The role of plasmapheresis in severe acute disseminated encephalomyelitis with clinical findings of transverse myelitis.

INTRODUCTION: Acute disseminated encephalomyelitis is a rare acute demyelinating disease of the central nervous system (CNS). The pathogenesis remains unclear but is suspected to be autoimmune. High doses of methylprednisolone (HDMP) are currently considered standard of treatment. Plasmapheresis (PE) is typically given in steroid refractory cases. There is currently limited evidence supporting its use in ADEM. MATERIALS AND METHODS: We report a 16-year-old girl with ADEM who improved rapidly after initiating PE. RESULTS: The patient presented with acute onset of multifocal CNS symptoms, including encephalopathy, requiring intensive care unit management. Despite HDMP administration, her clinical condition continued to deteriorate. PE was therefore initiated on the same day as HDMP. Her clinical condition improved significantly following the first session. She was extubated and discharged from the intensive care unit the following day. CONCLUSION: HDMP combined with PE may be an effective first-line treatment in patients with fulminant ADEM.

Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic.

Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro-a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.

A novel homoplasmic mt-tRNAGlu m.14701C>T variant presenting with a partially reversible infantile respiratory chain deficiency.

BACKGROUND: Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial disorder associated with variable penetrance and partial to full remission of symptoms. OBJECTIVE: To describe features of maternally related individuals with a novel variant associated with RIRCD. MATERIALS AND METHODS: Nine maternally related individuals aged 23 months to 64 years are described through physical examinations, muscle biopsies, histochemical and biochemical analyses, genome sequencing, and cerebral imaging. RESULTS: A homoplasmic mitochondrial transfer ribonucleic acid for glutamic acid (mt-tRNAGlu) m.14701C>T variant was identified in eight tested individuals out of nine maternally related individuals. Two individuals presented with hypotonia, muscle weakness, feeding difficulties and lactic acidosis at age 3-4 months, and improvement around age 15-23 months with mild residual symptoms at last examination. One individual with less severe symptoms had unknown age at onset and improved around age 4-5 years. Five individuals developed lipoma on the upper back, and one adult individual developed ataxia, while one was unaffected. CONCLUSIONS: We have identified a novel homoplasmic mt-tRNAGlu m.14701C>T variant presenting with phenotypic and paraclinical features associated with RIRCD as well as ataxia and lipomas, which to our knowledge are new features associated to RIRCD.

CPT1A Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders.

BACKGROUND: Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders. METHODS AND RESULTS: Using array-based and targeted genotyping, we found that rs80356779, a p.Pro479Leu variant in CPT1A, was strongly associated with markers of n-3 fatty acid metabolism, including degree of unsaturation (P=1.16×10-34), levels of polyunsaturated fatty acids, n-3 fatty acids, and docosahexaoenic acid relative to total fatty acid levels (P=2.35×10-15, P=4.02×10-19, and P=7.92×10-27). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm (P=1.04×10-9). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779. CONCLUSION: Our study shows that a common CPT1A missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations.

Climate change and infectious diseases in the Arctic: establishment of a circumpolar working group.

The Arctic, even more so than other parts of the world, has warmed substantially over the past few decades. Temperature and humidity influence the rate of development, survival and reproduction of pathogens and thus the incidence and prevalence of many infectious diseases. Higher temperatures may also allow infected host species to survive winters in larger numbers, increase the population size and expand their habitat range. The impact of these changes on human disease in the Arctic has not been fully evaluated. There is concern that climate change may shift the geographic and temporal distribution of a range of infectious diseases. Many infectious diseases are climate sensitive, where their emergence in a region is dependent on climate-related ecological changes. Most are zoonotic diseases, and can be spread between humans and animals by arthropod vectors, water, soil, wild or domestic animals. Potentially climate-sensitive zoonotic pathogens of circumpolar concern include Brucella spp., Toxoplasma gondii, Trichinella spp., Clostridium botulinum, Francisella tularensis, Borrelia burgdorferi, Bacillus anthracis, Echinococcus spp., Leptospira spp., Giardia spp., Cryptosporida spp., Coxiella burnetti, rabies virus, West Nile virus, Hantaviruses, and tick-borne encephalitis viruses.

Effectiveness of the targeted hepatitis B vaccination program in Greenland.

