Patterns of mosaicism for sequence and copy-number variants discovered through clinical deep sequencing of disease-related genes in one million individuals.

DNA variants that arise after conception can show mosaicism, varying in presence and extent among tissues. Mosaic variants have been reported in Mendelian diseases, but further investigation is necessary to broadly understand their incidence, transmission, and clinical impact. A mosaic pathogenic variant in a disease-related gene may cause an atypical phenotype in terms of severity, clinical features, or timing of disease onset. Using high-depth sequencing, we studied results from one million unrelated individuals referred for genetic testing for almost 1,900 disease-related genes. We observed 5,939 mosaic sequence or intragenic copy number variants distributed across 509 genes in nearly 5,700 individuals, constituting approximately 2% of molecular diagnoses in the cohort. Cancer-related genes had the most mosaic variants and showed age-specific enrichment, in part reflecting clonal hematopoiesis in older individuals. We also observed many mosaic variants in genes related to early-onset conditions. Additional mosaic variants were observed in genes analyzed for reproductive carrier screening or associated with dominant disorders with low penetrance, posing challenges for interpreting their clinical significance. When we controlled for the potential involvement of clonal hematopoiesis, most mosaic variants were enriched in younger individuals and were present at higher levels than in older individuals. Furthermore, individuals with mosaicism showed later disease onset or milder phenotypes than individuals with non-mosaic variants in the same genes. Collectively, the large compendium of variants, disease correlations, and age-specific results identified in this study expand our understanding of the implications of mosaic DNA variation for diagnosis and genetic counseling.

Parental Influence on Intracerebral Hemorrhage Onset in Hereditary Dutch-Type Cerebral Amyloid Angiopathy.

INTRODUCTION: Dutch-type cerebral amyloid angiopathy (D-CAA) is an autosomal dominant hereditary form of CAA causing intracerebral hemorrhage (ICH) and cognitive decline. The age of onset of ICH in D-CAA mutation carriers is strikingly variable and ranges from late thirties up to 70 years. We investigated the presence of genetic anticipation and assessed the influence of parental age at onset and sex on age of ICH onset in offspring. METHODS: We included (potential) D-CAA mutation carriers from our prospective D-CAA family database. Participants were sent a questionnaire by mail and asked for the onset age of symptomatic ICH and the onset age of symptomatic ICH of their affected first-degree relative(s), their siblings and affected parent. We used a Cox regression model with the age of onset of the parent as the covariate and the sex of the offspring as the factor. Next, we replaced the sex of the offspring with a factor with four levels: mother/daughter, mother/son, father/daughter, and father/son. We used a random effect per household. RESULTS: A total of 66 respondents completed the questionnaire. Reported mean age of first symptomatic ICH was similar (both 52 years, p = 0.87) for D-CAA parents (n = 60) and their offspring (n = 100). Offspring with a mother with D-CAA seemed to have an earlier ICH onset (50 years, standard deviation [SD] ± 7) than offspring with a paternal inheritance (54 years, SD ± 6, p = 0.03). There was no association between onset of first ICH of the parent and offspring after adding sex of the offspring to the Cox regression model: hazard ratio 0.99, 95% CI: 0.94-1.03, p = 0.51. The interaction between parent's sex and child's sex was not significant (p = 0.70). The results with and without random effect were essentially identical. CONCLUSION: We found no indication for genetic anticipation in D-CAA in general, although maternal inheritance seemed to be associated with an earlier ICH onset.

