Mulibrey nanismin kliininen taudinkuva sekä kasvuun, insuliiniresistenssiin ja kasvaimiin liittyvät erityispiirteet

Background: Mulibrey nanism (MUL; Muscle-liver-brain-eye nanism; OMIM 253250) is an autosomal recessive growth disorder more prevalent in Finland than elsewhere in the world. Clinical characteristics include severe prenatal onset growth restriction, cardiopathy, multiple organ manifestations but no major neurological handicap. MUL is caused by mutations in the TRIM37 gene on chromosome 17q22-23, encoding a peroxisomal protein TRIM37 with ubiquitin E3-ligase activity. Nineteen different mutations have been detected, four of them present in the Finnish patients. Objective: This study aimed to characterize clinical and histopathological features of MUL in the national cohort of Finnish patients. Patients and methods: A total of 92 Finnish patients (age 0.7 to 77 years) participated in the clinical follow-up study. Patients hospital records and growth charts were reviewed. Physical, radiographic and laboratory examinations were performed according to a clinical protocol. Thirty patients (18 females) were treated with recombinant human GH for a median period of 5.7 years. Biopsies and autopsy samples were used for the histopathological and immunohistochemical analyses. Results: MUL patients were born small for gestational age (SGA) with immature craniofacial features after prenatal-onset growth restriction. They experienced a continuous deceleration in both height SDS and weight-for-height (WFH) postnatally. In infancy feeding difficulties and frequent pneumonias were common problems. At the time of diagnosis (median age 2.1 years) characteristic craniofacial, radiological and ocular features were the most constant findings. MUL patients showed a dramatic change in glucose metabolism with increasing age. While the children had low fasting glucose and insulin levels, 90% of the adults were insulin resistant, half had type 2 diabetes and an additional 42% showed impaired glucose tolerance (IGT). Seventy percent fulfilled the National Cholesterol Education Program (NCEP) Adult Treatment Panel III criteria for metabolic syndrome as adults. GH therapy improved pre-pubertal growth but had only minor impact on adult height (+5 cm). Interestingly, treated subjects were slimmer and had less frequent metabolic concerns as young adults. MUL patients displayed histologically a disturbed architecture with ectopic tissues and a high frequency of both benign and malignant tumours present in several internal organs. A total of 232 tumorous lesions were detected in our patient cohort. The majority of the tumours showed strong expression of endothelial cell marker CD34 as well as α-smooth muscle actin (α-SMA). Fifteen of the tumours were malignant and seven of them (five Wilms tumours) occurred in the kidney. Conclusions: MUL patients present a distinct postnatal growth pattern. Short-term response of GH treatment is substantial but the long-term impact remains modest. Although MUL patients form a distinct clinical and diagnostic entity, their clinical findings vary considerably from infancy to adulthood. While failure to thrive dominates early life, MUL adults develop metabolic syndrome and have a tendency for malignancies and vascular lesions in several organs. This speaks for a central role of TRIM37 in regulation of key cellular functions, such as proliferation, migration, angiogenesis and insulin signalling.Mulibrey nanismi (MUL) on suomalaiseen tautiperintöön kuuluva, peittyvästi periytyvä lyhytkasvuisuusoireyhtymä. Maailmanlaajuisesti tiedossa on n. 130 potilasta, heistä valtaosa on Suomesta. Tautiin liittyy sikiöaikana alkava kasvuhäiriö, restriktiivinen sydäntauti ja erityiset ulkonäön piirteet. Tautiin ei liity kehityksellistä vammaisuutta. MUL on seurausta kromosomissa 17q22-23 sijaitsevan TRIM37-geenin mutaatioista. TRIM37-proteiini on paikallistettu peroksisomeihin ja toimii E3-ubiqutiini ligaasina. MUL:n patogeneesi on kuitenkin vielä avoin. Tutkimuksessa selvitettiin MUL-potilaiden kliinisiä löydöksiä, kasvua, sokeriaineenvaihduntaa ja kasvainriskiä. Aineistona oli 92 suomalaisen potilaan tiedot HYKS Lastenklinikalta yli 20 vuoden ajalta sekä vuonna 2002 käynnistyneen seurannan tulokset. Potilaiden ikäjakauma oli 0.7-77 vuotta. Kolmekymmentä potilasta sai kasvuhormonihoitoa keskimäärin 5.7 vuoden ajan. Histokemiallista tutkimusta varten kerättiin kudosnäytteet eri sairaaloiden patologian arkistoista. Näytteet tutkittiin histologisesti sekä immunohistokemiallisesti. Tutkimuksessa analysoitiin MUL:n keskeiset kliiniset löydökset eri ikäryhmissä ja niiden perusteella laadittiin uudet kansainväliset MUL:n diagnoosikriteerit. Sikiöajan ja lapsuuden kasvulle oli tyypillistä, että potilaat syntyivät pienikokoisina intrauteriinisen kasvuhäiriön seurauksena ja kasvu vaikeutui entisestään syntymän jälkeen. Varhaislapsuuden syömishäiriöt ja toistuvat hengitystieinfektiot olivat yleisiä ja vaikeuttivat MUL-lasten pärjäämistä. Sokeriaineenvaihdunnan tutkimuksessa osoitettiin, että lapsipotilaat ovat insuliiniherkkiä ja heillä on taipumus mataliin paastoverensokeriarvoihin. Iän myötä potilaille kehittyi kuitenkin vahva insuliiniresistenssi sekä sokeri- ja rasva-aineenvaihduntahäiriö. Aikuispotilaista puolella oli tyypin 2 diabetes, 42%:lla häiriintynyt sokerinsieto, ja 70% potilaista täytti metabolisen oireyhtymän kriteerit. Maksan ja haiman varhainen rasvoittuminen näyttäisi olevan diabeteksen kehittymisen taustalla MUL:ssa. Kasvuhormonihoidon vaste oli hoidon alkuvaiheessa huomattava, mutta sen vaikutus aikuispituuteen jäi vähäiseksi, keskimäärin +5 cm:ksi. Kasvuhormonihoidetut potilaat olivat kuitenkin aikuisina solakampia ja insuliiniresistenssi oli heillä lievempi kuin niillä, joille kasvuhormonia ei annettu. MUL-potilailla esiintyi runsaasti hyvänlaatuisia kasvaimia. Ne olivat pääosin endokriinisisten kudosten rakkulamaisia ja runsaasti verisuonitettuja tuumoreita. Maksan radiologiset kasvain-löydökset olivat pelioosimuutoksia eli laajentuneiden paksuseinäisten verisuonten muodostamia lammikkorykelmiä. Myös syöpäriski oli lisääntynyt. Erityisesti lapsuusiän harvinaisen Wilms in tuumorin insidenssi oli huomattava. Sisäelinten ja verisuonten histologisissa rakenteissa oli todettavissa myös kehityshäiriöitä. Yhtenvetona voidaan todeta, että MUL on taudinkuvaltaan monimuotoinen ja löydökset vaihtelevat iän myötä. Huono kasvu, infektiot, syömishäiriöt ja hypoglykemiataipumus hallitsevat varhaislapsuutta, mutta aikuisikää leimaavat metabolinen oireyhtymä ja suuri kasvainten insidenssi. Tutkimushavainnot viittaavat siihen, että TRIM37-proteiinilla on keskeinen merkitys paitsi sikiöajan kasvussa ja kudosten kehittymisessä myös sokeritaudin ja kasvainten kehittymisessä. Vaikka MUL on harvinainen tauti, se tarjoaa ainutlaatuisen mallin yleisten tautitilojen, kuten kasvuhäiriöiden, diabeteksen sekä syövän kliiniselle ja solutason tutkimukselle

