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Am J Hum Genet ; 109(10): 1885-1893, 2022 Oct 06.
Article En | MEDLINE | ID: mdl-36103875

GABAB receptors are obligatory heterodimers responsible for prolonged neuronal inhibition in the central nervous system. The two receptor subunits are encoded by GABBR1 and GABBR2. Variants in GABBR2 have been associated with a Rett-like phenotype (MIM: 617903), epileptic encephalopathy (MIM: 617904), and milder forms of developmental delay with absence epilepsy. To date, however, no phenotypes associated with pathogenic variants of GABBR1 have been established. Through GeneMatcher, we have ascertained four individuals who each have a monoallelic GABBR1 de novo non-synonymous variant; these individuals exhibit motor and/or language delay, ranging from mild to severe, and in one case, epilepsy. Further phenotypic features include varying degrees of intellectual disability, learning difficulties, autism, ADHD, ODD, sleep disorders, and muscular hypotonia. We functionally characterized the four de novo GABBR1 variants, p.Glu368Asp, p.Ala397Val, p.Ala535Thr, and p.Gly673Asp, in transfected HEK293 cells. GABA fails to efficiently activate the variant receptors, most likely leading to an increase in the excitation/inhibition balance in the central nervous system. Variant p.Gly673Asp in transmembrane domain 3 (TMD3) renders the receptor completely inactive, consistent with failure of the receptor to reach the cell surface. p.Glu368Asp is located near the orthosteric binding site and reduces GABA potency and efficacy at the receptor. GABA exhibits normal potency but decreased efficacy at the p.Ala397Val and p.Ala535Thr variants. Functional characterization of GABBR1-related variants provides a rationale for understanding the severity of disease phenotypes and points to possible therapeutic strategies.

Epilepsy , Intellectual Disability , Nervous System Malformations , Neurodevelopmental Disorders , Epilepsy/genetics , HEK293 Cells , Humans , Intellectual Disability/genetics , Neurodevelopmental Disorders/genetics , gamma-Aminobutyric Acid/metabolism
Mol Genet Metab ; 137(1-2): 164-172, 2022.
Article En | MEDLINE | ID: mdl-36087504

BACKGROUND: The Morquio A Registry Study (MARS) is an ongoing, multinational, observational study of patients with MPS IVA. Key objectives of MARS are to characterize the heterogeneity and natural history of disease and to evaluate long-term effectiveness and safety of elosulfase alfa enzyme replacement therapy (ERT). Enrollment began in September 2014; data on medical history, clinical outcomes, and safety assessments are collected as part of routine care. RESULTS: As of February 2021, 381 subjects from 17 countries had enrolled in MARS: 58 ERT-naïve subjects and 323 ERT-treated subjects (≥1 infusion), with a mean ERT exposure of 5.5 years (SD 2.8) and median age at first ERT treatment of 9.8 years. ERT-treated subjects were younger at diagnosis (median 3.4 vs 6.5 years) relative to ERT-naïve subjects. Among ERT-treated subjects, urinary keratan sulfate (uKS) levels declined from pre-ERT baseline to last follow-up on treatment (mean % change [95% confidence interval]: -52.5% [-57.5%, -47.4%]; n = 115) and 6-min walk test distance remained stable (mean change: -6.1 [-27.6, 15.5] m; n = 131) over a mean follow-up of 5.5 years. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) increased in subjects who were < 18 years of age at ERT initiation (mean change: +0.3 [0.1, 0.4] L and + 0.4 [0.3, 0.5] L; mean follow-up: ∼6 years; n = 82) and were stable in subjects ≥18 years (mean change: 0.0 [-0.0, 0.1] L and 0.0 [-0.1, 0.1] L; mean follow-up: 4.6 years; n = 38). Overall, 148 (47.1%) ERT-treated subjects experienced ≥1 adverse event (AE) and 110 subjects (35%) reported ≥1 serious AE. Drug-related AEs were reported in 39 (12.4%) subjects; the most common were hypersensitivity (9 subjects [2.9%]), urticaria (8 subjects [2.5%]), and pyrexia (7 subjects [2.2%]). CONCLUSIONS: MARS is the longest and largest observational study of MPS IVA patients to date, with a heterogenous population that is representative of the MPS IVA population overall. Data collected over the first 6 years of MARS provide real-world evidence for long-term stabilization of endurance and respiratory function among ERT-treated patients, with no new safety concerns identified.