Intragenic MFSD8 duplication and histopathological findings in a rabbit with neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinoses (NCL) are among the most prevalent neurodegenerative disorders of early life in humans. Disease-causing variants have been described for 13 different NCL genes. In this study, a refined pathological characterization of a female rabbit with progressive neurological signs reminiscent of NCL was performed. Cytoplasmic pigment present in neurons was weakly positive with Sudan black B and autofluorescent. Immunohistology revealed astrogliosis, microgliosis and axonal degeneration. During the subsequent genetic investigation, the genome of the affected rabbit was sequenced and examined for private variants in NCL candidate genes. The analysis revealed a homozygous ~10.7 kb genomic duplication on chromosome 15 comprising parts of the MFSD8 gene, NC_013683.1:g.103,727,963_103,738,667dup. The duplication harbors two internal protein coding exons and is predicted to introduce a premature stop codon into the transcript, truncating ~50% of the wild-type MFSD8 open reading frame encoding the major facilitator superfamily domain containing protein 8, XP_002717309.2:p.(Glu235Leufs*23). Biallelic loss-of-function variants in MFSD8 have been described to cause NCL7 in human patients, dogs and a single cat. The available clinical and pathological data, together with current knowledge about MFSD8 variants and their functional impact in other species, point to the MFSD8 duplication as a likely causative defect for the observed phenotype in the affected rabbit.

Porphyrin precursors and risk of primary liver cancer in acute intermittent porphyria: A case-control study of 188 patients.

Acute intermittent porphyria (AIP) is a rare hereditary metabolic disease characterized by acute attacks and accumulation of the porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Patients with AIP have a high risk of primary liver cancer (PLC). We aimed to assess the association between porphyrin precursor excretion and the risk for PLC in patients with AIP. We studied 48 patients with AIP who developed PLC between 1987 and 2015 and 140 age and sex matched controls with AIP but no PLC. Data on all available urinary PBG and ALA samples collected from 1975 until 1 year before PLC diagnosis were analyzed and compared between cases and controls using logistic regression. Porphyrin precursor excretion was higher in patients with PLC (PBG median 7.9 [IQR 4.4-21.9] mmol/mol creatinine) than in controls (3.8 [1.2-9.8]) (adjusted odds ratio 1.07, 95% confidence interval: 1.02-1.12). None of the 28 patients with all registered samples below the upper limit of normal (ULN) developed PLC, and only one of the 45 patients with all samples <2× ULN developed PLC. Among non-PLC controls, ALA and PBG levels decreased after age 50-60 while an increasing trend was observed after age 65 among those who developed PLC. Increased urinary porphyrin precursors are associated with a high risk of developing PLC. Patients with normal levels appear to have a low risk while high or increasing ALA and PBG after age 65 indicates high risk, which should be considered in surveillance decisions.

Hereditary dentin defects with systemic diseases.

OBJECTIVE: This review aimed to summarize recent progress on syndromic dentin defects, promoting a better understanding of systemic diseases with dentin malformations, the molecules involved, and related mechanisms. SUBJECTS AND METHODS: References on genetic diseases with dentin malformations were obtained from various sources, including PubMed, OMIM, NCBI, and other websites. The clinical phenotypes and genetic backgrounds of these diseases were then summarized, analyzed, and compared. RESULTS: Over 10 systemic diseases, including osteogenesis imperfecta, hypophosphatemic rickets, vitamin D-dependent rickets, familial tumoral calcinosis, Ehlers-Danlos syndrome, Schimke immuno-osseous dysplasia, hypophosphatasia, Elsahy-Waters syndrome, Singleton-Merten syndrome, odontochondrodysplasia, and microcephalic osteodysplastic primordial dwarfism type II were examined. Most of these are bone disorders, and their pathogenic genes may regulate both dentin and bone development, involving extracellular matrix, cell differentiation, and metabolism of calcium, phosphorus, and vitamin D. The phenotypes of these syndromic dentin defects various with the involved genes, part of them are similar to dentinogenesis imperfecta or dentin dysplasia, while others only present one or two types of dentin abnormalities such as discoloration, irregular enlarged or obliterated pulp and canal, or root malformation. CONCLUSION: Some specific dentin defects associated with systemic diseases may serve as important phenotypes for dentists to diagnose. Furthermore, mechanistic studies on syndromic dentin defects may provide valuable insights into isolated dentin defects and general dentin development or mineralization.

Delayed progressive sensorineural hearing loss due to a novel compound heterozygous PTPRQ mutation in a Chinese patient.