Liver pathology and biochemistry in patients with mutations in TRIM37 gene (Mulibrey nanism)

Background and Aims Mulibrey nanism (MUL) is a multiorgan disease caused by recessive mutations in the TRIM37 gene. Chronic heart failure and hepatopathy are major determinants of prognosis in MUL patients, which prompted us to study liver biochemistry and pathology in a national cohort of MUL patients. Methods Clinical, laboratory and imaging data were collected in a cross-sectional survey and retrospectively from hospital records. Liver histology and immunohistochemistry for 10 biomarkers were assessed. Results Twenty-one MUL patients (age 1-51 years) with tumour suspicion showed moderate congestion, steatosis and fibrosis in liver biopsies and marginally elevated levels of serum GGT, AST, ALT and AST to platelet ratio index (APRI) in 20%-66%. Similarly, GGT, AST, ALT and APRI levels were moderately elevated in 12%-69% of 17 MUL patients prior to pericardiectomy. In a cross-sectional evaluation of 36 MUL outpatients, GGT, total bilirubin and galactose half-life (Gal1/2) correlated with age (r = 0.45, p = .017; r = 0.512, p = .007; r = 0.44, p = .03 respectively). The frequency of clearly abnormal serum values of 15 parameters analysed, however, was low even in patients with signs of restrictive cardiomyopathy. Transient elastography (TE) of the liver revealed elevated levels in 50% of patients with signs of heart failure and TE levels correlated with several biochemistry parameters. Biomarkers of fibrosis, sinusoidal capillarization and hepatocyte metaplasia showed increased expression in autopsy liver samples from 15 MUL patients. Conclusion Liver disease in MUL patients was characterized by sinusoidal dilatation, steatosis and fibrosis with individual progression to cirrhosis and moderate association of histology with cardiac function, liver biochemistry and elastography.Peer reviewe

Trim37-deficient mice recapitulate several features of the multi-organ disorder Mulibrey nanism

