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Článek

Mucolipidosis type II with evidence of a novel storage site

Virchows Archiv. 1998 ; Roč. 433 (č. 6) : s. 575-578.

ISSN 0945-6317
Medvik
Zdroj

Článek online

Mucolipidosis IV: report of a case with ocular restricted phenotype caused by leaky splice mutation

... PURPOSE: To confirm and define a molecular basis for a case of mucolipidosis type IV (ML IV) with an ...

American journal of ophthalmology. 2007 ; 143 (4) : 663-671.

ISSN 0002-9394
Medvik
Zdroj

PURPOSE: To confirm and define a molecular basis for a case of mucolipidosis type IV (ML IV) with an extremely atypical phenotype pattern. DESIGN: Observational case report of a patient with ML IV with disease progression restricted to ocular symptoms. METHODS: Complete ophthalmologic and neurologic examination. Ultrastructural examination of white blood cells, skin, conjunctiva, and corneal epithelium. The MCOLN1 gene was sequenced from cDNA and the proportion of splicing variants were assessed by quantitative allele-specific polymerase chain reaction. RESULTS: Absence of any neurological abnormalities. Retinal pathologic features were the main cause of visual disability: low visual acuity and cloudy corneas since 2 years of age, progressive decrease in visual acuity since the age of 9 years. Ultrastructural examination showed storage lysosomes filled with either concentric membranes or lucent precipitate in corneal and conjunctive epithelia and in vascular endothelium. Cultured fibroblasts were free of any autofluorescence. Sequencing of the MCOLN1 gene identified compound heterozygosity for D362Y and A-->T transition leading to the creation of a novel donor splicing site and a 4-bp deletion from exon 13 at the mRNA level. Both normal and pathologic splice forms were detected in skin fibroblasts and leukocytes, with the normal form being more abundant. CONCLUSIONS: The case of this patient with ML IV is unique and is characterized by a curious lack of generalized symptoms. In this patient, the disorder was limited to the eyes and appeared without the usual psychomotor deterioration. The resulting phenotype is the mildest seen to date.

MeSH
alternativní sestřih genetika MeSH
degenerace retiny genetika patologie MeSH
dítě MeSH
elektroretinografie MeSH
epitelové buňky ultrastruktura MeSH
fenotyp MeSH
fibroblasty ultrastruktura MeSH
financování organizované MeSH
kationtové kanály TRPM genetika MeSH
kůže ultrastruktura MeSH
leukocyty ultrastruktura MeSH
lidé MeSH
lyzozomy genetika ultrastruktura MeSH
messenger RNA genetika MeSH
mukolipidózy genetika patologie MeSH
mutace MeSH
mutační analýza DNA MeSH
nemoci rohovky genetika patologie MeSH
nemoci spojivky genetika patologie MeSH
polymerázová řetězová reakce MeSH
rohovkový epitel ultrastruktura MeSH
Check Tag
dítě MeSH
lidé MeSH
ženské pohlaví MeSH
Publikační typ
kazuistiky MeSH

Článek online

Mukolipidóza II (I cell disease). Popis prvého případu v České republice a prenatální diagnóza v rodině
[Mucolipidosis II (I cell disease). Description of the first case in the Czech Republic and prenatal diagnosis in the family]

Časopis lékařů českých. 1997 ; Roč. 136 (č. 22) : s. 702-706.

ISSN 0008-7335
Medvik
Zdroj

Článek online

N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV

... Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability ...

Neurobiology of disease. 2017 ; 105 (-) : 257-270. [pub] 20170610

Neurobiol Dis
ISSN 1095-953X
Medvik
Zdroj

Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability, motor impairment, and premature death. There is currently no cure or corrective treatment. The disease results from mutations in the gene encoding mucolipin-1, a transient receptor potential channel believed to play a key role in lysosomal calcium egress. Loss of mucolipin-1 and subsequent defects lead to a host of cellular aberrations, including accumulation of glycosphingolipids (GSLs) in neurons and other cell types, microgliosis and, as reported here, cerebellar Purkinje cell loss. Several studies have demonstrated that N-butyldeoxynojirimycin (NB-DNJ, also known as miglustat), an inhibitor of the enzyme glucosylceramide synthase (GCS), successfully delays the onset of motor deficits, improves longevity, and rescues some of the cerebellar abnormalities (e.g., Purkinje cell death) seen in another lysosomal disease known as Niemann-Pick type C (NPC). Given the similarities in pathology between MLIV and NPC, we examined whether miglustat would be efficacious in ameliorating disease progression in MLIV. Using a full mucolipin-1 knockout mouse (Mcoln1-/-), we found that early miglustat treatment delays the onset and progression of motor deficits, delays cerebellar Purkinje cell loss, and reduces cerebellar microgliosis characteristic of MLIV disease. Quantitative mass spectrometry analyses provided new data on the GSL profiles of murine MLIV brain tissue and showed that miglustat partially restored the wild type profile of white matter enriched lipids. Collectively, our findings indicate that early miglustat treatment delays the progression of clinically relevant pathology in an MLIV mouse model, and therefore supports consideration of miglustat as a therapeutic agent for MLIV disease in humans.

Článek

Chorionic villus biopsy for the prenatal diagnosis of mucolipidosis type 2. Experience in 7 normal pregnancies from 4 families

Genetics in medicine. 1993 ; () : s. 20.

Medvik
Zdroj

Článek

Lisch Epithelial Corneal Dystrophy Is Caused by Heterozygous Loss-of-Function Variants in MCOLN1

... compound-heterozygous state, 4 of 9 LECD-associated variants cause the rare lysosomal storage disorder mucolipidosis ...

American journal of ophthalmology. 2024 ; 258 (-) : 183-195. [pub] 20231114

Am J Ophthalmol
ISSN 1879-1891
Medvik
Zdroj

PURPOSE: To report the genetic etiology of Lisch epithelial corneal dystrophy (LECD). DESIGN: Multicenter cohort study. METHODS: A discovery cohort of 27 individuals with LECD from 17 families, including 7 affected members from the original LECD family, 6 patients from 2 new families and 14 simplex cases, was recruited. A cohort of 6 individuals carrying a pathogenic MCOLN1 (mucolipin 1) variant was reviewed for signs of LECD. Next-generation sequencing or targeted Sanger sequencing were used in all patients to identify pathogenic or likely pathogenic variants and penetrance of variants. RESULTS: Nine rare heterozygous MCOLN1 variants were identified in 23 of 27 affected individuals from 13 families. The truncating nature of 7 variants and functional testing of 1 missense variant indicated that they result in MCOLN1 haploinsufficiency. Importantly, in the homozygous and compound-heterozygous state, 4 of 9 LECD-associated variants cause the rare lysosomal storage disorder mucolipidosis IV (MLIV). Autosomal recessive MLIV is a systemic disease and comprises neurodegeneration as well as corneal opacity of infantile-onset with epithelial autofluorescent lysosomal inclusions. However, the 6 parents of 3 patients with MLIV confirmed to carry pathogenic MCOLN1 variants did not have the LECD phenotype, suggesting MCOLN1 haploinsufficiency may be associated with reduced penetrance and variable expressivity. CONCLUSIONS: MCOLN1 haploinsufficiency is the major cause of LECD. Based on the overlapping clinical features of corneal epithelial cells with autofluorescent inclusions reported in both LECD and MLIV, it is concluded that some carriers of MCOLN1 haploinsufficiency-causing variants present with LECD.