BACKGROUND: The Protein tyrosine phosphatase receptor Q (PTPRQ) gene encodes a member of the type III receptor-like protein tyrosine phosphatase family found in the stereocilium. Mutations in PTPRQ are mostly associated with deafness, autosomal recessive type 84 (DFNB 84), which usually results in progressive familial hearing loss. METHODS: A 25-year-old woman and her sister, both with postlingual-delayed progressive sensorineural hearing loss, were examined. They were from a nonconsanguineous marriage and had no family history of hearing loss. New compound heterozygous PTPRQ gene mutations, nonsense (c.90C > A, p.Y30X) and splice (c.5426 + 1G > A) mutations in two PTPRQ alleles, were identified in the two sisters and were presumably autosomal recessive. The c.90C > A (p.Y30X) mutation was mapped to exon 2 of PTPRQ (NM_001145026). RESULTS: The c.90C > A mutation leads to a premature stop codon and a truncated protein. The c.5426 + 1G > A mutation leads to a truncated protein lacking the extracellular domain. Hence, both mutations were predicted to be pathogenic, leading to a deficiency of the extracellular, transmembrane, and phosphatase domains because of nonsense-mediated mRNA degradation. CONCLUSIONS: This study increases the spectrum of PTPRQ gene mutations that might be involved in delayed progressive autosomal recessive non-syndromic hearing loss.

Zebra-Sphinx: Modeling Sphingolipidoses in Zebrafish.

Sphingolipidoses are inborn errors of metabolism due to the pathogenic mutation of genes that encode for lysosomal enzymes, transporters, or enzyme cofactors that participate in the sphingolipid catabolism. They represent a subgroup of lysosomal storage diseases characterized by the gradual lysosomal accumulation of the substrate(s) of the defective proteins. The clinical presentation of patients affected by sphingolipid storage disorders ranges from a mild progression for some juvenile- or adult-onset forms to severe/fatal infantile forms. Despite significant therapeutic achievements, novel strategies are required at basic, clinical, and translational levels to improve patient outcomes. On these bases, the development of in vivo models is crucial for a better understanding of the pathogenesis of sphingolipidoses and for the development of efficacious therapeutic strategies. The teleost zebrafish (Danio rerio) has emerged as a useful platform to model several human genetic diseases owing to the high grade of genome conservation between human and zebrafish, combined with precise genome editing and the ease of manipulation. In addition, lipidomic studies have allowed the identification in zebrafish of all of the main classes of lipids present in mammals, supporting the possibility to model diseases of the lipidic metabolism in this animal species with the advantage of using mammalian lipid databases for data processing. This review highlights the use of zebrafish as an innovative model system to gain novel insights into the pathogenesis of sphingolipidoses, with possible implications for the identification of more efficacious therapeutic approaches.

Dystrophin (DMD) Missense Variant in Cats with Becker-Type Muscular Dystrophy.

Muscular dystrophy due to dystrophin deficiency in humans is phenotypically divided into a severe Duchenne and milder Becker type. Dystrophin deficiency has also been described in a few animal species, and few DMD gene variants have been identified in animals. Here, we characterize the clinical, histopathological, and molecular genetic aspects of a family of Maine Coon crossbred cats with clinically mild and slowly progressive muscular dystrophy. Two young adult male littermate cats exhibited abnormal gait and muscular hypertrophy with macroglossia. Serum creatine kinase activities were highly increased. Histopathologically, dystrophic skeletal muscle exhibited marked structural changes including atrophic, hypertrophic, and necrotic muscle fibers. Immunohistochemistry showed irregularly reduced expression of dystrophin but the staining of other muscle proteins such as ß- and γ-sarcoglycans as well as desmin was also diminished. Whole genome sequencing of one affected cat and genotyping of the littermate found both to be hemizygous mutant at a single DMD missense variant (c.4186C>T). No other protein-changing variants in candidate genes for muscular dystrophy were detected. In addition, one clinically healthy male littermate was hemizygous wildtype, while the queen and one female littermate were clinically healthy, but heterozygous. The predicted amino acid exchange (p.His1396Tyr) resides in a conserved central rod spectrin domain of dystrophin. Various protein modeling programs did not predict major disruption of the dystrophin protein by this substitution, but the altered charge of the region may still affect protein function. This study represents the first genotype-to-phenotype correlation of Becker-type dystrophin deficiency in companion animals.

