Úvod: Mukopolysacharidóza I. typu (MPS I) patří do skupiny lysosomálních střádavých onemocnění, jejichž příčinou je dědičná porucha enzymu katalyzujícího odbourávání glykosaminoglykanů, které se hromadí v tkáních. Onemocnění se projevuje různou tíží a variabilitou klinických příznaků, jež v čase progredují. Vzhledem k existenci cílené léčby, tj. enzymové substituční terapie a transplantace hematopoetických kmenových buněk, zabraňující rozvoji příznaků nebo významně zpomalující průběh onemocnění, je klíčové co nejčasnější diagnostikování nemoci. Metoda: Prezentujeme kazuistiku dívky s MPS I (fenotypem m. Hurler-Scheie) bez typických „hrubých rysů“ v obličeji, ale s dalším charakteristickým příznakem kontraktur obrazu „drápovitých rukou“, které se rozvinuly již na začátku druhého roku života a vyžadovaly operační řešení. Dále byla přítomná splenomegalie a nově rozvinutá pupeční kýla. Výsledky: Diagnóza byla stanovena až ve věku čtyř let na základě kombinace biochemických a enzymologických vyšetření s následnou konfirmací na molekulárněgenetické úrovni průkazem patogenních mutací v genu IDUA. Byla ihned zahájena enzymová substituční terapie laronidázou a pro riziko další progrese a rozvoje neurologické symptomatologie byla následně indikována k transplantaci hematopoetických kmenových buněk. Závěr: U pacienta s MPS I se vždy nemusí prezentovat charakteristická kraniofaciální dysmorfie, ale jsou popisovány další symptomy, organomegalie, syndrom karpálního tunelu a/nebo kontraktury na rukou. Vzhledem k dostupnosti laboratorní diagnostiky a cílené léčby je pro pacienty klíčové zkrácení doby mezi prvními příznaky onemocnění a diagnózou na minimum, protože s každou prodlevou se stav nenávratně horší a léčba dosahuje uspokojivých výsledků, pouze pokud je zahájena včas.
Introduction: Mucopolysaccharidosis type I (MPS I) belongs to the group of lysosomal storage diseases, the cause of which is an inherited disorder of an enzyme catalyzing catabolism of glycosaminoglycans, which accumulate in tissues. The disease manifests with varying severity and variability of clinical symptoms, that progress over time. Given the existence of targeted therapies, i.e. enzyme replacement therapy and hematopoietic stem cell transplantation, that prevent the development of the symptoms or significantly slow the progression of the disease, early diagnosis is crucial. Method: We present a case study of a girl, who suffers from MPS I (m. Hurler-Scheie phenotype), without the typical coarse facial features, but has another characteristic symptom and thus hand contractures forming a „claw hand“, which developed at the beginning of the second year of life and required a surgical management. In addition, splenomegaly and a newly developed umbilical hernia were present. Results: The diagnosis was established at the age of 4 years on the basis of a combination of biochemical and enzymological examinations, which were followed by confirmation at the molecular genetic level by detection of 2 pathogenic mutations of the IDUA gene. Enzyme replacement therapy with laronidase was initiated immediately. For a risk of further progression and development of neurological symptoms the hematopoietic stem cell transplantation was subsequently indicated. Conclusion: A patient with MPS I may not always present with the chracteristic craniofacial dysmorphia, but other symptoms such as organomegaly, carpal tunnel syndrom and/or hand contractures have been described. Given the availability of laboratory diagnostics and targeted treatment, it is crucial for the patients to minimalize the time between the first signs of the disease and the diagnosis, because with each delay the patient’s health condition irreversibly worsens, and the therapy achieves satisfactory results only if initiated in time. Key words: lysosomal storage disorders, mucopolysaccharidosis type I (MPS I), m. Hurler-Scheie, glycosaminoglycans, enzyme replacement therapy
- MeSH
- enzymová substituční terapie metody MeSH
- lidé MeSH
- lyzozomální nemoci z ukládání diagnóza patologie terapie MeSH
- mukopolysacharidóza I * diagnóza patologie terapie MeSH
- předškolní dítě MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
The aim of this study was to identify RS1 pathogenic variants in Czech patients with X-linked retinoschisis (XLRS) and to describe the associated phenotypes, including natural history, in some cases. Twenty-one affected males from 17 families were included. The coding region of RS1 was directly sequenced and segregation of the identified mutations was performed in available family members. In total, 12 disease-causing variants within RS1 were identified; of these c.20del, c.275G>A, c.[375_379del; 386A>T], c.539C>A and c.575_576insT were novel, all predicted to be null alleles. The c.539C>A mutation occurred de novo. Three patients (aged 8, 11 and 19 years) were misdiagnosed as having intermediate uveitis and treated with systemic steroids. Repeat spectral domain optical coherence tomography examinations in four eyes documented the transition from cystoid macular lesions to macular atrophy in the fourth decade of life. Four individuals were treated with topical dorzolamide and in two of them, complete resolution of the cystic macular lesions bilaterally was achieved, while one patient was noncompliant. Rebound phenomenon after discontinuation of dorzolamide for 7 days was documented in one case. Misdiagnosis of XLRS for uveitis is not uncommon; therefore, identification of disease-causing variants is of considerable benefit to the affected individuals.
