Κυριακή, 14 Μαΐου 2017
Germline mutations in SDHB predispose to hereditary paraganglioma syndrome type 4. The risk of developing paraganglioma (PGL) or pheochromocytoma (PHEO) in SDHB mutation carriers is subject of recent debate.
In the present nationwide cohort study of SDHB mutation carriers identified by the clinical genetics centers of the Netherlands, we have calculated the penetrance of SDHB associated tumors using a novel maximum likelihood estimator. This estimator addresses ascertainment bias and missing data on pedigree size and structure. 195 SDHB mutation carriers were included, carrying 27 different SDHB mutations. The 2 most prevalent SDHB mutations were Dutch founder mutations: a deletion in exon 3 (31% of mutation carriers) and the c.423+1G>A mutation (24% of mutation carriers). One hundred twelve carriers (57.4%) displayed no physical, radiological or biochemical evidence of PGL or PHEO. Fifty-four patients had a head and neck PGL (27.7%), 4 patients had a PHEO (2.1%), 26 patients an extra-adrenal PGL (13.3%). The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment.
These estimates are lower than previously reported penetrance estimates of SDHB-linked cohorts. Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers.
The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment.Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers.The maximum likelihood estimate of the age-related penetrance of SDHB mutations for paraganglioma and/or pheochromocytoma (continuous line) and 95% confidence interval (dashed line).
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Mismatch repair cancer syndrome (MMRCS) : Multiple hyperpigmented and hypopigmented skin areas, brain malformations, pilomatricomas, a second childhood malignancy, a Lynch syndrome (LS)-associated tumour in a relative and parental consanguinity.
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Polyploidy occurs frequently but is usually detrimental to survival; thus, few polyploids survive in the long term. Here, evidence linking the short-term evolutionary success of polyploids to environmental upheaval is reviewed and possible longer-term evolutionary benefits of polyploidy are discussed.
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WDR45B-related intellectual disability, spastic quadriplegia, epilepsy, and cerebral hypoplasia: a consistent neurodevelopmental syndrome
The advancement in genomic sequencing has greatly improved the diagnostic yield for neurodevelopmental disorders and led to the discovery of large number of novel genes associated with these disorders. WDR45B has been identified as a potential intellectual disability gene through genomic sequencing of two large cohorts of affected individuals. In this report we present six individuals from three unrelated families with homozygous pathogenic variants in WDR45B: c.799C>T (p.Q267*) in one family and c.673C>T (p.R225*) in two families. These individuals shared a similar phenotype including profound development delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations. Neuroimaging showed ventriculomegaly, reduced cerebral white matter volume, and thinning of cerebral gray matter. The consistency in the phenotype strongly supports that WDR45B is associated with this disease.
WDR45B-related intellectual disability, spastic quadriplegia, epilepsy, and cerebral hypoplasia syndrome
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Constitutional mismatch repair deficiency (CMMRD) is a rare, recessively inherited childhood cancer predisposition syndrome caused by bi-allelic germline mutations in one of the mismatch repair genes. The CMMRD phenotype overlaps with that of neurofibromatosis type 1 (NF1), since many patients have multiple café-au-lait macules (CALM) and other NF1 signs, but no germline NF1 mutations.
We report of a case of a healthy six-year-old girl who fulfilled the diagnostic criteria of NF1 with >6 CALM and freckling. Since molecular genetic testing was unable to confirm the diagnosis of NF1 or Legius syndrome and the patient was a child of consanguineous parents, we suspected CMMRD and found a homozygous PMS2 mutation that impairs MMR function.
Current guidelines advise testing for CMMRD only in cancer patients. However, this case illustrates that including CMMRD in the differential diagnosis in suspected sporadic NF1 without causative NF1 or SPRED1 mutations may facilitate identification of CMMRD prior to cancer development. We discuss the advantages and potential risks of this CMMRD testing scenario.
CMMRD diagnosis in a child with café-au-lait macules and axillary freckling, but without malignancies: raising the question of when to test a healthy child.
