Lysosomal Disorder Research Articles

Structure of a truncated human GlcNAc-1-phosphotransferase variant reveals the basis for its hyperactivity

Mutations that cause loss of function of GlcNAc-1-phosphotransferase (PTase) lead to the lysosomal storage disorder mucolipidosis II. PTase is the key enzyme of the mannose 6-phosphate (M6P) targeting system that is responsible for tagging lysosomal hydrolases with the M6P moiety for their delivery to the lysosome. We had previously generated a truncated hyperactive form of PTase termed S1S3 which was shown to notably increase the phosphorylation level of secreted lysosomal enzymes and enhance their uptake by cells. Here, we report the 3.4Å cryo-EM structure of soluble S1S3 lacking both transmembrane domains and cytosolic tails. The structure reveals a high degree of conservation of the catalytic core to full-length PTase. In this dimeric structure, the EF-hand of one protomer is observed interacting with the conserved region four of the other. In addition, we present a high-quality EM 3D map of the UDP-GlcNAc bound form of the full-length soluble protein showing the key molecular interactions between the nucleotide sugar donor and side chain amino acids of the protein. Finally, although the domain organization of S1S3 is very similar to that of the Drosophila melanogaster (fruit fly) PTase homolog, we establish that the latter does not act on lysosomal hydrolases.

Relationship between Capillaroscopic Architectural Patterns and Different Variant Subgroups in Fabry Disease: Analysis of Cases from a Multidisciplinary Center.

Anderson-Fabry disease (AFD) is a genetic lysosomal storage disorder caused by mutations in the α-galactosidase A gene, leading to impaired lysosomal function and resulting in both macrovascular and microvascular alterations. AFD patients often exhibit increased intima-media thickness (IMT) and reduced flow-mediated dilation (FMD), indicating non-atherosclerotic arterial thickening and the potential for cardiovascular events. Nailfold capillaroscopy, a non-invasive diagnostic tool, has shown potential in diagnosing and monitoring microcirculatory disorders in AFD, despite limited research. This study evaluates nailfold capillaroscopy findings in AFD patients, exploring correlations with GLA gene variant subgroups (associated with classical or late-onset phenotypes and variants of uncertain significance (VUSs)), and assessing morpho-functional differences between sexes. It aims to determine whether capillaroscopy can assist in the early identification of individuals with multiorgan vascular involvement. A retrospective observational study was conducted with 25 AFD patients from AOUP "G. Rodolico-San Marco" in Catania (2020-2023). Patients underwent genetic testing, enzyme activity evaluation, and nailfold capillaroscopy using Horus basic HS 200 videodermatoscopy. Parameters like angiotectonic disorder, vascular areas, capillary density, and intimal thickening were assessed. The study identified significant differences in capillaroscopy findings among patients with different GLA gene variant subgroups. Classic AFD variant patients showed reduced capillary length and signs of erythrocyte aggregation and dilated subpapillary plexus. No correlation was found between enzymatic activity and capillaroscopy parameters. However, Lyso-Gb3 levels were positively correlated with average capillary length (ῤ = 0.453; p = 0.059). Sex-specific differences in capillaroscopy findings were observed in neoangiogenesis and average capillary length, with distinct implications for men and women. This study highlights the potential of nailfold capillaroscopy in the diagnostic process and clinical management of AFD, particularly in relation to specific GLA gene mutations, as a valuable tool for the early diagnosis and monitoring of AFD.

