Publications by authors named "Frank Rutsch"

84 Publications

Alkaline Phosphatases Account for Low Plasma Levels of Inorganic Pyrophosphate in Chronic Kidney Disease.

Front Cell Dev Biol 2020 3;8:586831. Epub 2020 Dec 3.

Faculty of Medicine, Côte d'Azur University, Nice, France.

Introduction: Patients on dialysis and kidney transplant recipients (KTR) present the syndrome of mineral and bone disorders (MBD), which share common traits with monogenic calcifying diseases related to disturbances of the purinergic system. Low plasma levels of inorganic pyrophosphate (PP) and ectopic vascular calcifications belong to these two conditions. This suggests that the purinergic system may be altered in chronic kidney disease with MBD. Therefore, we perform a transversal pilot study in order to compare the determinants of PPi homeostasis and the plasma levels of PPi in patients on dialysis, in KTR and in healthy people.

Patients And Methods: We included 10 controls, 10 patients on maintenance dialysis, 10 early KTR 3 ± 1 months after transplantation and nine late KTR 24 ± 3 months after transplantation. We measured aortic calcifications, plasma and urine levels of PP, the renal fractional excretion of PP (FePP), nucleoside triphosphate hydrolase (NPP) and ALP activities in plasma. Correlations and comparisons were assessed with non-parametric tests.

Results: Low PP was found in patients on dialysis [1.11 (0.88-1.35), = 0.004], in early KTR [0.91 (0.66-0.98), = 0.0003] and in late KTR [1.16 (1.07-1.45), = 0.02] compared to controls [1.66 (1.31-1.72) μmol/L]. Arterial calcifications were higher in patients on dialysis than in controls [9 (1-75) vs. 399 (25-526) calcium score/cm, < 0.05]. ALP activity was augmented in patients on dialysis [113 (74-160), = 0.01] and in early KTR [120 (84-142), = 0.002] compared to controls [64 (56-70) UI/L]. The activity of NPP and FePP were not different between groups. ALP activity was negatively correlated with PP ( = -0.49, = 0.001).

Discussion: Patients on dialysis and KTR have low plasma levels of PP, which are partly related to high ALP activity, but neither to low NPP activity, nor to increased renal excretion of PP. Further work is necessary to explore comprehensively the purinergic system in chronic kidney disease.
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http://dx.doi.org/10.3389/fcell.2020.586831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793922PMC
December 2020

Hereditary Disorders of Cardiovascular Calcification.

Arterioscler Thromb Vasc Biol 2021 01 12;41(1):35-47. Epub 2020 Nov 12.

Department of General Pediatrics, Muenster University Children's Hospital, Germany.

Arterial calcification is a common phenomenon in the elderly, in patients with atherosclerosis or renal failure and in diabetes. However, when present in very young individuals, it is likely to be associated with an underlying hereditary disorder of arterial calcification. Here, we present an overview of the few monogenic disorders presenting with early-onset cardiovascular calcification. These disorders can be classified according to the function of the respective disease gene into (1) disorders caused by an altered purine and phosphate/pyrophosphate metabolism, (2) interferonopathies, and (3) Gaucher disease. The finding of arterial calcification in early life should alert the clinician and prompt further genetic work-up to define the underlying genetic defect, to establish the correct diagnosis, and to enable appropriate therapy.
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http://dx.doi.org/10.1161/ATVBAHA.120.315577DOI Listing
January 2021

Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI).

Genet Med 2021 Feb 2;23(2):396-407. Epub 2020 Oct 2.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Purpose: Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion.

Methods: We performed deep phenotyping of 20 GACI survivors.

Results: Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies.

Conclusion: GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.
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http://dx.doi.org/10.1038/s41436-020-00983-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867608PMC
February 2021

Everyday Life, Dietary Practices, and Health Conditions of Adult PKU Patients: A Multicenter, Cross-Sectional Study.

Ann Nutr Metab 2020 30;76(4):251-258. Epub 2020 Sep 30.

Villa Metabolica, Department of Pediatric and Adolescent Medicine, University Medical Center Mainz, Mainz, Germany,

Background: Only few data on dietary management of adult phenylketonuria (PKU) patients are published.

Objectives: This study aimed to assess living situation, dietary practices, and health conditions of early-treated adult PKU patients.

Methods: A total of 183 early-treated PKU patients ≥18 years from 8 German metabolic centers received access to an online survey, containing 91 questions on sociodemographic data, dietary habits, and health conditions.

