Leopard syndrome

LEOPARD syndrome (LS, OMIM 151100) is a rare multiple congenital anomalies condition, mainly characterized by skin, facial and cardiac anomalies. LEOPARD is an acronym for the major features of this disorder, including multiple Lentigines, ECG conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness. About 200 patients have been reported worldwide but the real incidence of LS has not been assessed. Facial dysmorphism includes ocular hypertelorism, palpebral ptosis and low-set ears. Stature is usually below the 25th centile. Cardiac defects, in particular hypertrophic cardiomyopathy mostly involving the left ventricle, and ECG anomalies are common. The lentigines may be congenital, although more frequently manifest by the age of 4–5 years and increase throughout puberty. Additional common features are café-au-lait spots (CLS), chest anomalies, cryptorchidism, delayed puberty, hypotonia, mild developmental delay, sensorineural deafness and learning difficulties. In about 85% of the cases, a heterozygous missense mutation is detected in exons 7, 12 or 13 of the PTPN11 gene. Recently, missense mutations in the RAF1 gene have been found in two out of six PTPN11-negative LS patients. Mutation analysis can be carried out on blood, chorionic villi and amniotic fluid samples. LS is largely overlapping Noonan syndrome and, during childhood, Neurofibromatosis type 1-Noonan syndrome. Diagnostic clues of LS are multiple lentigines and CLS, hypertrophic cardiomyopathy and deafness. Mutation-based differential diagnosis in patients with borderline clinical manifestations is warranted. LS is an autosomal dominant condition, with full penetrance and variable expressivity. If one parent is affected, a 50% recurrence risk is appropriate. LS should be suspected in foetuses with severe cardiac hypertrophy and prenatal DNA test may be performed. Clinical management should address growth and motor development and congenital anomalies, in particular cardiac defects that should be monitored annually. Hypertrophic cardiomyopathy needs careful risk assessment and prophylaxis against sudden death in patients at risk. Hearing should be evaluated annually until adulthood. With the only exception of ventricular hypertrophy, adults with LS do not require special medical care and long-term prognosis is favourable

Functional brain activity constrained by structural connectivity reveals cohort-specific features for serum neurofilament light chain

Background: Neuro-axonal brain damage releases neurofilament light chain (NfL) proteins, which enter the blood. Serum NfL has recently emerged as a promising biomarker for grading axonal damage, monitoring treatment responses, and prognosis in neurological diseases. Importantly, serum NfL levels also increase with aging, and the interpretation of serum NfL levels in neurological diseases is incomplete due to lack of a reliable model for age-related variation in serum NfL levels in healthy subjects. Methods: Graph signal processing (GSP) provides analytical tools, such as graph Fourier transform (GFT), to produce measures from functional dynamics of brain activity constrained by white matter anatomy. Here, we leveraged a set of features using GFT that quantified the coupling between blood oxygen level dependent signals and structural connectome to investigate their associations with serum NfL levels collected from healthy subjects and former athletes with history of concussions. Results: Here we show that GSP feature from isthmus cingulate in the right hemisphere (r-iCg) is strongly linked with serum NfL in healthy controls. In contrast, GSP features from temporal lobe and lingual areas in the left hemisphere and posterior cingulate in the right hemisphere are the most associated with serum NfL in former athletes. Additional analysis reveals that the GSP feature from r-iCg is associated with behavioral and structural measures that predict aggressive behavior in healthy controls and former athletes. Conclusions: Our results suggest that GSP-derived brain features may be included in models of baseline variance when evaluating NfL as a biomarker of neurological diseases and studying their impact on personality traits

The moonlighting RNA-binding activity of cytosolic serine hydroxymethyltransferase contributes to control compartmentalization of serine metabolism