A PIKfyve modulator combined with an integrated stress response inhibitor to treat lysosomal storage diseases

Lysosomal degradation pathways coordinate the clearance of superfluous and damaged cellular components. Compromised lysosomal degradation is a hallmark of many degenerative diseases, including lysosomal storage diseases (LSDs), which are caused by loss-of-function mutations within both alleles of a lysosomal hydrolase, leading to lysosomal substrate accumulation. Gaucher's disease, characterized by <15% of normal glucocerebrosidase function, is the most common LSD and is a prominent risk factor for developing Parkinson's disease. Here, we show that either of two structurally distinct small molecules that modulate PIKfyve activity, identified in a high-throughput cellular lipid droplet clearance screen, can improve glucocerebrosidase function in Gaucher patient-derived fibroblasts through an MiT/TFE transcription factor that promotes lysosomal gene translation. An integrated stress response (ISR) antagonist used in combination with a PIKfyve modulator further improves cellular glucocerebrosidase activity, likely because ISR signaling appears to also be slightly activated by treatment by either small molecule at the higher doses employed. This strategy of combining a PIKfyve modulator with an ISR inhibitor improves mutant lysosomal hydrolase function in cellular models of additional LSD.

Current developments of gene therapy in human diseases.

Gene therapy has witnessed substantial advancements in recent years, becoming a constructive tactic for treating various human diseases. This review presents a comprehensive overview of these developments, with a focus on their diverse applications in different disease contexts. It explores the evolution of gene delivery systems, encompassing viral (like adeno-associated virus; AAV) and nonviral approaches, and evaluates their inherent strengths and limitations. Moreover, the review delves into the progress made in targeting specific tissues and cell types, spanning the eye, liver, muscles, and central nervous system, among others, using these gene technologies. This targeted approach is crucial in addressing a broad spectrum of genetic disorders, such as inherited lysosomal storage diseases, neurodegenerative disorders, and cardiovascular diseases. Recent clinical trials and successful outcomes in gene therapy, particularly those involving AAV and the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated proteins, are highlighted, illuminating the transformative potentials of this approach in disease treatment. The review summarizes the current status of gene therapy, its prospects, and its capacity to significantly ameliorate patient outcomes and quality of life. By offering comprehensive analysis, this review provides invaluable insights for researchers, clinicians, and stakeholders, enriching the ongoing discourse on the trajectory of disease treatment.

A Rare Case of Late Onset-Pompe’s Disease: Presented as Heart Failure

Pompe disease is a hereditary lysosomal storage disorder characterized by a deficiency in the acid alpha-glucosidase (GAA) enzyme, leading to glycogen accumulation in muscle and neurons. Clinical manifestations vary from severe infantile-onset with hypertrophic cardiomyopathy and early mortality due to respiratory insufficiency to late-onset with proximal muscle weakness, gross motor delay, and progressive respiratory insufficiency. A case of an 11-year-old boy who reported to the pediatric emergency department with a nine-year history of progressive muscle weakness and a one-month history of anemia symptoms (easy fatigue, shortness of breath, pale appearance) and heart failure (orthopnea, dyspnea). His family history included consanguineous marriages and similar conditions in his brother and maternal uncle. On examination, he appeared pale, malnourished, and exhibited signs of respiratory distress and tachypnea. His cardiovascular examination revealed apex beat displacement, elevated JVP, bilateral pedal edema, mild ascites, positive hepatojugular reflux, and systolic murmurs. Respiratory examination indicated bilateral crepitation and wheezes. Musculoskeletal examination showed decreased muscle mass and power, especially in proximal muscles. Abdominal examination revealed hepatosplenomegaly and mild ascites. Radiological findings included an enlarged cardiac shadow with pleural effusion and bilateral radio-opaque shadows on chest x-ray, while echocardiography showed impaired left ventricular systolic function with mild to moderate mitral and tricuspid regurgitation. Laboratory tests indicated elevated aspartate aminotransferase, LDH, and creatine kinase levels, along with normocytic, normochromic anemia. Muscle biopsy from the hamstring revealed PAS stain positive granules. These clinical, radiological, and laboratory findings strongly suggest late-onset Pompe disease, marking this as potentially the second reported case in Pakistan.

