Fabry disease: development and progression of left ventricular hypertrophy despite long-term enzyme replacement therapy.

BACKGROUND: Enzyme replacement therapy (ERT) may halt or attenuate disease progression in patients with Anderson-Fabry disease (AFD). However, whether left ventricular hypertrophy (LVH) can be prevented by early therapy or may still progress despite ERT over a long-term follow-up is still unclear. METHODS: Consecutive patients with AFD from the Independent Swiss-Fabry Cohort receiving ERT who were at least followed up for 5 years were included. Cardiac progression was defined as an increase of >10 g/m2 in left ventricular mass index (LVMI) between the first and the last available follow-up transthoracic echocardiography. RESULTS: 60 patients (35 (23-48) years, 39 (65%) men) were followed up for 10.5 (7.2-12.2) years. 22 had LVH at ERT start (LVMI of 150±38 g/m2). During follow-up, 22 (36%, 34±15 years) had LVMI progression of 12.1 (7-17.6) g/m2 per 100 patient-years, of these 7 (11%, 29±13 years) with no LVH at baseline. Three of them progressed to LVH. LVMI progression occurred mostly in men (17 of 39 (43%) vs 5 of 21 (24%), p<0.01) and after the age of 30 years (17 of 22 (77%)). LVH at ERT start was associated with LVMI progression (OR 1.3, 95% CI 1.1 to 2.6; p=0.02). A total of 19 (31%) patients experienced a major AFD-related event. They were predominantly men (17 of 19, 89%), older (45±11 vs 32±9 years) with baseline LVH (12 of 19, 63%), and 10 of 19 (52%) presented with LVMI progression. CONCLUSIONS: Over a median follow-up of >10 years under ERT, 36% of the patients still had LVMI cardiac progression, and 32%, predominantly older men, experienced major AFD-related events. LVH at treatment initiation was a strong predictor of LVMI progression and adverse events on ERT.

Long-Term Monitoring of Cardiac Involvement under Migalastat Treatment Using Magnetic Resonance Tomography in Fabry Disease.

Background: Fabry cardiomyopathy is characterized by left ventricular hypertrophy, myocardial fibrosis, arrhythmia, and premature death. Treatment with migalastat, an oral pharmacological chaperone, was associated with a stabilization of cardiac biomarkers and a reduction in left ventricular mass index, as measured by echocardiography. A recent study, using cardiac magnetic resonance (CMR) as the gold standard, found a stable course of myocardial involvement after 18 months of treatment with migalastat. Our study aimed to provide long-term CMR data for the treatment with migalastat. Methods: A total of 11 females and four males with pathogenic amenable GLA mutations were treated with migalastat and underwent 1.5T CMR imaging for routine treatment effect monitoring. The main outcome was a long-term myocardial structural change, reflected by CMR. Results: After migalastat treatment initiation, left ventricular mass index, end diastolic volume, interventricular septal thickness, posterior wall thickness, estimated glomerular filtration rate, and plasma lyso-Gb3 remained stable during the median follow-up time of 34 months (min.: 25; max.: 47). The T1 relaxation times, reflecting glycosphingolipid accumulation and subsequent processes up to fibrosis, fluctuated over the time without a clear trend. No new onset of late gadolinium enhancement (LGE) areas, reflecting local fibrosis or scar formation of the myocardium, could be detected. However, patients with initially present LGE showed an increase in LGE as a percentage of left ventricular mass. The median α-galactosidase A enzymatic activity increased from 37.3% (IQR 5.88-89.3) to 105% (IQR 37.2-177) of the lower limit of the respective reference level (p = 0.005). Conclusion: Our study confirms an overall stable course of LVMi in patients with FD, treated with migalastat. However, individual patients may experience disease progression, especially those who present with fibrosis of the myocardium already at the time of therapy initiation. Thus, a regular treatment re-evaluation including CMR is needed to provide the optimal management for each patient.

Deep next-generation proteomics and network analysis reveal systemic and tissue-specific patterns in Fabry disease.