Results: 144/183 patients (66% females) completed the questionnaire. Compared with German population, the proportion of single-person households was higher (22 vs. 47%), the rate of childbirth was lower (1.34 vs. 0.4%), but educational and professional status did not differ. 82% of the patients adhered to a low-protein diet, 45% consumed modified low-protein food almost daily, and 84% took amino acid mixtures regularly. 48% of the patients never interrupted diet, and 14% stopped diet permanently. 69% of the patients reported to feel better with diet, and 91% considered their quality of life at least as good. The prevalence of depressive symptoms was high (29%) and correlated significantly to phenylalanine blood concentrations (p = 0.046). However, depressive symptoms were only mild in the majority of patients.

Conclusion: This group of early-treated adult German PKU patients is socially well integrated, reveals a surprisingly high adherence to diet and amino acid intake, and considers the restrictions of diet to their daily life as low.
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http://dx.doi.org/10.1159/000510260DOI Listing
September 2020

Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial.

Lancet 2020 09;396(10252):684-692

BioMarin (UK), London, UK.

Background: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings.

Methods: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 μg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11.

Findings: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred.

Interpretation: Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be.

Funding: BioMarin Pharmaceutical.
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http://dx.doi.org/10.1016/S0140-6736(20)31541-5DOI Listing
September 2020

Crisponi syndrome/cold-induced sweating syndrome type 2: Reprogramming of CS/CISS2 individual derived fibroblasts into three clones of one iPSC line.

Stem Cell Res 2020 07 1;46:101855. Epub 2020 Jun 1.

Department of General Pediatrics, Muenster University Children's Hospital, Muenster, Germany.

Crisponi syndrome/cold-induced sweating syndrome type 2 (CS/CISS2) is a rare disease with severe dysfunctions of thermoregulatory processes. CS/CISS2 individuals suffer from recurrent episodes of hyperthermia in the neonatal period and paradoxical sweating at cold ambient temperatures in adolescence. Variants in CLCF1 (cardiotrophin-like-cytokine 1) cause CS/CISS2. Here, we summarize the generation of three clones of one stem cell line (iPSC) of a CS/CISS2 individual carrying the CLCF1 variant c.321C>G on both alleles. These patient derived iPSC clones show a normal karyotype, several pluripotency markers, and the ability to differentiate into the three germ layers.
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http://dx.doi.org/10.1016/j.scr.2020.101855DOI Listing
July 2020

Generation of induced pluripotent stem cell lines from a Crisponi/Cold induced sweating syndrome type 1 individual.

Stem Cell Res 2020 07 28;46:101820. Epub 2020 May 28.

Department of General Pediatrics, Muenster University Children's Hospital, Muenster, Germany.

Cytokine receptor like factor 1 (CRLF1) is the gene implicated, when mutated, in Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1). Here, we report the establishment of induced pluripotent stem cell lines (iPSCs) from fibroblasts of a Turkish CS/CISS1 individual with a homozygous variant in CRLF1 (c.708_709delinsT; p.[Pro238Argfs*6]). This variant is the most frequent variant associated to CS/CISS1 in the Turkish population. These patient derived iPSC lines show all pluripotency markers, a normal karyotype and the ability to differentiate into the three germ layers.
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http://dx.doi.org/10.1016/j.scr.2020.101820DOI Listing
July 2020

BCP crystals promote chondrocyte hypertrophic differentiation in OA cartilage by sequestering Wnt3a.

Ann Rheum Dis 2020 07 5;79(7):975-984. Epub 2020 May 5.

Division of Mol Medicine of Musculoskeletal Tissue, University Munster, Munster, Germany.

Objective: Calcification of cartilage with basic calcium phosphate (BCP) crystals is a common phenomenon during osteoarthritis (OA). It is directly linked to the severity of the disease and known to be associated to hypertrophic differentiation of chondrocytes. One morphogen regulating hypertrophic chondrocyte differentiation is Wnt3a.

Methods: Calcification and sulfation of extracellular matrix of the cartilage was analysed over a time course from 6 to 22 weeks in mice and different OA grades of human cartilage. Wnt3a and ß-catenin was stained in human and murine cartilage. Expression of sulfation modulating enzymes (HS2St1, HS6St1) was analysed using quantitative reverse transcription PCR (RT-PCR). The influence of BCP crystals on the chondrocyte phenotype was investigated using quantitative RT-PCR for the marker genes Axin2, Sox9, Col2, MMP13, ColX and Aggrecan. Using western blot for β-catenin and pLRP6 we investigated the activation of Wnt signalling. The binding capacity of BCP for Wnt3a was analysed using immunohistochemical staining and western blot.