- MeSH
- antihypertenziva aplikace a dávkování terapeutické užití MeSH
- dítě MeSH
- frekvence genu MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mutace MeSH
- oční proteiny genetika MeSH
- optická koherentní tomografie MeSH
- předškolní dítě MeSH
- retinoschisis farmakoterapie genetika patologie MeSH
- rodokmen MeSH
- sulfonamidy aplikace a dávkování terapeutické užití MeSH
- thiofeny aplikace a dávkování terapeutické užití MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD/MTPD) and medium chain acyl-CoA dehydrogenase deficiency (MCADD) were included in the expanded neonatal screening program (ENBS) in Czechia in 2009, allowing for the presymptomatic diagnosis and nutritional management of these patients. The aim of our study was to assess the nationwide impact of ENBS on clinical outcome. This retrospective study analysed acute events and chronic complications and their severity in pre-ENBS and post-ENBS cohorts. In total, 28 children (12 before, 16 after ENBS) were diagnosed with LCHADD/MTPD (incidence 0.8/100,000 before and 1.2/100,000 after ENBS). In the subgroup detected by ENBS, a significantly longer interval from birth to first acute encephalopathy was observed. In addition, improvement in neuropathy and cardiomyopathy (although statistically non-significant) was demonstrated in the post-ENBS subgroup. In the MCADD cohort, we included 69 patients (15 before, 54 after ENBS). The estimated incidence rose from 0.7/100,000 before to 4.3/100,000 after ENBS. We confirmed a significant decrease in the number of episodes of acute encephalopathy and lower proportion of intellectual disability after ENBS (p < 0.0001). The genotype-phenotype correlations suggest a new association between homozygosity for the c.1528C > G variant and more severe heart involvement in LCHADD patients.
