Importance:Neurofibromatosis type 1 (NF1) is a multisystem, tumor predisposition syndrome in which vascular manifestations, including cutaneous lesions, remain poorly characterized. Cherry angiomas (CAs) have been sporadically reported in NF1, but their prevalence and biological basis are unknown. Objective:To assess the association between NF1 and CAs and define the histopathologic, cellular, and genetic mechanisms underlying NF1-associated CAs. Design, Setting, and Participants:This prospective, comparative, cross-sectional epidemiological study was conducted from October 2020 to March 2021 at a French national referral center for neurofibromatoses within the dermatology department at Henri-Mondor University Hospital, Créteil, France. It was followed by integrated histopathologic, genomic, and cell-specific molecular analyses. The epidemiological analysis included individuals 15 years or older with confirmed NF1 and controls without NF1. Pathophysiological analyses were conducted on CAs from individuals with NF1 and healthy volunteers following written consent. Data were analyzed in 2022. Main Outcomes and Measures:Outcomes included the prevalence of CAs; age-adjusted and sex-adjusted odds ratios; histopathologic features; detection of somatic NF1 second-hit variants; identification of co-occurring oncogenic variants; localization of NF1 loss within vascular cell populations; and evidence of rat sarcoma-mitogen-activated protein kinase pathway activation. Results:Of 259 participants (125 female individuals [48.3%]), 102 (39.4%) individuals had NF1 (median [range] age, 34 [18-70] years) and 157 (60.6%) were controls (median [range] age, 40 [15-91] years). CAs were more frequent in individuals with NF1 than controls (48% vs 18%; odds ratio, 4.26; 95% CI, 2.44-7.56) and occurred at a younger age. This association persisted after adjustment for age and sex and in propensity score-matched analyses. Somatic NF1 loss-of-function second hits were identified in 26 of 39 of NF1-associated CAs (67%) and none from controls, indicating biallelic NF1 inactivation. Comprehensive genomic profiling revealed frequent co-occurring activating variants, most commonly in GNAQ. Cell-specific sequencing showed that NF1 second hits arose predominantly in endothelial cells and telocytes, with higher variant allele frequencies in endothelial cells. Immunofluorescence demonstrated increased phosphoextracellular signal-regulated kinase signaling in these vascular cell populations. Conclusions and Relevance:The results of this cross-sectional study suggest that CAs represent a frequent and previously unrecognized vascular manifestation of NF1, which is supported by epidemiological enrichment and mechanistic evidence of biallelic NF1 inactivation in vascular cells. These findings potentially expand the spectrum of NF1-associated neoplasms and establish CAs as a model for NF1-related vasculopathy.

Background:HSD10 mitochondrial disease (HSD10MD) is a rare X-linked disorder caused by pathogenic variants in the HSD17B10 gene, encoding the mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (HSD10). This enzyme is crucial for isoleucine degradation, neuroactive steroid metabolism, and mitochondrial function. HSD10MD typically presents in infancy or early childhood with severe neurodevelopmental regression, seizures, and cardiomyopathy, often leading to early mortality. Adult cases are extremely rare, with milder phenotypes associated with somatic mosaicism. Case Description:We describe a 49-year-old French male presenting with hypertrophic cardiomyopathy, intellectual disability, psychomotor delay, stereotypies, and epilepsy. Developmental delay was noted after 18 months, and the first seizure occurred at age 14 years, followed by a prolonged coma. Cardiac evaluation revealed left ventricular hypertrophy, dilation, and left ventricular ejection fraction of 45%. Neurodevelopmental features included behavioral disturbances, echolalia, and inability to acquire literacy. Genetic testing initially identified no abnormalities, but exome sequencing revealed a pathogenic HSD17B10 variant (c.388C>T, p. Arg130Cys) with a variant allele frequency of 55%, consistent with somatic mosaicism. This mosaicism may explain the milder phenotype compared to the severe, early-onset presentations typically associated with this mutation. Conclusions:This case underscores the clinical variability of HSD10MD and highlights the diagnostic importance of genetic testing, particularly in adults with atypical or milder phenotypes. The association of hypertrophic cardiomyopathy with HSD10MD, as demonstrated here, suggests that cardiac involvement can dominate the clinical picture in some cases. The role of somatic mosaicism in moderating disease severity warrants further exploration. This report contributes to the limited literature on adult presentations of HSD10MD and expands the phenotype associated with the p. Arg130Cys mutation.