Efficacy of an AAV vector encoding a thermostable form of glucocerebrosidase in alleviating symptoms in a Gaucher disease mouse model

Almost all attempts to date at gene therapy approaches for monogenetic disease have used the amino acid sequences of the natural protein. In the current study, we use a designed, thermostable form of glucocerebrosidase (GCase), the enzyme defective in Gaucher disease (GD), to attempt to alleviate neurological symptoms in a GD mouse that models type 3 disease, i.e. the chronic neuronopathic juvenile subtype. Upon injection of an AAVrh10 (adeno-associated virus, serotype rh10) vector containing the designed GCase (dGCase) into the left lateral ventricle of Gba−/−;Gbatg mice, a significant improvement in body weight and life-span was observed, compared to injection of the same mouse with the wild type enzyme (wtGCase). Moreover, a reduction in levels of glucosylceramide (GlcCer), and an increase in levels of GCase activity were seen in the right hemisphere of Gba−/−;Gbatg mice, concomitantly with a significant improvement in motor function, reduction of neuroinflammation and a reduction in mRNA levels of various genes shown previously to be elevated in the brain of mouse models of neurological forms of GD. Together, these data pave the way for the possible use of modified proteins in gene therapy for lysosomal storage diseases and other monogenetic disorders.

Gaucher disease type 3c: Expanding the clinical spectrum of an ultra‐rare disease

AbstractGaucher disease (GD) type 3 is an autosomal recessive lysosomal disease caused by deficiency of β‐glucocerebrosidase (GCase) and encompasses a spectrum of cardiac, neurological, and ophthalmological abnormalities. Although the clinical presentations can be diverse, a recognized clinical trajectory points to an early onset, predominantly before 18 years. GD type 3c is primarily caused by homozygosity for GBA pathogenic variant c.1342G&gt;C (p.Asp448His; historically referred to as D409H) and includes visceral, hematological, skeletal, and cardiac abnormalities. Notably, GD type 3c is distinct from other GD types because it is primarily characterized by valvular heart disease. Yet, with less than 50 patients with GD type 3c reported to date, the phenotypic spectrum and extent of cardiac involvement remains ill‐defined. We present a 20‐year‐old female with an atypical presentation of GD type 3c consisting of chronic intermediate uveitis as the presenting feature and the presence of extensive polyneuropathy starting in adolescence which has been previously unreported in GD type 3c. Distinctively, she has maintained normal cardiac function. Moreover, we compare our case with those reported in the literature to broaden awareness of the varied initial presentations of this disease. The diverse presentations seen in GD type 3c, underscored by our case and those previously reported, demonstrate the need for standardized evaluation and management protocols.

Contemporary Multimodality Imaging for Diagnosis and Management of Fabry Cardiomyopathy.

Fabry disease (FD) is an X-linked lysosomal storage disorder which leads to the accumulation of globotriaosylceramide (Gb3) in various organs, including the heart. FD can be subdivided into classic disease resulting from negligible residual enzyme activity and a milder, atypical phenotype with later onset and less severe clinical presentation. The use of multimodality cardiac imaging including echocardiography, cardiac magnetic resonance and nuclear imaging is important for the diagnostic and prognostic evaluation in these patients. There are gaps in the literature regarding the comprehensive description of cardiac findings of FD and its evaluation by multimodality imaging. In this review, we describe the contemporary practices and roles of multimodality cardiac imaging in individuals affected with Fabry disease.

The Role of the Gut Microbiota in Sanfilippo Syndrome's Physiopathology: An Approach in Two Affected Siblings.

