Northern European Origin Research Articles

Therapy for Dupuytren’s Disease: Collagenase Therapy—A Long-Term Follow-Up Study

Background: Dupuytren’s disease (DD) is a systemic connective tissue disorder of the palm. It particularly affects men of Northern European or Caucasian origin over the age of 55. In addition to the classical surgical therapy via limited fasciectomy, Dupuytren’s contracture can also be treated minimally invasively. A relatively new treatment method is the use of collagenase injections (Xiapex) to reduce the contracture of the fingers. The data regarding the long-term success of this therapy are currently limited. Methods: In this monocentric retrospective study, we examined 35 patients who were treated with collagenase (Xiapex) for Dupuytren’s contracture in the long fingers. Following the manufacturer’s recommendations, the injection was administered intralesionally, and the cord was ruptured through the passive extension of the finger under local anesthesia with Mepivacain the following day. The clinical follow-up examination was conducted after an average of 5.7 years. The stages of Dupuytren’s disease were documented using the Tubiana classification. Additionally, parameters of finger extension ability, differentiated by metacarpophalangeal (MCP), and proximal interphalangeal (PIP) joints, as well as patient-specific risk parameters, were evaluated Results: The long-term results of collagenase therapy after an average of 5.7 years showed a significant improvement in the contracture of the affected fingers. In the MCP joints, the flexion contracture decreased from 42° to 17° (p ≤ 0.001), and in the PIP joints, it decreased from 56° to 33° (p ≤ 0.001). The primary recurrence rate was 11% for the MCP joints and 19% for the PIP joints, respectively. The analysis of risk factors showed a significant risk for worse long-term outcomes in patients with diabetes and those with nicotine abuse. Conclusions: Collagenase therapy for Dupuytren’s disease achieved significant long-term improvements in contracture in both MCP and PIP joints. In accordance with general risk factors for DD, patients with diabetes and those with nicotine abuse are at risk of worse long-term outcomes. Overall, it is a time-saving, low-risk, and straightforward technique for treating the disabling contracture component of this disease.

Prevalence of C282Y, H63D and S65C gene mutations in patients with hyperferritinemia undergoing therapeutic phlebotomy suspected of having hereditary hemochromatosis

Background: Hemochromatosis is an autosomal recessive disorder caused by excessive iron overload in parenchymal organs. In Brazil, the prevalence of hereditary hemochromatosis (HH) may vary compared to other countries due to different ethnical backgrounds according to the geographic region studied. The prevalence of C282Y mutation of the HFE gene ranges from three to eight times lower in Brazilians than in Caucasians of Northern European origin. Methods: A retrospective cross-sectional study was carried out in 222 patients submitted to therapeutic phlebotomy between March 2011 and July 2014 in a tertiary hospital blood center. The prevalence of HH was determined in 89 (47.3%) out of 188 (84.6%) patients presenting hyperferritinemia, and divided in two genotype groups: C282Y mutation and other mutations. The HH patients’ geographical and clinical characteristics, serum ferritin rate (SF) and transferrin saturation (TS) were analyzed. Results: The HH group consisted of 71 males (79.7%) and 18 (20.3%) females, with a median age of 51.5 ± 10.6 years. There were 36 (40.0%) symptomatic patients and 65 (73.0%) tested positive for the HFE mutation. The initial baseline TS values were significantly higher in primary HH patients (48.6%, IC 95% 43.2% - 55.7%) compared to those with secondary HH (35.0%, IC 95% 27.5% 41.8%, p=0.001). Conclusion: The prevalence of C282Y mutation was higher in this population from the South region compared to previous reports in the Brazilian population, yet inferior to that of Northern Europeans.

Variation in the fibroblast growth factor 23 (FGF23) gene associates with serum FGF23 and bone strength in infants.

