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Molecular Therapy. Methods & Clinical... Jun 2024Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits, and progressive vision loss. Using...
Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits, and progressive vision loss. Using adeno-associated vector 9 (AAV9) and AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying disease course in a mouse model of MLIV by the human gene transfer. Here, using a primate-enabling capsid AAV.CPP.16 (CPP16), we constructed a new, clinic-oriented gene expression vector and demonstrated its efficacy in the preclinical model of MLIV. Systemic administration of CPP16-MCOLN1 in adult symptomatic mice at a dose of 1e12 vg per mouse resulted in expression in the brain and peripheral tissues, alleviated brain pathology, rescued neuromotor function, and completely prevented paralysis. Notable expression of transcripts was also detected in the retina of the mouse, which had exhibited significant degeneration at the time of the treatment. However, no increase in retinal thickness was observed after gene therapy treatment. Our results suggest a new AAV-based systemic gene replacement therapy for the treatment of MLIV that could be translated into clinical studies.
PubMed: 38934011
DOI: 10.1016/j.omtm.2024.101269 -
Chembiochem : a European Journal of... Jun 2024Autophagic flux plays a crucial role in various diseases. Recently, the lysosomal ion channel TRPML1 has emerged as a promising target in lysosomal storage diseases,...
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.
PubMed: 38923811
DOI: 10.1002/cbic.202400506 -
Cornea Jun 2024Utilization of multimodal imaging techniques to diagnose cases of mucolipidosis type IV (ML-IV) and report a new genetic variant.
PURPOSE
Utilization of multimodal imaging techniques to diagnose cases of mucolipidosis type IV (ML-IV) and report a new genetic variant.
METHODS
This study is a case report.
RESULTS
Case 1 involves a 4-year-old boy with corneal haziness and global developmental delay who showed an increased reflectivity of the corneal epithelium on anterior segment optical coherence tomography (AS-OCT). In addition, neurologic evaluation was suggestive of ML-IV. Further genetics evaluation confirmed ML-IV. Histology of the button revealed a thickened epithelial basement membrane. Case 2, the younger sibling, showed a milder corneal haze with similar changes on AS-OCT prompting us to further evaluate for ML-IV by genetics (positive MCOLN1 gene mutation). Both instances highlighted varied ML-IV presentations, but a persistent feature was hyperreflective epithelium.
CONCLUSIONS
Our study emphasizes AS-OCT's role in screening ML-IV and advocates the role of genetic counseling of affected parents. We present 2 South-Asian siblings with ML-IV with a new genetic variant, emphasizing the utility of detailed ophthalmic and neurologic assessments using multimodal imaging.
PubMed: 38913974
DOI: 10.1097/ICO.0000000000003612 -
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 -
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 -
Orphanet Journal of Rare Diseases May 2024To investigate the peripheral nervous system involvement in sialidosis with typical features of myoclonus, seizure, and giant waves in somatosensory evoked potentials...
BACKGROUND
To investigate the peripheral nervous system involvement in sialidosis with typical features of myoclonus, seizure, and giant waves in somatosensory evoked potentials suggesting hyperexcitability in the central nervous system.
METHODS
The clinical presentation of patients with genetically confirmed sialidosis was recorded. Neurophysiological studies, including nerve conduction studies (NCSs), F-wave studies, and needle electromyography (EMG), were performed on these patients.
RESULTS
Six patients (M/F: 2:4) were recruited. In addition to the classical presentation, intermittent painful paresthesia was noted in four patients, and three of whom reported it as the earliest symptom. In the NCSs, one patient had reduced compound muscle action potential amplitudes in the right ulnar nerve, while another patient had prolonged distal motor latency in the bilateral tibial and peroneal nerves. Prolonged F-wave latency (83.3%), repeater F-waves (50%), and neurogenic polyphasic waves in EMG (in 2 out of 3 examined patients) were also noted. Interestingly, a very late response was noted in the F-wave study of all patients, probably indicating lesions involving the proximal peripheral nerve or spinal cord.
CONCLUSION
In addition to the central nervous system, the peripheral nervous system is also involved in sialidosis, with corresponding clinical symptoms. Further study on these phenomena is indicated.
Topics: Humans; Male; Female; Adult; Mucolipidoses; Electromyography; Neural Conduction; Young Adult; Peripheral Nerves; Adolescent; Peripheral Nervous System; Evoked Potentials, Somatosensory; Middle Aged; Child
PubMed: 38790028
DOI: 10.1186/s13023-024-03216-8 -
Annals of Medicine and Surgery (2012) Apr 2024Sialidosis is a rare variety of lysosomal storage disease that results in intracellular accumulation of sialic acid containing compounds. The authors report the first...
