A personalized treatment decision for Gaucher disease (GD) patients should be based on relevant markers that are specific to GD, play a direct role in GD pathophysiology, exhibit low genetic variation, reflect the therapy, and can be used for all patients. Thirty-four GD patients treated with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) were analyzed for platelet count, chitotriosidase, and tartrate-resistant acid phosphatase activity in plasma samples, and quantitative measurement of Lyso-Gb1 was performed in dried blood spots. In our ERT and SRT study cohorts, plasma lyso-GL1 correlated significantly with chito-triosidase (ERT: r = 0.55, p < 0.001; SRT: r = 0.83, p < 0.001) and TRAP (ERT: r = 0.34, p < 0.001; SRT: r = 0.88, p < 0.001), irrespective of treatment method. A platelet count increase was associated with a Lyso-Gb1 decrease in both treatment groups (ERT: p = 0.021; SRT: p = 0.028). The association of Lyso-Gb1 with evaluated markers was stronger in the SRT cohort. Our results indicate that ERT and SRT in combination or in a switch manner could offer the potential of individual drug effectiveness for particular GD symptoms. Combination of the key biomarker of GD, Lyso-Gb1, with other biomarkers can offer improved response assessment to long-term therapy.

• Klíčová slova
• chitotriosidase, glucosylsphingosine, long term therapy, lyso-Gb1, type 1 Gaucher disease,
• MeSH
• biologické markery MeSH
• enzymová substituční terapie MeSH
• Gaucherova nemoc * diagnóza   farmakoterapie   MeSH
• lidé MeSH
• počet trombocytů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• biologické markery MeSH

BACKGROUND: The Roma are a European ethnic minority threatened by several recessive diseases. Variants in MANBA cause a rare lysosomal storage disorder named beta-mannosidosis whose clinical manifestation includes deafness and mental retardation. Since 1986, only 23 patients with beta-mannosidosis and biallelic MANBA variants have been described worldwide. RESULTS: We now report on further 10 beta-mannosidosis patients of Roma origin from eight families in the Czech and Slovak Republics with hearing loss, mental retardation and homozygous pathogenic variants in MANBA. MANBA variant c.2158-2A>G screening among 345 anonymized normal hearing controls from Roma populations revealed a carrier/heterozygote frequency of 3.77%. This is about 925 times higher than the frequency of this variant in the gnomAD public database and classifies the c.2158-2A>G variant as a prevalent, ethnic-specific variant causing hearing loss and mental retardation in a homozygous state. The frequency of heterozygotes/carriers is similar to another pathogenic variant c.71G>A (p.W24*) in GJB2, regarded as the most frequent variant causing deafness in Roma populations. CONLCUSION: Beta-mannosidosis, due to a homozygous c.2158-2A>G MANBA variant, is an important and previously unknown cause of hearing loss and mental retardation among Central European Roma.

• Klíčová slova
• Beta-mannosidosis, Ethnic-specific variant, Hearing loss, Mental retardation, Roma,
• MeSH
• beta-mannosidóza * MeSH
• etnicita MeSH
• hluchota * genetika   MeSH
• lidé MeSH
• menšiny MeSH
• nedoslýchavost * genetika   MeSH
• Romové * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Slovenská republika epidemiologie   MeSH

BACKGROUND: Fabry disease is an inherited rare metabolic disease caused by mutation in the GLA gene, encoding lysosomal enzyme alpha-galactosidase A. The disorder is a systemic disease that manifests as cerebrovascular and cardiac disease, chronic renal failure, skin lesion, peripheral neuropathy, and other abnormalities. Ventricular tachycardia as a Fabry disease presentation is very rare. CASE SUMMARY: A 36-year-old man self-presented to a general practitioner complaining of episodes of shortness of breath together with a 6-month history of malaise. The 12-lead electrocardiogram (ECG) prompted a decision to transfer him immediately to a percutaneous coronary intervention (PCI) capable hospital under the suspicion of acute coronary syndrome. Whilst awaiting transport, he experienced acute onset of dyspnoea together with non-specific chest heaviness. A repeat ECG monitor strip showed ventricular tachycardia transforming to ventricular fibrillation. The patient was successfully defibrillated. Coronary angiography was performed upon arrival at hospital and demonstrated unobstructed coronary arteries. Transthoracic echocardiography revealed concentric left ventricular hypertrophy (LVH) and normal systolic function, with severe diastolic dysfunction. Magnetic resonance imaging (MRI) confirmed the LVH, and did not demonstrate any late gadolinium enhancement. DISCUSSION: Our case illustrates the pivotal role of critical clinical thinking in the diagnosis of rare but treatable hereditary cardiomyopathy. The uncommon cardiac presentation of Fabry disease promotes further research linking different phenotypes of Fabry disease with different pathogenic mutations.

