Aims
Lamin A/C mutations are generally believed to be associated with a severe prognosis. The aim of this study was to investigate disease expression in three affected families carrying different ...LMNA missense mutations. Furthermore, the potential molecular disease mechanisms of the mutations were investigated in fibroblasts obtained from mutation carriers.
Methods and results
A LMNA‐p.Arg216Cys missense mutation was identified in a large family with 36 mutation carriers. Disease expression was unusual with a late onset and a favourable prognosis. Two smaller families with severe disease expression were shown to carry a LMNA‐p.Arg471Cys and LMNA‐p.Arg471His mutation, respectively. LMNA gene and protein expression was investigated in eight different mutation carriers by quantitative reverse transcriptase polymerase chain reaction, Western blotting, immunohistochemistry, and protein mass spectrometry. The results showed that all mutation carriers incorporated mutated lamin protein into the nuclear envelope. Interestingly, the ratio of mutated to wild‐type protein was only 30:70 in LMNA‐p.Arg216Cys carriers with a favourable prognosis while LMNA‐p.Arg471Cys and LMNA‐p.Arg471His carriers with a more severe outcome expressed significantly more of the mutated protein by a ratio of 50:50.
Conclusion
The clinical findings indicated that some LMNA mutations may be associated with a favourable prognosis and a low risk of sudden death. Protein expression studies suggested that a severe outcome was associated with the expression of high amounts of mutated protein. These findings may prove to be helpful in counselling and risk assessment of LMNA families.
Context: The autosomal dominantly inherited condition familial hypocalciuric hypercalcemia (FHH) is characterized by elevated plasma calcium levels, relative or absolute hypocalciuria, and normal to ...moderately elevated plasma PTH. The condition is difficult to distinguish clinically from primary hyperparathyroidism and is caused by inactivating mutations in the calcium sensing receptor (CASR) gene.
Objective: We sought to define the mutation spectrum of the CASR gene in a Danish FHH population and to establish genotype-phenotype relationships regarding the different mutations.
Design and Participants: A total of 213 subjects clinically suspected to have FHH, and 121 subjects enrolled as part of a family-screening program were studied. Genotype-phenotype relationships were established in 66 mutation-positive index patients and family members.
Main Outcome Measures: We determined CASR gene mutations, and correlating levels of plasma calcium (albumin corrected), ionized calcium (pH 7.4), and PTH were measured.
Results: We identified 22 different mutations in 39 FHH families. We evaluated data on circulating calcium and PTH for 11 different mutations, representing a spectrum of clinical phenotypes, ranging from calcium concentrations moderately above the upper reference limit, to calcium levels more than 20% above the upper reference limit. Furthermore, the mean plasma PTH concentration was within the normal range in eight of 11 studied mutations, but mild to moderately elevated in families with the mutations p.C582Y, p.C582F, and p.G553R.
Conclusions: The present data add 19 novel mutations to the catalog of inactivating CASR mutations and illustrate a variety of biochemical phenotypes in patients with the molecular genetic diagnosis FHH.
Abstract
Protein S (PS) deficiency is a risk factor for venous thromboembolism (VTE) and can be caused by variants of the gene encoding PS (
PROS1
). This study aimed to evaluate the clinical value ...of molecular analysis of the
PROS1
gene in PS-deficient participants. We performed Sanger sequencing of the coding region of the
PROS1
gene and multiplex ligation-dependent probe amplification to exclude large structural rearrangements. Free PS was measured by a particle-enhanced immunoassay, while PS activity was assessed by a clotting method.
A total of 87 PS-deficient participants and family members were included. In 22 index participants, we identified 13
PROS1
coding variants. Five variants were novel. In 21 index participants, no coding sequence variants or structural rearrangements were identified. The free PS level was lower in index participants carrying a
PROS1
variant compared with index participants with no variant (0.51 0.32–0.61 vs. 0.62 0.57–0.73 × 10
3
IU/L;
p
< 0.05). The p.(Thr78Met) variant was associated with only slightly decreased free PS levels (0.59 0.53–0.66 × 10
3
IU/L) compared with the p.(Glu390Lys) variant (0.27 0.24–0.37 × 10
3
IU/L,
p
< 0.01). The frequency of VTE in participants with a coding
PROS1
variant was 43 and 17% in the group with normal
PROS1
gene (
p
= 0.05).
In conclusion, we report 13
PROS1
coding variants including five novel variants. PS levels differ by
PROS1
variant and the frequency of VTE was higher when a coding
PROS1
variant was present. Hence, molecular analysis of the
PROS1
gene may add clinical value in the diagnostic work-up of PS deficiency.