Mucopolysaccharidosis IV , Humans , Child , Keratan Sulfate/urine , Double-Blind Method , Enzyme Replacement Therapy/adverse effects , Registries
Acta Medica (Hradec Kralove) ; 65(1): 41-43, 2022.
Article En | MEDLINE | ID: mdl-35793509

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and the presence of restricted interests and repetitive behaviors. Transient hyperphosphatasemia of infancy and early childhood (THI) is a benign laboratory disorder characterized by transiently extremely elevated activity of serum alkaline phosphatase (S-ALP). CASE REPORT: We present a 21-month-old girl with a right leg limp, most probably due to reactive arthritis after febrile viral infection, and deterioration of psychomotor development with concomitant transient elevation of S-ALP (61.74 µkat/L; normal 2.36-7.68 µkat/L). Normal values of serum creatinine, aspartate-aminotransferase, alanin-aminotransferase, calcium, phosphate, together with normal wrist X-ray ruled out rickets or other bone or hepatic cause of high S-ALP. The S-ALP gradually decreased within 3 months, thus fulfilling the THI criteria. Screening for inborn errors of metabolism was negative and meticulous neurologic, psychologic and psychiatric assessment pointed to the diagnosis of autism spectrum disorder (ASD). There was no causal relationship between THI and ASD, as high S-ALP was an accidental and transient finding within the routine laboratory assessment. However, when THI occurs in a child with an onset of a new disorder, or with a pre-existing bone or liver disease, it might seriously concern the physician. CONCLUSION: Children with THI should be spared from extensive evaluations and unnecessary blood draws.

Autism Spectrum Disorder , Hyperphosphatemia , Autism Spectrum Disorder/complications , Autism Spectrum Disorder/diagnosis , Female , Humans , Hyperphosphatemia/diagnosis , Hyperphosphatemia/etiology , Infant , Reference Values
JMIR Res Protoc ; 11(6): e32986, 2022 Jun 07.
Article En | MEDLINE | ID: mdl-35671071

BACKGROUND: Mild to moderate hearing loss is common in patients with mucopolysaccharidosis (MPS) IVA. The hearing loss can be conductive, sensorineural, or mixed. However, in these patients, the mixed form is frequent, attributed to the combination of conductive and neurosensory elements, with slowly progressive evolution. Conductive hearing loss may be secondary to recurrent upper respiratory tract infections, serous otitis media, and deformities of the ear ossicles due to the accumulation of glycosaminoglycans (GAGs). Meanwhile, the sensorineural form is mainly attributed to the accumulation of GAGs in the auditory system. OBJECTIVE: The aim of this scoping review is to understand the extent and type of evidence in relation to the physiopathology, classification, epidemiology, and clinical management of hearing loss and the effect of therapy for hearing loss in patients with MPS IVA. METHODS: This scoping review includes participants across all genders and of no particular age group who are diagnosed with MPS IVA and develop hearing loss as a comorbidity. No exclusion criteria (country, language, or document type) will be applicable. The information sources will include experimental and quasi-experimental, analytical observational, observational, and qualitative studies. Unpublished literature will not be covered. Grey literature will be covered. A total of 2 independent reviewers will participate in the process of screening the literature, paper selection, and data extraction, and this process will be performed blindly. When all manuscripts have been selected, disagreements that arise between the 2 reviewers at each stage of the selection process will be resolved through discussion or with an additional reviewer. Results will be reported with descriptive statistics and information will be displayed in a diagrammatic or tabular manner, as explained in the JBI guidelines. RESULTS: The literature search was performed in November 2021 in MEDLINE, LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde), the Cochrane Library, ScienceDirect, Google Scholar, and OpenGrey; a total of 780 results were retrieved. Completion of the review is expected in mid-2022. CONCLUSIONS: This scoping review will be the first to describe the extent of the information regarding the development of hearing loss in the MPS IVA population. The data gathered by this review may lead to an understanding of the grade of hearing loss in this population and allow for the assessment of possible interventions according to the disease pattern. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/32986.

