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Orphanet Journal of Rare Diseases Aug 2023Inborn metabolic diseases (IMD) are rare conditions that can be diagnosed during adulthood. Patients with IMD may have joint symptoms and the challenge is to establish... (Review)
Review
Inborn metabolic diseases (IMD) are rare conditions that can be diagnosed during adulthood. Patients with IMD may have joint symptoms and the challenge is to establish an early diagnosis in order to institute appropriate treatment and prevent irreversible damage. This review describes the joint manifestations of IMD that may be encountered in adults. The clinical settings considered were arthralgia and joint stiffness as well as arthritis. Unspecific arthralgias are often the first symptoms of hereditary hemochromatosis, chronic low back pain may reveal an intervertebral disc calcification in relation with alkaptonuria, and progressive joint stiffness may correspond to a mucopolysaccharidosis or mucolipidosis. Gaucher disease is initially revealed by painful acute attacks mimicking joint pain described as "bone crises". Some IMD may induce microcrystalline arthropathy. Beyond classical gout, there are also gouts in connection with purine metabolism disorders known as "enzymopathic gouts". Pyrophosphate arthropathy can also be part of the clinical spectrum of Gitelman syndrome or hypophosphatasia. Oxalate crystals arthritis can reveal a primary hyperoxaluria. Destructive arthritis may be indicative of Wilson's disease. Non-destructive arthritis may be seen in mevalonate kinase deficiency and familial hypercholesterolemia.
Topics: Humans; Adult; Chondrocalcinosis; Gout; Joint Diseases; Metabolism, Inborn Errors; Hepatolenticular Degeneration
PubMed: 37563694
DOI: 10.1186/s13023-023-02810-6 -
Ceskoslovenska Patologie 2023We present a comprehensive review dealing with rare genetic skeletal disorders. More than 400 entities are included in the latest classification. The most severe or... (Review)
Review
We present a comprehensive review dealing with rare genetic skeletal disorders. More than 400 entities are included in the latest classification. The most severe or lethal phenotypes are identifiable in the prenatal period and the pregnancy can be terminated. Perinatal autopsy and posmortem X-rays are crucial in providing a definitive diagnosis. The number of cases confirmed by genetic testing is increasing. We report our own experience with genetic skeletal disorders based on 41 illustrative fetal and neonatal cases which we encountered over a 10-year period. Thanatophoric dysplasia and osteogenesis imperfecta represent approximately half of the cases coming to autopsy. Achondrogenesis type 2 and hypochondrogenesis, short-rib dysplasia, chondrodysplasia punctata, campomelic dysplasia and achondroplasia are less common. Skeletal dysplasias with autosomal recessive inheritance are the least frequent, e.g. perinatally lethal hypophophatasia, achondrogenesis type 1A, diastrophic dysplasia/atelosteogenesis type 2 or mucolipidosis type 2 (I cell disease).
Topics: Pregnancy; Female; Humans; Osteochondrodysplasias; Thanatophoric Dysplasia; Campomelic Dysplasia; Receptor, Fibroblast Growth Factor, Type 3; Fetus
PubMed: 37468326
DOI: No ID Found -
Autophagy Mar 2024MCOLN1/TRPML1 is a nonselective cationic channel specifically localized to the late endosome and lysosome. With its property of mediating the release of several divalent... (Review)
Review
MCOLN1/TRPML1 is a nonselective cationic channel specifically localized to the late endosome and lysosome. With its property of mediating the release of several divalent cations such as Ca, Zn and Fe from the lysosome to the cytosol, MCOLN1 plays a pivotal role in regulating a variety of cellular events including endocytosis, exocytosis, lysosomal biogenesis, lysosome reformation, and especially in Macroautophagy/autophagy. Autophagy is a highly conserved catabolic process that maintains cytoplasmic integrity by removing superfluous proteins and damaged organelles. Acting as the terminal compartments, lysosomes are crucial for the completion of the autophagy process. This review delves into the emerging role of MCOLN1 in controlling the autophagic process by regulating lysosomal ionic homeostasis, thereby governing the fundamental functions of lysosomes. Furthermore, this review summarizes the physiological relevance as well as molecular mechanisms through which MCOLN1 orchestrates autophagy, consequently influencing mitochondria turnover, cell apoptosis and migration. In addition, we have illustrated the implications of MCOLN1-regulated autophagy in the pathological process of cancer and myocardial ischemia-reperfusion (I/R) injury. In summary, given the involvement of MCOLN1-mediated autophagy in the pathogenesis of cancer and myocardial I/R injury, targeting MCOLN1 May provide clues for developing new therapeutic strategies for the treatment of these diseases. Exploring the regulation of MCOLN1-mediated autophagy in diverse diseases contexts will surely broaden our understanding of this pathway and offer its potential as a promising drug target. CCCP:carbonyl cyanide3-chlorophenylhydrazone; CQ:chloroquine; HCQ: hydroxychloroquine;I/R: ischemia-reperfusion; MAP1LC3/LC3:microtubule associated protein 1 light chain 3; MCOLN1/TRPML1:mucolipin TRP cation channel 1; MLIV: mucolipidosis type IV; MTORC1:MTOR complex 1; ROS: reactive oxygenspecies; SQSTM1/p62: sequestosome 1.