Fabry disease (FD) is an X-linked lysosomal rare disease due to a deficiency of α-galactosidase A activity. The accumulation of glycosphingolipids mainly affects the kidney, heart, and central nervous system, considerably reducing life expectancy. Although the accumulation of undegraded substrate is considered the primary cause of FD, it is established that secondary dysfunctions at the cellular, tissue, and organ levels ultimately give rise to the clinical phenotype. To parse this biological complexity, a large-scale deep plasma targeted proteomic profiling has been performed. We analyzed the plasma protein profiles of FD deeply phenotyped patients (n = 55) compared to controls (n = 30) using next-generation plasma proteomics including 1463 proteins. Systems biology and machine learning approaches have been used. The analysis enabled the identification of proteomic profiles that unambiguously separated FD patients from controls (615 differentially expressed proteins, 476 upregulated, and 139 downregulated) and 365 proteins are newly reported. We observed functional remodeling of several processes, such as cytokine-mediated pathways, extracellular matrix, and vacuolar/lysosomal proteome. Using network strategies, we probed patient-specific tissue metabolic remodeling and described a robust predictive consensus protein signature including 17 proteins CD200, SPINT1, CD34, FGFR2, GRN, ERBB4, AXL, ADAM15, PTPRM, IL13RA1, NBL1, NOTCH1, VASN, ROR1, AMBP, CCN3, and HAVCR2. Our findings highlight the pro-inflammatory cytokines' involvement in FD pathogenesis along with extracellular matrix remodeling. The study shows a tissue-wide metabolic remodeling connection to plasma proteomics in FD. These results will facilitate further studies to understand the molecular mechanisms in FD to pave the way for better diagnostics and therapeutics.

Agalsidase-ß should be proposed as first line therapy in classic male Fabry patients with undetectable α-galactosidase A activity.

BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A (GLA) gene leading to deficiency of α-galactosidase A (α-gal A). This results in progressive multisystemic glycosphingolipid accumulation, especially globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). Enzyme replacement therapy with two recombinant enzymes, agalsidase-α and -ß is approved for two different dosages. However, little is known about which enzyme is more effective in decreasing the metabolite load in male and female patients with the classic form of the disease. METHODS: In this prospective observational study, 14 consecutive adult Fabry patients (10 males) with a classic GLA-mutation, were switched from agalsidase-α to agalsidase-ß at the respective licensed doses. Lyso-Gb3 levels were measured before the switch and for a period of 12 months after the switch in dried blood spots by tandem mass spectrometry. RESULTS: Mean age at start of the switch was 36.7 ± 14 years. Plasma Lyso-Gb3 levels decreased from 27.2 ± 17.9 ng/mL before the switch to 16.8 ± 10.5 ng/mL after the switch (mean reduction of 30.1%; p = 0.004). The decrease was maximal in the subgroup of 7 male patients with no or very low residual enzyme activity (mean reduction of 40.4%). However, two females with high residual enzyme activity also showed a reduction >30% after the switch. In male patients, the reduction of plasma Lyso-Gb3 correlated negatively with the residual α-gal A activity: r = -0.803; p = 0.009. CONCLUSION: Agalsidase-ß at licensed dose is significantly more effective than agalsidase-α to reduce Lyso-Gb3 levels in classic Fabry patients, and should be used as first line therapy in classic males with no residual enzyme activity.

A knock-in rat model unravels acute and chronic renal toxicity in glutaric aciduria type I.