OBJECTIVES: To evaluate the effectiveness of the hepatitis B virus (HBV) vaccination program in Greenland, which targets children born to mothers who are positive for HBV surface antigen (HBsAg), we determined vaccination coverage, levels of postvaccination antibodies, and frequency of breakthrough infections in at-risk children. METHODS: We conducted a population-based retrospective cohort study with data from nationwide registries. We identified all children born to HBsAg-positive mothers from 1992 to 2007 and collected data on their HBV vaccination status. In 2008 to 2010, we tested the children for HBV core antibody, HBsAg, and anti-HBsAg antibody (HBsAb). RESULTS: Of 4050 pregnant women, 3.2% were HBsAg positive. Of 207 children born to these women, 20% received no vaccinations, and only 58% received at least 3 vaccinations. At follow-up, HBsAb levels in vaccinated children were much lower than expected, and 8 (6%) of 140 at-risk children had breakthrough infections, with 4 chronically infected (persistently HBsAg positive). CONCLUSIONS: The prevention program targeting children at risk for HBV in Greenland is ineffective. HBV vaccination should be included in the universal childhood vaccination program, and postvaccination HBsAb levels should be monitored.

Hepatocellular carcinoma and other liver disease among Greenlanders chronically infected with hepatitis B virus: a population-based study.

BACKGROUND: In Greenland, the prevalence of hepatitis B surface antigen carriers, reflecting chronic hepatitis B virus (HBV) infection, is 5%-10%. However, the incidence of cirrhosis and hepatocellular carcinoma in this population has been reported to be low. We investigated this discrepancy in a large population-based cohort study. METHODS: In total, 8879 Greenlanders (16% of the population) were recruited for population-based surveys performed from May 5 to July 7, 1987, and from November 1 to November 21, 1998, with follow-up until March 31, 2010. HBV status was based on serological testing, supplemented by data from all available HBV registries in Greenland to determine changes in HBV status over time. Information on morbidity and mortality was obtained from the Patient Discharge Registry, the Cancer Registry, and the Central Registration System. Sex, age, ethnicity, and period-adjusted incidence rate ratios (IRRs) were estimated using Poisson regression. World standardized rates were derived from these and World Health Organization data. RESULTS: The 650 chronically HBV-infected persons had higher rates of hepatocellular carcinoma (adjusted IRR = 8.70; 95% CI = 2.06 to 36.7), liver disease (adjusted IRR = 5.73, 95% CI = 3.52 to 9.34), and all-cause mortality (adjusted IRR = 1.47; 95% CI = 1.21 to 1.79) than the 5160 HBV-negative persons. However, the world standardized incidence rates of hepatocellular carcinoma (38.5 cancers per 100 000 person-years) and cirrhosis (24 cases per 100 000 person-years) among chronically HBV-infected persons were low compared with results from population-based studies from countries with low, intermediate, and high rates of endemic HBV infection. CONCLUSION: The relatively low incidence of hepatocellular carcinoma and other HBV-related morbidity among chronic HBV-infected persons in Greenland suggest a more benign course of HBV among the Greenlandic Inuit than in populations in other parts of the world.

Estimating glomerular filtration rate using the new CKD-EPI equation and other equations in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: No studies have compared the performance of equations for estimating glomerular filtration rate (GFR) in patients with autosomal dominant polycystic kidney disease (ADPKD), where the declining GFR typically is followed for many years or even decades. This was the purpose of the present investigation. METHODS: 101 ADPKD patients with chronic kidney disease stages 1-5 were recruited and GFR was measured with the (51)Cr-EDTA clearance method, and estimated with the Modification of Diet in Renal Disease Study (MDRD) equation with 4 variables, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Cockcroft-Gault equation adjusted for body surface area and the MDRD equation with cystatin C. Performance was evaluated by mean bias, precision and accuracy. RESULTS: The MDRD equation with cystatin C had 97% of GFR estimates within 30% of measured GFR (accuracy). Both the CKD-EPI and Cockcroft-Gault equations had an accuracy of 90% whereas the MDRD equation had an accuracy of 83%. This difference of accuracy was especially marked with GFR >60 ml/min/1.73 m(2). CONCLUSION: For estimating GFR in ADPKD patients the MDRD equation with cystatin C incorporated had the best performance. The CKD-EPI or the Cockcroft-Gault equations showed better performance compared to the 4-variable MDRD equation.

Asymmetric dimethylarginine and lipid peroxidation products in early autosomal dominant polycystic kidney disease.