Orphanet J Rare Dis ; 17(1): 190, 2022 05 10.
Article En | MEDLINE | ID: mdl-35538504

BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA), or Morquio A syndrome, is a rare inherited metabolic disorder caused by deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. A progressive systemic skeletal chondrodysplasia, leading to significant morbidity and reduced life expectancy is the main clinical feature of this multisystemic disease. Although enzyme replacement therapy with elosulfase alfa is established in Europe, the rarity of disease and other factors still set hurdles in having patients treated in some countries. Aim of this statement is to provide evidence-based guidance for the enzyme replacement treatment of Morquio A patients, harmonizing recommendations from published guidelines with the real-life clinical practice in the Central and South-Eastern European region. PARTICIPANTS: The Consensus Group, convened by 8 Steering Committee (SC) members from 7 Central and South-Eastern European countries, consisted of a multidisciplinary group of 17 experts in the management of MPS in Central and South-Eastern Europe. CONSENSUS PROCESS: The SC met in a first virtual meeting with an external scientific coordinator, to discuss on clinical issues to be analyzed in guidance statements. Statements were developed by the scientific coordinator, evaluated by the SC members in a first modified-Delphi voting and adapted accordingly, to be submitted to the widest audience in the Consensus Conference. Following discussion and further modifications, all participants contributed to a second round of modified-Delphi voting. RESULTS: Nine of ten statements, concerning general guidelines for management of MPS IVA patients and specific recommendations for treatment, received final consensus. CONCLUSIONS: European guidelines and evidence-based recommendations for Morquio A patients should be considered in the real life of Central and South-Eastern European countries and adapted to unique clinical practice approaches and criteria for patients' access to treatment and reimbursement in the region.

Mucopolysaccharidoses , Mucopolysaccharidosis IV , Amino Acid Metabolism, Inborn Errors , Consensus , Enzyme Replacement Therapy , Humans , Isovaleryl-CoA Dehydrogenase/deficiency , Mucopolysaccharidoses/drug therapy , Mucopolysaccharidosis IV/drug therapy
Orphanet J Rare Dis ; 17(1): 136, 2022 03 24.
Article En | MEDLINE | ID: mdl-35331284

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defects in genes coding for different lysosomal enzymes which degrade glycosaminoglycans. Impaired lysosomal degradation causes cell dysfunction leading to progressive multiorgan involvement, disabling consequences and poor life expectancy. Enzyme replacement therapy (ERT) is now available for most MPS types, offering beneficial effects on disease progression and improving quality of life of patients. The landscape of MPS in Europe is not completely described and studies on availability of treatment show that ERT is not adequately implemented, particularly in Southern and Eastern Europe. In this study we performed a survey analysis in main specialist centers in Southern and Eastern European countries, to outline the picture of disease management in the region and understand ERT implementation. Since the considerable number of MPS IVA patients in the region, particularly adults, the study mainly focused on MPS IVA management and treatment. RESULTS: 19 experts from 14 Southern and Eastern European countries in total responded to the survey. Results outlined a picture of MPS management in the region, with a high number of MPS patients managed in the centers and a high level of care. MPS II was the most prevalent followed by MPS IVA, with a particular high number of adult patients. The study particularly focused on management and treatment of MPS IVA patients. Adherence to current European Guidelines for follow-up of MPS IVA patients is generally adequate, although some important assessments are reported as difficult due to the lack of MPS skilled specialists. Availability of ERT in Southern and Eastern European countries is generally in line with other European regions, even though regulatory, organizational and reimbursement constrains are demanding. CONCLUSIONS: The landscape of MPS in Southern and Eastern European countries is generally comparable to that of other European regions, regarding epidemiology, treatment accessibility and follow up difficulties. However, issues limiting ERT availability and reimbursement should be simplified, to start treatment as early as possible and make it available for more patients. Besides, educational programs dedicated to specialists should be implemented, particularly for pediatricians, clinical geneticists, surgeons, anesthesiologists and neurologists.