Results: Here, we report that pericellular matrix sulfation is increased in human and murine OA. Wnt3a co-localised with heparan sulfate proteoglycans in the pericellular matrix of chondrocytes in OA cartilage, in which canonical Wnt signalling was activated. In vitro, BCP crystals physically bound to Wnt3a. Interestingly, BCP crystals were sufficient to induce canonical Wnt signalling as assessed by phosphorylation of LRP6 and stabilisation of β-catenin, and to induce a hypertrophic shift of the chondrocyte phenotype.

Conclusion: Consequently, our data identify BCP crystals as a concentrating factor for Wnt3a in the pericellular matrix and an inducer of chondrocyte hypertrophy.
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http://dx.doi.org/10.1136/annrheumdis-2019-216648DOI Listing
July 2020

Reversion of arterial calcification by elastin-targeted DTPA-HSA nanoparticles.

Eur J Pharm Biopharm 2020 May 6;150:108-119. Epub 2020 Mar 6.

Institute of Pharmaceutical Technology and Biopharmacy, University of Muenster, Corrensstraße 48, 48149 Muenster, Germany. Electronic address:

Generalized arterial calcification of infancy (GACI) and pseudoxanthoma elasticum (PXE) are characterized by pathologic calcifications in the media of large- and medium sized arteries. GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. Different treatment approaches including bisphosphonates and orally administered pyrophosphate (PP) were investigated in recent years, but reversion of calcification could not be achieved. With this study, we pursued the idea of a combination of controlled drug delivery through nanoparticles and active targeting via antibody conjugation to develop a treatment for GACI and PXE. To establish a suitable drug delivery system, the chelating drug diethylenetriamine pentaacetic acid (DTPA) was conjugated to nanoparticles composed of human serum albumin (HSA) as biodegradable and non-toxic particle matrix. To accomplish an active targeting of the elastic fibers exposed through calcification of the affected areas, the nanoparticle surface was functionalized with an anti-elastin antibody. Cytotoxicity and cell interaction studies revealed favorable preconditions for the intended i.v. application. The chelating ability was evaluated in vitro and ex vivo on aortic ring culture isolated from two mouse models of GACI and PXE. The positive results led to the conclusion that the produced nanoparticles might be a promising therapy in the treatment of GACI and PXE.
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http://dx.doi.org/10.1016/j.ejpb.2020.03.007DOI Listing
May 2020

Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.

Am J Med Genet A 2020 05 24;182(5):994-1007. Epub 2020 Feb 24.

Ehlers-Danlos Syndrome National Diagnostic Service, Northwick Park and St. Mark's Hospitals, Harrow, London, UK.

Arthrochalasia Ehlers-Danlos syndrome (aEDS) is a rare autosomal dominant connective tissue disorder that is characterized by congenital bilateral hip dislocations, severe generalized joint hypermobility, recurrent joint (sub)luxations, and skin hyperextensibility. To date, 42 patients with aEDS have been published. We report 12 patients with aEDS from 10 families with 6 unpublished individuals and follow-up data on 6 adult patients. The clinical features are largely comparable with patients reported in the literature. Most (n = 10) patients had variants leading to (partial) loss of exon 6 of the COL1A1 or COL1A2 genes. One patient did not have a previously reported likely pathogenic COL1A1 variant. Data regarding management were retrieved. Hip surgery was performed in 5/12 patients and 3/12 patients underwent spinal surgery. As much as 4/12 patients were wheelchair-bound or unable to walk unaided. Fractures were present in 9/12 individuals with 1 patient requiring bisphosphonate treatment. Echocardiograms were performed in 10 patients and 2 individuals showed an abnormality likely unrelated to aEDS. One patient gave birth to two affected children and went through preterm labor requiring medication but had no additional complications. Of the eight adults in our cohort, the majority entered a career. Our data point toward a genotype-phenotype relationship with individuals with aEDS due to pathogenic COL1A1 variants causing complete or partial loss of exon 6 being more severely affected regarding musculoskeletal features. There is a significant lack of knowledge with regard to management of aEDS, particularly in adulthood. As such, systematic follow-up and multidisciplinary treatment is essential.
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http://dx.doi.org/10.1002/ajmg.a.61523DOI Listing
May 2020

Generation of three induced pluripotent cell lines (iPSCs) from an Aicardi-Goutières syndrome (AGS) patient harboring a deletion in the genomic locus of the sterile alpha motif and HD domain containing protein 1 (SAMHD1).

Stem Cell Res 2020 03 9;43:101697. Epub 2020 Jan 9.