The genes encoding the LDL receptor and apoB were screened for mutations associated with familial hypercholesterolemia (FH) in 408 patients referred to the Lipid Clinic in 1995–2003. The study aimed ...at testing the ability of three different sets of clinical criteria to predict the results of molecular genetic analysis, and secondly test whether population-based age- and sex-specific percentiles of LDL-cholesterol offer useful supplemental information in the selection of patients for molecular genetic analysis. The patients were retrospectively categorised according to Simon Broome Register Group criteria, Make Early Diagnosis to Prevent Early Death criteria (MEDPED) and the Dutch Lipid Clinic Network criteria, and the distribution of patients was compared to the results of the molecular genetic analysis. The study illustrates a classical dilemma. Mutation detection rates (and specificities) are high only if sensitivity is very low and vice versa: to find most mutation carriers, even patients with only possible FH must be examined by molecular genetic testing leading to mutation detection rates as low as 30–40%.
Vita Radbodi Nissen, Peter; Hunink, Vincent
2023
eBook
Odprti dostop
The Low Countries in the early Middle Ages. Christianity is on the rise, partly due to the efforts of missionaries such as Willibrord and Boniface. Yet the process of Christianisation is laborious. ...This is well illustrated in Vita Radbodi, a tenth-century Latin biography of bishop Radboud of Utrecht (c. 850-917). In it, Radboud is depicted as a pious, serious and studious young man, who is called to the episcopate after many years of study. As bishop, he encounters problems with unbelieving Frisians and ferocious Normans. Thus, he is forced to move his seat from Utrecht to the safer Deventer. The text offers a positive portrait of Radboud as a holy role model figure. He acts energetically, performs miracles and, of course, also possesses prophetic gifts. For instance, he predicts his own end well in time. The text ends with a vision of the Mother of God and Radboud's death and burial. Some twenty years after the first edition by Peter Nissen and Vincent Hunink, the text is now being reissued on the occasion of Radboud University's centenary.
Pazopanib can induce liver toxicity in patients with metastatic renal cell carcinoma (mRCC). We assessed the effect of a TA repeat polymorphism in the UGT1A1 (uridine diphosphate ...glucuronosyltransferase 1A1) gene encoding uridine diphosphate glucuronosyltransferase 1A1 on liver toxicity, dose reductions, and patient outcomes.
Patients with mRCC treated with first-line pazopanib developing liver toxicity underwent genotyping for the UGT1A1 polymorphism. Liver toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. Progression-free survival and overall survival were assessed using the Kaplan-Meier and log-rank methods.
Of 261 patients, 34 (13%) had developed liver toxicity after a median of 29 days (range, 5-155 days). Grade 4, 3, and 2 alanine aminotransferase or bilirubin had increased in 2 (6%), 17 (50%), and 8 (24%) patients, respectively. The UGT1A1 assessment demonstrated that 18 patients (53%) had TA6/TA7, 7 (21%) had TA7/TA7, and 9 (26%) had wild-type TA6/TA6. The UGT1A1 polymorphism was associated with improved median progression-free survival (TA6/TA6, 5.5 months; TA6/TA7, 34.2 months; TA7/TA7, 22.3 months; unknown UGT1A1 status, 9.2 months; UGT1A1 polymorphisms combined vs. unknown status, P = .021). UGT1A1 polymorphism was associated with improved median overall survival (TA6/TA6, 8.1 months, TA6/TA7 or TA7/TA7 not reached, unknown UGT1A1 status, 16.6 months; UGT1A1 polymorphisms combined vs. unknown status, P = .033). Patients with UGT1A1 polymorphism safely resumed pazopanib at ultra-low doses determined by the degree of liver toxicity and UGT1A1 polymorphism.
UGT1A1 polymorphisms were associated with improved outcomes, despite pazopanib interruption and dose reductions. UGT1A1 assessment could improve the management of pazopanib-induced liver toxicity in patients with mRCC.
Treatment of patients with metastatic renal cell carcinoma with pazopanib has been associated with an increased probability of developing liver toxicity in the presence of polymorphisms in the gene UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1), leading to treatment interruptions and permanent discontinuation. We have demonstrated that UGT1A1-guided dosing can manage pazopanib-induced liver toxicity and also that UGT1A1 polymorphisms are associated with improved outcomes, despite pazopanib interruption and substantial dose reductions.