- MeSH
- 3-hydroxyacyl-CoA-dehydrogenasy nedostatek MeSH
- acyl-CoA-dehydrogenasa nedostatek MeSH
- dítě MeSH
- hodnocení výsledků zdravotní péče MeSH
- incidence MeSH
- kardiomyopatie diagnóza dietoterapie epidemiologie MeSH
- karnitin analogy a deriváty krev MeSH
- kojenec MeSH
- lidé MeSH
- mitochondriální myopatie diagnóza dietoterapie epidemiologie MeSH
- mitochondriální trifunkční protein nedostatek MeSH
- nemoci nervového systému diagnóza dietoterapie epidemiologie MeSH
- novorozenec MeSH
- novorozenecký screening metody MeSH
- předškolní dítě MeSH
- retrospektivní studie MeSH
- rhabdomyolýza diagnóza dietoterapie epidemiologie MeSH
- stupeň závažnosti nemoci MeSH
- vrozené poruchy metabolismu tuků diagnóza dietoterapie epidemiologie MeSH
- vrozené poruchy metabolismu diagnóza MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
PURPOSE: Danon disease (DD) is a rare X-linked disorder caused by pathogenic variants in LAMP2. DD primarily manifests as a severe cardiomyopathy. An early diagnosis is crucial for patient survival. The aim of the study was to determine the usefulness of ocular examination for identification of DD. METHODS: Detailed ocular examination in 10 patients with DD (3 males, 7 females) and a 45-year-old asymptomatic female somatic mosaic carrier of a LAMP2 disease-causing variant. RESULTS: All patients with manifest cardiomyopathy had pigmentary retinopathy with altered autofluorescence and diffuse visual field loss. Best corrected visual acuity (BCVA) was decreased (<0.63) in 8 (40%) out of 20 eyes. The severity of retinal pathology increased with age, resulting in marked cone-rod involvement overtime. Spectral-domain optical coherence tomography in younger patients revealed focal loss of photoreceptors, disruption and deposition at the retinal pigment epithelium/Bruch's membrane layer (corresponding to areas of marked increased autofluorescence), and hyperreflective foci in the outer nuclear layer. Cystoid macular oedema was seen in one eye. In the asymptomatic female with somatic mosaicism, the BCVA was 1.0 bilaterally. An abnormal autofluorescence pattern in the left eye was present; while full-field electroretinography was normal. CONCLUSIONS: Detailed ocular examination may represent a sensitive and quick screening tool for the identification of carriers of LAMP2 pathogenic variants, even in somatic mosaicism. Hence, further investigation should be undertaken in all patients with pigmentary retinal dystrophy as it may be a sign of a life-threatening disease.
- MeSH
- dospělí MeSH
- elektroretinografie MeSH
- glykogenóza typu IIb komplikace diagnóza genetika MeSH
- lidé MeSH
- membránový protein 2 asociovaný s lyzozomy biosyntéza genetika MeSH
- mladý dospělý MeSH
- optická koherentní tomografie metody MeSH
- regulace genové exprese * MeSH
- retinální pigmentový epitel patologie MeSH
- retinopathia pigmentosa diagnóza etiologie genetika MeSH
- RNA genetika MeSH
- rodokmen MeSH
- zraková ostrost * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
Cullin 4B (CUL4B), lysosomal-associated membrane protein Type 2 (LAMP2), ATP1B4, TMEM255A, and ZBTB33 are neighboring genes on Xq24. Mutations in CUL4B result in Cabezas syndrome (CS). Male CS patients present with dysmorphic, neuropsychiatric, genitourinary, and endocrine abnormalities. Heterozygous CS females are clinically asymptomatic. LAMP2 mutations cause Danon disease (DD). Cardiomyopathy is a dominant feature of DD present in both males and heterozygous females. No monogenic phenotypes have been associated with mutations in ATP1B4, TMEM255A, and ZBTB33 genes. To facilitate diagnostics and counseling in CS and DD families, we present a female DD patient with a de novo Alu-mediated Xq24 rearrangement causing a deletion encompassing CUL4B, LAMP2, and also the other three neighboring genes. Typical to females heterozygous for CUL4B mutations, the patient was CS asymptomatic, however, presented with extremely skewed X-chromosome inactivation (XCI) ratios in peripheral white blood cells. As a result of the likely selection against CUL4B deficient clones, only minimal populations (~3%) of LAMP2 deficient leukocytes were identified by flow cytometry. On the contrary, myocardial LAMP2 protein expression suggested random XCI. We demonstrate that contiguous CUL4B and LAMP2 loss-of-function copy number variations occur and speculate that male patients carrying similar defects could present with features of both CS and DD.
