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Verhandelingen - Koninklijke Academie... 1989"I-Cell disease" (ICD) has received its name because of the innumerable intracytoplasmatic inclusions in connective tissue cells and in vitro fibroblasts derived from... (Review)
Review
"I-Cell disease" (ICD) has received its name because of the innumerable intracytoplasmatic inclusions in connective tissue cells and in vitro fibroblasts derived from patients. It is a progressive disorder already recognizable in infancy. Severe disturbance of growth, coarsening facial features and moderate to severe psychomotor handicap are the most important clinical characteristics. ICD is fatal already in childhood. Prominent among many anatomo- and physiopathologic abnormalities is the paradox of a very reduced activity of many lysosomal hydrolases in connective tissue cells on the one hand and the strongly enhanced activity of these hydrolases in body fluids and culture media on the other hand. Similar, albeit less pronounced abnormalities are observed also in patients with pseudo-Hurler polydystrophy, (PHP) a related though milder disorder. In patients with either ICZ or PHP, phosphorylation of oligomannosyl type sidechains in acid hydrolases, known to be glycoproteins, does not occur. Because the mannose-6-phosphate (M-6-P) recognition marker necessary for normal transport of nascent hydrolases to the lysosomal compartment is not formed, these enzymes are not retained in the cells. The underlying cause is a functionally deficient N-acetylglucosaminephosphotransferase in ICD and PHP patients. The pathological consequences of this defect are more pronounced in fibroblasts than in parenchymatous cells, because the former lack alternative mechanisms by which hydrolases can reach lysosomes. The number of known secondary abnormalities in ICD remain useful for confirmation of the clinical diagnosis and for prenatal diagnosis. The elucidation of the metabolic defect in ICD, a rare monogenic disorder, has increased considerably knowledge on enzyme maturation and on the physiology of intracytoplasmic organelles.
Topics: Genetic Carrier Screening; Humans; Hydrolases; Infant, Newborn; Lysosomes; Mucolipidoses; Oligosaccharides
PubMed: 2686262
DOI: No ID Found -
International Journal of Molecular... Jun 2020Mucolipidosis type IV (MLIV) is an ultra-rare lysosomal storage disorder caused by biallelic mutations in gene encoding the transient receptor potential channel... (Review)
Review
Mucolipidosis type IV (MLIV) is an ultra-rare lysosomal storage disorder caused by biallelic mutations in gene encoding the transient receptor potential channel mucolipin-1. So far, 35 pathogenic or likely pathogenic MLIV-related variants have been described. Clinical manifestations include severe intellectual disability, speech deficit, progressive visual impairment leading to blindness, and myopathy. The severity of the condition may vary, including less severe psychomotor delay and/or ocular findings. As no striking recognizable facial dysmorphism, skeletal anomalies, organomegaly, or lysosomal enzyme abnormalities in serum are common features of MLIV, the clinical diagnosis may be significantly improved because of characteristic ophthalmological anomalies. This review aims to outline the pathophysiology and genetic defects of this condition with a focus on the genotype-phenotype correlation amongst cases published in the literature. The authors will present their own clinical observations and long-term outcomes in adult MLIV cases.
Topics: Adult; Female; Genetic Association Studies; Genetic Profile; Humans; Male; Mucolipidoses; Mutation; TRPM Cation Channels; Young Adult
PubMed: 32604955
DOI: 10.3390/ijms21124564 -
Reumatologia Clinica 2014
Topics: Bone and Bones; Humans; Male; Middle Aged; Mucolipidoses; Radiography
PubMed: 24286931
DOI: 10.1016/j.reuma.2013.10.001 -
Molecular Genetics and Metabolism Feb 2014Mucolipidosis type IV (MLIV) is an autosomal recessive disorder resulting from mutations in the MCOLN1 gene. This gene encodes the endosomal/lysosomal transient receptor... (Clinical Trial)
Clinical Trial
Mucolipidosis type IV (MLIV) is an autosomal recessive disorder resulting from mutations in the MCOLN1 gene. This gene encodes the endosomal/lysosomal transient receptor potential channel protein mucolipin-1 (TRPML1). Affected patients suffer from neurodevelopmental abnormalities and progressive retinal dystrophy. In a prospective natural history study we hypothesized the presence of an additional slow cerebral neurodegenerative process. We have recruited 5 patients, tested their neurodevelopmental status, and measured cerebral regional volumes and white matter integrity using MRI yearly. Over a period of up to 3 years, MLIV patients remained neurologically stable. There was a trend for increased cortical and subcortical gray matter volumes and increased ventricular size, while white matter and cerebellar volumes decreased. Mean diffusivity (MD) was increased and fractional anisotropy (FA) values were below normal in all analyzed brain regions. There was a positive correlation between motor scores of the Vineland Scale and the FA values in the corticospinal tract (corr coef 0.39), and a negative correlation with the MD values (corr coef -0.50) in the same brain region. We conclude from these initial findings that deficiency in mucolipin-1 affects the entire brain but that there might be a selective regional cerebral neurodegenerative process in MLIV. In addition, these data suggest that diffusion-weighted imaging might be a good biomarker for following patients with MLIV. Therefore, our findings may be helpful for designing future clinical trials.