Sanfilippo syndrome, or mucopolysaccharidosis type III (MPS III), is a rare lysosomal disease caused by congenital enzymatic deficiencies in heparan sulfate (HS) degradation, leading to organ dysfunction. The most severe hallmark of MPS III comprises neurological alterations, although gastrointestinal symptoms (GISs) have also been shown to be relevant in many patients. Here, we explored the contribution of the gut microbiota to MPS III GISs. We analyzed the composition and functionality of the gut microbiota in two MPS III siblings with the same mutation (c.544C > T, c.1080delC, in the SGSH gene) and the same diet, but with differences in their GISs, including recurrent diarrhea in one of them. Using 16S sequencing, we observed that the MPS III patients exhibited decreased alpha diversity and a lower abundance of Lachnospiraceae and Bifidobacteriaceae accompanied by a higher abundance of the Ruminococcaceae and Rikenellaceae families than the healthy control subjects. Comparing siblings, we found an increased abundance of Bacteroidaceae and a lower abundance of Ruminococcaceae and Akkermansiaceae in the GIS-free patient. This patient also had a higher relative abundance of Sus genes (SusA, SusB, SusE, and SusG) involved in glycosaminoglycan metabolism. We found higher HS levels in the stool of the two MPS III patients than in healthy volunteers, particularly in the patient with GISs. Functionally, whole fecal metabolites from the patient with GISs induced oxidative stress in vitro in healthy monocytes. Finally, the Bacteroides thetaiotaomicron strain isolated from MPS III stool samples exhibited HS degradation ability. Overall, our results reveal different microbiota compositions and functionalities in MPS III siblings, who exhibited differential gastrointestinal symptomatology. Our study may serve as a gateway to explore the impact of the gut microbiota and its potential to enhance the quality of life in Sanfilippo syndrome patients.

(S)-ML-SA1 Activates Autophagy via TRPML1-TFEB Pathway.

Autophagic flux plays a crucial role in various diseases. Recently, the lysosomal ion channel TRPML1 has emerged as a promising target in lysosomal storage diseases, such as mucolipidosis. The discovery of mucolipin synthetic agonist-1 (ML-SA1) has expanded our understanding of TRPML1's function and its potential therapeutic uses. However, ML-SA1 is a racemate with limited cellular potency and poor water solubility. In this study, we synthetized rac-ML-SA1, separated the enantiomers by chiral liquid chromatography and determined their absolute configuration by vibrational circular dichroism (VCD). In addition, we focused on investigating the impact of each enantiomer of ML-SA1 on the TRPML1-TFEB axis. Our findings revealed that (S)-ML-SA1 acts as an agonist for TRPML1 at the lysosomal membrane. This activation prompts transcription factor EB (TFEB) to translocate from the cytosol to the nucleus in a dose-dependent manner within live cells. Consequently, this signaling pathway enhances the expression of coordinated lysosomal expression and regulation (CLEAR) genes and activates autophagic flux. Our study presents evidence for the potential use of (S)-ML-SA1 in the development of new therapies for lysosomal storage diseases that target TRPML1.

Discovery of Selective Inhibitors for the Lysosomal Parkinson's Disease Channel TMEM175.

TMEM175 is a lysosomal potassium and proton channel that is associated with the development of Parkinson's disease. Advances in understanding the physiological roles of TMEM175 have been hampered by the absence of selective inhibitors, and studies involving genetic perturbations have yielded conflicting results. Here, we report the discovery and characterization of the first reported TMEM175-selective inhibitors, 2-phenylpyridin-4-ylamine (2-PPA), and AP-6. Cryo-EM structures of human TMEM175 bound by 2-PPA and AP-6 reveal that they act as pore blockers, binding at distinct sites in the pore and occluding the ion permeation pathway. Acute inhibition of TMEM175 by 2-PPA or AP-6 increases the level of lysosomal macromolecule catabolism, thereby accelerating macropinocytosis and other digestive processes. These inhibitors may serve as valuable tools to study the roles of TMEM175 in regulating lysosomal function and provide useful templates for future therapeutic development in Parkinson's disease.

Fabry Disease Rat Model Develops Age- and Sex-Dependent Anterior Segment Ocular Abnormalities.