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Baroreflex dysfunction and augmented sympathetic nerve responses during mental stress in veterans with posttraumatic stress disorder (PTSD)
Posttraumatic Stress Disorder (PTSD) is associated with increased cardiovascular (CV) risk. We tested the hypothesis that PTSD patients have augmented sympathetic nervous system (SNS) and hemodynamic reactivity during mental stress, and impaired arterial baroreflex sensitivity (BRS). 14 otherwise healthy Veterans with combat-related PTSD were compared to 14 matched Controls without PTSD. Muscle sympathetic nerve activity (MSNA), continuous blood pressure (BP), and electrocardiography were measured at baseline, and during two types of mental stress: combat-related mental stress using virtual reality combat exposure (VRCE); and noncombat related stress using mental arithmetic (MA). Cold pressor test (CPT) was administered for comparison. BRS was tested using pharmacologic manipulation of BP via the Modified Oxford technique at rest and during VRCE. Blood samples were analysed for inflammatory biomarkers. Baseline characteristics, MSNA and hemodynamics were similar between the groups. In PTSD versus Controls, MSNA (+8.2 ± 1.0 vs +1.2 ± 1.3 bursts/min P < 0.001) and heart rate (HR) responses (+3.2 ± 1.1 vs −2.3 ± 1.0 beats/min, P = 0.003) were significantly augmented during VRCE. Similarly, in PTSD versus Controls, MSNA (+21.0 ± 2.6 vs +6.7 ± 1.5 bursts/min, P < 0.001) and diastolic BP responses (+6.3 ± 1.0 vs +3.5 ± 1.0 mmHg, P = 0.011) were significantly augmented during MA, but not during CPT (P = NS). In the PTSD group, sympathetic BRS (-1.2 ± 0.2 vs -2.0 ± 0.3 BI mmHg−1, P = 0.026) and cardiovagal BRS (9.5 ± 1.4 vs 23.6 ± 4.3 ms mmHg−1, P = 0.008) were significantly blunted at rest. PTSD patients had significantly higher hs-CRP levels compared to Controls (2.1 ± 0.4 vs 1.0 ± 0.3 mg L−1, P = 0.047). Augmented SNS and hemodynamic responses to mental stress, blunted BRS, and inflammation may contribute to increased CV risk in PTSD.
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Life [ageing] is like riding a bicycle. To keep your [coronary and heart] balance you must keep moving
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- Heart size increases with age (called hypertrophy), and its ability to contract declines. However, these reflect average changes that may not be present, or present to the same extent, in all older individuals.
- That aging happens at different rates is well accepted clinically. People who are aging rapidly are frail and frailty is measured with a 'frailty index'.
- We quantified frailty with a validated mouse frailty index tool and evaluated the impacts of age and frailty on cardiac hypertrophy and contractile dysfunction.
- Hypertrophy increased with age, while contractions, calcium currents and calcium transients declined; these changes were graded by frailty scores.
- Overall health status, quantified as frailty, may promote maladaptive changes associated with cardiac aging and facilitate the development of diseases such as heart failure.
- To understand age-related changes in heart structure and function, it is essential to know both chronological age and the health status of the animal.
On average, cardiac hypertrophy and contractile dysfunction increase with age. Still, individuals age at different rates and their health status varies from fit to frail. We investigated the influence of frailty on age-dependent ventricular remodelling. Frailty was quantified as deficit accumulation in adult (≈7 months) and aged (≈27 months) C57BL/6J mice by adapting a validated frailty index (FI) tool. Hypertrophy and contractile function were evaluated in Langendorff-perfused hearts; cellular correlates/mechanisms were investigated in ventricular myocytes. FI scores increased with age. Mean cardiac hypertrophy increased with age, but values in the adult and aged groups overlapped. When plotted as a function of frailty, hypertrophy was graded by FI score (r = 0.67–0.55, P < 0.0003). Myocyte area also correlated positively with FI (r = 0.34, P = 0.03). Left ventricular developed pressure (LVDP) plus rates of pressure development (+dP/dt) and decay (−dP/dt) declined with age and this was graded by frailty (r = −0.51, P = 0.0007; r = −0.48, P = 0.002; r = −0.56, P = 0.0002 for LVDP, +dP/dt and −dP/dt). Smaller, slower contractions graded by FI score were also seen in ventricular myocytes. Contractile dysfunction in cardiomyocytes isolated from frail mice was attributable to parallel changes in underlying Ca2+ transients. These changes were not due to reduced sarcoplasmic reticulum stores, but were graded by smaller Ca2+ currents (r = −0.40, P = 0.008), lower gain (r = −0.37, P = 0.02) and reduced expression of Cav1.2 protein (r = −0.68, P = 0.003). These results show that cardiac hypertrophy and contractile dysfunction in naturally aging mice are graded by overall health and suggest that frailty, in addition to chronological age, can help explain heterogeneity in cardiac aging.
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