- MeSH
- chromozomální delece MeSH
- dospělí MeSH
- elementy Alu genetika MeSH
- exony genetika MeSH
- glykogenóza typu IIb diagnóza genetika patofyziologie MeSH
- inaktivace chromozomu X genetika MeSH
- kardiomyopatie genetika patofyziologie MeSH
- kulinové proteiny genetika MeSH
- lidé MeSH
- membránový protein 2 asociovaný s lyzozomy genetika MeSH
- mentální retardace vázaná na chromozom X genetika patofyziologie MeSH
- mutace ztráty funkce genetika MeSH
- myokard metabolismus MeSH
- sodíko-draslíková ATPasa genetika MeSH
- transkripční faktory genetika MeSH
- variabilita počtu kopií segmentů DNA genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
BACKGROUND: Niemann-Pick type C (NP-C) is a rare neurovisceral genetic disorder caused by mutations in the NPC1 or the NPC2 gene. NPC1 is a multipass-transmembrane protein essential for egress of cholesterol from late endosomes/lysosomes. To evaluate impacts of NPC1 mutations, we examined fibroblast cultures from 26 NP-C1 patients with clinical phenotypes ranging from infantile to adult neurologic onset forms. The cells were tested with multiple assays including NPC1 mRNA expression levels and allele expression ratios, assessment of NPC1 promoter haplotypes, NPC1 protein levels, cellular cholesterol staining, localization of the mutant NPC1 proteins to lysosomes, and cholesterol/cholesteryl ester ratios. These results were correlated with phenotypes of the individual patients. RESULTS: Overall we identified 5 variant promoter haplotypes. Three of them showed reporter activity decreased down to 70% of the control sequence. None of the haplotypes were consistently associated with more severe clinical presentation of NP-C. Levels of transcripts carrying null NPC1 alleles were profoundly lower than levels of the missense variants. Low levels of the mutant NPC1 protein were identified in most samples. The protein localised to lysosomes in cultures expressing medium to normal NPC1 levels. Fibroblasts from patients with severe infantile phenotypes had higher cholesterol levels and higher cholesterol/cholesteryl ester ratios. On the contrary, cell lines from patients with juvenile and adolescent/adult phenotypes showed values comparable to controls. CONCLUSION: No single assay fully correlated with the disease severity. However, low residual levels of NPC1 protein and high cholesterol/cholesteryl ester ratios associated with severe disease. The results suggest not only low NPC1 expression due to non-sense mediated decay or low mutant protein stability, but also dysfunction of the stable mutant NPC1 as contributors to the intracellular lipid transport defect.
- MeSH
- fibroblasty metabolismus MeSH
- intracelulární signální peptidy a proteiny MeSH
- lidé MeSH
- membránové glykoproteiny * genetika metabolismus MeSH
- mladiství MeSH
- mutace genetika MeSH
- transportní proteiny * genetika MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Tay-Sachs disease (TSD) is an inherited neurodegenerative disorder caused by a lysosomal β-hexosaminidase A deficiency due to mutations in the HEXA gene. The late-onset form of disease (LOTS) is considered rare, and only a limited number of cases have been reported. The clinical course of LOTS differs substantially from classic infantile TSD. METHODS: Comprehensive data from 14 Czech patients with LOTS were collated, including results of enzyme assays and genetic analyses. RESULTS: 14 patients (9 females, 5 males) with LOTS were diagnosed between 2002 and 2018 in the Czech Republic (a calculated birth prevalence of 1 per 325,175 live births). The median age of first symptoms was 21 years (range 10-33 years), and the median diagnostic delay was 10.5 years (range 0-29 years). The main clinical symptoms at the time of manifestation were stammering or slurred speech, proximal weakness of the lower extremities due to anterior horn cell neuronopathy, signs of neo- and paleocerebellar dysfunction and/or psychiatric disorders. Cerebellar atrophy detected through brain MRI was a common finding. Residual enzyme activity was 1.8-4.1% of controls. All patients carried the typical LOTS-associated c.805G>A (p.Gly269Ser) mutation on at least one allele, while a novel point mutation, c.754C>T (p.Arg252Cys) was found in two siblings. CONCLUSION: LOTS seems to be an underdiagnosed cause of progressive distal motor neuron disease, with variably expressed cerebellar impairment and psychiatric symptomatology in our group of adolescent and adult patients. The enzyme assay of β-hexosaminidase A in serum/plasma is a rapid and reliable tool to verify clinical suspicions.
- MeSH
- dospělí MeSH
- duševní poruchy diagnostické zobrazování epidemiologie psychologie MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mozeček diagnostické zobrazování MeSH
- svalová atrofie diagnostické zobrazování epidemiologie psychologie MeSH
- Tay-Sachsova nemoc diagnostické zobrazování epidemiologie psychologie MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