Friedreich ataxia (FRDA) is the most common type of inherited ataxia. It is a neurodegenerative disorder characterized by progressive gait and limb ataxia, dysarthria, areflexia, and reduced proprioception and vibration sensation. Although a number of clinical trials have been conducted, there is currently no cure for this disease. In this article we review those clinical trials with a focus on the instruments used as endpoints to assess clinical progression, and discuss the potential benefits of integrating additional measures, including assessments from overlooked domains. We also review tools used to evaluate cognitive functions in individuals with FRDA, particularly those employing quantitative, objective, and time-based measures. We argue for the inclusion of cognitive and speech-related assessments in clinical trials, and examine the potential of developments in cognitive neuroscience and technology to address current measurement challenges and support more accurate and comprehensive evaluation of treatment effects. These innovations have the potential to complement existing approaches, enhance trial design, and advance clinical care.

OBJECTIVES:Currently, there are two prognosis staging systems validated for transthyretin amyloidosis (ATTR). We sought to develop a new staging system dedicated to hereditary transthyretin amyloidosis (ATTRv) patients on specific treatments. METHODS AND RESULTS:A total of 258 patients diagnosed with ATTRv from two cardiac amyloidosis reference centres in France and Romania were stratified into three disease stages based on NT-proBNP, estimated glomerular filtration rate (eGFR) and global longitudinal strain (GLS). A staging system was created using the following criteria: GLS ≥ -11%, NT-proBNP ≥ 2000 ng/L and eGFR ≤ 65 mL/min. Stage I was defined as the presence of none of the criteria. Stage III was defined as GLS ≥ -11% and either one or both NT-proBNP and eGFR criteria, while the remaining patients were defined as Stage II. Stage I patients had a 98.5% (95% CI 94.8-100) 5-year survival rate, Stage II patients 75.1% (95% CI 64.8-87.1) and Stage III patients a 29.4% (95% CI 18.6-46.5) 5-year survival rate (Stage I vs. Stage II, P = 0.001; Stage II vs. Stage III, P < 0.001). After age is adjusted for, compared to Stage I, the hazard ratio (HR) for death was 9.9 (95% CI 1.28-76.27, P = 0.02) for Stage II and 39.75 (95% CI 5.28-299.54, P < 0.001) for Stage III patients. HRs and statistical significance were maintained across different ATTR genotypes. The staging system was validated in a cohort of 138 patients. CONCLUSIONS:We propose a novel staging system for ATTRv patients on specific treatment, based on two biological markers and one echocardiographic parameter, common in clinical practice.

BACKGROUND:Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders. NF1 is caused by dominant loss-of-function pathogenic variants (PVs) of the tumour-suppressor gene NF1, which encodes neurofibromin, a negative regulator of rat sarcoma proteins. NF1 is an autosomal dominant disorder with complete penetrance, but a highly variable expression. Identification of genotype-phenotype correlations is challenging because of the wide clinical variability, the progressive nature of the disorder and the extreme diversity of the mutation spectrum. Only a few NF1 point variants have been associated with a specific phenotype in NF1 patients. METHODS:We investigated a large, well-phenotyped NF1 cohort. RESULTS:We report analyses of genotype-phenotype correlations in 112 NF1 patients with specific NF1 point variants: p.Arg1809 missense variants were associated with a mild form of NF1 (n=24), while a more severe phenotype was associated with codons 844-848 (n=27), p.Arg1276 (n=25) and p.Lys1423 (n=35) missense variants. We describe a new correlation for p.Arg1204 missense variants (n=11), with no neurofibroma observed in patients. Functional studies will be critical for drawing conclusions on the potential hypomorphic or dominant-negative effects of these variants. CONCLUSION:The current data confirms several genotype-phenotype correlations in NF1, which may be relevant to the management and surveillance of NF1 patients with specific NF1 PVs.

