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J Biol Chem 2022 Jun 21:102159. Epub 2022 Jun 21.

Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA. Electronic address:

Lysosomal storage diseases result in various developmental and physiological complications, including cachexia. To study the causes for the negative energy balance associated with cachexia, we assessed the impact of sulfamidase deficiency and heparan sulfate storage on energy homeostasis and metabolism in a mouse model of Type IIIa mucopolysaccharidosis (MPS IIIa, Sanfilippo A syndrome). At 12 weeks of age, MPS IIIa mice exhibited fasting and postprandial hypertriglyceridemia compared to wild-type mice, with a reduction of white and brown adipose tissue depots. Read More

Pharmaceutics 2022 Jun 11;14(6). Epub 2022 Jun 11.

JCR Pharmaceuticals, Ashiya 659-0021, Hyogo, Japan.

Enzyme replacement therapy (ERT) has paved the way for treating the somatic symptoms of lysosomal storage diseases (LSDs), but the inability of intravenously administered enzymes to cross the blood-brain barrier (BBB) has left the central nervous system (CNS)-related symptoms of LSDs largely impervious to the therapeutic benefits of ERT, although ERT via intrathecal and intracerebroventricular routes can be used for some neuronopathic LSDs (in particular, mucopolysaccharidoses). However, the considerable practical issues involved make these routes unsuitable for long-term treatment. Efforts have been made to modify enzymes (e. Read More

J Pers Med 2022 Jun 1;12(6). Epub 2022 Jun 1.

Department of Paediatrics, Faculty of Medicine Comenius University in Bratislava and National Institute of Children's Diseases in Bratislava, 83340 Bratislava, Slovakia.

Fabry disease (FD, OMIM#301500) is a rare inborn error of the lysosomal enzyme α-galactosidase (α-Gal A, EC 3.2.1. Read More

Biomedicines 2022 Jun 3;10(6). Epub 2022 Jun 3.

Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain.

Exosomes/microvesicles originate from multivesicular bodies that allow the secretion of endolysosome components out of the cell. In the present work, we investigated the effects of rottlerin, a polyphenol, on exosome/microvesicle secretion in a model of intracellular lipid trafficking impairment, and elucidated the mechanism of action. In a model of lipid trafficking impairment in C6 glia cells, rottlerin increased ceramide levels, while decreasing hexosylceramide content. Read More

Cell Death Differ 2022 Jun 23. Epub 2022 Jun 23.

Department of Life Science, University of Seoul, Seoul, 02504, Republic of Korea.

Transcription factor EB (TFEB), a member of the MiT/TFE family of basic helix-loop-helix leucine zipper transcription factors, is an established central regulator of the autophagy/lysosomal-to-nucleus signaling pathway. Originally described as an oncogene, TFEB is now widely known as a regulator of various processes, such as energy homeostasis, stress response, metabolism, and autophagy-lysosomal biogenesis because of its extensive involvement in various signaling pathways, such as mTORC1, Wnt, calcium, and AKT signaling pathways. TFEB is also implicated in various human diseases, such as lysosomal storage disorders, neurodegenerative diseases, cancers, and metabolic disorders. Read More

Neurol Int 2022 Jun 1;14(2):497-505. Epub 2022 Jun 1.

Department of Osteopathic Neuromuscular Medicine, Larkin Community Hospital Palm Springs Campus, Hialeah, FL 33012, USA.

Background: Fabry disease (FD) is the second most common lysosomal storage disorder. This disorder affects multiple systems that include the cardiac, renal, and nervous system. The pulvinar sign (PS) is a relatively common sign seen in patients with FD. Read More

Front Neurol 2022 6;13:907317. Epub 2022 Jun 6.

Department of Pediatrics, International Center for Lysosomal Disorders, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Gaucher Disease (GD) 2 is a rare inherited lysosomal disorder. Early-onset and rapid progression of neurovisceral symptoms lead to fatal outcome in early childhood. Treatment is symptomatic, a curative therapy is currently not available. Read More

BMC Genomics 2022 Jun 21;23(1):458. Epub 2022 Jun 21.

FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Village Road, Satellite, Ahmedabad, Gujarat, 380015, India.

