Abnormalities of the immune system are rarely reported in patients affected by RASopathies. Aim of the current study was to investigate the prevalence of immune system dysfunction in a cohort of ...patients affected by RASopathies.
A group of 69 patients was enrolled: 60 at the Federico II University, Naples, 7 at University Magna Graecia of Catanzaro, 2 at "Scuola Medica Salernitana", Salerno. An age- and sex-matched control group was also enrolled. Autoimmune disorders were investigated according to international consensus criteria. Immune framework was also evaluated by immunoglobulin levels, CD3, CD4, CD8, CD19, CD56 lymphocyte subpopulations, autoantibodies levels and panel of inflammatory molecules, in both patients and controls.
Frequent upper respiratory tract infections were recorded in 2 patients; pneumonia, psoriasis and alopecia in single patients. Low IgA levels were detected in 8/44 patients (18.18%), low CD8 T cells in 13/35 patients (37.14%). Anti-tg and anti-TPO antibodies were detected in 3/24 patients (12.5%), anti r-TSH in 2 cases (8.33%), all in euthyroidism. Serum IgA and CD8 levels were significantly lower in patients than in controls (p 0.00685; p 0.000656 respectively). All tested patients showed increased inflammatory molecules compared to controls. These findings may anticipate the detection of overt autoimmune disease.
Patients affected by RASopathies are at risk to develop autoimmune disorders. Routine screening for autoimmunity is recommended in patients with RASopathy.
Endocrine complications have been described in patients affected by RASopathies but no systematic assessment has been reported. In this study, we investigate the prevalence of endocrine disorders in ...a consecutive unselected cohort of patients with RASopathies.
72 patients with a genetically confirmed RASopathy (Noonan syndrome NS, N=53; 29 LEOPARD syndrome LS, N=2; cardiofaciocutaneous syndrome CFCS, N=14; subjects showing co-occurring pathogenic variants in
and
, N=3) and an age- and sex-matched healthy controls were included in the study. Endocrine system involvement was investigated by assessing the thyroid function, pubertal development, auxological parameters, adrenal function and bone metabolism.
Short stature was detected in 40% and 64% of the NS and CFCS subcohorts, respectively. Patients showed lower Z-scores at DXA than controls (p<0.05) when considering the entire case load and both NS and CFCS groups. Vitamin D and Calcitonin levels were significantly lower (p< 0.01), Parathormone levels significantly higher (p<0.05) in patients compared to the control group (p<0.05). Patients with lower BMD showed reduced physical activity and joint pain. Finally, anti-TPO antibody levels were significantly higher in patients than in controls when considering the entire case load and both NS and CFCS groups.
The collected data demonstrate a high prevalence of thyroid autoimmunity, confirming an increased risk to develop autoimmune disorders both in NS and CFCS. Reduced BMD, probably associated to reduced physical activity and inflammatory cytokines, also occurs. These findings are expected to have implications for the follow-up and prevention of osteopenia/osteoporosis in both NS and CFCS.
Background
Fabry disease (FD) is an X-linked lysosomal storage disorder, caused by deficient activity of the alpha-galactosidase A enzyme leading to progressive and multisystemic accumulation of ...globotriaosylceramide. Recent data point toward oxidative stress signalling which could play an important role in both pathophysiology and disease progression.
Methods
We have examined oxidative stress biomarkers Advanced Oxidation Protein Products (AOPP), Ferric Reducing Antioxidant Power (FRAP), thiolic groups in blood samples from 60 patients and 77 healthy controls.
Results
AOPP levels were higher in patients than in controls (
p
< 0.00001) and patients presented decreased levels of antioxidant defences (FRAP and thiols) with respect to controls (
p
< 0.00001). In a small group of eight treatment-naïve subjects with FD-related mutations, we found altered levels of oxidative stress parameters and incipient signs of organ damage despite normal lyso-Gb3 levels.
Conclusions
Oxidative stress occurs in FD in both treated and naïve patients, highlighting the need of further research in oxidative stress-targeted therapies. Furthermore, we found that oxidative stress biomarkers may represent early markers of disease in treatment-naïve patients with a potential role in helping interpretation of FD-related mutations and time to treatment decision.