Topics: Adolescent; Brain Mapping; Cerebellum; Cerebral Cortex; Child; Diffusion Magnetic Resonance Imaging; Female; Humans; Male; Mucolipidoses; Neuroimaging; Neuropsychological Tests; Prospective Studies; Pyramidal Tracts; Young Adult
PubMed: 24332805
DOI: 10.1016/j.ymgme.2013.11.007 -
Advances in Experimental Medicine and... 1980While mucolipidosis I and its variants are well defined as sialidosis, the basic defect in mucolipidosis II and III is still discussed. The neuraminidase defect in these... (Review)
Review
While mucolipidosis I and its variants are well defined as sialidosis, the basic defect in mucolipidosis II and III is still discussed. The neuraminidase defect in these disorders is generally considered as one of many lysosomal hydrolase deficiencies, accompanied by a high extracellular activity of these enzymes. Our hypothesis of a specific alpha-neuraminidase defect, in these cases, is based on the fact that it is common to numerous tissues and extracellular fluids, in opposite to other hydrolases activities. The choice of the substrate for the alpha-neuraminidase determination appears to be very important, in view of their peculiar specificities.
Topics: Carbohydrate Conformation; Carbohydrate Metabolism, Inborn Errors; Carbohydrate Sequence; Genetic Variation; Glycoproteins; Humans; Mucolipidoses; Neuraminidase
PubMed: 6987835
DOI: 10.1007/978-1-4684-7844-0_35 -
Clinical Dysmorphology Jan 2022
Topics: Early Diagnosis; Humans; Mucolipidoses; Radiography
PubMed: 34561315
DOI: 10.1097/MCD.0000000000000388 -
American Journal of Medical Genetics Jul 1982We review all reported cases of Mucolipidosis IV, add a new one, and present evidence for a generalized phospholipid storage. All phospholipids were increased in the...
We review all reported cases of Mucolipidosis IV, add a new one, and present evidence for a generalized phospholipid storage. All phospholipids were increased in the liver, skin fibroblasts and urine. Lysobisphosphatydic acid which was markedly elevated in these samples was the only lipid stored in muscle. A slowly progressive neurological disease with mental retardation and corneal opacities, but lacking mucopolysaccharide excretion, skeletal changes and organomegaly should raise the suspicion of this disease. At this time, the diagnosis is made by EM studies of skin or conjunctiva which should be done if results of tests on serum or bone marrow for lysosomal diseases are normal. We found some of the typical inclusions in skin fibroblasts from an obligate carrier, which suggests that distinction between the homozygote and heterozygote may be difficult. Despite this, two succeeding pregnancies with normal outcomes were successfully monitored.
Topics: Child, Preschool; Corneal Opacity; Female; Fibroblasts; Humans; Intellectual Disability; Liver; Lysophospholipids; Microscopy, Electron; Monoglycerides; Mucolipidoses; Muscles; Phosphatidic Acids; Phospholipids; Skin
PubMed: 7114093
DOI: 10.1002/ajmg.1320120308 -
NeoReviews Sep 2020Mutations in the myosin 5β, syntaxin-binding protein 2, and syntaxin 3 genes lead to microvillus inclusion disease (MVID), an autosomal recessive congenital...