Introduction: The effects of genetic variation in fibroblast growth factor 23 (FGF23) are unclear. This study explores the associations of single-nucleotide polymorphisms (SNPs) of FGF23 with phosphate and vitamin D metabolism and bone strength in early childhood. Methods: The study is part of the vitamin D intervention in infant (VIDI) trial (2013-2016), in which healthy term infants born to mothers of Northern European origin received vitamin D3 supplementation of 10 or 30μg/day from 2 weeks to 24months of age (ClinicalTrials.gov NCT01723852). Intact and C-terminal FGF23 (cFGF23), 25-hydroxyvitamin D (25-OHD), parathyroid hormone, phosphate, and peripheral quantitative computed tomography (pQCT)-derived bone strength parameters were analyzed at 12 and 24months. The study included 622 VIDI participants with genotyping data on FGF23 SNPs rs7955866, rs11063112, and rs13312770. Results: Rs7955866 minor allele homozygotes had lowest cFGF23at both time-points (mixed model for repeated measurements, pvariant = 0.009). Minor alleles of rs11063112 were associated with a greater age-related decrease in phosphate concentration (pinteraction = 0.038) from 12 to 24months. Heterozygotes of rs13312770 had the greatest total bone mineral content (total BMC), cross-sectional area (total CSA), and polar moment of inertia (PMI) at 24months (ANOVA p = 0.005, 0.037, and 0.036, respectively). Rs13312770 minor alleles were associated with a greater increase of total BMC, but a smaller increase of total CSA and PMI, during follow-up (pinteraction <0.001, 0.043, and 0.012, respectively). Genotype of FGF23 did not modify 25-OHD. Conclusion: The study finds that genetic variation in FGF23 modifies cFGF23, phosphate, and pQCT-derived bone strength parameters from 12 to 24months of age. These findings potentially promote an understanding of the regulation of FGF23 and its role in bone metabolism and temporal changes thereof during early childhood.

Two Portrayals of Public Debt in the Formation of Modern Italy: From the Ancien Régime to Modern Capitalism

The unification of Italian public debts in 1861 has been analysed until now without any detailed investigation into the changes that occurred in pre-existent public finance models, particularly as regards the contextualisation of public debt within the evolving framework of Italian capitalism. The Kingdom of Sardinia imposed on the other Italian regions not merely a state, bureaucratic and administrative system, but also an economic and financial one: a modern liberal-capitalist model of northern European origin and inspiration. The transition and incorporation of the Neapolitan public debt into the Great Book of the Italian Public Debt bear witness to this change. The aim of the present article is to investigate the transformation of the Italian public debt's structure. I explore specifically the effects of the shift from registered bonds to bearer bonds in Naples, as exemplifying a more radical metamorphosis and the transition from a public finance model typical of the ancien régime to the modern liberal-capitalist one, which is characterised by the Kingdom of Sardinia.

Nitric Oxide Precursors and Dimethylarginines as Risk Markers for Accelerated Measured GFR Decline in the General Population

Nitric oxide (NO) deficiency is associated with endothelial dysfunction, hypertension, atherosclerosis, and chronic kidney disease (CKD). Reduced NO bioavailability is hypothesized to play a vital role in kidney function impairment and CKD. We investigated the association of serum levels of endogenous inhibitors of NO, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), and precursors of NO, arginine, citrulline, and ornithine, with a decline in glomerular filtration rate (GFR) and new-onset CKD. In a prospective cohort study of 1407 healthy, middle-aged participants of Northern European origin in the Renal Iohexol Clearance Survey (RENIS), GFR was measured repeatedly with iohexol clearance during a median follow-up time of 11 years. GFR decline rates were analyzed using a linear mixed model, new-onset CKD (GFR< 60 ml/min per 1.73 m2) was analyzed with interval-censored Cox regression, and accelerated GFR decline (the 10% with the steepest GFR decline) was analyzed with logistic regression. Higher SDMA was associated with slower annual GFR decline. Higher levels of citrulline and ornithine were associated with accelerated GFR decline (odds ratio [OR], 1.43; 95% confidence interval [CI] 1.16-1.76 per SD higher citrulline and OR 1.23; 95% CI 1.01 to 1.49 per SD higher ornithine). Higher citrulline was associated with new-onset CKD, with a hazard ratio of 1.33 (95% CI 1.07-1.66) per SD higher citrulline. Associations between NO precursors and the outcomes suggest that NO metabolism plays a significant role in the pathogenesis of age-related GFR decline and the development of CKD in middle-aged people.

