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Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. Type-1 Gaucher disease, which affects the majority of patients (90% in Europe and USA, but less in other regions), is characterized by effects on the viscera, whereas types 2 and 3 are also associated with neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the GBA1 gene should be identified as they may be of prognostic value in some cases. Patients with type-1 GD—but also carriers of GBA1 mutation—have been found to be predisposed to developing Parkinson’s disease, and the risk of neoplasia associated with the disease is still subject to discussion. Disease-specific treatment consists of intravenous enzyme replacement therapy (ERT) using one of the currently available molecules (imiglucerase, velaglucerase, or taliglucerase). Orally administered inhibitors of glucosylceramide biosynthesis can also be used (miglustat or eliglustat).

Background Clinical features, complications and treatments of Gaucher’s disease (GD), a rare autosomal–recessive disorder due to a confirmed lysosomal enzyme (glucocerebrosidase) deficiency, are described. Methods All patients with known GD, living in France, with ≥1 consultations (1980–2010), were included in the French GD registry, yielding the following 4 groups: the entire cohort, with clinical description; and its subgroups: patients with ≥1 follow-up visits, to investigate complications; recently followed (2009–2010) patients; and patients treated during 2009–2010, to examine complications before and during treatment. Data are expressed as medians (range) for continuous variables and numbers (%) for categorical variables. Results Among the 562 registry patients, 265 (49.6%) were females; 454 (85.0%) had type 1, 22 (4.1%) type 2, 37 (6.9%) perinatal–lethal type and 21 (3.9%) type 3. Median ages at first GD symptoms and diagnosis, respectively, were 15 (0–77) and 22 (0–84) years for all types. The first symptom diagnosing GD was splenomegaly and/or thrombocytopenia (37.6% and 26.3%, respectively). Bone-marrow aspiration and/or biopsy yielded the diagnosis for 54.7% of the patients, with enzyme deficiency confirming GD for all patients. Birth incidence rate was estimated at 1/50,000 and prevalence at 1/136,000. For the 378 followed patients, median follow-up was 16.2 (0.1–67.6) years. Major clinical complications were bone events (BE; avascular necrosis, bone infarct or pathological fracture) for 109 patients, splenectomy for 104, and Parkinson’s disease for 14; 38 patients died (neurological complications for 15 type-2 and 3 type-3 patients, GD complications for 11 type-1 and another disease for 9 type-1 patients). Forty-six had monoclonal gammopathy. Among 283 recently followed patients, 36 were untreated and 247 had been treated during 2009–2010; 216 patients received treatment in December 2010 (126 with imiglucerase, 45 velaglucerase, 24 taliglucerase, 21 miglustat). BE occurred before (130 in 67 patients) and under treatment (60 in 41 patients) with respective estimated frequencies (95% CI) of first BE at 10 years of 20.3% (14.1%–26.5%) and 19.8% (13.5%–26.1%). Conclusion This registry enabled the epidemiological description of GD in France and showed that BE occur even during treatment.