Background: Mucopolysaccharidosis IVA (Morquio syndrome A, MPS IVA) is an autosomal recessive lysosomal storage disorder caused due to biallelic variants in the N-acetylgalactoseamine-6-sulfate sulfatase (GALNS) gene. The mutation spectrum in this condition is determined amongst sub-populations belonging to the north, south and east India geography, however, sub-populations of west Indian origin, especially Gujarati-Indians, are yet to be studied. We aimed to analyse the variants present in the GLANS gene amongst the population of Gujarat by sequencing all exons and exon-intron boundaries of the GALNS gene in patients from 23 unrelated families. Read More

J Mol Neurosci 2022 Jun 21. Epub 2022 Jun 21.

Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.

Niemann-Pick type A disease (NPA) is a rare lysosomal storage disorder caused by mutations in the gene coding for the lysosomal enzyme acid sphingomyelinase (ASM). ASM deficiency leads to the consequent accumulation of its uncatabolized substrate, the sphingolipid sphingomyelin (SM), causing severe progressive brain disease. To study the effect of the aberrant lysosomal accumulation of SM on cell homeostasis, we loaded skin fibroblasts derived from a NPA patient with exogenous SM to mimic the levels of accumulation characteristic of the pathological neurons. Read More

J Int Med Res 2022 Jun;50(6):3000605221106412

Department of Pediatrics, Chattogram Medical College Hospital, Panchlaish, Chattogram, Bangladesh.

In resource-constrained settings, mucopolysaccharidosis (MPS) is a rare hereditary metabolic illness that frequently remains undiagnosed. We present a scenario that illustrates the challenges in diagnosing and managing MPS because of test inaccessibility, and we propose potential approaches to minimize the hurdles. We recommend that physicians anticipate a rare genetic disease, such as MPS, based on the clinical history findings from routine radiological investigations. Read More

Orphanet J Rare Dis 2022 06 20;17(1):238. Epub 2022 Jun 20.

Department of Genetics, UFRGS, Medical Genetics Service, HCPA, Porto Alegre, Brazil.

Background: Patient registries provide long-term, real-world evidence that aids the understanding of the natural history and progression of disease, and the effects of treatment on large patient populations with rare diseases. The year 2021 marks the 20th anniversary of the Fabry Outcome Survey (FOS), an international, multicenter, observational registry (NCT03289065). The primary aims of FOS are to broaden the understanding of Fabry disease (FD), an X-linked lysosomal storage disorder, and to improve the clinical management of affected patients. Read More

Orphanet J Rare Dis 2022 06 20;17(1):237. Epub 2022 Jun 20.

Renal Division, Department of Internal Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.

Background: Fabry disease (FD, OMIM #301500) is an X-linked lysosomal disorder caused by the deficiency of α-galactosidase A (α-GalA), encoded by the GLA gene. Among more than 1100 reported GLA mutations, few were deep intronic mutations which have been linked to classic and cardiac variants of FD.

Methods And Results: We report a novel hemizygous deep intronic GLA mutation (IVS4+1326C>T) in a 33-year-old Chinese man with a mild α-GalA deficiency phenotype involving isolated proteinuria and predominant globotriaosylceramide deposits in podocytes. Read More

Front Pediatr 2022 1;10:908657. Epub 2022 Jun 1.

Center for Advanced Medical and Pharmaceutical Research, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Targu Mures, Romania.

Inherited renal diseases represent 20% of the causes of end-stage renal diseases. Fabry disease, an X-linked lysosomal storage disorder, results from α-galactosidase A deficient or absent activity followed by globotriaosylceramide (Gb3) accumulation and multiorgan involvement. In Fabry disease, kidney involvement starts early, during intrauterine life by the Gb3 deposition. Read More

Semin Nephrol 2022 Mar;42(2):114-121

Division of Pediatric Nephrology, Department of Pediatrics, University of Minnesota Masonic Children's Hospital, Minneapolis, MN. Electronic address:

A number of genes that cause inherited kidney disorders reside on the X chromosome. Given that males have only a single active X chromosome, these disorders clinically manifest primarily in men and boys. However, phenotypes in female carriers of X-linked kidney conditions are becoming more and more recognized. Read More

J Pharmacol Exp Ther 2022 Jun 18. Epub 2022 Jun 18.

BioMarin Pharmaceutical Inc., United States.

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2. Read More

Orphanet J Rare Dis 2022 06 18;17(1):234. Epub 2022 Jun 18.

Department of Human Pathophysiology, Institute of Medical Sciences, University of Rzeszow, Rzeszow, Poland.