Хронология памятников X в. на территории Окско-Донского водораздела

The article deals with the problems of chronology of the 10th century sites, located between the Oka and Don rivers. Analysis of the topography of the settlements and the range of finds from them allows them to be divided into three periods — early, middle and late. In the first half of the 10th century there are still sites from the early period that appeared in the 9th century. They are associated with the Upper Oka section of the Don trade route. These sites are located on the banks of its main thoroughfares. Their ceramic complex consists of ceramics of the Romensky type, and a small percentage of circular pottery of the Saltovsky and Volintsev types. The early settlements cease to exist as a result of military invasion. This event is archaeologically documented at the Suprut hill fort. After that, the settlements of the middle period appear. This process is linked to the termination of the Upper Oka section of the Don trade route. The sites of the middle period are situated at a distance from the major waterways of the region. Their complexes contain items of Northern European and Old Russian origin. The ceramic complex consists of stucco ceramics of the Romensky type and a small percentage of wheel-thrown pottery vessels. The sites of the middle period exist throughout the second half of the 10th century. The late stage settlements appear at the end of the 10th century. They retain a topography similar to that of the middle period settlements. Their ceramic complex contains a large percentage of Old Russian pottery. Life at the late stage settlements continues into the 11th century.

Whole-exome sequencing in moyamoya patients of Northern-European origin identifies gene variants involved in Nitric Oxide metabolism: A pilot study

IntroductionMoyamoya disease (MMD) is a chronic cerebrovascular steno-occlusive disease of largely unknown etiology. Variants in the RNF213 gene are strongly associated with MMD in East-Asia. In MMD patients of Northern-European origin, no predominant susceptibility variants have been identified so far. Research questionAre there specific candidate genes associated with MMD of Northern-European origin, including the known RNF213 gene? Can we establish a hypothesis for MMD phenotype and associated genetic variants identified for further research? Material and methodsAdult patients of Northern-European origin, treated surgically for MMD at Oslo University Hospital between October 2018 to January 2019 were asked to participate. WES was performed, with subsequent bioinformatic analysis and variant filtering. The selected candidate genes were either previously reported in MMD or known to be involved in angiogenesis. The variant filtering was based on variant type, location, population frequency, and predicted impact on protein function. ResultsAnalysis of WES data revealed nine variants of interest in eight genes. Five of those encode proteins involved in nitric oxide (NO) metabolism: NOS3, NR4A3, ITGAV, GRB7 and AGXT2. In the AGXT2 gene, a de novo variant was detected, not previously described in MMD. None harboured the p.R4810K missense variant in the RNF213 gene known to be associated with MMD in East-Asian patients. Discussion and conclusionOur findings suggest a role for NO regulation pathways in Northern-European MMD and introduce AGXT2 as a new susceptibility gene. This pilot study warrants replication in larger patient cohorts and further functional investigations.

Primary sclerosing cholangitis-A long night's journey into day.

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Population structure and inbreeding in wild house mice (Mus musculus) at different geographic scales.

House mice (Mus musculus) have spread globally as a result of their commensal relationship with humans. In the form of laboratory strains, both inbred and outbred, they are also among the most widely used model organisms in biomedical research. Although the general outlines of house mouse dispersal and population structure are well known, details have been obscured by either limited sample size or small numbers of markers. Here we examine ancestry, population structure, and inbreeding using SNP microarray genotypes in a cohort of 814 wild mice spanning five continents and all major subspecies of Mus, with a focus on M. m. domesticus. We find that the major axis of genetic variation in M. m. domesticus is a south-to-north gradient within Europe and the Mediterranean. The dominant ancestry component in North America, Australia, New Zealand, and various small offshore islands are of northern European origin. Next we show that inbreeding is surprisingly pervasive and highly variable, even between nearby populations. By inspecting the length distribution of homozygous segments in individual genomes, we find that inbreeding in commensal populations is mostly due to consanguinity. Our results offer new insight into the natural history of an important model organism for medicine and evolutionary biology.