Enzymes of intermediary metabolism are often reported to have moonlighting functions as RNA-binding proteins and have regulatory roles beyond their primary activities. Human serine hydroxymethyltransferase (SHMT) is essential for the one-carbon metabolism, which sustains growth and proliferation in normal and tumour cells. Here, we characterize the RNA-binding function of cytosolic SHMT (SHMT1) in vitro and using cancer cell models. We show that SHMT1 controls the expression of its mitochondrial counterpart (SHMT2) by binding to the 5'untranslated region of the SHMT2 transcript (UTR2). Importantly, binding to RNA is modulated by metabolites in vitro and the formation of the SHMT1-UTR2 complex inhibits the serine cleavage activity of the SHMT1, without affecting the reverse reaction. Transfection of UTR2 in cancer cells controls SHMT1 activity and reduces cell viability. We propose a novel mechanism of SHMT regulation, which interconnects RNA and metabolites levels to control the cross-talk between cytosolic and mitochondrial compartments of serine metabolism

PTPN11 mutations are not responsible for the Cardiofaciocutaneous (CFC) syndrome

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomalies/mental retardation syndrome characterized by congenital heart defects, characteristic facial appearance, short stature, ectodermal abnormalities and mental retardation. It was described in 1986, and to date is of unknown genetic etiology. All reported cases are sporadic, born to non-consanguineous parents and have apparently normal chromosomes. Noonan and Costello syndromes remain its main differential diagnosis. the recent finding of PTPN11 missense mutations in 45-50% of the Noonan patients studied with penetrance of almost 100% and the fact that in animals mutations of this gene cause defects of semilunar valvulogenesis, made PTPN11 mutation screening in CFC patients a matter of interest. We sequenced the entire coding region of the PTPN11 gene in ten well-characterised CFC patients and found no base changes. We also studied PTPN11 cDNA in our patients and demonstrated that there are no interstitial deletions either. the genetic cause of CFC syndrome remains unknown, and PTPN11 can be reasonably excluded as a candidate gene for the CFC syndrome, which we regard as molecular evidence that CFC and Noonan syndromes are distinct genetic entities.Univ Sacred Heart, Ist Genet Med, I-00168 Rome, ItalyUniversidade Federal de São Paulo, Escola Paulista Med, Ctr Med Genet, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Dermatol, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Ctr Med Genet, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Dermatol, São Paulo, BrazilWeb of Scienc

Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study

OBJECTIVE: To determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD. METHODS: GENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer's disease (AD) and 10 healthy controls (HCs) of similar age. RESULTS: In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98). CONCLUSIONS: Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD

Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation

Noonan syndrome (NS) is characterized by short stature, facial dysmorphisms and congenital heart defects. PTPN11 mutations are the most common cause of NS. Patients with NS have a predisposition for leukemia and certain solid tumors. Data on the incidence of malignancies in NS are lacking. Our objective was to estimate the cancer risk and spectrum in patients with NS carrying a PTPN11 mutation. In addition, we have investigated whether specific PTPN11 mutations result in an increased malignancy risk. We have performed a cohort study among 297 Dutch NS patients with a PTPN11 mutation (mean age 18 years). The cancer histories were collected from the referral forms for DNA diagnostics, and by consulting the Dutch national registry of pathology and the Netherlands Cancer Registry. The reported frequencies of cancer among NS patients were compared with the expected frequencies using population-based incidence rates. In total, 12 patients with NS developed a malignancy, providing a cumulative risk for developing cancer of 23% (95% confidence interval (CI), 8–38%) up to age 55 years, which represents a 3.5-fold (95% CI, 2.0–5.9) increased risk compared with that in the general population. Hematological malignancies occurred most frequently. Two malignancies, not previously observed in NS, were found: a malignant mastocytosis and malignant epithelioid angiosarcoma. No correlation was found between specific PTPN11 mutations and cancer occurrence. In conclusion, this study provides first evidence of an increased risk of cancer in patients with NS and a PTPN11 mutation, compared with that in the general population. Our data do not warrant specific cancer surveillance