Host-Pathogen Interactions, Paul-Ehrlich-Institut, 63225 Langen, Germany; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, United States. Electronic address:

Aicardi-Goutières syndrome (AGS) is a hereditary early onset encephalopathy. AGS patients display variable clinical manifestations including intracranial calcification, cerebral atrophy, white matter abnormalities and characteristic leukocytosis as well as a constitutive upregulation of type I IFN production indicative of a type I interferonopathy. Seven genes (SAMHD1, TREX1, RNASEH2B, RNASEH2C, RNASEH2A, ADAR1, IFIH1) have been associated with the AGS phenotype, up to now. Here, we describe the generation of three induced pluripotent stem cell lines from a patient with a deletion of coding exons 14 and 15 of the SAMHD1 gene.
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http://dx.doi.org/10.1016/j.scr.2019.101697DOI Listing
March 2020

Diagnostic utility of small fiber analysis in skin biopsies from children with chronic pain.

Muscle Nerve 2020 02 9;61(2):173-181. Epub 2019 Dec 9.

Institute of Neuropathology, Justus-Liebig-University Giessen, Giessen, Germany.

Introduction: Small fiber neuropathies (SFN) are associated with a reduction in quality of life. In adults, epidermal nerve fiber density (END) analysis is recommended for the diagnosis of SFN. In children, END assessment is not often performed. We analyzed small nerve fiber innervation to elucidate the potential diagnostic role of skin biopsies in young patients with pain.

Methods: Epidermal nerve fiber density and sudomotor neurite density (SND) were assessed in skin biopsies from 26 patients aged 7 to 20 years (15 female patients) with unexplained chronic pain. The results were compared with clinical data.

Results: Epidermal nerve fiber density was abnormal in 50% and borderline in 35% of patients. An underlying medical condition was found in 42% of patients, including metabolic, autoimmune, and genetic disorders.

Discussion: Reduction of epidermal nerve fibers can be associated with treatable conditions. Therefore, the analysis of END in children with pain may help to uncover a possible cause and guide potential treatment options.
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http://dx.doi.org/10.1002/mus.26766DOI Listing
February 2020

Untreated PKU Patients without Intellectual Disability: What Do They Teach Us?

Nutrients 2019 Oct 25;11(11). Epub 2019 Oct 25.

University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, 9700 RB Groningen, The Netherlands.

Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive. In total, we identified 16 such cases. While intellectual functioning in these patients was relatively unaffected, they often did present other neurological, psychological, and behavioral problems. Thereby, these "unusual" PKU patients show that the classical symptomatology of untreated or late-treated PKU may have to be rewritten. Moreover, these cases show that a lack of intellectual dysfunction despite high plasma phenylalanine concentrations does not necessarily imply that these high phenylalanine concentrations have not been toxic to the brain. Also, these cases may suggest that different mechanisms are involved in PKU pathophysiology, of which the relative importance seems to differ between patients and possibly also with increasing age. Further research should aim to better distinguish PKU patients with respect to their cerebral effects to high plasma phenylalanine concentrations.
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http://dx.doi.org/10.3390/nu11112572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893397PMC
October 2019

Crisponi/cold-induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts.

Clin Genet 2020 01 16;97(1):209-221. Epub 2019 Sep 16.

Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy.

Crisponi/cold-induced sweating syndrome (CS/CISS) is an autosomal recessive disease characterized by hyperthermia, camptodactyly, feeding and respiratory difficulties often leading to sudden death in the neonatal period. The affected individuals who survived the first critical years of life, develop cold-induced sweating and scoliosis in early childhood. The disease is caused by variants in the CRLF1 or in the CLCF1 gene. Both proteins form a heterodimeric complex that acts on cells expressing the ciliary neurotrophic factor receptor (CNTFR). CS/CISS belongs to the family of "CNTFR-related disorders" showing a similar clinical phenotype. Recently, variants in other genes, including KLHL7, NALCN, MAGEL2 and SCN2A, previously linked to other diseases, have been associated with a CS/CISS-like phenotype. Therefore, retinitis pigmentosa and Bohring-Optiz syndrome-like (KLHL7), Congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome (NALCN), Chitayat-Hall/Schaaf-Yang syndrome (MAGEL2), and early infantile epileptic encephalopathy-11 syndrome (SCN2A) all share an overlapping phenotype with CS/CISS, especially in the neonatal period. This review aims to summarize the existing literature on CS/CISS, focusing on the current state of differential diagnosis, pathogenesis and treatment concepts in order to achieve an accurate and rapid diagnosis. This will improve patient management and enable specific treatments for the affected individuals.
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http://dx.doi.org/10.1111/cge.13639DOI Listing
January 2020

Long-term comparative effectiveness of pegvaliase versus standard of care comparators in adults with phenylketonuria.