ESTIMATION OF THE FREQUENCY OF GENETIC VARIANTS ASSOCIATED WITH VITAMIN D LEVELS AND OSTEOPOROSIS IN THE POPULATION OF UKRAINE

Circulating vitamin D levels and the risk of osteoporosis have significant inheritance. Single nucleotide polymorphisms (SNPs) in the GC, DHCR7/NADSYN1, CYP2R1, CYP24A1, and SEC23A genes have shown significant association with these conditions in previous genome-wide association studies (GWAS). Objective: to study the frequency of alleles associated with circulating levels of vitamin D and osteoporosis in the cohort of Ukrainians, as well as to compare the frequencies of these variants with individuals of Western and Northern European origin. Materials and Methods. This paper presents the results of the study of the frequencies of genomic variants associated with vitamin D levels and osteoporosis in a cohort of 97 Ukrainians based on genome data obtained by whole genome sequencing (WGS), as well as comparing their frequencies with the combined European population (CEU) of the "1000 genomes" project (persons of Western and Northern European ancestry). Files with the primary publicly available genomic data of Ukrainians were annotated using ANNOVAR and SNPEff software using the reference database of the human genome version hg38. Comparison of allele frequencies between populations was performed using Fisher's exact test using the number of alleles in the two studied populations and the construction of conjugated 2x2 tables. Results. It was found that of the 22 single nucleotide polymorphisms included in the analysis, 10, namely rs2282679; rs4855; rs10033936; rs3755967; rs17467825; rs12639968; rs1155563; rs17216707; rs10745742; rs180119, significantly differ in the Ukrainian cohort comparatively to CEU. Using correlation analysis, we also found that the genotypes of SNPs rs3755967, rs17467825, rs2282679 and rs4855 in Ukrainians are completely correlated with each other (r = 1), which means that they are in a state of complete linkage in Ukrainians of the given cohorts. Conclusion. Such findings may be the evidence of evolutionary and adaptation processes in the regulation of vitamin D levels and bone mineral density in the population of Ukraine and requires further studies of phenotype-genotype relationship.

Material Culture of the Horizon of the 10th Century at the Hillfort near Spitsino Village

The article presents the results of research in 2019-2020 of the 10th century settlement on a multi-layered hillfort near the village of Spitsino (4th -5th, 10th centuries). The monument is located at a considerable distance from the main river routes in the region, which excludes its relationship with the Upper Oka section of the Don trade route in the 9th -10th centuries. A significant part of the finds discovered during exploration 2019, are of Northern European origin and date back to the mid. - 2nd half 10th century. There are also a few finds related to steppe antiquities. According to the materials of the excavations, the buildings of two construction periods are identified. The ceramic complex of buildings of the early construction period is represented by fragments of stucco vessels of the Romaine type and redeposited fragments of vessels of the 4th - 5th century. Fragments of early vessels made on a potter's wheel dating from the second half of the 10th century are found in the ceramic complex of the late construction period. Thus, the monument can be attributed to the period of the middle - second half of the 10th century. This period until recently represented a chronological lacuna in the period of Slavic colonization of the region.

The role of Natura 2000 network in protecting the orchid flora of East Macedonia (NE Greece)

East Macedonia (northeast Greece) is a relatively small part of Greece, where a considerable number of orchid taxa occurs. Some of these orchids can only be found there and this fact makes the specific area of Greece unique. In this study, an up-to date database of orchid records was used to assess the effectiveness of the existing Natura 2000 network. Specifically, the effectiveness of the Natura 2000 network was evaluated by identifying the number of orchids whose distribution is overlapping to a lesser or greater extent with the network, which chorological categories are included/excluded from it, and whether the rare and threatened orchid taxa are adequately distributed within that. Out of the 73 orchid taxa recorded in East Macedonia so far, 14 taxa are exclusively distributed outside the Natura 2000 network. Specifically, the Natura 2000 network is not overlapped with a number of Balkan and Mediterranean orchid taxa, which are only sparsely found in East Macedonia. Moreover, most of the orchid taxa that have been classified in the threat categories of the IUCN are distributed within the Natura 2000 network of East Macedonia, and specifically, some of the most threatened ones are almost exclusively distributed within that network. Consequently, although the Natura 2000 network is not congruent with the distribution of a number of species of southern origin, which are widely distributed elsewhere in Greece, it can conserve important floristic elements of Greece, which are orchid taxa of northern or central European origin.