Fabry disease is an X-linked lysosomal storage disorder that results in multi-systemic renal, cardiovascular, and neuropathological damage, including in the eyes. We evaluated anterior segment ocular abnormalities based on age, sex (male and female), and genotype (wild-type, knockout [KO] male, heterozygous [HET] female, and KO female) in a rat model of Fabry disease. The α-Gal A KO and WT rats were divided into young (6-24 weeks), adult (25-60 weeks), and aged (61+ weeks) groups. Intraocular pressure (IOP) was measured. Eyes were clinically scored for corneal and lens opacity as well as evaluated for corneal epithelial integrity and tear break-up time (TBUT). Anterior chamber depth (ACD) and central corneal thickness (CCT) using anterior segment-optical coherence tomography (AS-OCT). The Fabry rats showed an age-dependent increase in IOP, predominantly in the male genotype. TBUT was decreased in both male and female groups with aging. Epithelial integrity was defective in KO males and HET females with age. However, it was highly compromised in KO females irrespective of age. Corneal and lens opacities were severely affected irrespective of sex or genotype in the aging Fabry rats. AS-OCT quantification of CCT and ACD also demonstrated age-dependent increases but were more pronounced in Fabry versus WT genotypes. Epithelial integrity, corneal, and lens opacities worsened in Fabry rats, whereas IOP and TBUT changes were age-dependent. Similarly, CCT and ACD were age-related but more pronounced in Fabry rats, providing newer insights into the anterior segment ocular abnormalities with age, sex, and genotype in a rat model of Fabry disease.

A GLB1 transgene with enhanced therapeutic potential for the preclinical development of ex-vivo gene therapy to treat mucopolysaccharidosis type IVB

Mucopolysaccharidosis type IVB (MPSIVB) is a lysosomal storage disorder caused by β-galactosidase (β-GAL) deficiency characterized by severe skeletal and neurological alterations without approved treatments. To develop hematopoietic stem progenitor cell-gene therapy (HSPC-GT) for MPSIVB, we designed lentiviral vectors (LVs) encoding human β-GAL to achieve supraphysiological release of the therapeutic enzyme in human HSPCs and metabolic correction of diseased cells. Transduced HSPCs displayed proper colony formation, proliferation, and differentiation capacity, but their progeny failed to release the enzyme at supraphysiological levels. Therefore, we tested alternative LVs to overexpress an enhanced β-GAL deriving from murine (LV-enhGLB1) and human selectively mutated GLB1 sequences (LV-mutGLB1). Only human HSPCs transduced with LV-enhGLB1 overexpressed β-GAL in vitro and in vivo without evidence of overexpression-related toxicity. Their hematopoietic progeny efficiently released β-GAL, allowing the cross-correction of defective cells, including skeletal cells. We found that the low levels of human GLB1 mRNA in human hematopoietic cells and the improved stability of the enhanced β-GAL contribute to the increased efficacy of LV-enhGLB1. Importantly, the enhanced β-GAL enzyme showed physiological lysosomal trafficking in human cells and was not associated with increased immunogenicity in vitro. These results support the use of LV-enhGLB1 for further HSPC-GT development and future clinical translation to treat MPSIVB multisystem disease.

Gaucher disease provides a unique window into Parkinson disease pathogenesis.

An exciting development in the field of neurodegeneration is the association between the rare monogenic disorder Gaucher disease and the common complex disorder Parkinson disease(PD). Gaucher disease is a lysosomal storage disorder resulting from an inherited deficiency of the enzyme glucocerebrosidase, encoded by GBA1, which hydrolyses the glycosphingolipids glucosylceramide and glucosylsphingosine. The observation of parkinsonism in a rare subgroup of individuals with Gaucher disease first directed attention to the role of glucocerebrosidase deficiency in the pathogenesis of PD. PD occurs more frequently in people heterozygous forGaucher GBA1mutations, and 3-25% of people with Parkinson disease carry a GBA1 variant. However, only a small percentage of individuals with GBA1 variants develop parkinsonism, suggesting that the penetrance is low. Despite over a decade of intense research in this field, including clinical and radiological evaluations, genetic studies and investigations using model systems, the mechanism underlying GBA1-PD is still being pursued. Insights from this association have emphasized the role of lysosomal pathways in parkinsonism. Furthermore, different therapeutic strategies considered or developed for Gaucher disease can now inform drug development for PD.