Gaucher disease (GD) is a rare autosomal recessive lysosomal disorder caused by glucocerebrosidase deficiency, with a prevalence in France of around 1/130,000 people. The clinical picture of GD is very heterogeneous, ranging from lifelong asymptomatic forms to severe forms with onset during childhood, such as GD type 2 (< 1% of cases). GD type 1, the most common form (95% of cases), manifests with varying degrees of organomegaly, cytopenia and bone manifestations. Progressive encephalopathy of varying severity is also observed in GD type 3. Symptoms may result in acute and/or chronic pain and asthenia, and lead to disability. The aim of the French National Diagnosis and Care Protocol (Protocole National de Diagnostic et de Soins; PNDS) is to provide health care professionals with guidance for the optimal management and care of patients with GD. GD diagnosis is usually based on laboratory analyses revealing low or absent glucocerebrosidase activity, and can be confirmed by identification of glucocerebrosidase ( GBA1 ) gene pathogenic variants. Additional assessments should include biological analyses (hemogram test, serum protein electrophoresis, and measurement of GD biomarkers), imaging examinations (X-rays, abdominal and bone magnetic resonance imaging, bone densitometry, echocardiography), and electrocardiogram. Patient management in France is multidisciplinary and should be coordinated by a GD specialist, in conjunction with the Committee for the Evaluation and Treatment of Gaucher Disease, the Reference Center for Lysosomal Diseases or a reference/competence center for inherited metabolic diseases. The indication for treatment is not systematic and is based on the presence of clinical, biological, and imaging criteria. Current treatments such as intravenous enzyme replacement therapy or oral substrate reduction therapy, generally lead to significant improvements in disease characteristics within one to five years and early initiation can prevent complications. Follow-up should include a clinical examination, biological analyses to monitor disease biomarkers twice a year then yearly for stable patients, and imaging evaluations initially every year and then every 3 to 4 years for patients with stable disease in whom therapeutic objectives have been achieved. Intercurrent pathologies can be managed by the attending physician in collaboration with a GD specialist.

Background Diagnostic work-up of patients with hypertrophic cardiomyopathy is crucial for appropriate management. However, the optimal genetic strategy remains debatable. We compared two strategies: targeted testing based on careful examination of clinical red flags versus large multigene panel analysis without gene prioritization. We applied the strategy to the diagnosis of Fabry disease or Hereditary Transthyretin Amyloidosis ( GLA or TTR genes respectively). Results We studied 341 hypertrophic cardiomyopathy index patients. Patients of subgroup 1 (n = 42) had careful clinical analysis and high suspicion of Hereditary Transthyretin Amyloidosis or Fabry disease. They underwent targeted Sanger sequencing. Patients in subgroup 2 (n = 299) did not have clinical selection, and underwent next-generation sequencing analysis of 107 cardiac genes. The yield of genetic testing for pathogenic/likely pathogenic variants in GLA and/or TTR was 28.6% in subgroup 1 (12/42: 5 TTR and 7 GLA ) versus 1.0% in subgroup 2 (3/299: 1 TTR and 2 GLA ), p  < 0.01. Genetic results were obtained after a median of 26.0 days [IQR = 18–59.8] in subgroup 1 versus 193.5 days [IQR = 174–218] in subgroup 2, p  < 0.01. Finally, genetic testing cost was 615.60€ or 769.50€ for TTR or GLA targeted analysis respectively, versus 1503.90€ for multigene panel analysis. Conclusions Both molecular strategies in hypertrophic cardiomyopathy patients are useful for the identification of pathogenic/likely pathogenic variants in TTR/GLA genes. However, targeted genetic testing based on clinical red flags identified causal mutations more efficiently, faster and at a lower cost. Careful clinical analysis is therefore important in guiding molecular strategy and may reduce diagnostic wandering and accelerate delivery of appropriate therapy.

Fabry disease (OMIM #301 500), the most prevalent lysosomal storage disease, is caused by enzymatic defects in alpha-galactosidase A (GLA gene; Xq22.1). Fabry disease has historically been characterized by progressive renal failure, early stroke and hypertrophic cardiomyopathy, with a diminished life expectancy. A nonclassical phenotype has been described with an almost exclusive cardiac involvement. Specific therapies with enzyme substitution or chaperone molecules are now available depending on the mutation carried. Numerous clinical and fundamental studies have been conducted without stratifying patients by phenotype or severity, despite different prognoses and possible different pathophysiologies. We aimed to identify a simple and clinically relevant way to classify and stratify patients according to their disease severity. Based on data from the French Fabry Biobank and Registry (FFABRY; n = 104; 54 males), we applied unsupervised multivariate statistics to determine clusters of patients and identify clinical criteria that would allow an effective classification of adult patients. Thanks to these criteria and empirical clinical considerations we secondly elaborate a new score that allow the severity stratification of patients. We observed that the absence of acroparesthesia or cornea verticillata is sufficient to classify males as having the nonclassical phenotype. We did not identify criteria that significantly cluster female patients. The classical phenotype was associated with a higher risk of severe renal (HR = 35.1; p <10-3) and cardiac events (HR = 4.8; p = 0.008) and a trend toward a higher risk of severe neurological events (HR = 7.7; p = 0.08) compared to nonclassical males. Our simple, rapid and clinically-relevant FFABRY score gave concordant results with the validated MSSI. Acroparesthesia and cornea verticillata are simple clinical criteria that efficiently stratify Fabry patients, defining 3 different groups: females and males with nonclassical and classical phenotypes of significantly different severity. The FFABRY score allows severity stratification of Fabry patients.