• Klíčová slova
• Alpha-galactosidase A, Case report, Fabry disease, Hypertrophic cardiomyopathy, Metabolic disease, Ventricular tachycardia,
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Niemann-Pick Type C (NPC) is a progressive and life limiting autosomal recessive disorder caused by mutations in either the NPC1 or NPC2 gene. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of multiple tissue specific lipids in the lysosomes. The clinical spectrum of NPC disease ranges from a neonatal rapidly progressive fatal disorder to an adult-onset chronic neurodegenerative disease. The age of onset of the first (beyond 3 months of life) neurological symptom may predict the severity of the disease and determines life expectancy.NPC has an estimated incidence of ~ 1: 100,000 and the rarity of the disease translate into misdiagnosis, delayed diagnosis and barriers to good care. For these reasons, we have developed clinical guidelines that define standard of care for NPC patients, foster shared care arrangements between expert centres and family physicians, and empower patients. The information contained in these guidelines was obtained through a systematic review of the literature and the experiences of the authors in their care of patients with NPC. We adopted the Appraisal of Guidelines for Research & Evaluation (AGREE II) system as method of choice for the guideline development process. We made a series of conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. These guidelines can inform care providers, care funders, patients and their carers of best practice of care for patients with NPC. In addition, these guidelines have identified gaps in the knowledge that must be filled by future research. It is anticipated that the implementation of these guidelines will lead to a step change in the quality of care for patients with NPC irrespective of their geographical location.

• Klíčová slova
• Diagnosis, Guidelines, Management, NPC, Niemann-Pick Type C,
• MeSH
• lidé MeSH
• Niemannova-Pickova nemoc typu C terapie   MeSH
• směrnice pro lékařskou praxi jako téma * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

PURPOSE: Mucopolysaccharidosis IVA (MPS IVA) is a multisystemic storage disorder. Patient's disability and life expectancy depends upon skeletal complications, including cervical myelopathy due to upper cervical compression or instability. Posterior decompression followed by occipitocervical fixation or C1-2 fusion are the most frequently recommended surgical interventions. The bony elements of C1 and C2 are often inadequately developed making routine screw insertion difficult. The main purpose of this work was to present novel technique of occipitocervical fixation using two C2 laminar screws. METHODS: Four children with MPS IVA underwent decompression and C0-C2 instrumented fusion using two C2 bilateral laminar screws. The dimensions of the C2 lamina were measured. Clinical and radiological results were monitored prospectively for a minimum 3 years. RESULTS: The mean laminar length was 24 ± 1.15 mm, width 6.15 ± 0.55 mm and height 7.4 ± 0.6 mm. Patients remained in a stable neurological condition. The mean antero-posterior diameter of the spinal canal on the pre-operative MR was 6.2 ± 0.74 mm and it was enlarged to 11.4 ± 0.8 mm after 3 years. All screws were placed adequately. In all patients, the control CT scan 2 years post-operatively revealed a stable position of the treated segments, but solid bony fusion was not registered in any patient. CONCLUSIONS: Decompression and fusion of the upper cervical spine is a generally accepted approach to treat upper cervical spine instability and myelopathy in MPS IVA patients. The feasibility and the suitability of the technique of C0-C2 stabilization using bilateral C2 laminar screws have been presented.

• Klíčová slova
• Laminar, Mucopolysaccharidosis, Screw, Stabilization,
• MeSH
• atlantookcipitální kloub chirurgie   MeSH
• chirurgická dekomprese přístrojové vybavení   metody   MeSH
• dítě MeSH
• fúze páteře přístrojové vybavení   metody   MeSH
• komprese míchy diagnóza   etiologie   chirurgie   MeSH
• kostní šrouby * MeSH
• krční obratle chirurgie   MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• mladiství MeSH
• mukopolysacharidóza IV komplikace   MeSH
• nestabilita kloubu chirurgie   MeSH
• počítačová rentgenová tomografie metody   MeSH
• studie proveditelnosti MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• práce podpořená grantem MeSH