PubMed: 38522082
DOI: 10.1080/15548627.2024.2333715 -
Bioorganic & Medicinal Chemistry Letters Jan 2024Screening a library of >100,000 compounds identified the substituted tetrazole compound 1 as a selective TRPML1 agonist. Both enantiomers of compound 1 were separated...
Screening a library of >100,000 compounds identified the substituted tetrazole compound 1 as a selective TRPML1 agonist. Both enantiomers of compound 1 were separated and profiled in vitro and in vivo. Their selectivity, ready availability and CNS penetration should enable them to serve as the tool compounds of choice in future TRPML1 channel activation studies. SAR studies on conformationally locked macrocyclic analogs further improved the TRPML1 agonist potency while retaining the selectivity.
Topics: Transient Receptor Potential Channels; Structure-Activity Relationship; Tetrazoles
PubMed: 38141860
DOI: 10.1016/j.bmcl.2023.129595 -
Indian Journal of Pediatrics Jun 2024Congenital diarrhea and enteropathies (CODEs) constitute a group of rare genetic disorders characterized by severe diarrhea and malabsorption in the neonatal period or... (Review)
Review
Congenital diarrhea and enteropathies (CODEs) constitute a group of rare genetic disorders characterized by severe diarrhea and malabsorption in the neonatal period or early infancy. Timely diagnosis and treatment is essential to prevent life-threatening complications, including dehydration, electrolyte imbalance, and malnutrition. This review offers a simplified approach to the diagnosis of CODEs, with a specific focus on microvillus inclusion disease (MVID), congenital tufting enteropathy (CTE), congenital chloride diarrhea (CLD), and congenital sodium diarrhea (CSD). Patients with CODEs typically present with severe watery or occasionally bloody diarrhea, steatorrhea, dehydration, poor growth, and developmental delay. Therefore, it is crucial to thoroughly evaluate infants with diarrhea to rule out infectious, allergic, or anatomical causes before considering CODEs as the underlying etiology. Diagnostic investigations for CODEs encompass various modalities, including stool tests, blood tests, immunological studies, endoscopy and biopsies for histology and electron microscopy, and next-generation sequencing (NGS). NGS plays a pivotal role in identifying the genetic mutations responsible for CODEs. Treatment options for CODEs are limited, often relying on total parenteral nutrition for hydration and nutritional support. In severe cases, intestinal transplantation may be considered. The long-term prognosis varies among specific CODEs, with some patients experiencing ongoing intestinal failure and associated complications. In conclusion, the early recognition and accurate diagnosis of CODEs are of paramount importance for implementing appropriate management strategies. Further research and advancements in genetic testing hold promise for enhancing diagnostic accuracy and exploring potential targeted therapies for these rare genetic disorders.
Topics: Humans; Diarrhea; Malabsorption Syndromes; Infant, Newborn; Infant; Metabolism, Inborn Errors; Mucolipidoses; Microvilli; Intestinal Diseases; Abnormalities, Multiple; Diarrhea, Infantile
PubMed: 38105403
DOI: 10.1007/s12098-023-04929-7 -
Molecular Therapy : the Journal of the... May 2024Sialidosis (mucolipidosis I) is a glycoprotein storage disease, clinically characterized by a spectrum of systemic and neurological phenotypes. The primary cause of the...