The complex of Vacuolar Protein Sorting 34 and 15 (Vps34 and Vps15) has Class III phosphatidylinositol 3‐kinase activity and putative roles in nutrient sensing, mammalian Target Of Rapamycin (mTOR) activation by amino acids, cell growth, vesicular trafficking and autophagy. Contrary to expectations, here we show that Vps15 ‐deficient mouse tissues are competent for LC3‐positive autophagosome formation and maintain mTOR activation. However, an impaired lysosomal function in mutant cells is traced by accumulation of adaptor protein p62, LC3 and Lamp2 positive vesicles, which can be reverted to normal levels after ectopic overexpression of Vps15. Mice lacking Vps15 in skeletal muscles, develop a severe myopathy. Distinct from the autophagy deficient Atg7 −/− mutants, pathognomonic morphological hallmarks of autophagic vacuolar myopathy (AVM) are observed in Vps15 −/− mutants, including elevated creatine kinase plasma levels, accumulation of autophagosomes, glycogen and sarcolemmal features within the fibres. Importantly, Vps34/Vps15 overexpression in myoblasts of Danon AVM disease patients alleviates the glycogen accumulation. Thus, the activity of the Vps34/Vps15 complex is critical in disease conditions such as AVMs, and possibly a variety of other lysosomal storage diseases. Graphical Abstract Mice lacking Vps15 in skeletal muscles develop the pathological features of autophagic vacuolar myopathy (AVM). Vps34/Vps15 complex activity is shown to be critical in disease conditions such as AVMs, and possibly other lysosomal storage diseases.

Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs' disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G (ARSG) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis.

Pompe disease (PD) is caused by a deficiency of lysosomal acid α-glucosidase resulting from mutations in the GAA gene. The clinical spectrum ranges from a rapidly fatal multisystemic disorder (classic PD, onset < 1 year) to a milder adult onset myopathy. The aims of this study were to characterize the GAA mutations, to establish the disease epidemiology, and to identify potential genotype-phenotype correlations in French late-onset PD patients (onset ≥ 2 years) diagnosed since the 1970s. Data were collected from the two main laboratories involved in PD diagnosis and from the French Pompe registry. Two hundred forty-six patients (130 females and 116 males) were included, with a mean age at diagnosis of 43 years. Eighty-three different mutations were identified in the GAA gene, among which 28 were novel. These variants were spread all over the sequence and included 42 missense (one affecting start codon), 8 nonsense, 15 frameshift, 14 splice mutations, 3 small in-frame deletions, and one large deletion. The common c.-32-13T>G mutation was detected in 151/170 index cases. Other frequent mutations included the exon 18 deletion, the c.525del, and the missense mutations c.1927G>A (p.Gly643Arg) and c.655G>A (p.Gly219Arg). Patients carrying the c.-32-13T>G mutation had an older mean age at onset than patients non-exhibiting this mutation (36 versus 25 years). Patients with the same genotype had a highly variable age at onset. We estimated the frequency of late-onset PD in France around 1/69,927 newborns. In conclusion, we characterized the French cohort of late-onset PD patients through a nationwide study covering more than 40 years.