Ventricular volume expansion in presymptomatic genetic frontotemporal dementia

OBJECTIVE: To characterize the time course of ventricular volume expansion in genetic frontotemporal dementia (FTD) and identify the onset time and rates of ventricular expansion in presymptomatic FTD mutation carriers. METHODS: Participants included patients with a mutation in MAPT, PGRN, or C9orf72, or first-degree relatives of mutation carriers from the GENFI study with MRI scans at study baseline and at 1 year follow-up. Ventricular volumes were obtained from MRI scans using FreeSurfer, with manual editing of segmentation and comparison to fully automated segmentation to establish reliability. Linear mixed models were used to identify differences in ventricular volume and in expansion rates as a function of time to expected disease onset between presymptomatic carriers and noncarriers. RESULTS: A total of 123 participants met the inclusion criteria and were included in the analysis (18 symptomatic carriers, 46 presymptomatic mutation carriers, and 56 noncarriers). Ventricular volume differences were observed 4 years prior to symptom disease onset for presymptomatic carriers compared to noncarriers. Annualized rates of ventricular volume expansion were greater in presymptomatic carriers relative to noncarriers. Importantly, time-intensive manually edited and fully automated ventricular volume resulted in similar findings. CONCLUSIONS: Ventricular volume differences are detectable in presymptomatic genetic FTD. Concordance of results from time-intensive manual editing and fully automatic segmentation approaches support its value as a measure of disease onset and progression in future studies in both presymptomatic and symptomatic genetic FTD

Atypical cardiac defects in patients with RASopathies: Updated data on CARNET study

Background: RASopathies are a set of relatively common autosomal dominant clinically and genetically heterogeneous disorders. Cardiac outcomes in terms of mortality and morbidity for common heart defects (such as pulmonary valve stenosis and hypertrophic cardiomyopathy) have been reported. Nevertheless, also Atypical Cardiac Defects (ACDs) are described. The aim of the present study was to report both prevalence and cardiac outcome of ACDs in patients with RASopathies. Methods: A retrospective, multicentric observational study (CArdiac Rasopathy NETwork—CARNET study) was carried out. Clinical, surgical, and genetic data of the patients who were followed until December 2019 were collected. Results: Forty‐five patients out of 440 followed in CARNET centers had ACDs. Noonan Syndrome (NS), NS Multiple Lentigines (NSML) and CardioFacioCutaneous Syndrome (CFCS) were present in 36, 5 and 4 patients, respectively. Median age at last follow‐up was 20.1 years (range 6.9–47 years). Different ACDs were reported, including mitral and aortic valve dysfunction, ascending and descending aortic arch anomalies, coronary arteries dilation, enlargement of left atrial appendage and isolated pulmonary branches diseases. Five patients (11%) underwent cardiac surgery and one of them underwent a second intervention for mitral valve replacement and severe pericardial effusion. No patients died in our cohort until December 2019. Conclusions: Patients with RASopathies present a distinct CHD spectrum. Present data suggest that also ACDs must be carefully investigated for their possible impact on the clinical outcome. A careful longitudinal follow up until the individuals reach an adult age is recommended

Cooperativity among Short Amyloid Stretches in Long Amyloidogenic Sequences

Amyloid fibrillar aggregates of polypeptides are associated with many neurodegenerative diseases. Short peptide segments in protein sequences may trigger aggregation. Identifying these stretches and examining their behavior in longer protein segments is critical for understanding these diseases and obtaining potential therapies. In this study, we combined machine learning and structure-based energy evaluation to examine and predict amyloidogenic segments. Our feature selection method discovered that windows consisting of long amino acid segments of ∼30 residues, instead of the commonly used short hexapeptides, provided the highest accuracy. Weighted contributions of an amino acid at each position in a 27 residue window revealed three cooperative regions of short stretch, resemble the β-strand-turn-β-strand motif in A-βpeptide amyloid and β-solenoid structure of HET-s(218–289) prion (C). Using an in-house energy evaluation algorithm, the interaction energy between two short stretches in long segment is computed and incorporated as an additional feature. The algorithm successfully predicted and classified amyloid segments with an overall accuracy of 75%. Our study revealed that genome-wide amyloid segments are not only dependent on short high propensity stretches, but also on nearby residues