Primera localización de un dormidero de milano real Milvus milvus L., 1758 en un eucaliptal en Álava

During the 2020-2021 census to determine the wintering population of Red kite (Milvus milvus) in the Iberian peninsula by counting the number of communal roosts, one such roost was observed in a small reforested area of eucalyptus (genus Eucalyptus) in the northwest of the province of Álava (Basque Country-Spain). Although roosts located on this kind of arboreal substrate are rare, our observation suggests the hypothesis that Red kites will use eucalyptus if the atmospheric conditions are particularly adverse. Therefore, we propose that the distribution and winter ecology of Iberian breeding populations of Red kite be clarified with urgency, the study of which is hampered by the arrival of a multitude of conspecifics of central and northern-European origin in winter

Enteropathy-Associated T cell Lymphoma.

Enteropathy-associated T cell lymphoma (EATL) is a rare subtype of mature T cell lymphoma. The available literature about this rare type T cell lymphoma is relatively limited. This article provides a summary and review of the available literature addressing this entity in terms of risk factors, pathogenesis, diagnostic, and therapeutic options. EATL has two distinct subtypes. Type I EATL, now known as EATL, is closely, but not exclusively linked to celiac disease (CD), and it is primarily a disease of Northern European origin. It accounts for < 5% of peripheral T cell lymphoma (PTCL). Risk factors for EATL include advanced age, male sex, and most importantly, genetic susceptibility in the form of HLA-DQ2 homozygosity. The pathogenesis of EATL is closely related to celiac disease as it shares common pathogenic features with refractory celiac disease. The gold standard of diagnosis is histological diagnosis. EATL carries an aggressive course and a poor prognosis. Treatment of EATL includes surgery, induction chemotherapy, and consolidation in first complete remission and autologous stem cell transplant. The role of targeted and biologic therapies in newly diagnosed EATL patients along with relapsed, refractory cases is evolving and discussed in this review. EATL is an aggressive peripheral T cell lymphoma with poor overall treatment outcome using currently available therapy options. Clinical trials are considered the best approach for treatment of EATL. Early diagnosis and early referral to specialized centers would be the best way to deal with such patients. Development of new prognostic models and early surgical intervention are warranted. Prevention is where all the efforts should be spent, by counseling patients with CD regarding the importance of adherence to gluten-free diet and development of periodic surveillance programs in celiac disease patients for early detection of pre-lymphoma lesions.

Origin, structure and genetic diversity of synanthropic populations of Fragaria moschata in Germany

Former and present cultivation of plant species impacts their distribution patterns and today's composition of floras. If native and feral populations are overlapping, the local status of a species remains often questionable. The musk strawberry (Fragaria moschata) is such an example: It is native to Central Europe but has been extensively cultivated until the end of 19th century. The border between native and synanthropic distribution runs presumably from Northeastern to Southwestern Germany. To analyse the relationship between native and synanthropic populations of F. moschata, we performed a population genetic analysis using seven microsatellite markers: We compared native populations from Germany and the Czech Republic, proposed synanthropic occurrences from Germany and cultivars of F. moschata from the germplasm repository “Professor Staudt Collection”. Synanthropic populations were genetically less diverse than native ones and consisted often of one clone only. The results revealed four clones frequently found in synanthropic populations across Germany and moreover, we detected a clear genetic separation between synanthropic and native populations. Furthermore, synanthropic populations were differentiated in a Northern and a Southern German cluster, each comprising cultivars of Northern or Southern European origin as well. We conclude that the synanthropic populations in Germany were actively spread by humans. Dispersal of these populations is extremely limited due to fragmentation and the lack of mating partners. Synanthropic populations were not established by collecting nearby native occurrences but are rather related to different cultivation centres in Europe.

