[Diagnostics, clinical aspects and genetics of congenital corneal opacities]. / Diagnostik, Klinik und Genetik kongenitaler Hornhauttrübungen.

BACKGROUND: Congenital corneal opacities are comparatively rare diseases with high amblyogenic potential. PURPOSE: The present work provides an overview of the diagnostics, clinical aspects and genetics of congenital corneal opacities. METHODS: A literature search was carried out to compile an overview and illustration with own clinical case examples. RESULTS: Differentiated diagnostics are of high importance in the treatment of patients with congenital corneal opacities. A close cooperation between the medical departments involved and also the parents is absolutely essential. The structured classification of congenital corneal opacities provides the basis for a targeted treatment. DISCUSSION: The causes and the clinical symptoms of congenital corneal opacities are manifold. The correct diagnosis should be made early and in an interdisciplinary manner. Based on this, conservative and surgical treatment measures can be planned and an impending development of amblyopia can be specifically counteracted.

Exercise during pregnancy and its impact on mothers and offspring in humans and mice.

Exercise during pregnancy has beneficial effects on maternal and offspring's health in humans and mice. The underlying mechanisms remain unclear. This comparative study aimed to determine the long-term effects of an exercise program on metabolism, weight gain, body composition and changes in hormones [insulin, leptin, brain-derived neurotrophic factor (BDNF)]. Pregnant women (n=34) and mouse dams (n=44) were subjected to an exercise program compared with matched controls (period I). Follow-up in the offspring was performed over 6 months in humans, corresponding to postnatal day (P) 21 in mice (period II). Half of the mouse offspring was challenged with a high-fat diet (HFD) for 6 weeks between P70 and P112 (period III). In period I, exercise during pregnancy led to 6% lower fat content, 40% lower leptin levels and an increase of 50% BDNF levels in humans compared with controls, which was not observed in mice. After period II in humans and mice, offspring body weight did not differ from that of the controls. Further differences were observed in period III. Offspring of exercising mouse dams had significantly lower fat mass and leptin levels compared with controls. In addition, at P112, BDNF levels in offspring were significantly higher from exercising mothers while this effect was completely blunted by HFD feeding. In this study, we found comparable effects on maternal and offspring's weight gain in humans and mice but different effects in insulin, leptin and BDNF. The long-term potential protective effects of exercise on biomarkers should be examined in human studies.

[Cologne Statement for Medical Care of Refugees]. / Kölner Statement zur medizinischen Versorgung von Flüchtlingen.

The Cologne statement resulted from both regional and nationwide controversial discussions about meaning and purpose of an initial examination for infectious diseases of refugees with respect to limited time, personnel and financial resources. Refugees per se are no increased infection risk factors for the general population as well as aiders, when the aiders comply with general hygiene rules and are vaccinated according to the recommendations of the German Standing Committee on Vaccination (STIKO). This is supported by our own data. Based on individual medical history, refugees need medical care, which is offered purposeful, economic, humanitarian and ethical. In addition to medical confidentiality, the reporting obligation according § 34 Infection Protection Act (IPA) and the examination concerning infectious pulmonary tuberculosis according to § 36 (4) IPA must be considered.

The placental mTOR-pathway: correlation with early growth trajectories following intrauterine growth restriction?

Idiopathic intrauterine growth restriction (IUGR) is a result of impaired placental nutrient supply. Newborns with IUGR exhibiting postnatal catch-up growth are of higher risk for cardiovascular and metabolic co-morbidities in adult life. Mammalian target of rapamycin (mTOR) was recently shown to function as a placental nutrient sensor. Thus, we determined possible correlations of members of the placental mTOR signaling cascade with auxologic parameters of postnatal growth. The protein expression and activity of mTOR-pathway signaling components, Akt, AMP-activated protein kinase α, mTOR, p70S6kinase1 and insulin receptor substrate-1 were analysed via western blotting in IUGR v. matched appropriate-for-gestational age (AGA) placentas. Moreover, mTOR was immunohistochemically stained in placental sections. Data from western blot analyses were correlated with retrospective auxological follow-up data at 1 year of age. We found significant catch-up growth in the 1st year of life in the IUGR group. MTOR and its activated form are immunohistochemically detected in multiple placental compartments. We identified correlations of placental mTOR-pathway signaling components to auxological data at birth and at 1 year of life in IUGR. Analysis of the protein expression and phosphorylation level of mTOR-pathway components in IUGR and AGA placentas postpartum, however, did not reveal pathognomonic changes. Our findings suggest that the level of activated mTOR correlates with early catch-up growth following IUGR. However, the complexity of signals converging at the mTOR nexus and its cellular distribution pattern seem to limit its potential as biomarker in this setting.