Mutations in the myosin 5β, syntaxin-binding protein 2, and syntaxin 3 genes lead to microvillus inclusion disease (MVID), an autosomal recessive congenital enteropathy. This rare disease is characterized by lack of microvilli on the surface of enterocytes in the small intestine, the presence of pathognomonic intracellular microvillus inclusions, and vesicular bodies within these enterocytes. This pathology leads to the characteristic intractable, life-threatening, watery diarrhea. In the more common early-onset form, affected patients present in the first few days after birth, whereas in the late-onset form, clinical manifestations appear at approximately 2 to 3 months of age. Genetic testing can confirm the diagnosis, but the infant's medical history, clinical presentation, and small intestinal biopsy results are strongly suggestive of the diagnosis. The prevalence of MVID is thought to be higher in countries with a high degree of consanguinity. Patients with MVID cannot tolerate feedings and require continuous total parenteral nutrition. Mortality is extremely high in the early-onset type with reports of survival in patients treated with small intestinal transplantation. Medical counseling for parents of infants with MVID needs to reflect our current understanding of the various genetic forms of this disease, the feasible management, and anticipated outcomes.
Topics: Humans; Infant; Infant, Newborn; Intensive Care Units, Neonatal; Malabsorption Syndromes; Microvilli; Mucolipidoses
PubMed: 32873653
DOI: 10.1542/neo.21-9-e600 -
Neurology Aug 2002Mucolipidosis type IV (MLIV) is an autosomal recessive disease caused by mutations in the MCOLN1 gene that codes for mucolipin, a member of the transient receptor...
BACKGROUND
Mucolipidosis type IV (MLIV) is an autosomal recessive disease caused by mutations in the MCOLN1 gene that codes for mucolipin, a member of the transient receptor potential (TRP) gene family.
OBJECTIVE
To comprehensively characterize the clinical and genetic abnormalities of MLIV.
METHODS
Twenty-eight patients with MLIV, aged 2 to 25 years, were studied. Ten returned for follow-up every 1 to 2 years for up to 5 years. Standard clinical, neuroimaging, neurophysiologic, and genetic techniques were used.
RESULTS
All patients had varying degrees of corneal clouding, with progressive optic atrophy and retinal dystrophy. Twenty-three patients had severe motor and mental impairment. Motor function deteriorated in three patients and remained stable in the rest. All had a constitutive achlorhydria with elevated plasma gastrin level, and 12 had iron deficiency or anemia. Head MRI showed consistent characteristic findings of a thin corpus callosum and remained unchanged during the follow-up period. Prominent abnormalities of speech, hand usage, and swallowing were also noted. Mutations in the MCOLN1 gene were present in all patients. Correlation of the genotype with the neurologic handicap and corpus callosum dysplasia was found.
CONCLUSIONS
MLIV is both a developmental and a degenerative disorder. The presentation as a cerebral palsy-like encephalopathy may delay diagnosis.
Topics: Adolescent; Adult; Child; Child, Preschool; Corpus Callosum; Diagnosis, Differential; Electroencephalography; Female; Follow-Up Studies; Genotype; Humans; Male; Membrane Proteins; Mucolipidoses; Mutation; Phenotype; Prospective Studies; TRPM Cation Channels; Transient Receptor Potential Channels
PubMed: 12182165
DOI: 10.1212/wnl.59.3.306 -
Pediatrics and Neonatology Apr 2015A preterm male neonate was diagnosed as having microvillus inclusion disease based on the characteristics of histological and ultrastructural findings. The peripheral...
A preterm male neonate was diagnosed as having microvillus inclusion disease based on the characteristics of histological and ultrastructural findings. The peripheral blood sample also revealed MYO5B mutation. He had been on long-term parenteral nutrition. However, a bowel segment was seen in the baby's diaper during hospitalization when he was 5 months old. Serial abdominal ultrasound demonstrated progressive dissection of the bowel wall with detached mucosa in real-time. Small intestinal epithelia were seen on the histology of the detached bowel segment. He died 2 weeks after the episode; postmortem autopsy showed diffuse detachment of mucosa of small bowels without perforation. This is the first report of an infant with microvillus inclusion disease that presented with bowel "dissection". Weakened adhesion and integrity of intestinal epithelial cells caused by MYO5B mutation was speculated to result in the dissection and detachment of the epithelia of the gastrointestinal tract.
Topics: Humans; Infant, Newborn; Intestine, Small; Malabsorption Syndromes; Male; Microvilli; Mucolipidoses; Mutation; Parenteral Nutrition
PubMed: 23608388
DOI: 10.1016/j.pedneo.2013.03.004