., Prieto-Morin, C., Mackowiak, A., Manchon, E., Hosseini, H., Cordonnier, C., Girard-Buttaz, I., Rosenstingl, S., and 9 others. Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy. Ann. Neurol. 80: 741-753, 2016. [PubMed: 27666438] [Full Text: https://doi.org/10.1002/ana.24782]