Neurological and Psychiatric Aspects of Biological Markers for the Provision of Medical Care to Patients with Spinal Muscular Atrophy 5q.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare genetic disorder, in which, for the common childhood onset forms, loss of function of the SMA 5q gene leads to disability and death before adulthood. Symptomatic treatment focusses on respiratory and nutritional support, and physical therapy, but there is little consideration of psychiatric manifestations of SMA. The aim of this study was to explore blood biomarker levels, electromyography (EMG) data, and clinical manifestations, including psychiatric impairments, in patients with SMA 5q. Our objectives were twofold: First, to assess the clinical relevance of standard biomarkers, i.e., creatinine, creatine kinase (CK), and lactate dehydrogenase (LDH) levels, and second, to obtain data supporting the development of an effective prognostic algorithm for the course of this disease. RESULTS: We analyzed retrospective data from 112 medical records of 58 registered patients (2008-2022) with SMA. At the time of last registration, the 58 patients had a mean age 38.4 years [13.68; 55.0], of whom 32 (52%) were female. The subgroup of 21 pediatric patients had a mean age 12.32 years [6.57; 13.93], of whom 14 (24%) were girls. The ICD-10 diagnoses were as follows: G12.0 (n=7, 12%, children), G12.1 (n=14, 24% children; n=29, 50% adults), G12.8 (n=6, 10% adults), G12.9 (n=2, 1% adults). The archival data on psychiatric status indicated emotional lability (n=6, 10.3%), fatigue (n=10, 17.2%), and tearfulness (n=3, 5.2%) in some patients. There were no significant subgroup differences in serum creatinine and CK levels, but there were significant differences in LDH levels between the G12.0, G12.1, G12.8, and G12.9 subgroups. Among the serum biomarkers, only LDH levels showed significant differences among the subgroups of SMA 5q patients; higher levels in the G12.1, G12.8, and G12.9 groups compared to the G12.0 (infantile) group related to age, weight, gender, and level of physical activity. Data on psychiatric status were insufficient to identify group differences and associations with biomarker levels. Likewise, longitudinal data on repeat hospitalizations did not indicate associations with biomarker levels. CONCLUSIONS: Creatinine, CK, and LDH levels were insufficient for monitoring and predicting the course of SMA. Further prospective research is needed to elaborate the weak relationships between CK levels, the dynamics of the clinical presentation, and therapeutic interventions, and to investigate psychiatric co-morbidities in SMA 5q patients.

A progressive and refractory case of breast cancer with Cowden syndrome.

BACKGROUND: Cowden syndrome is a rare autosomal-dominant disease with a high risk of malignant tumors of the breast, commonly caused by germline mutations in the PTEN gene. Most breast cancers related to Cowden syndrome showed typically a slow-growing and favorable clinical course. Here, we report a progressive case of triple-negative breast cancer in a patient who was diagnosed with Cowden syndrome. CASE PRESENTATION: A 35-year-old female with breast cancer was referred to our hospital. Histopathological examination of the tumor showed that it was triple-negative breast cancer with high proliferation marker. Preoperative positron emission tomography-computed tomography showed abnormal uptake in the left cerebellar hemisphere in addition to the right breast and axillary lymph node. Brain T2-weighted magnetic resonance imaging revealed hyperintense bands in the left cerebellar hemisphere lesion, which demonstrated a "tiger-stripe" appearance. The patient's mother had died of endometrial cancer. Subsequently, she underwent genetic testing, leading to a diagnosis of Cowden syndrome with a pathogenic variant c.823_840del.18 at exon 8 in PTEN. She was treated with neoadjuvant chemotherapy of eribulin and cyclophosphamide followed by adriamycin and cyclophosphamide. However, her tumors increased after these treatments. She was immediately surgically treated and received adjuvant chemotherapy of capecitabine. Unfortunately, the cancer recurred in the lung nine months after surgery. We then administered paclitaxel and bevacizumab therapy, but the disease rapidly progressed. Consequently, the patient died due to breast cancer about three months after recurrence. CONCLUSION: We report an aggressive case of cancer with Cowden syndrome which was resistant to standard chemotherapy. Alteration of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin pathway due to inactivating PTEN protein may be associated with chemoresistance and serves as a candidate for therapeutic intervention in PTEN-related cancers.