Mucopolysaccharidoses , Mucopolysaccharidosis II , Mucopolysaccharidosis IV , Adult , Enzyme Replacement Therapy/methods , Humans , Mucopolysaccharidoses/drug therapy , Mucopolysaccharidoses/therapy , Mucopolysaccharidosis II/drug therapy , Mucopolysaccharidosis IV/drug therapy , Quality of Life
Am J Med Genet A ; 188(7): 1979-1989, 2022 07.
Article En | MEDLINE | ID: mdl-35338595

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding alpha-galactosidase A (AGAL). The impact of X-chromosome inactivation (XCI) on the phenotype of female FD patients remains unclear. In this study we aimed to determine pitfalls of XCI testing in a cohort of 35 female FD patients. XCI was assessed by two methylation-based and two allele-specific expression assays. The results correlated, although some variance among the four assays was observed. GLA transcript analyses identified crossing-over in three patients and detected mRNA instability in three out of four analyzed null alleles. AGAL activity correlated with XCI pattern and was not influenced by the mutation type or by reduced mRNA stability. Therefore, AGAL activity may help to detect crossing-over in patients with unstable GLA alleles. Tissue-specific XCI patterns in six patients, and age-related changes in two patients were observed. To avoid misinterpretation of XCI results in female FD patients we show that (i) a combination of several XCI assays generates more reliable results and minimizes possible biases; (ii) correlating XCI to GLA expression and AGAL activity facilitates identification of cross-over events; (iii) age- and tissue-related XCI specificities of XCI patterning should be considered.

Fabry Disease , Chromosomes , Fabry Disease/diagnosis , Fabry Disease/genetics , Female , Humans , Mutation , Phenotype , X Chromosome Inactivation/genetics , alpha-Galactosidase/genetics
Neurol Sci ; 43(5): 3273-3281, 2022 May.
Article En | MEDLINE | ID: mdl-34800199

PURPOSE: Late-onset Tay-Sachs disease (LOTS) is a form of GM2 gangliosidosis, an autosomal recessive neurodegenerative disorder characterized by slowly progressive cerebellar ataxia, lower motor neuron disease, and psychiatric impairment due to mutations in the HEXA gene. The aim of our work was to identify the characteristic brain MRI findings in this presumably underdiagnosed disease. METHODS: Clinical data and MRI findings from 16 patients (10F/6 M) with LOTS from two centers were independently assessed by two readers and compared to 16 age- and sex-related controls. RESULTS: Lower motor neuron disease (94%), psychiatric symptoms-psychosis (31%), cognitive impairment (38%) and depression (25%)-and symptoms of cerebellar impairment including dysarthria (94%), ataxia (81%) and tremor (69%), were the most common clinical features. On MRI, pontocerebellar atrophy was a constant finding. Compared to controls, LOTS patients had smaller mean middle cerebellar peduncle diameter (p < 0.0001), mean superior cerebellar peduncle diameter (p = 0.0002), mesencephalon sagittal area (p = 0.0002), pons sagittal area (p < 0.0001), and larger 4th ventricle transversal diameter (p < 0.0001). Mild corpus callosum thinning (37.5%), mild cortical atrophy (18.8%), and white matter T2 hyperintensities (12.5%) were also present. CONCLUSION: Given the characteristic clinical course and MRI findings of the pontocerebellar atrophy, late-onset Tay-Sachs disease should be considered in the differential diagnosis of adult-onset cerebellar ataxias.