Strong hypoxia reduces leptin synthesis in purified primary human trophoblasts.

INTRODUCTION: Oxygen availability severely affects placental function. During placental hypoxia, stabilization of hypoxia inducible factors (HIFs) affects transcription, and leptin gene expression concomitantly increases in vivo and in vitro. However, a causal relationship is uncertain. METHODS: We investigated the effect of oxygen availability on HIF-1 alpha (HIF1A) and leptin regulation in primary human trophoblasts isolated from six normal term placentae cultured at 0.1%, 1%, 3%, and 8% oxygen for 6 h, 24 h and 48 h. Gene expressions of leptin (LEP), leptin receptors (LEPR), HIF1A, insulin receptor (INSR) and further genes relevant in hypoxia (VEGFA, EPO, NOS2) or apoptosis (BCL2, BAX, Tp53) were examined. Leptin, HIF1A, INSR, phospho-AKT/AKT (insulin receptor signaling), caspase 3 and cleaved caspase 3 (apoptosis) proteins were measured. RESULTS: A hypoxic reaction with stabilization of HIF1A protein as well as up-regulation of HIF1A and VEGFA gene expressions, but without any hint for apoptosis, was present at 0.1% and 1% oxygen. However, leptin protein concentration (cell supernatants) peaked at 8% oxygen (normoxia) and was significantly reduced at 0.1% oxygen. There was no significant correlation between leptin and HIF1A, neither on the gene nor on the protein level. DISCUSSION: Elevated leptin gene expression in hypoxic placentas may not originate from trophoblasts, but from other placental cells, or from interaction of trophoblasts with other cells. Not only fetal hyperleptinemia, but also fetal hypoleptinemia under hypoxic conditions is conceivable. Strategies to prevent leptin dysregulation during pregnancy should be elucidated to protect the offspring from fetal programming of leptin resistance and adiposity in later life.

Leptin does not induce an inflammatory response in the murine placenta.

Leptin is described as a pro-inflammatory signal in fat tissue, which is released from adipocytes and in turn activates immune cells. Also, leptin levels are known to be increased in pregnancies complicated with enhanced inflammatory processes in the placenta. Hence, we assumed that increased leptin amounts might contribute to inducing an inflammatory response in the placenta. To test this hypothesis, pregnant mice were continuously infused with recombinant murine leptin s. c. from day g13 to g16, resulting in a 3-fold increase of maternal circulating serum leptin levels. Dissected placentas were examined for the expression of pro-inflammatory cytokines IL-6 and TNF-alpha and the anti-inflammatory cytokine IL-10 using qPCR analysis. No changes were found except for TNF-alpha, which was slightly elevated upon leptin stimulation. However, TNF-alpha protein levels were not significantly higher in placentas from leptin treated mice. Also, leukocyte infiltration in the labyrinth section of placentas was not increased. In summary, our data demonstrate for the first time that elevated leptin levels alone do not induce an inflammatory response in the placenta.

Two cases of lupus vulgaris in childhood and review of the clinical challenges.

BACKGROUND: Lupus vulgaris (LV) is the most common form of cutaneous tuberculosis (TB) in Europe, nevertheless the overall incidence is low. It constitutes about 1.5% of all extra-pulmonary cases worldwide. A slight raise in TB incidence rates among children was recently registered in Germany, which can be explained by the increased immigration. PATIENTS AND METHODS: We present 2 cases of immigrated children who were diagnosed with Lupus vulagris, both clinically and histopathologically. Although the symptoms and the duration of the skin lesions were very different, both patients had a non-healing skin ulceration.In our cases cultures of the skin biopsy were positive for Mycobacterium tuberculosis and the lesions showed marked improvement in response to antituberculous treatment. In the first patient, it took 6 years between occurrence of skin lesions and final diagnosis. The second patient had an extracutaneous focus, namely abdominal TB. CONCLUSION: We report our experience and emphasize on recent advances in the diagnosis and treatment of paediatric skin TB.