Determination of Gb3 and Lyso-Gb3 in Fabry Disease-Affected Patients by LC-MRM/MS

Limited or absent activity of the enzyme α-galactosidase A (α-Gal A), due to mutation in the related gene on the X chromosome, leads to the development of a rare hereditary and genetic disease known as Fabry disease (FD). This pathology involves a progressive accumulation in various organs of the substrates of the enzyme e.g., globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (Lyso-Gb3), suggesting these molecules as biomarkers of Fabry disease. The present paper describes the development of an analytical strategy for the identification and quantification of Gb3 and Lyso-Gb3, in serum and blood samples by using liquid chromatography (LC) coupled to mass spectrometry in multiple reaction monitoring (MRM/MS) ion mode. The best experimental conditions were obtained by extracting the glycolipids with chloroform/methanol/H2O (2/1/0.3) and by separating them on a C4 column with a linear gradient (A: H2O with 2 mM ammonium formate. B: methanol with 1 mM ammonium formate, both acidified with 0.2% formic acid). The best transitions (a combination of precursor and fragment ions—m/z) were 786.8 m/z &gt; 268.3 m/z for Lyso-GB3, 1137.3 m/z &gt; 264.3 m/z for Gb3, 1039.3 m/z &gt; 264.4 m/z for N-heptadecanoyl-ceramide trihexoside, and 843.5 m/z &gt; 264.3 m/z for N-glycinated lyso-ceramide trihexoside, the latter being used as an internal standard. The developed method provided a reliable, fast, and effective procedure for direct measurements of GB3 and Lyso-GB3 in serum and blood for diagnosis of Fabry disease, suggesting this method as a complementary assay to the current enzymatic test. Therefore, this approach could open new insights into the clinical diagnostics of lysosomal storage disorders.

What is confirmed in the treatment of Fabry's disease?

Fabry's disease is arare X chromosome-linked inherited lysosomal storage disease characterized by insufficient metabolism of the substrate globotriaosylceramide (Gb3) due to reduced alpha-galactosidaseA (AGAL) activity. Lysosomal Gb3 accumulation causes amultisystemic disease which, if untreated, reduces the life expectancy in females and males by around 10and 20years, respectively, due to progressive renal dysfunction, hypertrophic cardiomyopathy, cardiac arrhythmia and early occurrence of cerebral infarction. The diagnosis is confirmed by determining the reduced AGAL activity in leukocytes in males and molecular genetic detection of a-mutation causing the disease in females. The treatment comprises enzyme replacement therapy (ERT), agalsidase alfa, 0.2 mg/kg body weight (BW), agalsidase beta 1.0 mg/kg BW or pegunigalsidase alfa 1.0 mg/kg BW every 2weeks i.v. or oral chaperone therapy (one capsule of migalastat 123 mg every other day) in the presence of amenable mutations. This article summarizes the data on the treatment of Fabry's disease and on complications in practice. The current guideline recommendations are addressed and new study results that could expand the therapeutic repertoire in the future are discussed.

Real-world pharmacovigilance analysis of galsulfase: a study based on the FDA adverse event reporting system (FAERS) database.

