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Three index patients with hyperhomocysteinemia and ocular anomalies were screened for cystathionine beta synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms. Genotyping of hyperhomocysteinemia associated MTHFR polymorphisms C677T (rs1801133) and A1298C (rs1801131) was done by PCR-restriction fragment length polymorphism. Sanger sequencing was performed for CBS exonic sequences along with consensus splice sites. In the case of MTHFR polymorphisms, all the patients were heterozygous CT for the single nucleotide polymorphism (SNP) C677T and were therefore carriers of the risk allele (T), while the patients were homozygous CC for the risk genotype of the SNP A1298C. CBS sequencing resulted in the identification of two novel mutations, a missense change (c.467T>C; p.Leu156Pro) in exon 7 and an in-frame deletion (c.808_810del; p.Glu270del) in exon 10. In addition, a recurrent missense mutation (c.770C>T; p.Thr257Met) in exon 10 of the gene was also identified. The mutations were present homozygously in the patients and were inherited from the carrier parents. This is the first report from Pakistan where novel as well as recurrent CBS mutations causing hyperhomocysteinemia and lens dislocation in three patients from different families are being reported with the predicted effect of the risk allele of the MTHFR SNP in causing hyperhomocysteinemia.
Three index patients with hyperhomocysteinemia and ocular anomalies were screened for cystathionine beta synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms. Genotyping of hyperhomocysteinemia associated MTHFR polymorphisms C677T (rs1801133) and A1298C (rs1801131) was done by PCR-restriction fragment length polymorphism. Sanger sequencing was performed for CBS exonic sequences along with consensus splice sites. In the case of MTHFR polymorphisms, all the patients were heterozygous CT for the single nucleotide polymorphism (SNP) C677T and were therefore carriers of the risk allele (T), while the patients were homozygous CC for the risk genotype of the SNP A1298C. CBS sequencing resulted in the identification of two novel mutations, a missense change (c.467T>C; p.Leu156Pro) in exon 7 and an in-frame deletion (c.808_810del; p.Glu270del) in exon 10. In addition, a recurrent missense mutation (c.770C>T; p.Thr257Met) in exon 10 of the gene was also identified. The mutations were present homozygously in the patients and were inherited from the carrier parents. This is the first report from Pakistan where novel as well as recurrent CBS mutations causing hyperhomocysteinemia and lens dislocation in three patients from different families are being reported with the predicted effect of the risk allele of the MTHFR SNP in causing hyperhomocysteinemia.
Background Microbleeds are frequently detected in normal elderly population, and their presence is associated with an increased risk of intracerebral hemorrhage, ischemic stroke and cognitive impairment. Previous histopathologic findings mainly focused on arteries and capillaries. Nevertheless, few studies investigated the relationship between venous disruption and microbleeds. Objective We aimed to evaluate the extent of venous disruption in vivo and assess the correlation between deep medullary veins (DMVs) disruption and the severity and distribution of intracranial microbleeds in patients with cerebral small vessel disease (cSVD). Methods We retrospectively reviewed the clinical, laboratory and imaging data of the patients admitted to our department who received brain MRI and presented with CSVD imaging markers. Susceptibility weighted imaging (SWI) phase images were used to observe characteristics of DMVs and derive a brain region-based DMVs visual score. SWI magnitude images were used to evaluate microbleeds. We recorded the number and distribution (lobar or deep or infratentorial) of microbleeds. One-way ANOVA and logistic-regression analysis were used to examine the association between the DMVs score and microbleeds. Results A total of 369 cSVD patients were analyzed, including 177 (48.0%) patients with microbleeds, among whom 81(45.8%) patients had 1–2 microbleeds and 96 (54.2%) patients had ≥3 microbleeds (extensive microbleeds). The patients' DMVs score ranged from 0 to18, with a median score of 8(6–12). Higher DMVs score was independently associated with extensive microbleeds (OR = 1.108, 95%Cl: 1.010–1.215, p = 0.03) after adjusting for gender, hypertension, hyperhomocysteinemia, Fazekas score and number of lacunas. According to the distribution, 38 (21.5%) patients were found with strict lobar microbleeds, while 139 (78.5%) patients had non-strict lobar microbleeds. Higher DMVs score was also independently associated with non-strict lobar microbleeds (OR = 1.106, 95% Cl: 1.019–1.200, p = 0.016) after adjusting for gender, hypertension, hyperhomocysteinemia, Fazekas score and number of lacunas. DMVs score was not associated with strict lobar microbleeds (p = 0.307). Conclusion DMVs disruption might be involved in the development of extensive microbleeds, especially non-strict lobar cerebral microbleeds.
Our purpose is to assess the role of deep medullary veins (DMVs) in pathogenesis of MRI-visible perivascular spaces (PVS) in patients with cerebral small vessel disease (cSVD). Consecutive patients recruited in the CIRCLE study (ClinicalTrials.gov ID: NCT03542734) were included. Susceptibility Weighted Imaging-Phase images were used to evaluate DMVs based on a brain region-based visual score. T2 weighted images were used to evaluate PVS based on the five-point score, and PVS in basal ganglia (BG-PVS), centrum semiovale (CSO-PVS) and hippocampus (H-PVS) were evaluated separately. 270 patients were included. The severity of BG-PVS, CSO-PVS and H-PVS was positively related to the increment of age (all p < 0.05). The severity of BG-PVS and H-PVS was positively related to DMVs score (both p < 0.05). Patients with more severe BG-PVS had higher Fazekas scores in both periventricle and deep white matter (both p < 0.001) and higher frequency of hypertension ( p = 0.008). Patients with more severe H-PVS had higher frequency of diabetes ( p < 0.001). Besides, high DMVs score was an independent risk factor for more severe BG-PVS ( β = 0.204, p = 0.001). Our results suggested that DMVs disruption might be involved in the pathogenesis of BG-PVS.
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