Mol Genet Metab 2019 Sep - Oct;128(1-2):92-101. Epub 2019 Aug 7.

Oregon Health & Science University, Portland, OR, USA. Electronic address:

Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency, resulting in high blood and brain Phenylalanine (Phe) concentrations that can lead to impaired brain development and function. Standard treatment involves a Phe-restricted diet alone or in conjunction with sapropterin dihydrochloride in responsive patients. The Food and Drug Administration approved pegvaliase enzyme substitution therapy for adults with blood Phe >600 μmol/L in the US. Recently, the European Commission also approved pegvaliase for treatment of PKU patients aged 16 years or older with blood Phe >600 μmol/L. The analyses presented below were conducted to provide comparative evidence on long-term treatment effectiveness of pegvaliase versus standard of care in adults with PKU. Adult patients (≥18 years) with baseline blood Phe >600 μmol/L who had enrolled in the pegvaliase phase 2 and phase 3 clinical trials were propensity score-matched to historical cohorts of patients treated with "sapropterin + diet" or with "diet alone". These cohorts were derived from the PKU Demographics, Outcome and Safety (PKUDOS) registry and compared for clinical outcomes including blood Phe concentration and natural intact protein intake after 1 and 2 years. Propensity scores were estimated using logistic regression with probability of treatment as outcome (i.e. pegvaliase, "sapropterin + diet", or "diet alone") and patient demographic and disease severity covariates as predictors. An additional analysis in adult PKU patients with baseline blood Phe ≤600 μmol/L comparing non-matched patient groups "sapropterin + diet" to "diet alone" using PKUDOS registry data only was also conducted. The analyses in patients with baseline blood Phe >600 μmol comparing pegvaliase with "sapropterin + diet" (N = 64 matched pairs) showed lower mean blood Phe concentrations after 1 and 2 years with pegvaliase (505 and 427 μmol/L) versus "sapropterin + diet" (807 and 891 μmol/L); mean natural intact protein intake after 1 and 2 years was 49 and 57 g/day respectively with pegvaliase versus 23 and 28 g/day with "sapropterin + diet". The analysis comparing pegvaliase with "diet alone" (N = 120 matched pairs) showed lower mean blood Phe at 1 and 2 years with pegvaliase (473 and 302 μmol/L) versus "diet alone" (1022 and 965 μmol/L); mean natural intact protein intake after 1 and 2 years was 47 and 57 g/day with pegvaliase and 27 and 22 g/day with "diet alone". Considerably more patients achieved blood Phe ≤600, ≤360, and ≤120 μmol/L and reductions from baseline of ≥20%, ≥30%, and ≥50% in blood Phe after 1 and 2 years of pegvaliase versus standard treatments. The analysis in patients with baseline blood Phe ≤600 μmol/L showed lower blood Phe after 1 and 2 years with "sapropterin + diet" (240 and 324 μmol/L) versus "diet alone" (580 and 549 μmol/L) and greater percentages of patients achieving blood Phe targets ≤600, ≤360, and ≤120 μmol/L and reductions from baseline of ≥20%, ≥30%, and ≥50% in blood Phe. These results support pegvaliase as the more effective treatment option to lower Phe levels in adults with PKU who have difficulty keeping blood Phe ≤600 μmol/L with "diet alone". For patients with blood Phe ≤600 μmol/L, adding sapropterin to dietary management is an appropriate treatment option, for those responsive to the treatment.
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http://dx.doi.org/10.1016/j.ymgme.2019.07.018DOI Listing
April 2020

Exome sequencing in Crisponi/cold-induced sweating syndrome-like individuals reveals unpredicted alternative diagnoses.

Clin Genet 2019 05 28;95(5):607-614. Epub 2019 Mar 28.

Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.

Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS-like). Here, a whole exome sequencing approach in individuals with CS/CISS-like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf-Yang syndrome, and the early infantile epileptic encephalopathy-11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow-up.
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http://dx.doi.org/10.1111/cge.13532DOI Listing
May 2019

Endogenous Calcification Inhibitors in the Prevention of Vascular Calcification: A Consensus Statement From the COST Action EuroSoftCalcNet.

Front Cardiovasc Med 2018 18;5:196. Epub 2019 Jan 18.

UMR 7365 CNRS-Université de Lorraine, IMoPA, Vandoeuvre-lès-Nancy, France.