Mimush Sheep and the Spectre of Inbreeding: Historical Background for Festetics's Organic and Genetic Laws Four Decades Before Mendel's Experiments in Peas.

The upheavals of late eighteenth century Europe encouraged people to demand greater liberties, including the freedom to explore the natural world, individually or as part of investigative associations. The Moravian Agricultural and Natural Science Society, organized by Christian Carl André, was one such group of keen practitioners of theoretical and applied scientific disciplines. Headquartered in the "Moravian Manchester" Brünn (nowadays Brno), the centre of the textile industry, society members debated the improvement of sheep wool to fulfil the needs of the Habsburg armies fighting in the Napoleonic Wars. Wool, as the raw material of soldiers' clothing, could influence the war's outcome. During the early nineteenth century, wool united politics, economics, and science in Brno, where breeders and natural scientists investigated the possibilities of increasing wool production. They regularly discussed how "climate" or "seed" characteristics influenced wool quality and quantity. Breeders and academics put their knowledge into immediate practice to create sheep with better wool traits through consanguineous matching of animals and artificial selection. This apparent disregard for the incest taboo, however, was viewed as violating natural laws and cultural norms. The debate intensified between 1817 and 1820, when a Hungarian veteran soldier, sheep breeder, and self-taught natural scientist, Imre (Emmerich) Festetics, displayed his inbred Mimush sheep, which yielded wool extremely well suited for the fabrication of light but strong garments. Members of the Society questioned whether such "bastard sheep" would be prone to climatic degeneration, should be regarded as freaks of nature, or could be explained by natural laws. The exploration of inbreeding in sheep began to be distilled into hereditary principles that culminated in 1819 with Festetics's "laws of organic functions" and "genetic laws of nature," four decades before Gregor Johann Mendel's seminal work on heredity in peas.

[Clinical Characteristics and Gene Mutations in 186 Cases of Kindler Syndrome].

Objective To investigate the clinical characteristics and genetic mutations in Kindler syndrome(KS)and provide a theoretical basis for the diagnosis and treatment of KS. Methods The clinical data of one case of KS from Peking Union Medical College Hospital and 185 cases reported in literature were collected. The gene mutation types,patient clinical data,and tumor characteristics were statistically analyzed. Results A total of 186 cases were enrolled,including 110 males and 76 females,with the mean age of(28±16)years. The data of gene mutation and specific clinical manifestations were available in 151 and 94 patients,respectively. The main clinical manifestations of KS included poikiloderma,occurrence of blister in childhood,and photosensitivity,and the secondary clinical manifestations included oral inflammation,palmoplantar keratoderma,webbing/pseudoainhum,dysphagia,urethral stricture and so on.Oral inflammation(r=0.234,P=0.023),palmoplantar keratoderma(r=0.325,P=0.001),webbing/pseudoainhum(r=0.247,P=0.016),dysphagia(r=0.333,P=0.001),urethral stricture(r=0.280,P=0.006)were significantly correlated with age,showing significantly higher incidence in the patients over 32 years old.Urethral stricture(χ2=11.292,P=0.001)and anal stenosis(χ2=4.014,P=0.045)were significantly correlated with sex,with higher incidence in males.Eighty different mutations were found in 151 patients,and the most common gene mutation was c.676C>T.Forty-one tumors occurred in 27 patients,among which squamous cell carcinoma accounted for 92.7%. The gene mutation site had no significant correlation with squamous cell carcinoma or patient country. Conclusions The c.676C>T in FERMT1 gene is the most common mutation in KS.The patients are prone to squamous cell carcinoma and mainly attacked at the exposure sites(hand and mouth).

X-linked dominant RPGR gene mutation in a familial Coats angiomatosis.

BACKGROUND: Retinitis Pigmentosa (RP) is the most frequent retinal hereditary disease and every kind of transmission pattern has been described. The genetic etiology of RP is extremely heterogeneous and in the last few years the large application of Next Generation Sequencing (NGS) approaches improved the diagnostic yield, elucidating previously unexplained RP causes and new genotype-phenotype correlations. The objective of this study was to reevaluate a previously reported family affected by Coats'-type RP without genetic diagnosis and to describe the new genetic findings. CASE PRESENTATION: Cohort, prospective, and single-center observational family case. Three individuals of a family, consisting of a mother and four sons, with a Coats phenotype were revaluated after 25 years of clinical follow-up using visual acuity tests, ophthalmoscopy, Goldmann visual field, electroretinography (ERG), and spectral domain-optical coherence tomography (SD-OCT). Specifically, a RP NGS panel was performed on one member of the family and segregation analysis was required for the other affected and unaffected members. NGS analysis disclosed a RPGR (Retinitis Pigmentosa GTPase Regulator) gene truncating variant segregating with the phenotype in all the three affected members. RPGR mutations are reported as causative of an X-linked RP. CONCLUSIONS: This is the first reported family with a Coats'-type RP associated to a RPGR mutation and segregating as a dominant X-linked disease, confirming the hypothesis of the genetic origin of this condition and expanding the phenotypic spectrum of diseases caused by RPGR gene mutations. The Authors suggest RPGR gene screening mutations in patients presenting this phenotype.

A large deletion in the Plasminogen gene is associated with ligneous membranitis in a Maltese dog.

Ligneous membranitis/conjunctivitis (LM, OMIM 217090) is a hereditary disorder caused by a congenital plasminogen (PLG) deficiency. In veterinary medicine, LM (OMIA 002020-9615) has rarely been reported in Golden Retrievers, Yorkshire Terriers, Doberman Pinschers and Scottish Terriers. In the latter breed, an A>T variation in an intron donor site of the PLG gene (PLG, c.1256+2T>A) has been found to be the sole causative molecular defect reported to date in dogs. Owing to the absence of plasmin enzymatic clearance which in turn depends on the lack of its proenzyme plasminogen, fibrin deposits tend to accumulate in viscous membranes on the eyes, triggering and sustaining an intense inflammatory response. A case of LM was diagnosed in a 7-month-old male Maltese dog. The dog was examined for severe recurrent conjunctivitis. A diagnosis of ligneous conjunctivitis was made by an ophthalmologist after a thorough eye examination and was confirmed by a complete lack of plasma activity of plasminogen. The main local signs were redness of the conjunctiva with persistent membranes having ligneous (wood-like) membranes on the eyes. The disease was associated with a complex rearrangement involving the plasminogen gene loci, causing the complete deletion of exon 1. This study provides a spontaneous animal model for LM associated with complete plasminogen deficiency and provides a method for detecting affected or carrier dogs.

Chorionic villus sampling experience of a reference perinatal medicine center.

AIM: To share the chorionic villus sampling (CVS) experience of a single surgeon in our institution. METHODS: This retrospective study consists of CVS cases performed between 2000 and 2018. A total of 66 types of indications were classified under two main categories, the screening group (SG) and the inherited disease group (IDG). The SG and IDG were compared in terms of clinical characteristics of the patients, Beksaç obstetrics index (BOI), timing of CVS in terms of gestational week, and complications and termination of pregnancy (TOP) rate. RESULTS: CVS was performed at 656 women, 69 and 587 of whom were included in the SG and IDG, respectively. CVS indications of the SG were determined as advanced maternal age, high risk in combined test, fetal anomaly suspicion in ultrasonography, and increased nuchal translucency in 23, 23, 14 and 9 cases, respectively. On the other hand, CVS indications of the IDG were hereditary disorders related to hematological, muscular, and metabolic systems for 233, 179, and 116 cases, respectively. Furthermore, 32 patients had a single-gene disorder and 14 had a neurodegenerative disease. According to the results of CVS, 359 fetuses were found to be normal (54.73%), while 205 (31.25%) and 92 (14.02%) fetuses were found to be disorder-positive or carriers, respectively. Two hundred pregnant women accepted TOP. Eight (1.2%) pregnancies ended with abortion after CVS. Statistically significant differences were observed in BOI and TOP rate between SG and IDG (p: 0.042 and 0.013). CONCLUSION: Hereditary disorders were the most common CVS indications and the acceptance of TOP was significantly higher in this group.

Organ Transplantation in Hereditary Fibrinogen A α-Chain Amyloidosis: A Case Series of French Patients.

RATIONALE & OBJECTIVE: Fibrinogen A α-chain amyloidosis (AFib amyloidosis) is a form of amyloidosis resulting from mutations in the fibrinogen A α-chain gene (FGA), causing progressive kidney disease leading to kidney failure. Treatment may include kidney transplantation (KT) or liver-kidney transplantation (LKT), but it is not clear what factors should guide this decision. The aim of this study was to characterize the natural history and long-term outcomes of this disease, with and without organ transplantation, among patients with AFib amyloidosis and various FGA variants. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 32 patients with AFib amyloidosis diagnosed by genetic testing in France between 1983 and 2014, with a median follow-up of 93 (range, 4-192) months, were included. RESULTS: Median age at diagnosis was 51.5 (range, 12-77) years. Clinical presentation consisted of proteinuria (93%), hypertension (83%), and kidney failure (68%). Manifestations of kidney disease appeared on average at age 57 (range, 36-77) years in patients with the E526V variant, at age 45 (range, 12-59) years in those with the R554L variant (P<0.001), and at age 24.5 (range, 12-31) years in those with frameshift variants (P<0.001). KT was performed in 15 patients and LKT was performed in 4. In KT patients with the E526V variant, recurrence of AFib amyloidosis in the kidney graft was less common than with a non-E526V (R554L or frameshift) variant (22% vs 83%; P=0.03) and led to graft loss less frequently (33% vs 100%). Amyloid recurrence was not observed in patients after LKT. LIMITATIONS: Analyses were based on clinically available historical data. Small number of patients with non-E526V and frameshift variants. CONCLUSIONS: Our study suggests phenotypic variability in the natural history of AFib amyloidosis, depending on the FGA mutation type. KT appears to be a viable option for patients with the most common E526V variant, whereas LKT may be a preferred option for patients with frameshift variants.

Exploring the burden of X-linked hypophosphatemia: a European multi-country qualitative study.

INTRODUCTION: X-linked hypophosphatemia (XLH) is a rare, lifelong, progressive disease characterised by renal phosphate wasting and abnormal bone mineralisation. Symptoms begin in early childhood, with the development of rickets and related skeletal deformities and reduced growth, progressing to long-term complications, including pseudofractures and fractures, as well as pain, stiffness and fatigue. The present study was designed to explore the patient experience of pain, stiffness and fatigue and the psychosocial impact of XLH in detail. METHODS: A cross-sectional qualitative study was conducted in the United Kingdom (18), Finland (6), France (4), Germany (1) and Luxembourg (1) with XLH patients aged 26 and over. Interview discussion guides were developed in consultation with clinical experts and patient associations. Data were analysed thematically. RESULTS: Participants (N = 30) described pain, stiffness and fatigue as frequently experienced symptoms with a significant impact on physical functioning and activities of daily living (ADLs). Some also described the symptoms as impacting their mood/mental health, relationships, social life and leisure activities. Participants described how common symptoms could interact or aggravate other symptoms. Symptoms had often worsened over time, and for many, were associated with concern about the future. Most participants were worried or felt guilty about having children with XLH. The findings confirmed and extended the existing model of the burden of XLH. CONCLUSION: The present study is the first to provide an in-depth analysis of pain, stiffness and fatigue, their impact and the interrelatedness of these symptoms among adults with XLH. The study also described the psychosocial impact of XLH as a hereditary, lifelong progressive disease.

[Influence of genetics in intracranial aneurysms]. / Genetischer Einfluss bei intrakraniellen Aneurysmen.

BACKGROUND: The prevalence of unruptured intracranial aneurysms is approximately 3-5%. Subarachnoid hemorrhage caused by rupture of an aneurysm often affects middle-aged people and harbors high morbidity and mortality. The increasing availability of noninvasive imaging techniques over time is accompanied by an increase in the incidental detection of aneurysms. METHODS: The etiology in aneurysm development is heterogeneous. Besides polygenic multifactorial diseases, often triggered by well-established vascular risk factors, monogenic diseases should also be considered. Advances in genetics has helped to identify genes that contribute to the risk of intracranial aneurysm development. CONCLUSION: The genetic basis of intracranial aneurysms shows a broad heterogeneity and complexity. Currently, besides imaging there is no reliable diagnostic test to identify patients who are at higher risk for asymptomatic intracranial aneurysms.

TRPV1 variants impair intracellular Ca2+ signaling and may confer susceptibility to malignant hyperthermia.

PURPOSE: Malignant hyperthermia (MH) is a pharmacogenetic disorder arising from uncontrolled muscle calcium release due to an abnormality in the sarcoplasmic reticulum (SR) calcium-release mechanism triggered by halogenated inhalational anesthetics. However, the molecular mechanisms involved are still incomplete. METHODS: We aimed to identify transient receptor potential vanilloid 1 (TRPV1) variants within the entire coding sequence in patients who developed sensitivity to MH of unknown etiology. In vitro and in vivo functional studies were performed in heterologous expression system, trpv1-/- mice, and a murine model of human MH. RESULTS: We identified TRPV1 variants in two patients and their heterologous expression in muscles of trpv1-/- mice strongly enhanced calcium release from SR upon halogenated anesthetic stimulation, suggesting they could be responsible for the MH phenotype. We confirmed the in vivo significance by using mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation associated with MH in humans. We showed that the TRPV1 antagonist capsazepine slows the heat-induced hypermetabolic response in this model. CONCLUSION: We propose that TRPV1 contributes to MH and could represent an actionable therapeutic target for prevention of the pathology and also be responsible for MH sensitivity when mutated.

Cognitive Indicators of Preclinical Behavioral Variant Frontotemporal Dementia in MAPT Carriers.

OBJECTIVES: The cognitive indicators of preclinical behavioral variant Frontotemporal Dementia (bvFTD) have not been identified. To investigate these indicators, we compared cross-sectional performance on a range of cognitive measures in 12 carriers of pathogenic MAPT mutations not meeting diagnostic criteria for bvFTD (i.e., preclinical) versus 32 demographically-matched familial non-carriers (n = 44). Studying preclinical carriers offers a rare glimpse into emergent disease, environmentally and genetically contextualized through comparison to familial controls. METHODS: Evaluating personnel blinded to carrier status administered a standardized neuropsychological battery assessing attention, speed, executive function, language, memory, spatial ability, and social cognition. Results from mixed effect modeling were corrected for multiplicity of comparison by the false discovery rate method, and results were considered significant at p < .05. To control for potential interfamilial variation arising from enrollment of six families, family was treated as a random effect, while carrier status, age, gender, and education were treated as fixed effects. RESULTS: Group differences were detected in 17 of 31 cognitive scores and spanned all domains except spatial ability. As hypothesized, carriers performed worse on specific measures of executive function, and social cognition, but also on measures of attention, speed, semantic processing, and memory storage and retrieval. CONCLUSIONS: Most notably, group differences arose on measures of memory storage, challenging long-standing ideas about the absence of amnestic features on neuropsychological testing in early bvFTD. Current findings provide important and clinically relevant information about specific measures that may be sensitive to early bvFTD, and advance understanding of neurocognitive changes that occur early in the disease. (JINS, 2019, 25, 184-194).