Associated with enzyme deficiencies causing glycosaminoglycans (GAGs) accumulation, mucopolysaccharidosis type VI (MPS VI) is lysosomal storage disorder. In the treatment of MPS VI, galsulfase (Naglazyme) is commonly used as an enzyme replacement therapy (ERT). There remains a need for comprehensive real-world data on its safety and associated adverse events (AEs). An analysis of the FDA Adverse Event Reporting System (FAERS) database will be conducted to identify potential risks and adverse reactions associated with galsulfase in real-life settings. The FAERS database was used to extract data from Q2 2005 to Q4 2023. A total of 20,281,876 reports were analyzed after duplicate elimination, with 3,195 AE reports related to galsulfase identified. The association between galsulfase and AEs was investigated by utilizing four algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). The analysis focused on the timing of onset, signs of AEs, and clinical significance. Twenty seven organ systems were involved, and significant system organ classes (SOCs) included respiratory, thoracic and mediastinal disorders, and infections and infestations. At the PT level, 72PTs corresponding to 15 SOCs were identified, with some AEs not previously mentioned in the product label. AEs associated with galsulfase had a median onset time of 1,471days, with over half of the cases occurred within the first 5years of treatment initiation. This investigation delivers an exhaustive and indicative assessment of galsulfase's safety profile, grounded in authentic, real-world evidence. The findings emphasis the importance of continuous safety surveillance and the emergence of new AEs. The identification of previously unreported urologic adverse events, such as glomerulonephritis membranous and nephritic syndrome, warrants further investigation. The study emphasizes the need for enhanced pharmacovigilance to ensure patient safety and the effectiveness of galsulfase treatment.

Hematopoietic stem cell transplantation leads to biochemical and functional correction in two mouse models of acid ceramidase deficiency

Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die in childhood while SMA-PME patients can live until adulthood. There is no treatment for FD or SMA-PME. Hematopoietic stem cell transplantation (HSCT) and gene therapy strategies for the treatment of ACDase deficiency are being investigated. We have previously generated and characterized mouse models of both FD and SMA-PME that recapitulate the symptoms described in patients. Here, we show that HSCT improves lifespan, behavior, hematopoietic system anomalies, plasma cytokine levels, and significantly reduces histiocytic infiltration and ceramide accumulation throughout the tissues investigated, including the CNS, in both models of ACDase deficient mice. HSCT was also successful in preventing lesion development and significant demyelination of the spinal cord seen in SMA-PME mice. Importantly, we note that only early and generally pre-symptomatic treatment was effective and kidney impairment was not improved in either model.

The Role of Genetic Testing in Diagnosing Fabry's Disease and Its Overlapping with Cardiomyopathies: A Case Series

Abstract Background Fabry's disease, an X-linked lysosomal storage disorder, shares cardiac manifestations with hypertrophic cardiomyopathy (HCM). We underscore the importance of considering Fabry's disease as a differential diagnosis in HCM patients, highlighting genetic testing's role in cardiomyopathy evaluation. Case Summary Three male patients with LVH were initially diagnosed with HCM but were later found to have Fabry's disease through genetic testing. Atypical features such as renal dysfunction and conduction abnormalities raised suspicion. Genetic testing confirmed diagnosis, guiding tailored management. Discussion Fabry's disease poses diagnostic challenges due to its resemblance to HCM. Genetic testing enables precise diagnosis and personalized management, especially in cases with atypical presentations. Early recognition and intervention, facilitated by genetic testing, can improve patient outcomes in Fabry's disease.

Prevalence of Fabry disease in patients with chronic pain: Lessons from the DOUFAB and DOUFABIS studies.

Fabry disease (FD) is a rare X-linked lysosomal disorder caused by alpha-galactosidase deficiency consecutive to a pathogenic variant in the GLA gene. Age at onset is highly variable, with a wide clinical spectrum including frequent renal, cardiac, skin and nervous system manifestations. Since pain can be an indicator of underlying FD, we wanted to estimate the prevalence of FD in a population of chronic pain patients. Two studies, DOUFAB and DOUFABIS, were carried out in expert centers for chronic pain to assess the prevalence of FD by measuring alpha galactosidase A activity in men and analysing the GLA gene in women. Analysis of 893 patients, essentially adults, led to the diagnosis of FD in one female patient, now treated with enzyme replacement therapy. The prevalence of FD is estimated about 1/1000 in our population of men and women suffering from various chronic pain. This is nearly the prevalence of FD observed in other previously screened high-risk populations with renal failure. Although a systematic search for FD does not seem relevant in the context of unexplained chronic pain in adults, a positive family history of FD or the presence of additional FD related organ features must lead to consider this rare disease diagnosis. Therefore, pain specialists need to be aware of main features of FD, including pain characteristics.