Background Fabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies (ERT) have been available. We aimed to determine the epidemiology and the functional characteristics of anti-drug antibodies. Patients from the French multicenter cohort FFABRY ( n  = 103 patients, 53 males) were prospectively screened for total anti-agalsidase IgG and IgG subclasses with a home-made enzyme-linked immunosorbent assay (ELISA), enzyme-inhibition assessed with neutralization assays and lysoGb3 plasma levels, and compared for clinical outcomes. Results Among the patients exposed to agalsidase, 40% of men ( n  = 18/45) and 8% of women ( n  = 2/25) had antibodies with a complete cross-reactivity towards both ERTs. Antibodies developed preferentially in men with non-missense GLA mutations (relative risk 2.88, p  = 0.006) and classic phenotype (58.6% (17/29) vs 6.7% (1/16), p  = 0.0005). Specific anti-agalsidase IgG1 were the most frequently observed (16/18 men), but the highest concentrations were observed for IgG4 (median 1.89 μg/ml, interquartile range (IQR) [0.41–12.24]). In the men exposed to agalsidase, inhibition was correlated with the total IgG titer ( r  = 0.67, p  < 0.0001), especially IgG4 ( r  = 0.75, p = 0.0005) and IgG2 ( r  = 0.72, p  = 0.001). Inhibition was confirmed intracellularly in Fabry patient leucocytes cultured with IgG-positive versus negative serum (median: 42.0 vs 75.6%, p  = 0.04), which was correlated with IgG2 (r = 0.67, p  = 0.017, n  = 12) and IgG4 levels ( r  = 0.59, p  = 0.041, n  = 12). Plasma LysoGb3 levels were correlated with total IgG ( r  = 0.66, p  = 0.001), IgG2 (r = 0.72, p  = 0.004), IgG4 ( r  = 0.58, p  = 0.03) and IgG1 ( r  = 0.55, p  = 0.04) titers. Within the classic group, no clinical difference was observed but lysoGb3 levels were higher in antibody-positive patients (median 33.2 ng/ml [IQR 20.6–55.6] vs 12.5 [10.1–24.0], p  = 0.005). Conclusion Anti-agalsidase antibodies preferentially develop in the severe classic Fabry phenotype. They are frequently associated with enzyme inhibition and higher lysoGb3 levels. As such, they could be considered as a hallmark of severity associated with the classic phenotype. The distinction of the clinical phenotypes should now be mandatory in studies dealing with Fabry disease and its current and future therapies.

BackgroundBidirectional intraflagellar transport (IFT) consists of two major protein complexes, IFT-A and IFT-B. In contrast to the IFT-B complex, all components of IFT-A have recently been linked to human ciliopathies when defective. We therefore hypothesised that mutations in additional IFT-B encoding genes can be found in patients with multisystemic ciliopathies.MethodsWe screened 1628 individuals with reno-ocular ciliopathies by targeted next-generation sequencing of ciliary candidate genes, including all IFT-B encoding genes.ResultsConsequently, we identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. Further, we detected a loss-of-stop mutation with extension of the deduced protein by 10 amino acids in an individual with neuronal ceroid lipofuscinosis-1. This proband presented with retinal dystrophy and brain lesions including cerebellar atrophy, a phenotype to which the IFT81 variant might contribute. Cultured fibroblasts of this latter affected individual showed a significant decrease in ciliated cell abundance compared with controls and increased expression of the transcription factor GLI2 suggesting deranged sonic hedgehog signalling.ConclusionsThis work describes identification of mutations of IFT81 in individuals with symptoms consistent with the clinical spectrum of ciliopathies. It might represent the rare case of a core IFT-B complex protein found associated with human disease. Our data further suggest that defects in the IFT-B core are an exceedingly rare finding, probably due to its indispensable role for ciliary assembly in development.