Sialidosis (mucolipidosis I) is a glycoprotein storage disease, clinically characterized by a spectrum of systemic and neurological phenotypes. The primary cause of the disease is deficiency of the lysosomal sialidase NEU1, resulting in accumulation of sialylated glycoproteins/oligosaccharides in tissues and body fluids. Neu1 mice recapitulate the severe, early-onset forms of the disease, affecting visceral organs, muscles, and the nervous system, with widespread lysosomal vacuolization evident in most cell types. Sialidosis is considered an orphan disorder with no therapy currently available. Here, we assessed the therapeutic potential of AAV-mediated gene therapy for the treatment of sialidosis. Neu1 mice were co-injected with two scAAV2/8 vectors, expressing human NEU1 and its chaperone PPCA. Treated mice were phenotypically indistinguishable from their WT controls. NEU1 activity was restored to different extent in most tissues, including the brain, heart, muscle, and visceral organs. This resulted in diminished/absent lysosomal vacuolization in multiple cell types and reversal of sialyl-oligosacchariduria. Lastly, normalization of lysosomal exocytosis in the cerebrospinal fluids and serum of treated mice, coupled to diminished neuroinflammation, were measures of therapeutic efficacy. These findings point to AAV-mediated gene therapy as a suitable treatment for sialidosis and possibly other diseases, associated with low NEU1 expression.
PubMed: 38796704
DOI: 10.1016/j.ymthe.2024.05.029 -
The Journal of Clinical Investigation Oct 2023Microvillus inclusion disease (MVID), caused by loss-of-function mutations in the motor protein myosin Vb (MYO5B), is a severe infantile disease characterized by...
Microvillus inclusion disease (MVID), caused by loss-of-function mutations in the motor protein myosin Vb (MYO5B), is a severe infantile disease characterized by diarrhea, malabsorption, and acid/base instability, requiring intensive parenteral support for nutritional and fluid management. Human patient-derived enteroids represent a model for investigation of monogenic epithelial disorders but are a rare resource from MVID patients. We developed human enteroids with different loss-of function MYO5B variants and showed that they recapitulated the structural changes found in native MVID enterocytes. Multiplex immunofluorescence imaging of patient duodenal tissues revealed patient-specific changes in localization of brush border transporters. Functional analysis of electrolyte transport revealed profound loss of Na+/H+ exchange (NHE) activity in MVID patient enteroids with near-normal chloride secretion. The chloride channel-blocking antidiarrheal drug crofelemer dose-dependently inhibited agonist-mediated fluid secretion. MVID enteroids exhibited altered differentiation and maturation versus healthy enteroids. γ-Secretase inhibition with DAPT recovered apical brush border structure and functional Na+/H+ exchange activity in MVID enteroids. Transcriptomic analysis revealed potential pathways involved in the rescue of MVID cells including serum/glucocorticoid-regulated kinase 2 (SGK2) and NHE regulatory factor 3 (NHERF3). These results demonstrate the utility of patient-derived enteroids for developing therapeutic approaches to MVID.
Topics: Humans; Microvilli; Myosin Heavy Chains; Myosin Type V; Enterocytes; Malabsorption Syndromes; Mucolipidoses
PubMed: 37643022
DOI: 10.1172/JCI169234 -
Glycoconjugate Journal Dec 2023Neuraminidase 1 (NEU1) is a lysosomal sialidase that cleaves terminal α-linked sialic acid residues from sialylglycans. NEU1 is biosynthesized in the rough endoplasmic... (Review)
Review
Neuraminidase 1 (NEU1) is a lysosomal sialidase that cleaves terminal α-linked sialic acid residues from sialylglycans. NEU1 is biosynthesized in the rough endoplasmic reticulum (RER) lumen as an N-glycosylated protein to associate with its protective protein/cathepsin A (CTSA) and then form a lysosomal multienzyme complex (LMC) also containing β-galactosidase 1 (GLB1). Unlike other mammalian sialidases, including NEU2 to NEU4, NEU1 transport to lysosomes requires association of NEU1 with CTSA, binding of the CTSA carrying terminal mannose 6-phosphate (M6P)-type N-glycan with M6P receptor (M6PR), and intralysosomal NEU1 activation at acidic pH. In contrast, overexpression of the single NEU1 gene in mammalian cells causes intracellular NEU1 protein crystallization in the RER due to self-aggregation when intracellular CTSA is reduced to a relatively low level. Sialidosis (SiD) and galactosialidosis (GS) are autosomal recessive lysosomal storage diseases caused by the gene mutations of NEU1 and CTSA, respectively. These incurable diseases associate with the NEU1 deficiency, excessive accumulation of sialylglycans in neurovisceral organs, and systemic manifestations. We established a novel GS model mouse carrying homozygotic Ctsa IVS6 + 1 g/a mutation causing partial exon 6 skipping with simultaneous deficiency of Ctsa and Neu1. Symptoms developed in the GS mice like those in juvenile/adult GS patients, such as myoclonic seizures, suppressed behavior, gargoyle-like face, edema, proctoptosis due to Neu1 deficiency, and sialylglycan accumulation associated with neurovisceral inflammation. We developed a modified NEU1 (modNEU1), which does not form protein crystals but is transported to lysosomes by co-expressed CTSA. In vivo gene therapy for GS and SiD utilizing a single adeno-associated virus (AAV) carrying modNEU1 and CTSA genes under dual promoter control will be created.