Functional null mutations in the gonosomal homologue gene TBL1Y are associated with non-syndromic coarctation of the aorta.

In patients with congenital heart defects, chromosomal anomalies are 100 times more frequent than in control subjects. Coarctation of the aorta can be detected in 15-20% of patients with Ullrich-Turner syndrome. By extensively reviewing literature involving breakpoint analysis of gonosomal deletions in Ullrich- Turner syndrome patients with and without coarctation of the aorta, we identified several gonosomal homolgous gene pairs of interest. Four of these homologous gene pairs were investigated by standard DNA sequencing in a cohort of 83 patients with non-syndromic coarctation of the aorta. Subsequently stability of mutant RNA and protein was analyzed to verify functional relevance of detected mutations. We identified two unreported missense mutations in Exon 8 (p.D69H) and 9 (p.R176W) of TBL1Y. Bioinformatic analysis and 3D modelling predicted that both mutations lead to TBL1Y loss of function. In RT-PCR and Western blot analyses of HEK293 cells transfected with a vector carrying the full-length TBL1Y (wild-type and mutant), we documented the predicted protein instability by showing protein decay for both mutant proteins. TBL1Y is similar to its gonosomal homologue, TBL1X, and its autosomal homologue, TBLR1, on chromosome 3. Both genes are part of co-repressor machineries and required for transcriptional activation by transcription factors that involve CtBP1/2, which contributes to Notch signaling. Several studies have shown that Notch signalling is important for proper development of the left ventricular outflow tract. Our findings suggest that TBL1Y is involved in the genesis of non-syndromic coarctation of the aorta.

Correlations between high level sport-climbing and the development of adolescents.

Over the last years concerns have been raised about the health effects particularly on young climbers due to the observation of short stature with low body weight and body fat in sports climbers. The aim of this study was to investigate anthropometric and hormonal data for climbers of the German Junior national team. 16 climbers were compared with 14-age matched nonclimbers with respect to several anthropometric variables, leptin level, and climbing characteristics. Height, weight and body mass index (BMI) standard deviation scores (SDS) for boys were not significantly different from the controls, whereas girls had significantly lower SDS-values for weight and BMI. In comparison with the control group boys and girls had a lower skinfold thickness. The leptin values were lower than the calculated leptin levels but only reached significance for the girls. The young athletes of the GJNT were neither of short stature nor thin when compared with a physically active control group. The low body fat in boys and girls was within expected limits. The lower leptin levels might be attributed to a decrease in total body fat.

Contribution of different placental cells to the expression and stimulation of antimicrobial proteins (AMPs).

The placenta is a major barrier that prevents potentially infectious agents from causing fetal diseases or related complications during pregnancy. Therefore, we postulated that the placenta might express a broad repertoire of antimicrobial proteins as well as inflammatory chemokines and cytokines to combat invading microorganisms. Here we demonstrate that placental cells indeed express a wide range of AMPs (antimicrobial peptides and proteins) including bactericidal/permeability-increasing protein (BPI), secretory leukocyte protease inhibitor (SLPI), human ß-defensin 2 (hBD2), acyloxyacyl hydrolase (AOAH), and cathelicidin (CAP18). In addition, these cells also secrete pro-inflammatory cytokines and chemokines upon stimulation with bacterial ligands. Notably, we show that BPI expression by placental cells could be completely attributed to granulocytes while highly purified placental trophoblasts expressed only a subset of the AMPs like SLPI. Unexpectedly, trophoblast AMPs did not exhibit inducible secretion in response to various TLR ligands and further investigations showed that the unresponsiveness of trophoblasts to lipopolysaccharide (LPS) was due to a lack of TLR4 expression. In summary, we have shown that the expression of different AMPs can be allocated to various cells in the placenta and the repertoire of the AMPs expressed by placental cells is a result of a cooperation of leukocytes as well as cells from embryonic origin.

Early weight gain and outcome in Henoch-Schönlein nephritis.