The physicochemical deposition of calcium-phosphate in the arterial wall is prevented by calcification inhibitors. Studies in cohorts of patients with rare genetic diseases have shed light on the consequences of loss-of-function mutations for different calcification inhibitors, and genetic targeting of these pathways in mice have generated a clearer picture on the mechanisms involved. For example, generalized arterial calcification of infancy (GACI) is caused by mutations in the enzyme ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (eNPP1), preventing the hydrolysis of ATP into pyrophosphate (PP). The importance of PP for inhibiting arterial calcification has been reinforced by the protective effects of PP in various mouse models displaying ectopic calcifications. Besides PP, Matrix Gla Protein (MGP) has been shown to be another potent calcification inhibitor as Keutel patients carrying a mutation in the encoding gene or -deficient mice develop spontaneous calcification of the arterial media. Whereas PP and MGP represent locally produced calcification inhibitors, also systemic factors contribute to protection against arterial calcification. One such example is Fetuin-A, which is mainly produced in the liver and which forms calciprotein particles (CPPs), inhibiting growth of calcium-phosphate crystals in the blood and thereby preventing their soft tissue deposition. Other calcification inhibitors with potential importance for arterial calcification include osteoprotegerin, osteopontin, and klotho. The aim of the present review is to outline the latest insights into how different calcification inhibitors prevent arterial calcification both under physiological conditions and in the case of disturbed calcium-phosphate balance, and to provide a consensus statement on their potential therapeutic role for arterial calcification.
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http://dx.doi.org/10.3389/fcvm.2018.00196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345677PMC
January 2019

Antibodies against PEGylated enzymes: Treat them with respect!

Authors:
Frank Rutsch

EBioMedicine 2018 12 16;38:15-16. Epub 2018 Nov 16.

Department of General Pediatrics, Muenster University Children's Hospital, Albert-Schweitzer Campus 1, D-48149 Münster, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2018.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306382PMC
December 2018

ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP.

Exp Mol Med 2018 10 29;50(10):1-12. Epub 2018 Oct 29.

Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany.

Generalized arterial calcification of infancy (GACI) is associated with widespread arterial calcification and stenoses and is caused by mutations in ENPP1. ENPP1 encodes for ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which cleaves ATP to generate inorganic pyrophosphate (PP) and adenosine monophosphate (AMP) extracellularly. The current study was designed to define the prevalence of arterial stenoses in GACI individuals and to identify the mechanism through which ENPP1 deficiency causes intimal proliferation. Furthermore, we aimed to effectively prevent and treat neointima formation in an animal model of GACI through the systemic administration of recombinant human (rh)ENPP1-Fc protein. Based on a literature review, we report that arterial stenoses are present in at least 72.4% of GACI cases. We evaluated the effect of rhENPP1-Fc on ENPP1-silenced human vascular smooth muscle cells (VSMCs) and on induced intimal proliferation in Enpp1-deficient ttw/ttw mice treated with carotid ligation. We demonstrate that silencing ENPP1 in VSMCs resulted in a tenfold increase in proliferation relative to that of cells transfected with negative control siRNA. The addition of rhENPP1-Fc, AMP or adenosine restored the silenced ENPP1-associated proliferation. In contrast, neither PP nor etidronate, a current off-label treatment for GACI, had an effect on VSMC proliferation. Furthermore, subcutaneous rhENPP1-Fc protein replacement was effective in preventing and treating intimal hyperplasia induced by carotid ligation in an animal model of GACI. We conclude that ENPP1 inhibits neointima formation by generating  AMP. RhENPP1-Fc may serve as an approach for the effective prevention and treatment of arterial stenoses in GACI.
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http://dx.doi.org/10.1038/s12276-018-0163-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204430PMC
October 2018

Can untreated PKU patients escape from intellectual disability? A systematic review.

Orphanet J Rare Dis 2018 08 29;13(1):149. Epub 2018 Aug 29.

Dietmar-Hopp Metabolic Center, University Children's Hospital, Heidelberg, Germany.

Background: Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients.

Methods: To this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 μmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers.

Results: In total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms.

Conclusions: Based on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.
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http://dx.doi.org/10.1186/s13023-018-0890-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116368PMC
August 2018

Prevalence of shoulder calcification in pseudoxanthoma elasticum patients.

Joint Bone Spine 2018 12 6;85(6):777-778. Epub 2018 Apr 6.

Reference Centre for PXE, Angers University Hospital, 49933 Angers, France; Department of Dermatology, Angers University Hospital, 49933 Angers, France. Electronic address:

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http://dx.doi.org/10.1016/j.jbspin.2018.03.008DOI Listing
December 2018

Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.

Ann Neurol 2017 Dec;82(6):1004-1015

Pediatric Neurology, Brussels University Hospital, Brussels, Belgium.

Objective: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1.

Methods: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported.

Results: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills.