Glutaric aciduria type I (GA-I, OMIM # 231670) is an autosomal recessive inborn error of metabolism caused by deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH). The principal clinical manifestation in GA-I patients is striatal injury most often triggered by catabolic stress. Early diagnosis by newborn screening programs improved survival and reduced striatal damage in GA-I patients. However, the clinical phenotype is still evolving in the aging patient population. Evaluation of long-term outcome in GA-I patients recently identified glomerular filtration rate (GFR) decline with increasing age. We recently created the first knock-in rat model for GA-I harboring the mutation p.R411W (c.1231 C>T), corresponding to the most frequent GCDH human mutation p.R402W. In this study, we evaluated the effect of an acute metabolic stress in form of high lysine diet (HLD) on young Gcdhki/ki rats. We further studied the chronic effect of GCDH deficiency on kidney function in a longitudinal study on a cohort of Gcdhki/ki rats by repetitive 68Ga-EDTA positron emission tomography (PET) renography, biochemical and histological analyses. In young Gcdhki/ki rats exposed to HLD, we observed a GFR decline and biochemical signs of a tubulopathy. Histological analyses revealed lipophilic vacuoles, thinning of apical brush border membranes and increased numbers of mitochondria in proximal tubular (PT) cells. HLD also altered OXPHOS activities and proteome in kidneys of Gcdhki/ki rats. In the longitudinal cohort, we showed a progressive GFR decline in Gcdhki/ki rats starting at young adult age and a decline of renal clearance. Histopathological analyses in aged Gcdhki/ki rats revealed tubular dilatation, protein accumulation in PT cells and mononuclear infiltrations. These observations confirm that GA-I leads to acute and chronic renal damage. This raises questions on indication for follow-up on kidney function in GA-I patients and possible therapeutic interventions to avoid renal damage.

[Chaperone molecules: The example of Fabry disease]. / Molécules chaperons : exemple de la maladie de Fabry.

Fabry disease is due to mutations in the GLA gene that cause a deficiency of the activity of the lysosomal enzyme alpha-galactosidase A (α-gal A) resulting in intra-tissue accumulation of globotriaosylceramide. Recently, a novel therapeutic approach based on the pharmacological chaperone migalastat has been developed. It binds, in a specific and reversible manner, to the catalytic site of α-gal A mutants, to prevent their degradation by the quality control system of the endoplasmic reticulum and allow them to catabolize globotriaosylceramide in the lysosomes. This treatment concerns approximately 35% of the GLA gene mutations recognized as sensitive to migalastat according to an in vitro pharmacogenetic test. Two pivotal Phase III studies, FACETS: migalastat vs. placebo and ATTRACT: migalastat vs. enzyme replacement therapy analyzed the in vivo effects of migalastat. Despite some methodological limitations, promising results were found. Migalastat seems to be more effective than enzyme replacement therapy in reducing left ventricular mass index in case of cardiac hypertrophy and has comparable renal effects. This oral treatment is the first personalized treatment, based on the genetic profile of Fabry patients and opens a new era in the management of conformational diseases.

The use of 68Ga-EDTA PET allows detecting progressive decline of renal function in rats.

INTRODUCTION: Evaluation of glomerular filtration rate is very important in both preclinical and clinical setting, especially in the context of chronic kidney disease. It is typically performed using 51Cr-EDTA or by imaging with 123I-Hippuran scintigraphy, which has a significantly lower resolution and sensitivity as compared to PET. 68Ga-EDTA represents a valid alternative due to its quick availability using a 68Ge/68Ga generator, while PET/CT enables both imaging of renal function and accurate quantitation of clearance of activity from both plasma and urine. Therefore, we aimed at investigating the use of 68Ga-EDTA as a preclinical tracer for determining renal function in a knock-in rat model known to present progressive decline of renal function. METHODS: 68Ga-EDTA was injected in 23 rats, either wild type (n=10) or knock-in (n=13). By applying a unidirectional, two-compartment model and Rutland-Patlak Plot linear regression analysis, split renal function was determined from the age of 6 weeks to 12 months. RESULTS: Glomerular filtration ranged from 0.025±0.01 ml/min at 6 weeks to 0.049±0.05 ml/min at 6 months in wild type rats. Glomerular filtration was significantly lower in knock-in rats at 6 and 12 months (P<0.01). No significant difference was observed in renal volumes between knock-in and wild type animals, based on imaging-derived volume calculations. CONCLUSIONS: 68Ga-EDTA turned out to be a very promising PET/CT tracer for the evaluation of split renal function. This method allowed detection of progressive renal impairment in a knock-in rat model. Additional validation in a human cohort is warranted to further assess clinical utility in both, healthy individuals and patients with renal impairment.