Background: Neuronopathic Gaucher Disease (nGD) describes the condition of a subgroup of patients with the Lysosomal Storage Disorder (LSD), Gaucher disease with involvement of the central nervous system (CNS) which results from inherited deficiency of β-glucosylceramidase. Although systemic manifestations of disease are now corrected by augmentation with macrophage-targeted therapeutic enzyme (enzyme replacement therapy, ERT), neurological disease progresses unpredictably as a result of failure of therapeutic enzyme to cross the blood-brain barrier (BBB). Without therapy, the systemic and neurological effects of the disease progress and shorten life: investigators, principally in Sweden and the UK, pioneered bone marrow transplantation (BMT; Haematopoietic Stem Cell Transplantation HSCT) to supply healthy marrow-derived macrophages and other cells, to correct the peripheral disease. Read More

Front Genet 2022 27;13:892457. Epub 2022 May 27.

Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the gene, which produces the glucocerebrosidase (GCase) protein. There are more than 500 mutations reported in , among which L444P (p.Leu444Pro) and F213I (p. Read More

Sci Rep 2022 Jun 16;12(1):10142. Epub 2022 Jun 16.

URPhyM, Intracellular Trafficking Biology, NARILIS, University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium.

Mucopolysaccharidosis IX is a lysosomal storage disorder caused by a deficiency in HYAL1, an enzyme that degrades hyaluronic acid at acidic pH. This disease causes juvenile arthritis in humans and osteoarthritis in the Hyal1 knockout mouse model. Our past research revealed that HYAL1 is strikingly upregulated (~ 25x) upon differentiation of bone marrow monocytes into osteoclasts. Read More

Orphanet J Rare Dis 2022 06 16;17(1):231. Epub 2022 Jun 16.

Nacuity Pharmaceuticals, Inc., Fort Worth, TX, USA.

Background: Cystinosis is a rare autosomal recessive lysosomal storage disease, associated with high morbidity and mortality. Mutations in the CTNS gene disable a membrane protein responsible for the transport of cystine out of the lysosome. Loss of transporter function leads to intralysosomal cystine accumulation and long-term damage to various tissues and organs, including the kidneys, eyes, liver, muscles, pancreas, and brain. Read More

GEN Biotechnol 2022 Apr 20;1(2):156-162. Epub 2022 Apr 20.

Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, NC 27606, USA.

With the increasing interest in developing gene therapies for rare diseases, it is easy to overlook that there are numerous rare lysosomal storage diseases (LSD) with treatments that have been approved by regulatory agencies in the United States and Europe. These primarily consist of enzyme replacement therapies (ERT), which are recombinant human proteins that are delivered for the life of the patient via different routes and may have distinct safety and distribution advantages over gene therapies. The research and development of ERT is a lengthy and expensive process, which is usually performed in academic laboratories before transfer to pharmaceutical companies and is hence a process ripe for disruption. Read More

Arch Pediatr 2022 May 23. Epub 2022 May 23.

Division of Pediatric Metabolism and Nutrition, Department of Pediatrics, Çukurova University Faculty of Medicine, Adana, Turkey.

Background: COVID-19 and lysosomal storage disorders (LSDs) share a common immunological pathway as they cause the release of cytokines in a similar pattern. We aimed to evaluate the immunity status and reveal the course of COVID-19 in patients with LSDs.

Results: The median age of 110 patients with LSDs was 129 months (range: 21-655), and all but one patient with mucopolysaccharidosis (MPS) type III were regularly receiving enzyme replacement therapy (ERT). Read More

J Exp Med 2022 Aug 15;219(8). Epub 2022 Jun 15.

Centre Hospitalier Universitaire Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada.

The majority of mucopolysaccharidosis IIIC (MPS IIIC) patients have missense variants causing misfolding of heparan sulfate acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT), which are potentially treatable with pharmacological chaperones. To test this approach, we generated a novel HgsnatP304L mouse model expressing misfolded HGSNAT Pro304Leu variant. HgsnatP304L mice present deficits in short-term and working/spatial memory 2-4 mo earlier than previously described constitutive knockout Hgsnat-Geo mice. Read More

Am J Physiol Renal Physiol 2022 Jun 13. Epub 2022 Jun 13.

Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand.