Rogvolod’s polity and formation of an ethnopolitical organization on the territory of the Middle Dvina in the Хth century

The article discusses the first stages in the formation of an ethnopolitical community on the territory of the Belarusian Dvina, known from the annals as «Polochane». Using basic principles developed by the Vienna School of Historical Ethnography, the author identifies significant socio-political changes in the early medieval (9th–10th centuries) history of Eastern Europe due to the emergence of new elites. The formation of stable ethnopolitical communities is associated with the emergence of these elite groups . The absence of particular artifacts of northern European origin in Polotsk and the Polotsk okrug in the 9th – the first half of the 10th century suggests the independent formation of this center on the basis of local social structures. Significant socio-political changes in Eastern Europe arose during the Viking era (9th–10th centuries), and penetration of the North European military-trade groups into the territory of the Middle Dvina was associated with the beginnings of the active functioning of the West-Dvina branch of the Baltic-Black Sea route (the trade route «from the Varangians to the Greeks»). The development of this route became the main reason why Scandinavian leader Rogvolod came to the Polotsk region and formed a territorial and political organization, conditionally referred to as the «Rogvolod Polity». After the middle to the second half of the 10th century, a social transformation took place on the territory of the Middle Dvina, associated with the formation of elite military-trade groups and the formation of a brigade culture. The Rogvolod Polity, as the first stable territorial and political organization in the Dvina basin, created the institutional foundations for the subsequent consolidating ideology (the «core of tradition» according to R. Wenskus), embodied in the 11th century Polotsk princes Rogvolodovichi in the formation of the ethno-political community «Polochane».

Transient elevation of serum ferritin in a Sri Lankan with homozygosity for H63D mutation in the HFE gene: a case report

IntroductionHereditary hemochromatosis is an inherited disorder of iron metabolism, characterized by excessive iron deposition in major organs of the body, leading to multi-organ dysfunction. It is a genetically heterogeneous disease caused by mutations in one or more different genes, the most common being mutations in the HFE gene. HFE hereditary hemochromatosis is mostly found in Europeans and is almost always a result of two mutations: C282Y and H63D. The H63D mutation is not as penetrant as the C282Y mutation, but there are rare reported cases of hereditary hemochromatosis with homozygous H63D genotype. While the C282Y mutation is primarily confined to persons of Northern European origin, the H63D mutation is spread worldwide. Other types of hereditary hemochromatosis are rare and broadly defined as non-HFE hereditary hemochromatosis and include mutations in the hemojuvelin gene, hepcidin (HAMP gene), transferrin receptor 2 gene, and ferroportin gene.Hereditary hemochromatosis is commonly found in populations of European origin; in contrast, it is rare and less well understood in Asia. It can be masked by the presence of concurrent iron deficiency or secondary iron overload in thalassemias.Case presentationWe report the case of a 42-year-old Sri Lankan man investigated for fatigue during a brief upper respiratory tract infection and found to have high liver transaminases and high serum ferritin, which persisted even after complete resolution of the infection. Homozygosity for H63D mutation in the HFE gene was detected. Liver enzymes, serum ferritin, and transferrin saturation normalized following venesections.ConclusionThis case adds to the literature on the importance of being vigilant and investigating patients suspected for iron overload, including genetic studies for hereditary hemochromatosis, even though it is a rare clinical entity in Asians.

Genetic Connectedness Between Norwegian White Sheep and New Zealand Composite Sheep Populations With Similar Development History