Mucopolysaccharidosis type II or Hunter syndrome is an X-linked lysosomal storage disease caused by a mutation in the gene encoding the lysosomal enzyme iduronate-2-sulfatase. The consequent enzyme ...deficiency causes a progressive, multisystem accumulation of glycosaminoglycans, which is the cause of the clinical manifestations involving also Central Nervous System for patients with the severe form of disease. The limits of the currently available therapies for Hunter syndrome, hematopoietic stem cell transplantation and recombinant enzyme replacement therapy, mainly regarding brain achievement, have encouraged several studies which recognized gene therapy as a potential therapeutic option for this condition. In vitro studies firstly aimed at the demonstration that viral vector- mediated IDS gene expression could lead to high levels of enzyme activity in transduced cells. The encouraging results obtained allowed the realization of many preclinical studies investigating the utilization of gene therapy vectors in animal models of Mucopolysaccharidosis II, together with a phase I clinical trial approved for Hunter patients affected by the mild form of the disease. Together to in vivo studies in which recombinant vectors are directly administered, systematically or by direct injection into Central Nervous System, also ex vivo gene therapy, consisting in transplantation of autologous hematopoietic stem cells, modified in vitro, into the animal or patient, has been tested. A wider clinical application of the results obtained so far is essential to ensure that gene therapy can be definitively validated as a therapeutic option available and usable for this rare but life-threatening disorder.
We analysed the clinical history of 16 hemizygous males affected by Anderson‐Fabry Disease, from four families, to verify their intrafamilial phenotypic variability. Seven male patients, ranging from ...26 to 61 years of age, died, whereas nine (age range 23–55) are alive. Eleven patients have undergone enzyme replacement therapy (ERT) for a period of 5–10 years. We have found a wide range of intrafamilial phenotypic variability in these families, both in terms of target‐organs and severity of the disease. Overall, our findings confirm previous data from the literature showing a high degree of intrafamilial phenotypic variability in patients carrying the same mutation. Furthermore, our results underscore the difficulty in giving accurate prognostic information to patients during genetic counselling, both in terms of rate of disease progression and involvement of different organs, when such prognosis is solely based on the patient's family history.
The pulvinar sign refers to exclusive T1WI hyperintensity of the lateral pulvinar. Long considered a common sign of Fabry disease, the pulvinar sign has been reported in many pathologic conditions. ...The exact incidence of the pulvinar sign has never been tested in representative cohorts of patients with Fabry disease. The aim of this study was to assess the prevalence of the pulvinar sign in Fabry disease by analyzing T1WI in a large Fabry disease cohort, determining whether relaxometry changes could be detected in this region independent of the pulvinar sign positivity.
We retrospectively analyzed brain MR imaging of 133 patients with Fabry disease recruited through specialized care clinics. A subgroup of 26 patients underwent a scan including 2 FLASH sequences for relaxometry that were compared with MRI scans of 34 healthy controls.
The pulvinar sign was detected in 4 of 133 patients with Fabry disease (3.0%). These 4 subjects were all adult men (4 of 53, 7.5% of the entire male population) with renal failure and under enzyme replacement therapy. When we tested for discrepancies between Fabry disease and healthy controls in quantitative susceptibility mapping and relaxometry maps, no significant difference emerged for any of the tested variables.
The pulvinar sign has a significantly lower incidence in Fabry disease than previously described. This finding, coupled with a lack of significant differences in quantitative MR imaging, allows hypothesizing that selective involvement of the pulvinar is a rare neuroradiologic sign of Fabry disease.