Background: Although the optimal approach is debated, systematic genetic screening for hypertrophic cardiomyopathy (HCM) is recommended. Aims: The performance of this approach was tested in GEREMY, a HCM prospective observational French register. Methods: Screening was based on a 12-gene panel, including the Fabry disease (GLA) and the transthyretin (TTR) genes. In case of a negative result and according to the clinical profile, 17-80 gene panels of were used. Results: A 748 adult cohort was examined: 68.9 % male, 54.6 +/- 18.1 years, 27.5 % with a HCM family history, maximal wall thickness 19.1 +/- 4.8 mm. Pathogenic or likely pathogenic variants were identified in 296 (39.6 %) patients, localized 1) in sarcomeric genes in 233, most frequently MYBPC3 (150) and MYH7 (42), with 24 identified only by large panels, with multiple variants in 8 patients and 2) in non-sarcomeric genes in 63, identified only with large panels in 26, predominantly TTR (26) and GLA (9), representing 8.8 % and 3.0 % of positive studies, respectively. Performance was 57.1 % before 40 years and 68.6 % in case of FH (vs otherwise 28.7 % and 26.1 % respectively, p < 0.001). In patients with a negative study, 148 had variants of unknown significance and 95 had senile or AL amyloidosis. Conclusions: Systematic genetic screening with a limited panel showed good performance, with diagnosis of Fabry disease (similar to 1 %) and hereditary TTR amyloidosis (similar to 3.5 %). Larger targeted panels were conclusive in 35.3 % of patients, of which 12 % had a negative initial approach.

AbstractAimsTransthyretin cardiac amyloidosis (ATTR‐CM) may be an underestimated cause of heart failure among geriatric patients and represent a unique phenotype and prognostic profile.Methods and resultsThis retrospective, observational, cohort study characterizes cardiac and extracardiac disorders at diagnosis and assesses prognosis among ATTR‐CM patients based on age (geriatric vs. non‐geriatric) and amyloidosis subtype (wild type, ATTRwt and hereditary, ATTRv). In total, 943 patients with ATTR‐CM were included, of which 306 had ATTRv and 637 had ATTRwt. Among these, 331 (35.1%) were non‐geriatric (<75 years), and 612 (64.9%) were geriatric (≥75 years). The population exhibited conduction abnormalities, atrial fibrillation and ischaemic heart disease that progressively deteriorated with age. Among ATTRwt patients, peripheral neuropathy, neurovegetative symptoms, and hearing loss were present across all age groups, but reports of carpal tunnel symptoms or surgery decreased with age. Conversely, among ATTRv patients, reports of extracardiac symptoms increased with age and Val122ILe mutation was highly prevalent among geriatric patients. The 3‐year survival was higher among non‐geriatric ATTR‐CM patients (76%) than geriatric patients (55%) and predictors of 3‐year mortality differed. Notably, predictors identified among geriatric patients were alkaline phosphatase (ALP) (HR = 1.004, 95% CI: [0.001–1.100)], troponin T hs (HR = 1.005, 95% CI: [1.001–1.120)] and tricuspid insufficiency (HR = 1.194, 95% CI: [1.02–1.230)]. Whereas, among non‐geriatric patients, NT‐proBNP (HR = 1.002, 95% CI: [1.02–1.04], global longitudinal strain (HR = 0.95, 95% CI: [0.922–0.989], and glomerular filtration rate (HR = 0.984, 95% CI: [0.968–1.00) were identified. We propose a 3‐stage prognostic staging system combining troponin T hs (≥44 ng/L) and ALP levels (≥119 UI/L). In the geriatric population, this model discriminated survival more precisely than the National Amyloidosis Centre staging, particularly for classifying between stage 1 (82%), stage 2 (50%) and stage 3 (32%) for ATTRv and ATTRwt.ConclusionsThese diagnostic and prognostic indicators, along with ATTR subtype, highlight the distinct characteristics of this important, geriatric ATTR‐CM patient group. Recognizing these mortality markers can be valuable for geriatricians to improve the prognostic quality management of geriatric patients with ATTR‐CM.