The Norwegian White sheep (NWS) and New Zealand Terminal Sire Composite (NZC) sheep breeds have been developed based on crossing of multiple breeds, mainly of Northern European origin. A close genetic relationship between these populations could enable across-country genomic evaluations. The main objectives of this study were to assess the genetic connectedness between Norwegian and New Zealand sheep populations and estimate numerous genetic diversity metrics for these two populations. A total of 792 NWS and 16,912 NZC animals were genotyped using a high-density Illumina SNP chip panel (∼606K SNPs). The NZC animals were grouped based on their breed composition as: Finn, Lamb Supreme, Primera, Texel, “Other Dual Purpose”, and “Other Terminal Sire”. The average level of linkage disequilibrium ranged from 0.156 (for Primera) to 0.231 (for Finn). The lowest consistency of gametic phase was estimated between NWS and Finn (0.397), and between NWS and Texel (0.443), respectively. Similar consistency of gametic phase was estimated between NWS and the other NZC populations (∼ 0.52). For all composite sheep populations analyzed in this study, the majority of runs of homozygosity (ROH) segments identified had short length (<2,500 kb), indicating ancient (instead of recent) inbreeding. The variation in the number of ROH segments observed in the NWS was similar to the variation observed in Primera and Lamb Supreme. There was no clear discrimination between NWS and NZC based on the first few principal components. In addition, based on admixture analyses, there seems to be a significant overlap of the ancestral populations that contributed to the development of both NWS and NZC. There were no evident signatures of selection in these populations, which might be due to recent crossbreeding. In conclusion, the NWS composite breed was shown to be moderately related to NZC populations, especially Primera and Lamb Supreme. The findings reported here indicate a promising opportunity for collaborative genomic analyses involving NWS and NZC sheep populations.

Genotype and phenotype classification of 29 patients affected by Krabbe disease.

Krabbe disease is a rare neurodegenerative lysosomal storage disorder caused by mutations in the galactocerebrosidase gene, GALC. Krabbe disease usually affects infants, but has also been reported in older children and adults. Different phenotypes are described based on age at onset. The gene encoding the galactocerebrosidase enzyme was cloned and expressed in 1993, and up until today 117 mutations have been described. In a patient population of Northern European origin, a 30‐kb deletion and two missense mutations, c.1586C>T; p.T529M and c.1700A>C; p.Y567S, are expected to account for 50%‐60% of pathogenic alleles. In this study, we present information on genetic variation, enzyme activity, and phenotypes of 29 patients affected by Krabbe disease. Patient data were collected from patient files at the Department of Clinical Genetics, Rigshospitalet. Ten previously unreported mutations were identified, including four missense mutations; c.1142C>T; p.T381I, c.596G>T; p.R199M, c.443G>A; p.G148E, c.1858G>A; p.G620R, two nonsense mutations; c.863G>A; p.W288*, c.1214c>G; p.S405*, one splice site mutation; c.442+1G>A, one insertion; c.293insT and two deletions; c.1003_1004del, c.887delA. For all of the new mutations, we were able to classify them in phenotype groups. Furthermore, we present a combined allele frequency of the three frequent mutations p.T529M, p.Y567S, and the 30‐kb deletion of 62%, and we describe a broadening of the phenotypes associated with the mutations p.T529M and p.Y567S.

Persistent Müllerian duct syndrome: an update.

Male sex differentiation is driven by two hormones, testosterone and anti-Müllerian hormone (AMH), responsible for regression of Müllerian ducts in male fetuses. Mutations inactivating AMH or AMH receptor type 2 (AMHR2) are responsible for persistent Müllerian duct syndrome (PMDS) in otherwise normally virilised 46,XY males. This review is based on published cases, including 157 personal ones. PMDS can present in one of three ways: bilateral cryptorchidism, unilateral cryptorchidism with contralateral hernia and transverse testicular ectopia. Abnormalities of male excretory ducts are frequent. Testicular malignant degeneration occurs in 33% of adults with PMDS. Cancer of Müllerian derivatives is less frequent. Fertility is rare but possible if at least one testis is scrotal and its excretory ducts are intact. Up to January 2019, 81 families with 65 different mutations of the AMH gene, mostly in exons 1, 2 and 5, have been identified. AMHR2 gene mutations comprising 64 different alleles have been discovered in 79 families. The most common mutation, a 27-bp deletion in the kinase domain, was found in 30 patients of mostly Northern European origin. In 12% of cases, no mutation of AMH or AMHR2 has been detected, suggesting a disruption of other pathways involved in Müllerian regression.