Interpretation: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.
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http://dx.doi.org/10.1002/ana.25110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847115PMC
December 2017

When one disease is not enough: succinyl-CoA: 3-oxoacid coenzyme A transferase (SCOT) deficiency due to a novel mutation in OXCT1 in an infant with known phenylketonuria.

J Pediatr Endocrinol Metab 2017 Oct;30(10):1121-1124

.

A 9-month-old Turkish girl was admitted several times within 3 months to the hospital in reduced general condition and with extreme tachypnea. The patient had been diagnosed with phenylketonuria (PKU) in newborn screening and has been treated with a low phenylalanine diet and amino acid supplements. Each time an unexplained pronounced metabolic acidosis was noted, and the child was treated with sodium-bicarbonate and glucose-electrolyte infusions. The acidosis with only slightly abnormal glucose, normal lactate levels and pronounced ketonuria suggested a defect in ketone body utilization. Succinyl-CoA: 3-oxoacid CoA transferase (SCOT) enzyme activity was low in patient's fibroblasts. Mutation analysis of the corresponding OXCT1 gene revealed that the patient was a homozygous carrier of the mutation c.1523T>C (p.V508A). We conclude that SCOT deficiency should be considered in the differential diagnosis in patients with recurrent metabolic acidotic episodes, even if they are already known to have a metabolic disease unrelated to this.
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http://dx.doi.org/10.1515/jpem-2017-0177DOI Listing
October 2017

Inherited Arterial Calcification Syndromes: Etiologies and Treatment Concepts.

Curr Osteoporos Rep 2017 08;15(4):255-270

Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany.

Purpose Of Review: We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease.

Recent Findings: Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.
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http://dx.doi.org/10.1007/s11914-017-0370-3DOI Listing
August 2017

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients.

Mol Genet Metab 2017 07 22;121(3):206-215. Epub 2017 May 22.

Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany; Division of Clinical Chemistry & Biochemistry and Children's Research Center, University Children's Hospital, Zürich, Switzerland; Bioanalytics & Biochemistry, Department of Natural Sciences, University of Applied Sciences, Rheinbach, Germany. Electronic address:

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare inborn error of ketone body synthesis and leucine degradation, caused by mutations in the HMGCL gene. In order to obtain a comprehensive view on this disease, we have collected clinical and biochemical data as well as information on HMGCL mutations of 37 patients (35 families) from metabolic centers in Belgium, Germany, The Netherlands, Switzerland, and Turkey. All patients were symptomatic at some stage with 94% presenting with an acute metabolic decompensation. In 50% of the patients, the disorder manifested neonatally, mostly within the first days of life. Only 8% of patients presented after one year of age. Six patients died prior to data collection. Long-term neurological complications were common. Half of the patients had a normal cognitive development while the remainder showed psychomotor deficits. We identified seven novel HMGCL mutations. In agreement with previous reports, no clear genotype-phenotype correlation could be found. This is the largest cohort of HMGCLD patients reported so far, demonstrating that HMGCLD is a potentially life-threatening disease with variable clinical outcome. Our findings suggest that the clinical course of HMGCLD cannot be predicted accurately from HMGCL genotype. The overall outcome in HMGCLD appears limited, thus rendering early diagnosis and strict avoidance of metabolic crises important.
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http://dx.doi.org/10.1016/j.ymgme.2017.05.014DOI Listing
July 2017

MDA5-Associated Neuroinflammation and the Singleton-Merten Syndrome: Two Faces of the Same Type I Interferonopathy Spectrum.

J Interferon Cytokine Res 2017 05;37(5):214-219

1 Department of General Pediatrics, Muenster University Children's Hospital , Muenster, Germany .

In 1973, Singleton and Merten described a new syndrome in 2 female probands with aortic and cardiac valve calcifications, early loss of secondary dentition, and widened medullary cavities of the phalanges. In 1984, Aicardi and Goutières defined a phenotype resembling congenital viral infection with basal ganglia calcification and increased protein content in the cerebrospinal fluid. Between 2006 and 2012, mutations in 6 different genes were described to be associated with Aicardi-Goutières syndrome, specifically-TREX1, RNASEH2A, RNASEH2B, RNASEH2C, ADAR, and SAMHD1. More recently, mutations in IFIH1 were reported in a variety of neuroimmunological phenotypes, including Aicardi-Goutières syndrome, while a specific Arg822Gln mutation in IFIH1 was described in 3 discrete families with Singleton-Merten syndrome (SMS). IFIH1 encodes for melanoma differentiation-associated gene 5 (MDA5), and all mutations identified to date have been associated with an enhanced interferon response in affected individuals. In this study, we present a male child demonstrating recurrent febrile episodes, spasticity, and basal ganglia calcification suggestive of Aicardi-Goutières syndrome, who carries the same Arg822Gln mutation in IFIH1 previously associated with SMS. We conclude that both diseases are part of the interferonopathy grouping and that the Arg822Gln mutation in IFIH1 can cause a spectrum of disease, including neurological involvement.
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http://dx.doi.org/10.1089/jir.2017.0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439407PMC
May 2017

Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial.