Cerebellar Diseases , Gangliosidoses, GM2 , Motor Neuron Disease , Tay-Sachs Disease , Adult , Atrophy , Humans , Late Onset Disorders , Magnetic Resonance Imaging , Tay-Sachs Disease/diagnostic imaging , Tay-Sachs Disease/genetics
Foods ; 10(8)2021 Aug 19.
Article En | MEDLINE | ID: mdl-34441704

Broccoli sprouts contain 10-100 times higher levels of sulforaphane than mature plants, something that has been well known since 1997. Sulforaphane has a whole range of unique biological properties, and it is especially an inducer of phase 2 detoxication enzymes. Therefore, its use has been intensively studied in the field of health and nutrition. The formation of sulforaphane is controlled by the epithiospecifier protein, a myrosinase co-factor, which is temperature-specific. This paper studies the influence of temperature, heating time, the addition of myrosinase in the form of Raphanus sativus sprouts in constant ratio to broccoli sprouts, and other technological steps on the final sulforaphane content in broccoli sprout homogenates. These technological steps are very important for preserving sulforaphane in broccoli sprouts, but there are some limitations concerning the amount of sulforaphane. We focused, therefore, on the extraction process, using suitable ß-cyclodextrin, hexane and ethanol, with the goal of increasing the amount of sulforaphane in the final extract, thus stabilizing it and reducing the required amount sulforaphane needed, e.g., as a dietary supplement.

Cardiovasc Pathol ; 50: 107297, 2021.
Article En | MEDLINE | ID: mdl-33045360

Mucopolysaccharidosis type VII (MPS VII) is a rare autosomal recessive lysosomal storage disorder. MPS VII is caused by mutations in the GUSB gene that encodes ß-glucuronidase. Adult MPS VII patients present with musculoskeletal abnormalities, coarse features, and corneal clouding. Cardiac and valvular impairment are common; however, severe valvular disease necessitating surgery has not yet been reported. We present a 32-year-old male MPS VII patient admitted to our hospital with decompensated heart failure. We identified aortic valve disease with severe stenosis (valve area 0.69 cm2) and moderate regurgitation. Severe mitral valve stenosis (valve area 1 cm2) with moderate to severe regurgitation was also found in the patient. In addition, an occlusion of the right coronary artery (RCA) was documented. The patient underwent surgical replacement of the mitral and aortic valves with mechanical prostheses and implantation of a venous bypass graft to his RCA. The surgery led to a significant improvement of his clinical symptoms. Six months after the procedure, both mechanical valves function normally. Histopathological assessment identified chronic inflammatory infiltrates, fibrosis and calcifications in both resected valves. Foamy cytoplasmic transformation was most evident in the valvular interstitial cells. The ultrastructural vacuolar abnormality seen in these cells corresponded to storage changes observed in other MPSs. In conclusion, we describe clinical findings and valvular pathology in an MPS VII patient with the first-reported successful combined surgical valve replacement and myocardial revascularization. The histological and ultrastructural analyses revealed that the lysosomal storage predominantly affected the valvular interstitial cells.

Aortic Valve Insufficiency/surgery , Aortic Valve Stenosis/surgery , Coronary Artery Bypass , Coronary Occlusion/surgery , Heart Valve Prosthesis Implantation , Mitral Valve Insufficiency/surgery , Mitral Valve Stenosis/surgery , Mucopolysaccharidosis VII/complications , Adult , Aortic Valve Insufficiency/diagnostic imaging , Aortic Valve Insufficiency/etiology , Aortic Valve Stenosis/diagnostic imaging , Aortic Valve Stenosis/etiology , Coronary Occlusion/diagnostic imaging , Coronary Occlusion/etiology , Humans , Male , Mitral Valve Insufficiency/diagnostic imaging , Mitral Valve Insufficiency/etiology , Mitral Valve Stenosis/diagnostic imaging , Mitral Valve Stenosis/etiology , Mucopolysaccharidosis VII/diagnosis , Severity of Illness Index , Treatment Outcome
Mol Genet Metab ; 132(3): 189-197, 2021 03.
Article En | MEDLINE | ID: mdl-33317989