We report our 5-year experience in neurofibromatosis type 1 prenatal diagnosis (PND): 205 PNDs in 146 women (chorionic villus biopsies, 88% or amniocentesis, 12%). The NF1 variant was present in 85 (41%) and absent in 122 (59%) fetuses. Among 205 pregnancies (207 fetuses), 135 were carried to term (119 unaffected and 16 NF1 affected children), 69 pregnancy terminations (affected fetuses), 2 miscarriages, and 1 in utero death. The majority of PND requests came from parents with sporadic NF1. We describe two PNDs in women with mosaic NF1. In both families, direct PND showed the absence of the maternal NF1 variant in the fetus. However, microsatellite markers analysis showed that the risk haplotype had been transmitted. These rare cases of germline mosaicism illustrate the pitfall of indirect PND. Our study illustrates the crucial consequences of PND for medical and genetic counseling decisions. We also point to the challenges of germline mosaics.

Transthyretin amyloidosis (ATTR) is a severe and rare disease characterized by the progressive deposition of misfolded transthyretin proteins, causing irreversible organ damage. Transthyretin amyloidosis can present as a hereditary ATTR or acquired wild-type ATTR form. Genetic testing is critical for determining a hereditary predisposition and subsequently initiating appropriate family screening. In France, strict regulations govern genetic testing that aim to protect patients and their families affected by hereditary diseases such as ATTR. However, challenges persist in establishing an effective genetic testing pathway. A multidisciplinary group of French experts convened to discuss the challenges associated with an ATTR genetic diagnosis and to propose improvement strategies. Key challenges include the lack of pathway standardization, communication gaps between healthcare professionals (HCPs) and patients, and difficulties in complying with regulatory requirements. Concerns about patient data safety and outsourced testing quality further complicate matters. Proposed strategies included the development of stakeholder mapping tools for HCPs and patients, educational programs to improve literacy on genetic testing regulations, increase disease awareness among medical geneticists and genetic counselors, and strengthening HCP-patient communication through educational materials. These initiatives aim to streamline the genetic testing pathway, enhance compliance with regulations, and ultimately provide optimal support for patients and families with ATTR.

Sodium dependent multivitamin transporter (SMVT) deficiency is a very rare autosomal recessive disorder characterized by multisystemic clinical manifestations due to combined biotin, panthotenic acid and lipoic acid deficiency. About 10 families have been described so far. Accurate diagnosis is crucial because of the possibility of a supplementation treatment with proven efficacy. Here we describe 4 new patients (3 additional families) originating from the same world region (Algeria, Maghreb). All patients, born form consanguineous parents, were homozygous carriers of the same intronic variation, outside of canonical sites, in the SLC5A6 gene encoding SMVT. RNA study in one family allowed confirming the pathogenic effect of the variation and re-classifying this variant of uncertain significance as pathogenic, opening the possibility of genetic counseling and treatment. The identification of the same variation in three distinct and apparently unrelated families is suggestive of a founder effect. The phenotype of all patients was very similar, with systematic optic atrophy (initially considered as a very rare sign), severe cyclic vomiting, and rapidly progressive mixed axonal and demyelinating sensory motor neuropathy.

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

AIM AND METHODS:We conducted a retrospective observational study of the ATTRv heterozygous mutation frequency, phenotype, and all-cause mortality at two cardiac amyloidosis centers in Romania and France. RESULTS:291 patients were included: 26 Glu54Gln (all Romanian), 200 Val122Ile, 47 Val30Met and 18 Ser77Tyr. On diagnosis, Gu54Gln patients were younger than Val122Ile or late-onset Val30Met (median age: 46 [42-50], 76 [71-80] and 70 [61-76], respectively; p < 0.001) and had more autonomic dysfunction (50 %, 6.3 %, and 7.7 %, respectively; p < 0.001) and similar cardiac symptom profiles. They had fewer conduction disorders (11.5 %) than early-onset Val30Met (76.9 %, p < 0.001) and Ser77Tyr group, notably less cardiac pacemaker present on diagnosis: 3.8 % for Glu54Gln vs. 23.5 % for Ser77Tyr; p = 0.014. Glu54Gln, Val122Ile, late-onset Val30Met and Ser77Tyr patients had similar left ventricular mass and systolic function values. Median survival for Glu54Gln patients was 58.7 years (95 %CI 55.9 - upper bound indeterminable), significantly lower than that of Val122Ile (83.6 years 95 %CI 81.6-85.5, log-rank test p < 0.001), late-onset Val30Met (83.4 years 95 %CI 81.9-84.9, log-rank test p < 0.001) and Ser77Tyr (74.8 years 95 %CI 68.7-80.9, log-rank test p = 0.022). Median survival after diagnosis was 5.7 years for Glu54Gln patients (95 %CI 4.7-6.4). CONCLUSION:We established that the Glu54Gln variant has an aggressive, mixed phenotype, with an early onset of autonomic dysfunction and heart failure symptoms. We emphasize the need for systematic genetic testing in patients with ATTR as understanding genotype-phenotype correlations is key for the management and the counseling of patients and their family members.

