Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy.

OBJECTIVE: Cerebral small vessel disease (cSVD) is a heterogeneous group of disorders. Screening of known cSVD genes identifies the causative mutation in <15% of familial cSVD cases. We sought to identify novel causes of cSVD. METHODS: We used linkage analysis and exome sequencing to identify the causal mutation in a French cSVD family. The identified candidate gene was then screened in 202 cSVD unrelated probands, including 1 proband from the first reported pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) family. Sanger sequencing was used to confirm variants in all mutated probands and analyze their segregation in probands' relatives. Mutation consequences were assessed with luciferase reporter assays and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: A candidate heterozygous variant located in a predicted miR-29 microRNA binding site, within the 3' untranslated region of COL4A1, was identified in the large French cSVD family. Five additional unrelated probands, including the PADMAL proband, harbored heterozygous variants in this microRNA binding site. Variants cosegregated with the affected phenotype, and cumulative logarithm of odds score reached 6.03, establishing linkage to this locus. A highly significant difference was observed when comparing the number of variants within this binding site in cases and controls (p = 1.77 × 10E-12). RT-qPCR analyses of patients' primary fibroblasts and luciferase reporter assays strongly favor an upregulation of COL4A1 mediated by disruption of miR-29 binding to its target site. Magnetic resonance imaging features were characterized by the presence of multiple pontine infarcts in all symptomatic mutation carriers. INTERPRETATION: Mutations upregulating COL4A1 expression lead to PADMAL, a severe early onset ischemic cSVD, distinct from the various phenotypes associated with COL4A1 missense glycine mutations. Ann Neurol 2016;80:741-753.

[Psychocognitive impairment evaluation in early post-stroke period]. / Evaluarea afectarii psiho-cognitive in perioada precoce post-stroke (AVC).

UNLABELLED: There are many interconnections between pathological mechanism involved in production of dementia and cognitive impairment even in stroke patients. Early detection and management of these disorders provide better prevention of possible dementia. AIM: To explore the factors which can affect psychocognitive impairment of poststroke patients. METHOD: using the MMSE (mini-mental state examination), GDS (Geriatric Depression Scale), NIH (National Institute of Health) Stroke Scale we evaluated 47 consecutive patients with ischemic stroke, admitted in I Neurological Clinic of "N. Oblu" Hospital from Iassy. RESULTS: Our patients had relative important cognitive impairment (11 individuals--MMSE < 20, but only 4 below 10) and important depression (GDS > 10 in 35 cases and > 20 in 7 cases). We found correlation between some risk factors and cognitive impairment / depression (hypertension, overweight, dyslipidemia, diabetes, arrhythmia, carotid system lesion). CONCLUSION: Cerebrovascular disease can produce important cognitive and psychological impairment, which we can easily evaluate using some "bedside" tools MMSE, GDS.