OBJECTIVE: Despite profound neurological symptomatology there are only few MRI studies focused on the brain abnormalities in alpha-mannosidosis (AM). Our aim was to characterize brain MRI findings in a large cohort of AM patients along with clinical manifestations. METHODS: Twenty-two brain MRIs acquired in 13 untreated AM patients (8 M/5F; median age 17 years) were independently assessed by three experienced readers and compared to 16 controls. RESULTS: Focal and/or diffuse hyperintense signals in the cerebral white matter were present in most (85%) patients. Cerebellar atrophy was common (62%), present from the age of 5 years. Progression was observed in two out of 6 patients with follow-up scans. Cortical atrophy (62%) and corpus callosum thinning (23%) were already present in a 13-month-old child. The presence of low T2 signal intensity in basal ganglia and thalami was excluded by the normalized signal intensity profiling. The enlargement of perivascular spaces in white matter (38%), widening of perioptic CSF spaces (62%), and enlargement of cisterna magna (85%) were also observed. Diploic space thickening (100%), mucosal thickening (69%) and sinus hypoplasia (54%) were the most frequent non-CNS abnormalities. CONCLUSION: White matter changes and cerebellar atrophy are proposed to be the characteristic brain MRI features of AM. The previously reported decreased T2 signal intensity in basal ganglia and thalami was not detected in this quantitative study. Rather, this relative MR appearance seems to be related to the diffuse high T2 signal in the adjacent white matter and not the gray matter iron deposition that has been hypothesized.

Atrophy/diagnosis , Cerebellum/diagnostic imaging , White Matter/diagnostic imaging , alpha-Mannosidosis/diagnosis , Adolescent , Adult , Atrophy/diagnostic imaging , Atrophy/pathology , Brain/diagnostic imaging , Brain/pathology , Cerebellum/pathology , Child , Child, Preschool , Female , Humans , Infant , Magnetic Resonance Imaging/methods , Male , Nervous System Malformations/diagnosis , Nervous System Malformations/diagnostic imaging , Nervous System Malformations/pathology , Neuroimaging/methods , White Matter/pathology , Young Adult , alpha-Mannosidosis/diagnostic imaging , alpha-Mannosidosis/pathology
Front Pediatr ; 8: 597736, 2020.
Article En | MEDLINE | ID: mdl-33304869

During the COVID-19 pandemics of 2020, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), both adults and children were shown to mount a specific antibody response to the virus. As infected children often exhibit mild symptoms or even remain asymptomatic, they are likely to be under tested for the direct presence of the virus. Mapping the SARS-CoV-2 antibodies frequency informs more accurately on the disease prevalence and helps guide the protective and therapeutic strategies. To date, only few seroprevalence studies included children. In the Czech Republic, in April 2020, the overall SARS-CoV-2 seroprevalence was estimated not to exceed 1.3%. In July and August, 2020, we screened 200 children (0-18 years of age), who attended the pediatric department of a large hospital in Prague for various COVID-19-unrelated reasons, for the presence of SARS-CoV-2 antibodies. Zero seropositive subjects were found. Therefore, we hereby report a low (<0.5%) seroprevalence amongst children in Prague, as of August, 2020.