Background: Hereditary transthyretin (ATTRv) p.Val142Ile (V122I) mutation is the most common inherited cause of cardiac amyloidosis and little is known about the phenotype and outcome of the rare homozygotic genotype. This study aimed to compare phenotypic characteristics and outcomes between heterozygous and homozygous patients with ATTRv V122I amyloidosis.Material and Methods: This monocentric, observational, retrospective study conducted at the French National Referral Centre for Cardiac Amyloidosis (Henri Mondor Hospital, Creteil), described clinical, electrocardiographic, cardiac imaging features and prognostic data for patients with ATTRv V122I amyloidosis.Results: Among 185 ATTRv V122I patients identified, 161 were heterozygous and 24 were homozygous. The homozygous frequency was 13%. Onset occured significantly earlier in the homozygotes compared to heterozygotes with earlier median age at diagnosis (67[63-71] years vs 76[70-79] years, p < .001), age at first cardiac symptom (66[61-71] years vs 74[68-78] years, p < .001) and age at first extracardiac symptom (59[52-70] years vs 69[62-75] years, p = .003). Homozygous ATTRv V122I was also associated with greater disease burden with earlier events (death, transplant or hospitalisation for acute heart failure) compared with heterozygotes (71[67-74] vs 78[76-79] years, p = .018).Conclusion: This rare, homozygous V122I cohort confirmed the earlier age of onset, death and cardiac events in this population.

Background Cardiac and neurological involvements are the main clinical features of hereditary transthyretin (ATTRv) amyloidosis. Few data are available about ATTRv amyloid nephropathy (ATTRvN). Methods We retrospectively included 30 patients with biopsy-proven ATTRvN [V30M (26/30) including two domino liver recipients, S77Y (2/30), V122I (1/30) and S50R (1/30) variants] from two French reference centers. We described the pathological features by comparing amyloid deposits distribution to patients with AL or AA amyloidosis, and sought to determine clinicopathological correlation with known disease-modifying factors such as TTR variant, gender and age at diagnosis. Results In comparison with AL and AA amyloidosis, ATTRv patients had similar glomerular, arteriolar and arterial amyloid deposits, but more cortical and medullary tubulointerstitial (33%, 44%, 77%, P = .03) involvement. While the presence of glomerular deposits is associated with the range of proteinuria, some patients with abundant glomerular ATTRv amyloidosis had no significant proteinuria. V30M patients had more glomerular (100% and 25%, odds ratio = 114, 95% confidence interval 3.85-3395.00, P = .001) deposits, and higher estimated glomerular filtration rate [50 (interquartile range 44-82) and 27 (interquartile range 6-31) mL/min/1.73 m(2), P = .004] than non-V30M patients. We did not find difference in amyloid deposition according to gender or age at diagnosis. Conclusion ATTRvN affects all kidney compartments, but compared with AL/AA amyloidosis, ATTRvN seems to involve more frequently tubulointerstitial areas. V30M patients represents the dominant face of the disease with a higher risk of glomerular/arteriolar involvement. ATTRvN should thus be considered in patients, and potential relatives, with ATTRv amyloidosis and kidney dysfunction, regardless of proteinuria level.