BACKGROUND
Sialidosis is a rare variety of lysosomal storage disease that results in intracellular accumulation of sialic acid containing compounds. The authors report the first case of type II sialidosis, juvenile subtype in a 30-month-old male child from Nepal.
CASE PRESENTATION
Progressive hearing loss with coarse facies, hepatomegaly, kyphoscoliosis, dysostosis multiplex were the major features in a 30-month-old child born to healthy non-consanguineous parents. With the suspicion of lysosomal storage disease, urinary oligosaccharides were tested and were positive. Whole-exome sequencing revealed a mutation in the neuraminidase gene (NEU1) and established the diagnosis of sialidosis.
CLINICAL DISCUSSION
Sialidosis is a rare autosomal recessive type of lysosomal storage disease resulting due to mutation of the neuraminidase gene leading to intracellular accumulation of sialic acid compounds. Based on the presence of visual symptoms, sialidosis is classified into type I and II varieties. Our case is of type II juvenile sialidosis.
CONCLUSION
Despite rare, sialidosis is a life-threatening, and disabling disease. Exploring targeted therapy is the utmost to treat this condition.
PubMed: 38576973
DOI: 10.1097/MS9.0000000000001768 -
Journal of Children's Orthopaedics Apr 2024Literature regarding total hip arthroplasty for pediatric hip diseases is scarce. This review aims to portray the various orthopedic conditions of childhood that can... (Review)
Review
PURPOSE
Literature regarding total hip arthroplasty for pediatric hip diseases is scarce. This review aims to portray the various orthopedic conditions of childhood that can lead to significant impairment of the hip joint and, ultimately, to total hip arthroplasty in adolescence and adulthood.
METHODS
In total, 61 out of 3666 articles were selected according to (1) the diagnosis of one of the 12 pediatric hip pathologies (Legg-Perthes-Calvé disease, developmental dysplasia of the hip, slipped capital femoral epiphysis, neuromuscular hip dysplasia, post-traumatic avascular necrosis of the proximal femur, juvenile rheumatoid arthritis, achondroplasia, spondyloepiphyseal dysplasia, mucopolysaccharidosis, mucolipidosis, hip infections, and tumors) that required total hip arthroplasty; (2) minimum follow-up of 16 months; (3) assessed outcome with a clinical or radiologic score; (4) Methodological Items for Non-Randomized Studies quality score of 9 or higher. The following information for each pathology was retrieved: mean age at total hip arthroplasty, reason for total hip arthroplasty, type of total hip arthroplasty, surgical technique, mean follow-up, and outcomes.
RESULTS
Overall, the mean age at total hip arthroplasty for pediatric hip disease is in the sixth and seventh decade, except for tumors and skeletal dysplasias. The reason for performing total hip arthroplasty is often osteoarthrosis and abnormal anatomy. Prosthesis types change based on patient's conditions and technological advances; custom-made implants are used for tumors, juvenile rheumatoid arthritis, and skeletal dysplasias; for other diseases, the most frequent are modular cementless implants. Outcomes are generally good, and all studies portray functional and pain improvements.
CONCLUSION
Total hip arthroplasty is performed more frequently than in the past in patients with pediatric hip pathologies; it enhances patients' quality of life by reducing pain and improving function. However, revision rate in these patients is not negligible.
PubMed: 38567046
DOI: 10.1177/18632521241229608 -
The Canadian Journal of Neurological... Mar 2024Mucolipidosis type IV (MLIV) is a rare, progressive lysosomal storage disorder characterized by severe intellectual disability, delayed motor milestones and...
BACKGROUND
Mucolipidosis type IV (MLIV) is a rare, progressive lysosomal storage disorder characterized by severe intellectual disability, delayed motor milestones and ophthalmologic abnormalities. MLIV is an autosomal recessive disease caused by mutations in the gene, encoding mucolipin-1 which is responsible for maintaining lysosomal function.
OBJECTIVES AND METHODS
Here, we report a family of four Iranian siblings with cognitive decline, progressive visual and pyramidal disturbances, and abnormal movements manifested by severe oromandibular dystonia and parkinsonism. MRI scans of the brain demonstrated signal abnormalities in the white matter and thinning of the corpus callosum.
RESULTS AND CONCLUSIONS
Whole-exome sequencing identified a novel homozygous variant, c.362C > T:p. Thr121Met in the gene consistent with a diagnosis of MLIV. The presentation of MLIV may overlap with a variety of other neurological diseases, and genetic analysis is an important strategy to clarify the diagnosis. This is an important point that clinicians should be familiar with. The novel variant c.362C > T:p. Thr121Met herein described may be related to a comparatively older age at onset. Our study also expands the clinical spectrum of MLIV associated with the variants and introduces a novel likely pathogenic variant for testing in MLIV cases that remain unresolved.
PubMed: 38532569
DOI: 10.1017/cjn.2024.47 -
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