BACKGROUND: Patients with autosomal dominant polycystic kidney disease (ADPKD) with normal renal function have endothelial dysfunction and decreased nitric oxide synthase activity in subcutaneous resistance vessels. We investigated asymmetric dimethylarginine (ADMA) as a marker of an inhibitor of nitric oxide synthase and the lipid peroxidation product 13-hydroxyoctadecadienoic acid (HODE) as a marker of oxidative stress in patients with early ADPKD. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Patients with early ADPKD (n = 27) and age-matched volunteers (n = 30) from a single academic medical center. FACTOR: Patients with ADPKD versus controls. OUTCOMES & MEASUREMENT: Plasma (P) levels, urinary (U) excretion, and urinary clearance (C) of ADMA and HODE. Because of multiple comparisons, P for significance is considered less than 0.0167. RESULTS: Patients with ADPKD had significantly increased P(ADMA) levels (604 +/- 131 versus 391 +/- 67 nmol/L; P < 0.01) and U(ADMA) excretion (22 +/- 4 versus 15.2 +/- 3 nmol/micromol creatinine; P = 0.01), decreased C(ADMA) (25 +/- 3 versus 33 +/- 4 mL/min; P = 0.01), increased P(HODE) levels (316 +/- 64 versus 230 +/- 38 nmol/L; P < 0.01) and U(HODE) excretion (467 +/- 67 versus 316 +/- 40 nmol/micromol creatinine; P < 0.01), and decreased plasma nitrite plus nitrate (P(NOx)) levels (21 +/- 5 versus 32 +/- 6 micromol/L; P < 0.01) and U(NOx) excretion (59 +/- 7 versus 138 +/- 27 micromol/micromol creatinine; P < 0.01). LIMITATIONS: Small sample size, cross-sectional nature of study, and limited number of markers of oxidative stress. CONCLUSIONS: P(ADMA) and P(HODE) levels are increased in patients with early ADPKD. Increased P(ADMA) level is related to decreased C(ADMA) and is accompanied by oxidative stress.

Classification of hepatitis B virus genotype B into 2 major types based on characterization of a novel subgenotype in Arctic indigenous populations.

Hepatitis B virus genotype B (HBV/B) has been classified into 5 subgenotypes. Except for Bj/B1 in Japan, the subgenotypes (Ba/B2-B5) have undergone recombination with HBV/C in the core promoter/precore/core genomic region. Phylogenetic analyses of complete sequences show that the Arctic strains belong to a novel subgenotype (HBV/B6) without the recombination, analogous to what is seen with Bj/B1. Comparison of 50 HBV/B6 carriers from the Arctic versus 50 Bj and 50 Ba age- and sex-matched carriers from Asia revealed that clinical characteristics of HBV/B6 carriers were similar to those of Bj/B1 carriers in Japan. The results suggest that HBV/B may be classified into nonrecombinant (Bj/B1 and B6) and recombinant (Ba/B2-B5) types.

Pulse wave reflection is amplified in normotensive patients with autosomal-dominant polycystic kidney disease and normal renal function.

BACKGROUND: In young ADPKD patients, we have previously found an impaired endothelium-dependent relaxation in small resistance vessels but a normal flow-mediated dilatation of the brachial artery. The present study investigated arterial stiffness in early ADPKD by pulse-wave analysis (PWA) and measurement of pulse-wave velocity (PWV). METHODS: 18 young normotensive ADPKD patients with normal renal function and 18 controls were studied by applanation tonometry with the SphygmoCor equipment. Parameters included an estimate of aortic blood pressure, augmentation index (AIx), AIx standardized to heart rate 75 (AIx(HR75)) and PWV. Glomerular filtration rate (GFR) was measured by the 51Cr-EDTA plasma clearance method. Statistical comparisons were made with t tests and multiple linear regression analysis. RESULTS: GFR was the same in the two groups. Brachial diastolic blood pressure was slightly but significantly higher in ADPKD patients than in controls (81 +/- 9 vs. 73 +/- 9 mm Hg, p < 0.05). No significant difference was present in brachial systolic blood pressure. AIx was significantly higher in ADPKD than in controls: 21.6 +/- 11.3 vs. 11.4 +/- 11.2%, p < 0.02. AIx(HR75) and estimated aortic systolic and diastolic blood pressure was likewise significantly higher in ADPKD than in controls. Multiple linear regression analysis showed AIx and AIx(HR75) to be independently correlated to group (ADPKD/control), p < 0.02 and p < 0.05, respectively. No difference was found between PWV in the two groups. CONCLUSION: Reflection of the pulse wave was amplified in young normotensive ADPKD patients, demonstrating early pathology in the arterial system.