Magnesium salts, the prevalent minerals in Dead Sea water, are known to exhibit favorable effects in inflammatory diseases. We examined the efficacy of bathing atopic subjects in a salt rich in ...magnesium chloride from deep layers of the Dead Sea (Mavena® Dermaline Mg46 Dead Sea salt, Mavena AG, Belp, Switzerland).
Volunteers with atopic dry skin submerged one forearm for 15 min in a bath solution containing 5% Dead Sea salt. The second arm was submerged in tap water as control. Before the study and at weeks 1–6, transepidermal water loss (TEWL), skin hydration, skin roughness, and skin redness were determined.
We found one subgroup with a normal and one subgroup with an elevated TEWL before the study. Bathing in the Dead Sea salt solution significantly improved skin barrier function compared with the tap water‐treated control forearm in the subgroup with elevated basal TEWL. Skin hydration was enhanced on the forearm treated with the Dead Sea salt in each group, which means the treatment moisturized the skin. Skin roughness and redness of the skin as a marker for inflammation were significantly reduced after bathing in the salt solution. This demonstrates that bathing in the salt solution was well tolerated, improved skin barrier function, enhanced stratum corneum hydration, and reduced skin roughness and inflammation.
We suggest that the favorable effects of bathing in the Dead Sea salt solution are most likely related to the high magnesium content. Magnesium salts are known to bind water, influence epidermal proliferation and differentiation, and enhance permeability barrier repair.
Familial hypocalciuric hypercalcemia (FHH) is often due to inactivating variants in the calcium-sensing receptor (CASR) gene causing chronically elevated plasma calcium levels with inappropriately ...normal or elevated parathyroid hormone levels. In patients with primary hyperparathyroidism, the state of hyperparathyroid hypercalcemia is associated with reduced muscle strength and impaired quality of life (QoL).
To study whether FHH affects muscle function, postural stability, and QoL.
In a cross-sectional study, we investigated muscle strength (handgrip, elbow flexion/extension, and knee flexion/extension), balance function, physical activity, and QoL in 50 patients with FHH and in a similar number of age- and gender-matched population-based healthy controls. All but one of the FHH cases had genetically verified inactivating variants in the CASR gene.
Studied subjects (n=100, 68% females) had a mean age of 56.0 years. Muscle strength as assessed by measuring maximum force and maximum force production did not differ between the groups. Neither did groups differ in terms of QoL, physical activity, or postural stability, as assessed during normal standing with eyes open, normal standing with eyes closed, semi-tandem standing, or tandem standing. Adjustment for vitamin D status (plasma 25-hydroxyvitamin D levels) and BMI did not change results.
Despite a state of chronic hypercalcemia, muscle strength, balance function, and QoL are not impaired in patients with FHH. Our findings are reassuring for patients with FHH as they should not be considered as having a severe disease.
The typical spatial pattern of amyloid-β (Aβ) in diagnosed Alzheimer’s disease (AD) is that of a symmetrical hemispheric distribution. However, Aβ may be asymmetrically distributed in early stages of ...AD. Aβ distribution on PET has previously been explored in MCI and AD, but it has yet to be directly investigated in preclinical AD (pAD). We examined how Aβ was distributed in individuals with pAD and MCI using 11C-Pittsburgh Compound B (PiB) PET.
In this PET study, 79 subjects were retrospectively enrolled, including 34 controls, 24 pAD, and 21 MCI. All subjects underwent APOE genotyping, 11C-PiB PET, MRI, and cognitive testing. We explored differences in Aβ load, Aβ lateralisation, and Aβ distribution, as well as associations between Aβ distribution and cognition.
The Aβ asymmetry index (AI) differed between groups, with pAD having the highest Aβ AI as compared to both controls and MCI. There was no clear Aβ lateralisation in pAD, but there was a non-significant trend towards Aβ being more left-lateralised in MCI. There were no correlations between the cognitive scores and Aβ AI or Aβ lateralisation in pAD or MCI.
The distribution of Aβ is most asymmetrical in pAD, as Aβ first starts accumulating, and it then becomes less asymmetrical in MCI, when Aβ has spread further, suggesting that more pronounced asymmetrical Aβ distribution may be a distinguishing factor in pAD. Longitudinal studies examining the distribution of Aβ across the AD continuum are needed.
To determine the efficacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH).
Retrospectively, clinical ...parameters, biochemistry and histology were obtained from patient records.
Nine patients 8 females/1 male, median age 32 (range 16-64) years were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P=0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P=0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P=0.032), respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P=0.016), while the degree of fibrosis tended to decrease (P=0.049).
The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of fibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantial reduction of prednisone dose.
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