Topics: Animals; Humans; Mice; Neuraminidase; Mucolipidoses; Lysosomes; Mammals; Lysosomal Storage Diseases
PubMed: 38147151
DOI: 10.1007/s10719-023-10135-6 -
Cells Nov 2023The recently presented Azalea Hypothesis for Alzheimer's disease asserts that iron becomes sequestered, leading to a functional iron deficiency that contributes to... (Review)
Review
The recently presented Azalea Hypothesis for Alzheimer's disease asserts that iron becomes sequestered, leading to a functional iron deficiency that contributes to neurodegeneration. Iron sequestration can occur by iron being bound to protein aggregates, such as amyloid β and tau, iron-rich structures not undergoing recycling (e.g., due to disrupted ferritinophagy and impaired mitophagy), and diminished delivery of iron from the lysosome to the cytosol. Reduced iron availability for biochemical reactions causes cells to respond to acquire additional iron, resulting in an elevation in the total iron level within affected brain regions. As the amount of unavailable iron increases, the level of available iron decreases until eventually it is unable to meet cellular demands, which leads to a functional iron deficiency. Normally, the lysosome plays an integral role in cellular iron homeostasis by facilitating both the delivery of iron to the cytosol (e.g., after endocytosis of the iron-transferrin-transferrin receptor complex) and the cellular recycling of iron. During a lysosomal storage disorder, an enzyme deficiency causes undigested substrates to accumulate, causing a sequelae of pathogenic events that may include cellular iron dyshomeostasis. Thus, a functional deficiency of iron may be a pathogenic mechanism occurring within several lysosomal storage diseases and Alzheimer's disease.
Topics: Humans; Alzheimer Disease; Iron; Amyloid beta-Peptides; Lysosomal Storage Diseases; Lysosomes; Iron Deficiencies
PubMed: 37998376
DOI: 10.3390/cells12222641 -
Zeitschrift Fur Rheumatologie Jun 2024Lysosomal storage diseases are a group of rare hereditary metabolic diseases. Due to a deficiency of lysosomal enzymes, complex substrates accumulate in the lysosomes... (Review)
Review
Lysosomal storage diseases are a group of rare hereditary metabolic diseases. Due to a deficiency of lysosomal enzymes, complex substrates accumulate in the lysosomes of various organs. Depending on the affected enzyme, this results in clinically variable and chronic progressive multiorgan diseases. Diagnosis is often delayed. As clinical symptoms include the musculoskeletal system, an awareness of lysosomal storage diseases is of relevance to (pediatric) rheumatologists. This article is focused on Mucopolysaccharidosis type I‑S, Mucolipidosis type III, Gaucher disease and Fabry disease. When suspecting a lysosomal storage disease, enzyme activity should be determined in dried blood spots or leukocytes. For some diseases, specific biomarkers can additionally be analyzed. Diagnosis should be confirmed by genetic testing. As causal treatment options are available for three of the presented diseases, a timely diagnosis is very important.
Topics: Humans; Lysosomal Storage Diseases; Rheumatic Diseases; Rheumatology; Diagnosis, Differential; Evidence-Based Medicine
PubMed: 38802503
DOI: 10.1007/s00393-024-01521-y