Abstract Background and aims In Italy, the prevalence of hypertension, obesity and overweight in paediatric patients has increased in the past years. The purpose of this study was to analyse the ...relationship between obesity and hypertension and related factors in Italian students. Methods and results We studied 2007 healthy individuals between the ages of 6 and 17 years of age (998 males and 1009 females) attending schools in the cities of Varese (northern Italy), Rome (central Italy) and Catanzaro (southern Italy). The blood pressure, weight and height of the students were measured. We also assessed their daily intake of foods and the amount of physical activity they performed. A questionnaire was administered to the parents of the subjects to obtain information on the child's medical history and family lifestyle. Of the students, 27.2% were overweight, and 6.6% were obese, with the highest percentages in southern Italy. A total of 6.2% of students had hypertension, and the region with the highest percentage was found to be northern Italy. Obese students had a risk of developing hypertension that was four times greater than those subjects who were of normal weight. Conclusion Overweight and obese children/adolescents were more frequently found in southern Italy as opposed to northern and central Italy, and hypertensive children were more prevalent in the north. An unhealthy diet might explain the more widely spread obesity among children living in the south; an excess use of salt could explain the greater rate of hypertension found among children/adolescents living in the north.
Phenylketonuria (PKU) is an autosomal recessive disease caused by deficient activity of phenylalanine hydroxylase. A low phenylalanine (Phe) diet is used to treat PKU. The diet is very restrictive, ...and dietary adherence tends to decrease as patients get older. Methods to improve dietary adherence and blood Phe control are continuously under investigation.
A new formula Phe-neutral amino acid (PheLNAA) has been tested in this study with the purpose of improving the compliance and lowering blood phenylalanine. The formula has been tested for nitrogen balance, and it is nutritionally complete. It is fortified with more nutritional additives that can be deficient in the PKU diet, such as B12, Biotin, DHA, Lutein and increased levels of large neutral amino acids to help lower blood Phe. The new formula has been tested on 12 patients with a loading test of 4 weeks.
Fifty-eight percent of patients had a significant decline in blood Phe concentration from baseline throughout the study. The PheLNAA was well tolerated with excellent compliance and without illnesses during the study.
In conclusion, the new formula is suitable for life-long treatment of PKU, and it offers the PKU clinic a new choice for treatment.
Objective
To define the electroclinical phenotype and long‐term outcomes in a cohort of patients with inv dup (15) syndrome.
Material and Methods
The electroclinical data of 45 patients (25 males) ...affected by inv dup (15) and seizures were retrospectively analysed, and long‐term follow‐up of epilepsy was evaluated.
Results
Epilepsy onset was marked by generalized seizures in 53% of patients, epileptic spasms in 51%, focal seizures in 26%, atypical absences in 11% and epileptic falls in 9%. The epileptic syndromes defined were: generalized epilepsy (26.7%), focal epilepsy (22.3%), epileptic encephalopathy with epileptic spasms as the only seizure type (17.7%) and Lennox‐Gastaut syndrome (33.3%). Drug‐resistant epilepsy was detected in 55.5% of patients. There was a significant higher prevalence of seizure‐free patients in those with seizure onset after the age of 5 years and with focal epilepsy, with respect to those with earlier epilepsy onset because most of these later developed an epileptic encephalopathy (69.2% vs 34.4%; P = .03), usually Lennox‐Gastaut Syndrome in type. In fact, among patients with early‐onset epilepsy, those presenting with epileptic spasms as the only seizure type associated with classical hypsarrhythmia achieved seizure freedom (P < .001) compared to patients with spasms and other seizure types associated with modified hypsarrhythmia.
Conclusions
Epilepsy in inv dup (15) leads to a more severe burden of disease. Frequently, these patients show drug resistance, in particular when epilepsy onset is before the age of five and features epileptic encephalopathy.
•Mitochondrial impairment and oxidative stress could be implicated in Fabry disease (FD).•Haplogroups H and I and haplogroup cluster HV are overexpressed in FD.•Detection of haplogroup(s) related ...oxidative stress requires further investigation.
While the genetic origin of Fabry disease (FD) is well known, it is still unclear why the disease presents a wide heterogeneity of clinical presentation and progression, even within the same family. Emerging observations reveal that mitochondrial impairment and oxidative stress may be implicated in the pathogenesis of FD.
To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of FD, we have genotyped European mtDNA haplogroups in 77 Italian FD patients and 151 healthy controls.
Haplogroups H and I, and haplogroup cluster HV were significantly more frequent in patients than controls. However, no correlation with gender, age of onset, organ involvement was observed.
Our study seems to provide some evidence of a contribution of mitochondrial variation in FD pathogenesis, at least in Italy.
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