BACKGROUND: Intrauterine growth restriction seems to be a risk factor for an aggravated course of secondary renal diseases in children. Catch-up growth after birth may play a critical role. We tested if there is an association between an aggravated course of nephritis in Henoch-Schönlein Purpura (PSHN) and low birth weight or early weight gain during infancy. PATIENTS: We retrospectively analysed the clinical course of 34 children with PSHN. METHODS: Patients were sorted according their birth weight standard deviation score (SDS) in tertiles. Early weight gain was defined as gain of weight standard deviation score >0.67 between birth and 2 years of age. RESULTS: Patients with higher birth weight needed Cyclophosphamide in a higher rate than low birth weight children. In the high weight gain group (SDS gain >0.67) 9 of the 11 patients compared to 7 of 22 patients in the low weight gain group (SDS gain <0.67) presented with arterial hypertension during the initial manifestation of PSH nephritis (p=0.01). Median systolic blood pressure SDS in the high weight gain group was 1.54 (-1.39-4.71) versus 0.29 (0.52-4.05) in the low weight gain group (p=0.008). Nevertheless, other clinical parameters during first manifestation and follow-up were not relevantly different. CONCLUSION: In contrast to the data of children with idiopathic nephrotic syndrome or IgA nephropathy, this study does neither provide evidence for an association between low birth weight nor early weight gain and the later course of PSHN. Interestingly, early weight gain was associated with a higher systolic blood pressure during the initial manifestation of PSHN.

11beta-hydroxysteroid dehydrogenase type 1 of the subcutaneous adipose tissue is dysregulated but not associated with metabolic disorders in adults born small for gestational age.

INTRODUCTION: The mechanisms relating being born small for gestational age (SGA) and the later risk of metabolic disorders are not yet fully understood. Adipose 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity and expression have been positively associated with metabolic syndrome. In humans, no in vivo studies have explored 11beta-HSD1 activity and gene expression in sc adipose tissue of SGA subjects. SUBJECTS AND METHODS: Thirty-nine subjects SGA (birth weight<10th percentile) were matched on gender and age with 36 subjects born appropriate for gestational age (AGA) (25th percentile

[Benefits and risks of tube feeding via gastrostoma in infants and children with peritoneal dialysis]. / Nutzen und Risiko eines Gastrostomas bei Säuglingen und Kleinkindern mit chronischer Peritonealdialyse.

BACKGROUND: Nutrition of children with end-stage renal disease and peritoneal dialysis (PD) is often difficult. Tube feeding via a gastrostoma is discussed controversially, and some authors consider this as a contraindication because of the risk of peritonitis. METHODS: In our centre 16 infants and children with end-stage renal disease were treated with PD and tube feeding over a gastrostoma in the last 12 years. The patients showed dystrophy (mean BMI -1.73 SDS) and were too small (mean body length -4.56 SDS). Seven of them (median age 11 months) received a gastrostoma before insertion of a Tenkhoff-catheter and start of PD. Nine children (median age 5 months) had PD primarily before insertion of the gastrostoma and start of tube feeding. RESULTS: Patients with start of PD while a gastrostoma was already inserted had 15 events with peritonitis in the observation time of 91 months (1.98 per patient year). Patients with primary start of PD had 12 events with peritonitis in a total time of 43 month (3.34 per patient year), after insertion while PD was already running the number of events fell significantly to 25 peritonitis events in a total of 271 months (1.11 per patient year, p < 0.01). The children had a benefit from tube feeding via a gastrostoma in regard of body weight (BMI + 1.61 SDS, p < 0.01) as well as growth (body height + 2.29 SDS, p < 0.05). CONCLUSION: Tube feeding via a gastrostoma is a good and safe option for alimentation, even under peritoneal dialysis. A decrease of PD-associated peritonitis under tube feeding was observed while physical development was positively influenced.

Considering laparoscopic salvage options--is pre-emptive omentectomy necessary in paediatric peritoneal patients?