[Isolated left ventricular hypertrophy : is it a Fabry disease?] / Hypertrophie ventriculaire gauche isolée : et si c'était une maladie de Fabry ?

Fabry disease, an X-linked disease, results from a deficiency of the lysosomal enzyme alpha-galactosidase A, which causes glycosphingolipids accumulation in the body. On the basis of the residual enzymatic activity level, a classical, severe multisystemic form and an attenuated cardiac variant form are distinguished. In all cases, patients can develop hypertrophic cardiomyopathy in adulthood, the severity of which is the leading cause of morbidity and mortality of the disease. The cardiomyopathy is usually isolated in the cardiac variant form, the most common form of the disease, and should be suspected in the presence of relatively specific ECG, echocardiographic and MRI characteristics.

La maladie de Fabry est liée au chromosome X et résulte d'un déficit de l'enzyme lysosomale alpha-galactosidase A, responsable de l'accumulation de glycosphingolipides dans l'organisme. On distingue une forme classique, multisystémique, sévère, et une forme atténuée ou variant cardiaque. Dans tous les cas, les adultes peuvent développer une cardiomyopathie hypertrophique (CMH), principale cause de morbi-mortalité de la maladie. Dans la forme variant cardiaque, la plus fréquente de la maladie, la CMH est généralement isolée. Elle peut être suspectée en présence de certaines anomalies ECG, échocardiographiques et/ou IRM, et amener à un dépistage.

Fabry disease caused by the GLA p.Phe113Leu (p.F113L) variant: Natural history in males.

BACKGROUND, AIMS AND METHODS: The α-galactosidase gene (GLA) c.337T>C/p.Phe113Leu variant was originally described in patients with late-onset cardiac forms of Fabry disease (FD), who had residual α-galactosidase activity. It has since emerged as the most commonly reported GLA variant in Portuguese subjects diagnosed with FD but is also prevalent in the Italian population, where two boys carrying the GLA Leu113 allele were identified in a large-scale newborn screening program, the variant allele segregating in both cases with the same surrounding haplotype. To further delineate the genotype-phenotype correlations of this GLA variant, we have reviewed the natural history and clinical phenotypes of 11 symptomatic Portuguese males, from 10 unrelated families originating from several different areas in mainland Portugal and Madeira Island, who were diagnosed with FD associated with the GLA Leu113 allele in a diversity of clinical and screening settings. Nine of the patients were the probands of their respective families. To test whether the GLA Leu113 allele inherited by the 10 Portuguese and the two Italian families resulted from independent mutational events, we have additionally performed a haplotype analysis with 5 highly polymorphic, closely linked microsatellite markers surrounding the GLA gene. RESULTS AND CONCLUSIONS: Hemizygosity for the GLA Leu113 variant allele is associated with a late-onset form of FD, invariably presenting with severe cardiac involvement. Clinically relevant cerebrovascular and kidney involvement may also occur in some patients but the pathogenic relationship between the incomplete α-galactosidase deficiency and the risks of stroke and of chronic kidney disease is not straightforward. The observation that the Leu113 allele segregated within the same GLA microsatellite haplotype in both the Portuguese and Italian families suggests its inheritance from a common ancestor.

Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency. The progressive accumulation of globotriaosylceramide results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. The pharmacological chaperone migalastat was recently approved as an alternative to enzyme replacement therapy in patients with amenable mutations. In this article, we investigate the proportion of amenable mutations, related to phenotype, in a population of adult patients with FD in Switzerland. This study included 170 adult patients (n = 64 males) from 46 independent pedigrees with 39 different identified mutations over the last 59 years. Overall, 68% had the classic phenotype and 48% fulfilled the current amenability criteria. Migalastat was stopped in 2/11 (18%) patients: the only male classic patient, because of lack of efficacy based on lyso-Gb3 levels, and one patient with a benign variant. In males, the achieved enzyme activities in peripheral leucocytes under migalastat treatment differed from the activities in HEK-cells after incubation with migalastat (eg, 33% in PL vs 41% HEK-cells for p.F113L; 43% in leucocytes vs 36% in HEK-cells for p.N215S, 24-30% in leucocytes vs 96% in HEK-cells for S238N). In this national cohort, we found a relatively high proportion of patients with amenable GLA mutations, which, however, had heterogeneous extent of amenability: the higher the residual α-Gal A activity, the higher the chaperone effect. Further studies are required to investigate the long-term benefits of migalastat therapy depending on the achieved enzyme activities in different amenable mutations.