BACKGROUND: Niemann-Pick disease type C (NPC) is a rare, fatal neurovisceral disorder with autosomal recessive inheritance, and featuring striking clinical variability dependent on the age at onset of neurological symptoms. We report data from a large cohort of 56 Czech patients with NPC diagnosed over a period of 37 years. METHODS: An observational, retrospective analysis of historic and current clinical and laboratory information was performed among all NPC patients originating from the area of the contemporary Czech Republic and diagnosed between 1975 and 2012. All patients with ≥1 positive diagnostic test and relevant clinical information were included. Data on diagnostic methods (histopathological and/or ultrastructural; biochemical; genetic), clinical status and general information on treatment were collated. Data were examined in accordance with international guidelines for the management of NPC. RESULTS: Between 1975 and 1985 diagnoses were based exclusively on specific histopathological findings, often at autopsy. Bone marrow smear (BMS) analyses have proved to be a very specific indicator for NPC and have become an important part of our diagnostic algorithm. Filipin staining and cholesterol esterification assays became the definitive diagnostic tests after 1985 and were applied in 24 of our patients. Since 2005, more and more patients have been assessed using NPC1/NPC2 gene sequencing. Twelve patients were diagnosed with neonatal/early-infantile onset NPC, 13 with the late-infantile onset form, 20 with the juvenile onset form, and nine with the adolescent/adult onset form. Two diagnosed patients remained neurologically asymptomatic at study completion. Nineteen patients were siblings. Causal NPC1 mutations were determined in 38 patients; two identical NPC2 mutations were identified in one patient. In total, 30 different mutations were identified, 14 of which have been confirmed as novel. The frequency of individual mutated NPC1 alleles in our cohort differs compared with previous published data: the most frequent mutant NPC1 allele was p.R1186H (n = 13), followed by p.P1007A (n = 8), p.S954L (n = 8) and p.I1061T (n = 4). CONCLUSIONS: These data demonstrate the evolution of the diagnostic process in NPC over the last four decades. We estimate the contemporary birth prevalence of NPC in the Czech Republic at 0.93 per 100,000.

• MeSH
• lidé MeSH
• Niemannova-Pickova nemoc typu C diagnóza   epidemiologie   patofyziologie   MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH

BACKGROUND: IgA nephropathy (IgAN) is the most common glomerulonephritis, which may also coexist with other diseases. We present two patients with an unusual coincidence of IgAN and Fabry disease (FD). CASE PRESENTATION: A 26 year-old man underwent a renal biopsy in February 2001. Histopathology showed very advanced IgAN and vascular changes as a result of hypertension. Because of his progressive renal insufficiency the patient began hemodialysis in August 2001. By means of the blood spot test screening method the diagnosis of FD was suspected. Low activity of alpha-galactosidase A in the patient's plasma and leukocytes and DNA analysis confirmed the diagnosis of FD. Enzyme replacement therapy started in July 2004. Then the patient underwent kidney transplantation in November 2005. Currently, his actual serum creatinine level is 250 μmol/l. Other organ damages included hypertrophic cardiomyopathy, neuropathic pain and febrile crisis. After enzyme replacement therapy, myocardial hypertrophy has stabilized and other symptoms have disappeared. No further progression of the disease has been noted.The other patient, a 30 year-old woman, suffered from long-term hematuria with a good renal function. Recently, proteinuria (2.6 g/day) appeared and a renal biopsy was performed. Histopathology showed IgAN with remarkably enlarged podocytes. A combination of IgAN and a high suspicion of FD was diagnosed. Electron microscopy revealed dense deposits in paramesangial areas typical for IgAN and podocytes with inclusive zebra bodies and myelin figures characteristic of FD. FD was confirmed by the decreased alpha-galactosidase A activity in plasma and leukocytes and by DNA and RNA analysis. Enzyme replacement therapy and family screening were initiated. CONCLUSIONS: Our results emphasize the role of complexity in the process of diagnostic evaluation of kidney biopsy samples. Electron microscopy represents an integral part of histopathology, and genetic analysis plays a more and more important role in the final diagnosis, which is followed by causal treatment.

• MeSH
• diferenciální diagnóza MeSH
• dospělí MeSH
• Fabryho nemoc komplikace   diagnóza   MeSH
• IgA nefropatie komplikace   diagnóza   MeSH
• lidé MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH