Diffusion tensor imaging of two unrelated Chinese men with hereditary spastic paraplegia associated with thin corpus callosum

Hereditary spastic paraplegia (HSP) associated with thin corpus callosum is a rare autosomal recessive neurodegenerative disorder characterized by an abnormally thin corpus callosum, normal motor development, slowly progressive spastic paraparesis and cognitive deterioration. To investigate and localize abnormalities in the brains of two Chinese patients with HSP-TCC, with mutations in the spatacsin gene. Diffusion tensor imaging (DTI) was used to determine the mean diffusion (MD) and fractional anisotropy (FA) in the brains of the patients in comparison to 20 healthy subjects. Voxel-based analysis (VBA) of both the diffusion and anisotropy values were performed using statistical parametric mapping (SPM). Significant changes with MD increase and FA reduction were found in the already known lesions including the corpus callosum, cerebellum and thalamus. In addition, changes were also found in regions that appear to be normal in conventional MRI, such as the brain stem, internal capsule, cingulum and subcortical white matter including superior longitudinal fascicle and inferior longitudinal fascicle. Neither increase in FA nor reduction in MD was detected in the brain. Our study provides clear in vivo MR imaging evidence of a more widespread brain involvement of HSP-TCC. MD is more sensitive than FA in detecting lesions in thalamus and subcortical white matter, suggesting that MD may be a better marker of the disease progression.

[Hereditary nephrogenetic diabetes insipidus--case report and discussion]

The history of a patient with hereditary nephrogenic diabetes insipidus is discussed. The pathogenesis and the therapeutic approach is revised.

A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation.

Hereditary nasal parakeratosis (HNPK), an inherited monogenic autosomal recessive skin disorder, leads to crusts and fissures on the nasal planum of Labrador Retrievers. We performed a genome-wide association study (GWAS) using 13 HNPK cases and 23 controls. We obtained a single strong association signal on chromosome 2 (p(raw) = 4.4×10⁻¹⁴). The analysis of shared haplotypes among the 13 cases defined a critical interval of 1.6 Mb with 25 predicted genes. We re-sequenced the genome of one case at 38× coverage and detected 3 non-synonymous variants in the critical interval with respect to the reference genome assembly. We genotyped these variants in larger cohorts of dogs and only one was perfectly associated with the HNPK phenotype in a cohort of more than 500 dogs. This candidate causative variant is a missense variant in the SUV39H2 gene encoding a histone 3 lysine 9 (H3K9) methyltransferase, which mediates chromatin silencing. The variant c.972T>G is predicted to change an evolutionary conserved asparagine into a lysine in the catalytically active domain of the enzyme (p.N324K). We further studied the histopathological alterations in the epidermis in vivo. Our data suggest that the HNPK phenotype is not caused by hyperproliferation, but rather delayed terminal differentiation of keratinocytes. Thus, our data provide evidence that SUV39H2 is involved in the epigenetic regulation of keratinocyte differentiation ensuring proper stratification and tight sealing of the mammalian epidermis.

Hereditary thrombotic thrombocytopenic purpura and the hereditary TTP registry

Hereditary thrombotic thrombocytopenic purpura, Upshaw-Schulman syndrome, ADAMTS13 Hereditary thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome, is a rare recessively inherited disease. Underlying is a severe constitutional deficiency of the von Willebrand factor-cleaving protease, ADAMTS13, due to compound heterozygous or homozygous mutations in the ADAMTS13 gene. The clinical picture is variable and more and more patients with an adult-onset are diagnosed. In the majority of countries the only available treatment is plasma, which when administered regularly can efficiently prevent acute disease bouts. The decision to initiate regular prophylaxis is often not easy, as evidence based guidelines and long term outcome data are lacking. Through the hereditary TTP registry (www.ttpregistry.net, ClinicalTrials.gov identifier: NCT01257269), which was initiated in 2006 and is open to all patients diagnosed with Upshaw-Schulman syndrome and their family members, we aim to gain further information and insights into this rare disease, which eventually will help to improve clinical management of affected patients.

Low dose irinotecan improves advanced lupus nephritis in mice potentially by changing DNA relaxation and anti–double-stranded DNA binding

Objective Albeit clear advances in the treatment of SLE, many patients still present with refractory lupus nephritis requiring new treatment strategies for this disease. Here we determined whether reduced doses of the topoisomerase I inhibitor irinotecan, which is known as chemotherapeutic agent, were able to suppress SLE in NZB/W F1 mice. We further evaluated the potential mechanism how irinotecan influenced the course of SLE. Methods NZB/W F1 mice were treated with low dose irinotecan either from week 24 of age or from established glomerulonephritis defined by a proteinuria ≥grade 3+. Binding of anti-dsDNA antibodies was measured by ELISA; and DNA relaxation was visualized by gel electrophoresis. Results Significantly reduced irinotecan dosages improved lupus nephritis and prolonged survival in NZB/W F1 mice. The lowest dose successfully used for the treatment of established murine lupus nephritis was more than 50 times lower than the dose usually applied for chemotherapy in humans. As a mechanism, low dose irinotecan reduced B cell activity; however, the levels of B cell activity in irinotecan-treated mice were similar to those in Balb/c mice of the same age suggesting that irinotecan did not induce a clear immunosuppression. In addition, incubation of double-stranded (ds) DNA with topoisomerase I increased binding of murine and human anti-dsDNA antibodies showing for the first time that relaxed DNA is more susceptible to anti-dsDNA antibody binding. This effect was reversed by addition of the topoisomerase I inhibitor camptothecin. Conclusion Our results propose topoisomerase I inhibitors as a novel and targeted therapy for SLE. © 2014 American College of Rheumatology.

A mutation in the FAM83G gene in dogs with hereditary footpad hyperkeratosis (HFH)

Hereditary footpad hyperkeratosis (HFH) represents a palmoplantar hyperkeratosis, which is inherited as a monogenic autosomal recessive trait in several dog breeds, such as e.g. Kromfohrländer and Irish Terriers. We performed genome-wide association studies (GWAS) in both breeds. In Kromfohrländer we obtained a single strong association signal on chromosome 5 (p(raw) = 1.0×10(-13)) using 13 HFH cases and 29 controls. The association signal replicated in an independent cohort of Irish Terriers with 10 cases and 21 controls (p(raw) = 6.9×10(-10)). The analysis of shared haplotypes among the combined Kromfohrländer and Irish Terrier cases defined a critical interval of 611 kb with 13 predicted genes. We re-sequenced the genome of one affected Kromfohrländer at 23.5× coverage. The comparison of the sequence data with 46 genomes of non-affected dogs from other breeds revealed a single private non-synonymous variant in the critical interval with respect to the reference genome assembly. The variant is a missense variant (c.155G>C) in the FAM83G gene encoding a protein with largely unknown function. It is predicted to change an evolutionary conserved arginine into a proline residue (p.R52P). We genotyped this variant in a larger cohort of dogs and found perfect association with the HFH phenotype. We further studied the clinical and histopathological alterations in the epidermis in vivo. Affected dogs show a moderate to severe orthokeratotic hyperplasia of the palmoplantar epidermis. Thus, our data provide the first evidence that FAM83G has an essential role for maintaining the integrity of the palmoplantar epidermis.

Hepatic fungal infection in a young beagle with unrecognised hereditary cobalamin deficiency (Imerslund-Gräsbeck syndrome)

A 12-month-old beagle presented for anorexia, pyrexia and vomiting. The dog had been treated intermittently with antibiotics and corticosteroids for inappetence and lethargy since five months of age. Previous laboratory abnormalities included macrocytosis and neutropenia. At presentation, the dog was lethargic, febrile and thin. Laboratory examination findings included anaemia, a left shift, thrombocytopenia, hypoglycaemia and hyperbilirubinaemia. Multiple, small, hypoechoic, round hepatic lesions were observed on abdominal ultrasound. Cytological examination of hepatic fine needle aspirates revealed a fungal infection and associated pyogranulomatous inflammation. The dog's general condition deteriorated despite supportive measures and treatment with fluconazole, and owners opted for euthanasia before hypocobalaminaemia was identified. Subsequent genomic analysis revealed a CUBN:c.786delC mutation in a homozygous state, confirming hereditary cobalamin malabsorption (Imerslund-Gräsbeck syndrome). Similar to human infants, dogs with Imerslund-Gräsbeck syndrome may rarely be presented for infectious diseases, distracting focus from the underlying primary disorder.

Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis

Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention. Genetic loci associated with iron metabolism (TF, TMPRSS6, PCSK7, TFR2 and Chr2p14) in recent GWAS and liver fibrosis (PNPLA3) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden. Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7) was associated with cirrhosis or advanced fibrosis (P = 1.02 × 10(-5)) in the German cohort with genotypic odds ratios of 3.56 (95% CI 1.29-9.77) for CG heterozygotes and 5.38 (95% CI 2.39-12.10) for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes (P = 0.014; ORallelic = 1.82 (95% CI 1.12-2.95) but not in Swedish patients. Post hoc combined analyses of German/Swiss/Austrian patients with available liver histology (N = 244, P = 0.00014, ORallelic = 2.84) and of males only (N = 431, P = 2.17 × 10(-5), ORallelic = 2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH. PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutation.

Hereditary diseases in the horse: I. Monogenetic diseases

Overall, monogenetic hereditary diseases are less important for the breeding industry than polygenetic diseases because they are relatively rare. For the individual animal, however, these diseases have often a dramatic outcome and many of these diseases presently known are lethal. For several of them the exact pathogenesis is known and DNA-tests are available to confirm the exact diagnosis.

High prevalence of hereditary thrombotic thrombocytopenic purpura in Central Norway: from clinical observation to evidence.

BACKGROUND Hereditary thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 mutations is a rare, but serious condition. The prevalence is unknown, but seems to be high in Norway. OBJECTIVES To identify all patients with hereditary TTP in Central Norway and to investigate the prevalence of hereditary TTP and the population frequencies of two common ADAMTS13 mutations. Patients/Methods Patients were identified in a cross-sectional study within Central Norway Health Region by means of three different search strategies. Frequencies of ADAMTS13 mutations, c.4143_4144dupA and c.3178 C>T (p.R1060W) were investigated in a population-based cohort (500 alleles) and in healthy blood donors (2104 alleles) by taking advantage of the close neighbourhood of the ADAMTS13 and ABO blood group gene loci. The observed prevalence of hereditary TTP was compared to the rates of ADAMTS13 mutation carriers in different geographical regions. RESULTS We identified 11 families with hereditary TTP in Central Norway during the 10-year study period. The prevalence of hereditary TTP in Central Norway was 16.7 x 10(-6) . The most prevalent mutation was c.4143_4144dupA, accounting for two thirds of disease causing alleles among patients and having an allelic frequency of 0.33% in the Central, 0.10% in the Western, and 0.04% in the Southeastern Norwegian population. The allelic frequency of c.3178 C>T (p.R1060W) in the population was even higher (0.3-1%), but this mutation was infrequent among patients, with no homozygous cases. CONCLUSIONS We found a high prevalence of hereditary TTP in Central Norway and an apparently different penetrance of ADAMTS13 mutations. This article is protected by copyright. All rights reserved.

Whole-Genome Sequencing of a Canine Family Trio Reveals a FAM83G Variant Associated with Hereditary Footpad Hyperkeratosis

Over 250 Mendelian traits and disorders, caused by rare alleles have been mapped in the canine genome. Although each disease is rare in the dog as a species, they are collectively common and have major impact on canine health. With SNP-based genotyping arrays, genome-wide association studies (GWAS) have proven to be a powerful method to map the genomic region of interest when 10-20 cases and 10-20 controls are available. However, to identify the genetic variant in associated regions, fine-mapping and targeted re-sequencing is required. Here we present a new approach using whole-genome sequencing (WGS) of a family trio without prior GWAS. As a proof-of-concept, we chose an autosomal recessive disease known as hereditary footpad hyperkeratosis (HFH) in Kromfohrl änder dogs. To our knowledge, this is the first time this family trio WGS-approach, has successfully been used to identify a genetic variant that perfectly segregates with a canine disorder. The sequencing of three Kromfohrl änder dogs from a family trio (an affected offspring and both its healthy parents) resulted in an average genome coverage of 9.2X per individual. After applying stringent filtering criteria for candidate causative coding variants, 527 single nucleotide variants (SNVs) and 15 indels were found to be homozygous in the affected offspring and heterozygous in the parents. Using the computer software packages ANNOVAR and SIFT to functionally annotate coding sequence differences and to predict their functional effect, resulted in seven candidate variants located in six different genes. Of these, only FAM83G:c155G>C (p.R52P) was found to be concordant in eight additional cases and 16 healthy Kromfohrl änder dogs.