The lysosomal storage disease cystinosis is caused by mutations in CTNS, encoding a cystine transporter, and in its severest form leads to proximal tubule dysfunction followed by kidney failure. Patients receive the drug-based therapy cysteamine from diagnosis. However, despite long-term treatment, cysteamine only slows the progression of end-stage renal disease. Read More

Wellcome Open Res 2022 11;7:11. Epub 2022 Jan 11.

Translational Gastroenterology Unit, University of Oxford, Oxford, UK.

 Blockade of tumour necrosis factor (anti-TNF) is effective in patients with Crohn's Disease but has been associated with infection risk and neurological complications such as demyelination. Niemann-Pick disease Type C1 (NPC1) is a lysosomal storage disorder presenting in childhood with neurological deterioration, liver damage and respiratory infections. Some NPC1 patients develop severe Crohn's disease. Read More

Front Neurosci 2022 25;16:834780. Epub 2022 May 25.

Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, United States.

Batten disease is unique among lysosomal storage disorders for the early and profound manifestation in the central nervous system, but little is known regarding potential neuron-specific roles for the disease-associated proteins. We demonstrate substantial overlap in the protein interactomes of three transmembrane Batten proteins (CLN3, CLN6, and CLN8), and that their absence leads to synaptic depletion of key partners (i.e. Read More

J Biol Chem 2022 Jun 9:102118. Epub 2022 Jun 9.

School of Life Sciences, Chongqing University, Chongqing, 401331, China. Electronic address:

Sphingolipids are a class of bioactive complex lipids that have been closely associated with aging and aging-related diseases. However, the mechanism through which sphingolipids control aging has long been a mystery. Emerging studies reveal that sphingolipids exert tight control over lysosomal homeostasis and function, as evidenced by sphingolipid-related diseases, including but not limited to lysosomal storage disorders. Read More

Med Clin (Barc) 2022 Jun 7. Epub 2022 Jun 7.

Unidad de Enfermedades Mitocondriales-Metabólicas Hereditarias, Servicio de Pediatría, Centro de Referencia Nacional para Enfermedades Metabólicas Hereditarias, Hospital Universitario 12 de Octubre, Madrid, España.

Objectives: Identify the efficacy variables collected in the literature for therapies used in lysosomal storage diseases (LDS), evaluate the quality of this evidence, and know the effectiveness and safety of these treatments.

Material And Methods: Retrospective observational study that included patients with LDS treated with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT). Published clinical trials (CT) and LDS treatment guidelines were reviewed to select efficacy variables. Read More

Int J Mol Sci 2022 Jun 4;23(11). Epub 2022 Jun 4.

GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government PTS Granada-Avenida de la Ilustración 114, 18016 Granada, Spain.

Pompe disease (PD) is a rare disorder caused by mutations in the acid alpha-glucosidase (GAA) gene. Most gene therapies (GT) partially rely on the cross-correction of unmodified cells through the uptake of the GAA enzyme secreted by corrected cells. In the present study, we generated isogenic murine GAA-KO cell lines resembling severe mutations from Pompe patients. Read More

Cells 2022 06 4;11(11). Epub 2022 Jun 4.

Department of Pediatric Nephrology and Development and Regeneration, University Hospitals Leuven, University of Leuven, 3000 Leuven, Belgium.

Early diagnosis and effective therapy are essential for improving the overall prognosis and quality of life of patients with nephropathic cystinosis. The severity of kidney dysfunction and the multi-organ involvement as a consequence of the increased intracellular concentration of cystine highlight the necessity of accurate monitoring of intracellular cystine to guarantee effective treatment of the disease. Cystine depletion is the only available treatment, which should begin immediately after diagnosis, and not discontinued, to significantly slow progression of renal and extra-renal organ damage. Read More

Cells 2022 May 24;11(11). Epub 2022 May 24.

Department of Neurology, University of Würzburg, 97080 Würzburg, Germany.

Fabry disease (FD) is a rare life-threatening disorder caused by deficiency of the alpha-galactosidase A (GLA) enzyme with a characteristic pain phenotype. Impaired GLA production or function leads to the accumulation of the cell membrane compound globotriaosylceramide (Gb3) in the neurons of the dorsal root ganglia (DRG) of FD patients. Applying immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT PCR) analysis on DRG tissue of the GLA knockout (KO) mouse model of FD, we address the question of how Gb3 accumulation may contribute to FD pain and focus on the immune system and pain-associated ion channel gene expression. Read More