Mulibrey nanism (MUL) is a rare autosomal recessive multi-organ disorder characterized by severe prenatal-onset growth failure, infertility, cardiopathy, risk for tumors, fatty liver, and type 2 diabetes. MUL is caused by loss-of-function mutations in TRIM37, which encodes an E3 ubiquitin ligase belonging to the tripartite motif (TRIM) protein family and having both peroxisomal and nuclear localization. We describe a congenic Trim37 knock-out mouse (Trim37(-/-)) model for MUL. Trim37(-/-) mice were viable and had normal weight development until approximately 12 months of age, after which they started to manifest increasing problems in wellbeing and weight loss. Assessment of skeletal parameters with computer tomography revealed significantly smaller skull size, but no difference in the lengths of long bones in Trim37(-/-) mice as compared with wildtype. Both male and female Trim37(-/-) mice were infertile, the gonads showing germ cell aplasia, hilus and Leydig cell hyperplasia and accumulation of lipids in and around Leydig cells. Male Trim37(-/-) mice had elevated levels of follicle-stimulating and luteinizing hormones, but maintained normal levels of testosterone. Six-month-old Trim37(-/-) mice had elevated fasting blood glucose and low fasting serum insulin levels. At 1.5 years Trim37(-/-) mice showed non-compaction cardiomyopathy, hepatomegaly, fatty liver and various tumors. The amount and morphology of liver peroxisomes seemed normal in Trim37(-/-) mice. The most consistently seen phenotypes in Trim37(-/-) mice were infertility and the associated hormonal findings, whereas there was more variability in the other phenotypes observed. Trim37(-/-) mice recapitulate several features of the human MUL disease and thus provide a good model to study disease pathogenesis related to TRIM37 deficiency, including infertility, non-alcoholic fatty liver disease, cardiomyopathy and tumorigenesis.Peer reviewe

A Comparative Analysis of Dynamic Software Update Methods in regard to Safety-critical Systems

Software is an ever evolving product that is updated to extend the functionality and to reduce bugs within a system. Many systems are required to maintain a high availability to provide their services. Dynamic software update is a mechanism which allows the software to be updated during run-time. As a result, applying this technique to systems increases their overall availability. Systems that could benefit from this technique e.g. air-control systems, banking systems and other safety-critical systems, require minimal downtime. In this study, we compared two dynamic software update methods in regards to safety and efficiency in performing an update. The two methods were code relinking and reference indirection. This was done through model checking using the model checking tool UPPAAL as well as model simulation using the UPPAAL SMC extension.We started with a literature review to understand the fundamentals of the mechanism, before creating our models and conducting the experiment. The experiment simulated 2000 executions of each model. The experiment showed that using the method of code relinking is both faster and more consistent in terms of updatetime. Reference indirection, due to its need to update a shared indirection table, requires a safer overall system-state in order to successfully perform an update, thereby increasing both the update-time itself, as well as the inconsistency of it. Although inferior in the experiment, reference indirection is still a suitable method for safety critical-systems. As long as the system does not need to push an update within a certain amount of time, the two methods are more or less equally fitted to work in a safety-critical environment. The mechanism that causes the slowness and inconsistency off reference indirection is the method’s need to require a safer state before performing an update, which could positively benefit the safety of the system. This study is the first study to compare code relinking and reference indirection via model checking

Renal findings in patients with Mulibrey nanism

Background Mulibrey nanism (MUL) is a rare inherited disease caused by genetic defects affecting peroxisomal TRIM37 protein. MUL affects multiple organs, leading to growth retardation and early onset type 2 diabetes. We aimed to characterize the structure and function of kidneys and the urinary tract in a large cohort of Finnish MUL patients. Methods Ultrasound, magnetic resonance imaging (MRI), and autopsy findings of the kidneys and urinary tract from 101 MUL patients were retrospectively analyzed. Renal function was examined using blood and urine biochemistry. Kidney pathology was assessed by histology and immunohistochemistry from biopsy and autopsy samples. Results Structural anomalies of the kidneys and urinary tract were found in 13 % of MUL patients and renal tumors and macroscopic cystic lesions in 14 % and 43 % respectively. Overall, kidney histology was well preserved, but glomerular cysts with a wide Bowman's space were observed in most samples (87 %). Also, prominent and abundant blood vessels with thick walls were typically seen. Expression of endothelial cell markers and angiogenic growth factors PDGF-B and FGF1 (but not VEGF-A) was significantly increased in MUL kidneys. Markers of fibrosis and epithelial-mesenchymal transformation, a-SMA, and vimentin were moderately up-regulated. Despite radiological and histological changes, most MUL patients (age 0.2-51 years) had normal kidney function. However, 9 out of 36 patients (25 %) had hypertension and 6 out of 26 (23 %) had mildly decreased glomerular filtration. Conclusions Genetic defects in the TRIM37 gene lead to an increased risk for kidney anomalies, renal tumors, and solitary cysts in addition to glomerular cystic lesions, but not to progressive deterioration of renal function.Peer reviewe