Hepatosplenomegaly, pneumopathy, bone changes and fronto-temporal dementia: Niemann-Pick type B and SQSTM1-associated Paget's disease in the same individual.

Data from exome sequencing show that a proportion of individuals in whom a genetic disorder is suspected turn out to have not one, but two to four distinct ones. This may require an evolution in our diagnostic attitude towards individuals with complex disorders. We report a patient with splenomegaly, pneumopathy, bone changes and fronto-temporal dementia (FTD). "Sea-blue histiocytes" in his bone marrow pointed to a lysosomal storage disease. Homozygosity for a pathogenic mutation in the SMPD1 gene confirmed Niemann-Pick disease type B (NPD-B). Mild cognitive impairment and abnormal brain FDG PET were consistent with FTD. We initially tried to fit the skeletal and neurologic phenotype into the NPD-B diagnosis. However, additional studies revealed a pathogenic mutation in the SQSTM1 gene. Thus, our patient had two distinct diseases; NPD-B, and Paget's disease of bone with FTD. The subsequent finding of a mutation in SQSTM1 gene ended our struggle to explain the combination of findings by a singular "unifying" diagnosis and allowed us to make specific therapeutic decisions. SQSTM1 mutations have been reported in association with FTD, possibly because of defective autophagy. Bisphosphonates may be beneficial for PDB, but since they are known to inhibit acid sphingomyelinase activity, we refrained from using them in this patient. While the principle of looking for unifying diagnosis remains valid, physicians should consider the possibility of co-existing multiple diagnoses when clinical features are difficult to explain by a single one. Accurate diagnostic work-up can guide genetic counseling but also lead to better medical management.

Are heterozygous carriers for hereditary fructose intolerance predisposed to metabolic disturbances when exposed to fructose?

Background: High fructose intake causes hepatic insulin resistance and increases postprandial blood glucose, lactate, triglyceride, and uric acid concentrations. Uric acid may contribute to insulin resistance and dyslipidemia in the general population. In patients with hereditary fructose intolerance, fructose consumption is associated with acute hypoglycemia, renal tubular acidosis, and hyperuricemia. Objective: We investigated whether asymptomatic carriers for hereditary fructose intolerance (HFI) would have a higher sensitivity to adverse effects of fructose than would the general population. Design: Eight subjects heterozygous for HFI (hHFI; 4 men, 4 women) and 8 control subjects received a low-fructose diet for 7 d and on the eighth day ingested a test meal, calculated to provide 25% of the basal energy requirement, containing 13C-labeled fructose (0.35 g/kg), glucose (0.35 g/kg), protein (0.21 g/kg), and lipid (0.22 g/kg). Glucose rate of appearance (GRa, calculated with [6,6-2H2]glucose), fructose, net carbohydrate, and lipid oxidation, and plasma triglyceride, uric acid, and lactate concentrations were monitored over 6 h postprandially. Results: Postprandial GRa, fructose, net carbohydrate, and lipid oxidation, and plasma lactate and triglyceride concentrations were not significantly different between the 2 groups. Postprandial plasma uric acid increased by 7.2% compared with fasting values in hHFI subjects (P < 0.01), but not in control subjects (-1.1%, ns). Conclusions: Heterozygous carriers of hereditary fructose intolerance had no significant alteration of postprandial fructose metabolism compared with control subjects. They did, however, show a postprandial increase in plasma uric acid concentration that was not observed in control subjects in responses to ingestion of a modest amount of fructose. This trial was registered at the US Clinical Trials Registry as NCT02979106.

Long-term Outcomes of Kidney Transplantation in Fabry Disease.

BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene that obliterate or markedly reduce α-galactosidase A activity. This results in the systemic accumulation of its glycosphingolipid substrates in body fluids and organs, including the kidney. Fabry nephropathy can lead to end-stage renal disease requiring kidney transplantation. Little is known about its long-term outcomes and the overall patient survival after kidney transplantation. METHODS: Here, we report 17 Fabry patients (15 male and 2 female subjects) who received kidney transplants and their long-term treatment and follow-up at 4 specialized Fabry centers. RESULTS: The posttransplant follow-up ranged to 25 years, with a median of 11.5 (range, 0.8-25.5] years. Graft survival was similar, and death-censored graft survival was superior to matched controls. Fabry patients died with functioning kidneys, mostly from cardiac causes. In 2 male subjects 14 and 23 years posttransplant, the grafts had a few typical FD lamellar inclusions, presumably originating from invading host macrophages and vascular endothelial cells. CONCLUSIONS: We conclude that kidney transplantation has an excellent long-term outcome in FD.

Ascending aortic remodelling in Fabry disease after long-term enzyme replacement therapy.

BACKGROUND: Previous cross-sectional studies reported a high prevalence of ascending aorta dilations/aneurysms in male adults with Fabry disease, independently of cardiovascular risk factors. AIMS OF THE STUDY: To characterise the remodelling of the ascending aorta in classic Fabry disease under long-term enzyme replacement therapy. METHODS: Diameter of the ascending aorta was measured with magnetic resonance imaging at the sino-tubular junction (STJ), and proximal (pAsAo), and distal ascending aorta (dAsAo) at baseline, and after 5 and 10 years of enzyme replacement therapy in 15 adult Fabry patients (10 males; 5 females). RESULTS: Over a mean follow-up of 9.5 years, the annual expansion rates measured in 10 males with Fabry disease were 0.41 ± 0.16, 0.36 ± 0.25 and 0.41 ± 0.26 mm/y at the STJ, pAsAo and dAsAo, respectively. Expansion rate at the pAsAo level in male patients was significantly higher than the expected expansion projected from theoretical normal values: 0.36 ± 0.25 vs 0.13 ± 0.05, p = 0.017. In 5 females, the annual expansion rates at the STJ, pAsAo and dAsAo were 0.14 ± 0.11, 0.21 ± 0.18 and 0.26 ± 0.24 mm/y, respectively. There was no significant difference from the projected normal expansion rate at the level of the pAsAo: 0.21 ± 0.18 vs 0.13 ± 0.04, p = 0.39. CONCLUSION: Our data suggest that the remodelling of the ascending aorta is more pronounced in male patients with Fabry disease under long-term enzyme replacement therapy compared with the progression observed in a large population study.

Long-term follow-up of pulmonary function in Fabry disease: A bi-center observational study.

INTRODUCTION: Fabry disease (FD) is a lysosomal storage disorder leading to decreased α-galactosidase A enzyme activity and subsequent abnormal accumulation of glycosphingolipids in various organs. Although histological evidence of lung involvement has been demonstrated, the functional impact of these changes is less clear. MATERIALS AND METHODS: Adult patients with FD who had yearly pulmonary function tests (PFT) at two centers from 1999 thru 2015 were eligible for this observational study. Primary outcome measures were the change in forced expiratory volume in the first second (FEV1) and FEV1/FVC over time. As secondary outcome we investigated sex, smoking, enzyme replacement therapy (ERT), residual enzyme activity, and Mainz Severity Score Index as possible predictors. RESULTS: 95 patients (41% male, 38.2 ± 14.5 years) were included. The overall prevalence of bronchial obstruction (BO, (FEV1/FVC < 70%)) was 46%, with male sex, age and smoking as significant predictors. FEV1 decreased 29 ml per year (95% CI -36, -22 ml, p<0.0001). FEV1 decline was significantly higher in males (p = 0.009) and in patients on ERT (p = 0.004). Conclusion: Pulmonary involvement seems to be a relevant manifestation of Fabry disease, and routine PFTs should therefore be included in the multidisciplinary follow-up of these patients.