BACKGROUND: In paediatric peritoneal dialysis patients, pre-emptive omentectomy is discussed controversially and literature provides only little data concerning this issue. Our aim was to evaluate the rate of omentum-majus-related problems in our patients, in whom omentectomy was generally not performed. Furthermore, we were interested in the success rates of laparoscopic adhesiolysis. PATIENTS AND METHODS: Between 09/2006 and 03/2008, we regularly saw 18 peritoneal dialysis patients in whom we retrospectively analysed medical records to determine the rate of catheter-related complications. In addition, we evaluated the success rates of laparoscopic adhesiolysis. RESULTS: During 355 dialysis months in 18 patients, we observed 7 omentum-majus-related obstructions in 6 patients (1/50.7 PM). The median age of the patients affected was 9 years, median filling volume at the time of the obstruction was 671 ml/m (2). Laparoscopic adhesiolysis was successful in 4 out of 7 episodes. In 3 cases, the catheter lumen was plugged by necrotic portions of the omentum and the catheters had to be replaced. CONCLUSION: Our data confirm omentum-majus-related catheter obstruction as a major cause of catheter dysfunction. However, in comparison to literature, it remains unclear to which extent omentectomy can reduce the incidence of catheter obstruction in general (including e. g. obstruction due to coagulation). Thus, the decision to perform an omentectomy should be taken individually after careful consideration. In case of omentum-majus-associated obstruction, early but not late laparoscopic intervention proved to be a successful, minimally invasive technique to restore catheter function.

Differences in gene expression dependent on sampling site in placental tissue of fetuses with intrauterine growth restriction.

OBJECTIVE: The human placenta as part of the feto-placental unit may influence fetal endocrine systems and may therefore represent a very important link between intrauterine growth restriction (IUGR) and metabolic disorders in later life. We aimed to analyze the effect of sample origin on gene expression of placental factors potentially involved in fetal programming in IUGR versus appropriate for gestational age growth (AGA) to standardize sample collection procedure for a multicenter approach. DESIGN: Placental gene expression of insulin-like growth factor-binding protein (IGFBP)-1, prolactin, corticotropin releasing hormone (CRH) and leptin was measured and compared between proximal, intermediate and peripheral region of the placenta in 22 IUGR (proven by anomalous placental Doppler velocimetry) and 19 AGA neonates. RESULTS: Whereas no difference in gene expression was seen in the proximal portion, in the intermediate placental region mRNA expression of IGFBP-1 (p = 0.01), prolactin (p = 0.04), CRH (p = 0.01) and leptin (p = 0.04) was increased in IUGR samples compared to controls. At the placental periphery, gene expression of these placental transcripts showed a higher expression level in IUGR placentas without statistical significance, except for leptin (p = 0.03). CONCLUSION: Placental sampling site seems to be relevant for detecting differences in gene expression between IUGR and AGA neonates.

Microarray analysis of placental tissue in intrauterine growth restriction.

OBJECTIVE: Besides foetal or maternal disorders, placental dysfunction is a major cause of intrauterine growth restriction (IUGR). Although numerous macro- and histopathological changes have been described, little is known about the precise aetiology and the contribution of foetal/placental genes in this disorder. DESIGN: Placental tissues of 20 IUGR and control neonates were analysed by microarray technique. Four of the regulated genes with possible relevance in the pathogenesis of IUGR and its consequences were further studied in placentas of 27 IUGR and 35 control newborns. RESULTS: Elevated gene expression of leptin, corticotrophin-releasing hormone (CRH), and IGF-binding protein-1 (IGFBP-1) in IUGR placentas could be confirmed in the larger group by real-time PCR, whereas prolactin showed no significant difference. Accordingly, protein expression of leptin and IGFBP-1 depicted by Western blot was elevated in IUGR, prolactin was not different. Birthweight standard deviation score (SDS) correlated negatively to leptin, IGFBP-1, and CRH, whereas placental weight correlated only to IGFBP-1. Leptin correlated negatively to gestational age of IUGR patients and positively to placental score, a marker of severity of impaired foeto-placental circulation. CONCLUSIONS: As confirmed in a large group of IUGR and control samples, the up-regulated factors leptin, IGFBP-1, and CRH may serve as candidate genes for the prediction of subsequent metabolic consequences in IUGR newborns. These three factors may not only influence growth of the foetus, but might also interact with programming of its metabolic functions, which has to be determined in an ongoing study.

Experience with mycophenolate mofetil as maintenance therapy in five pediatric patients with severe systemic lupus erythematosus.