Orphanet J Rare Dis 2017 03 9;12(1):47. Epub 2017 Mar 9.

EMD Serono, Billerica, MA, USA.

Background: Sapropterin dihydrochloride, a synthetic formulation of BH, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children <4 years.

Results: In total, 109 male or female children <4 years with confirmed BH-responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7-42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters.

Conclusions: The addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients <4 years with BH-responsive phenylketonuria.

Trial Registration: ClinicalTrials.gov, NCT01376908 . Registered June 17, 2011.
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http://dx.doi.org/10.1186/s13023-017-0600-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343543PMC
March 2017

Sapropterin treatment does not enhance the health-related quality of life of patients with phenylketonuria and their parents.

Acta Paediatr 2017 Jun 19;106(6):953-959. Epub 2017 Mar 19.

Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany.

Aim: Sapropterin causes reductions in blood phenylalanine concentrations in sensitive patients with phenylketonuria (PKU). We examined whether the subsequent relaxation of dietary restrictions influenced the quality of life (QoL) of patients and parents.

Methods: The study cohort comprised 112 patients with PKU followed at the metabolic centre at Münster University Children's Hospital, Germany, from 2012 to 2015. A sapropterin response was defined as a ≥30% reduction in blood phenylalanine levels. The QoL of 38 children and adolescents from the study cohort, with a mean age of 12.4 (range 6.6-18.7) years, was assessed in an outpatient setting and 49 parents of children with PKU also commented on their child's QoL and their own. The participants' QoL was assessed before the start of therapy, and again after six months, using self-report questionnaires.

Results: After six months of continuous therapy or diet, QoL was largely unchanged in the patients, according to their self-reports and the parental reports. QoL also remained unchanged in the parents.

Conclusion: Sapropterin did not seem to improve QoL in PKU patients and their parents. Patients with PKU had already reached high levels of QoL following classic diets, and these levels were not easily improved by sapropterin.
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http://dx.doi.org/10.1111/apa.13799DOI Listing
June 2017

Vpx overcomes a SAMHD1-independent block to HIV reverse transcription that is specific to resting CD4 T cells.

Proc Natl Acad Sci U S A 2017 03 22;114(10):2729-2734. Epub 2017 Feb 22.

Institute of Medical Virology, University Hospital Frankfurt, 60596 Frankfurt, Germany;

Early after entry into monocytes, macrophages, dendritic cells, and resting CD4 T cells, HIV encounters a block, limiting reverse transcription (RT) of the incoming viral RNA genome. In this context, dNTP triphosphohydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) has been identified as a restriction factor, lowering the concentration of dNTP substrates to limit RT. The accessory lentiviral protein X (Vpx) proteins from the major simian immunodeficiency virus of rhesus macaque, sooty mangabey, and HIV-2 (SIVsmm/SIVmac/HIV-2) lineage packaged into virions target SAMHD1 for proteasomal degradation, increase intracellular dNTP pools, and facilitate HIV cDNA synthesis. We find that virion-packaged Vpx proteins from a second SIV lineage, SIV of red-capped mangabeys or mandrills (SIVrcm/mnd-2), increased HIV infection in resting CD4 T cells, but not in macrophages, and, unexpectedly, acted in the absence of SAMHD1 degradation, dNTP pool elevation, or changes in SAMHD1 phosphorylation. Vpx rcm/mnd-2 virion incorporation resulted in a dramatic increase of HIV-1 RT intermediates and viral cDNA in infected resting CD4 T cells. These analyses also revealed a barrier limiting HIV-1 infection of resting CD4 T cells at the level of nuclear import. Single amino acid changes in the SAMHD1-degrading Vpx mac239 allowed it to enhance early postentry steps in a Vpx rcm/mnd-2-like fashion. Moreover, Vpx enhanced HIV-1 infection of SAMHD1-deficient resting CD4 T cells of a patient with Aicardi-Goutières syndrome. These results indicate that Vpx, in addition to SAMHD1, overcomes a previously unappreciated restriction for lentiviruses at the level of RT that acts independently of dNTP concentrations and is specific to resting CD4 T cells.
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http://dx.doi.org/10.1073/pnas.1613635114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347584PMC
March 2017