[Raising the internist's know-how in the field of rare diseases: mitochondrial diseases as an illustrative example]. / L'interniste face aux maladies rares: quand y penser? L'exemple des maladies mitochondriales.

Rare Diseases, defined by a prevalence of less than 1 per 2000 persons, affect 36 million people in Europe, 500 000 in Switzerland, corresponding to 6-8% of the general population. 7000 rare diseases are currently recorded.Mitochondrial diseases are a heterogeneous group of genetic diseases. They are characterized by intracellular failure of energy production and affect predominantly energy-dependent tissues. The clinical presentation is not always suggestive, particularly in adulthood. In order to reach the diagnosis, a prerequisite is to think of them. In this article, we will focus on the clinical aspects of mitochondrial disorders in order to give the internist simple tools on how not to miss those rare diseases in his daily practice.

Les maladies rares, définies par une prévalence égale ou inférieure à 1 pour 2000 personnes, touchent 36 millions de personnes en Europe et 500 000 en Suisse, soit 6 à 8% de la population générale. On en dénombre quelque 7000 actuellement.Les maladies mitochondriales constituent un groupe hétérogène de maladies génétiques. Elles sont liées à des carences de production intracellulaire d'énergie et s'expriment principalement sur les tissus énergie-dépendants. L'expression phénotypique n'est pas toujours spontanément évocatrice, en particulier chez l'adulte. Nous proposons dans cet article une approche centrée sur la clinique des maladies mitochondriales permettant à l'interniste de les évoquer.

Clinical and molecular characterization of cystinuria in a French cohort: relevance of assessing large-scale rearrangements and splicing variants.

BACKGROUND: Cystinuria is an autosomal recessive disorder of dibasic amino acid transport in the kidney and the intestine leading to increased urinary cystine excretion and nephrolithiasis. Two genes, SLC3A1 and SLC7A9, coding respectively for rBAT and b0,+AT, account for the genetic basis of cystinuria. METHODS: This study reports the clinical and molecular characterization of a French cohort including 112 cystinuria patients and 25 relatives from 99 families. Molecular screening was performed using sequencing and Quantitative Multiplex PCR of Short Fluorescent Fragments analyses. Functional minigene-based assays have been used to characterize splicing variants. RESULTS: Eighty-eight pathogenic nucleotide changes were identified in SLC3A1 (63) and SLC7A9 (25) genes, of which 42 were novel. Interestingly, 17% (15/88) and 11% (10/88) of the total number of variants correspond, respectively, to large-scale rearrangements and splicing mutations. Functional minigene-based assays were performed for six variants located outside the most conserved sequences of the splice sites; three variants affect splice sites, while three others modify exonic splicing regulatory elements (ESR), in good agreement with a new in silico prediction based on ΔtESRseq values. CONCLUSION: This report expands the spectrum of SLC3A1 and SLC7A9 variants and supports that digenic inheritance is unlikely. Furthermore, it highlights the relevance of assessing large-scale rearrangements and splicing mutations to fully characterize cystinuria patients at the molecular level.

Pulmonary Involvement in Adult Patients with Inborn Errors of Metabolism.

Inborn errors of metabolism (IEM) are rare individually, but taken together, they affect 1 in 1,000 people. Most of the disease becomes apparent at the pediatric age; however, with the identification of late-onset forms, and with improved survival, several of these conditions may be found in adults of all ages. While the lung is not typically a primary site of clinical disease in patients with IEM, in some of them it can be a significantly affected organ with associated severe respiratory complications. Lung involvement can be a late- onset feature of a complex multisystemic disease, but sometimes it can also be the only manifestation of underlying IEM. The aim of this review is to focus on specific IEM associated with lung disease in adults and to provide the reader with an overview of the diagnostic workup, overall disease management, and specific treatments for the respiratory manifestations. Clinical suspicion, early recognition, prompt diagnosis, and appropriate care of the respiratory manifestation are crucial, as they can affect both the life expectancy and the quality of life of these patients.