Maintenance therapy of severe pediatric systemic lupus erythematosus (SLE) usually consists of azathioprine and prednisone . In adult SLE patients mycophenolate mofetil (MMF) is successfully used, superiority to azathioprine has not been shown yet. We hypothesized that a maintenance therapy with MMF is able to decrease disease activity as well as the dose of glucocorticoid needed in children and adolescents with SLE. Five girls with a mean age of 13.9 (range 12-15) years were treated with 1.2+/-0.20 g/m (2) MMF daily on individual medical decision. Three patients had severe renal (WHO IV) and one severe cerebral involvement. Three patients with frequent flares on azathioprine maintenance therapy were switched to MMF, two patients with severe renal and cerebral manifestation received MMF additionally after induction therapy. Flares, steroid dosage, and disease activity (SLEDAI) were monthly registered in all patients. The number of flares decreased from 1.28 to 0.25 episodes per patient year during a mean follow-up period of 39 (range 36-42) months after MMF initiation. In parallel prednisone dose could be reduced from 10.80+/-5.25 to 3.25+1.18 mg/d (p<0.01). SLEDAI score dropped from 15.20+/-2.8 before MMF to 3.60+/- 0.9 at the last visit under MMF (p<0.001). No severe adverse event occurred. In our cohort of five pediatric patients MMF was effective and safe for maintenance therapy of SLE over a period of 3.5 years. MMF seems to be successful in preventing flares even in adolescents having unfavorable course on azathioprine treatment before. This observation should be confirmed by a randomized multicenter clinical trial.

Syncytin-1 and glial cells missing a: hypoxia-induced deregulated gene expression along with disordered cell fusion in primary term human trophoblasts.

BACKGROUND/AIMS: Pre-eclampsia, a major cause of perinatal morbidity, is characterized by alterations in placental oxygen availability and trophoblast differentiation. We investigated how different levels of hypoxia alter the expression of syncytin-1, glial cells missing a (GCMa) and syncytin-1 receptor ASCT2 and affect syncytialization in primary term human trophoblasts. METHODS: Cells were incubated at 1, 3, 6 and 21% O(2) for 24, 48 and 72 h with or without cyclic adenosine monophosphate (cAMP). Gene expression was analyzed by real-time PCR. Syncytialization was assessed using beta-human chorionic gonadotropin measurement and desmoplakin immunostaining. RESULTS: Following incubation with cAMP at 21% O(2), peak gene expression of syncytin-1 and GCMa was found after 24 h along with syncytium formation at 72 h. Conversely, incubation at 1% O(2) led to a time-dependent reduction of GCMa and syncytin-1 at the transcriptional level. Cell fusion occurred at 21 and 6% O(2) and was suppressed at 1% O(2). ASCT2 mRNA levels were preserved at normoxia and downregulated at 1% O(2) after 48 h. CONCLUSION: Our data support the premise that the expression of GCMa and syncytin-1 precedes syncytialization of trophoblasts, e.g. at 6% O(2), which is assumed to resemble physiological conditions. Severe hypoxia is associated with reduced GCMa and syncytin-1 transcripts and altered fusion of primary trophoblasts.

Infantile hypophosphatasia due to a new compound heterozygous TNSALP mutation - functional evidence for a hydrophobic side-chain?

BACKGROUND: Infantile hypophosphatasia (IH) is an inherited disorder characterized by defective bone mineralization and a deficiency of alkaline phosphatase activity. OBJECTIVE/DESIGN: The aim of the study was to evaluate a new compound heterozygous TNSALP mutation for its residual enzyme activity and localization of the comprised amino acid residues in a 3D-modeling. PATIENT: We report on a 4-week old girl with craniotabes, severe defects of ossification, and failure to thrive. Typical clinical features as low serum alkaline phosphatase, high serum calcium concentration, increased urinary calcium excretion, and nephrocalcinosis were observed. Vitamin D was withdrawn and the patient was started on calcitonin and hydrochlorothiazide. Nonetheless, the girl died at the age of 5 months from respiratory failure. RESULTS: Sequence analysis of the patient's TNSALP gene revealed two heterozygous mutations [c.653T>C (I201T), c.1171C>T (R374C)]. Transfection studies of the unique I201T variant in COS-7 cells yielded a mutant TNSALP protein with only a residual enzyme activity (3.7%) compared with wild-type, whereas the R374C variant was previously shown to reduce normal activity to 10.3%. 3D-modeling of the mutated enzyme showed that I201T resides in a region that does not belong to any known functional site. CONCLUSION: We note that I201, which has been conserved during evolution, is buried in a hydrophobic pocket and, therefore, the I>T-change should affect its functional properties. Residue R374C is located in the interface between monomers and it has been previously suggested that this mutation affects dimerization. These findings explain the patient's clinical picture and severe course.