Brain Sci ; 10(11)2020 Oct 22.
Article En | MEDLINE | ID: mdl-33105723

BACKGROUND: In this retrospective study, we analysed clinical, biochemical and molecular genetic data of 47 Czech patients with Single, Large-Scale Mitochondrial DNA Deletions (SLSMD). METHODS: The diagnosis was based on the long-range PCR (LX-PCR) screening of mtDNA isolated from muscle biopsy in 15 patients, and from the buccal swab, urinary epithelial cells and blood in 32 patients. RESULTS: A total of 57% patients manifested before the age of 16. We did not find any significant difference between paediatric and adult manifestation in either the proportion of patients that would develop extraocular symptoms, or the timespan of its progression. The survival rate in patients with Pearson Syndrome reached 60%. Altogether, five patients manifested with atypical phenotype not fulfilling the latest criteria for SLSMD. No correlation was found between the disease severity and all heteroplasmy levels, lengths of the deletion and respiratory chain activities in muscle. CONCLUSIONS: Paediatric manifestation of Progressive External Ophthalmoplegia (PEO) is not associated with a higher risk of multisystemic involvement. Contrary to PEO and Kearns-Sayre Syndrome Spectrum, Pearson Syndrome still contributes to a significant childhood mortality. SLSMD should be considered even in cases with atypical presentation. To successfully identify carriers of SLSMD, a repeated combined analysis of buccal swab and urinary epithelial cells is needed.

Int J Pediatr Otorhinolaryngol ; 135: 110137, 2020 Aug.
Article En | MEDLINE | ID: mdl-32502916

OBJECTIVES: The mucopolysaccharidoses (MPS) are inherited lysosomal storage disorders with multisystemic and highly variable clinical manifestation. ENT symptoms are common and early signs of MPS. The most common ENT diagnoses are chronic/recurrent rhinosinusitis, acute otitis media, otitis media with effusion, hearing loss and airway obstruction. METHODS: A single-centre retrospective chart review of 61 patients (36 M/25F) with different MPS subtypes (MPS I (n = 15), MPS II (n = 10), MPS III (n = 17), MPS IV (n = 15) and MPS VI (n = 4)) was conducted. The age of ENT presentation and frequency of ENT symptoms, surgeries and their distribution among MPS subtypes was studied. The relationship between ENT presentation, first ENT surgery and the age of diagnosis was also evaluated. RESULTS: Median age at the first ENT manifestation was 2.8 years, median age at MPS diagnosis 4.1 years. The great majority of patients (90%) manifested at least one ENT diagnosis; often before the diagnosis of MPS (75%). Chronic/recurrent rhinosinusitis was the most prevalent ENT diagnosis (77%), followed by upper airway obstruction (65%) and hearing loss (53%). Chronic/recurrent rhinosinusitis was the first ENT symptom to appear (median age 2.2 years), followed by otitis media with effusion (3.7 years) and hearing loss (4.5 years). At least one ENT surgery was performed in 57% of patients; in 69% before MPS diagnosis was established. Median age of the first ENT surgery was 4.1 years. ENT symptoms and surgical procedures were earliest present in MPS II. CONCLUSIONS: Our study documents high and early occurrence of various otolaryngologic symptoms in MPS and thus highlights the role of ENT specialist in prompt diagnosis of these rare diseases and their long-term management.

Airway Obstruction/etiology , Hearing Loss/etiology , Mucopolysaccharidoses/complications , Rhinitis/etiology , Sinusitis/etiology , Adolescent , Age Factors , Child , Child, Preschool , Chronic Disease , Female , Humans , Infant , Male , Mucopolysaccharidoses/diagnosis , Mucopolysaccharidosis I/complications , Mucopolysaccharidosis I/diagnosis , Mucopolysaccharidosis II/complications , Mucopolysaccharidosis II/diagnosis , Mucopolysaccharidosis III/complications , Mucopolysaccharidosis III/diagnosis , Mucopolysaccharidosis IV/complications , Mucopolysaccharidosis IV/diagnosis , Mucopolysaccharidosis VI/complications , Mucopolysaccharidosis VI/diagnosis , Otitis Media with Effusion/etiology , Otorhinolaryngologic Surgical Procedures , Retrospective Studies , Young Adult
J Dermatol ; 47(6): 663-668, 2020 Jun.
Article En | MEDLINE | ID: mdl-32250467

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with tyrosine-kinase signaling activity, involved in many cellular functions including cell growth and differentiation. Germ line loss-of-function mutations in EGFR lead to a severe neonatal skin disorder (Online Mendelian Inheritance in Man #131550). We report 18 premature Roma children from 16 families with birthweights ranging 440-1470 g and multisystem diseases due to the homozygous mutation c.1283G˃A (p.Gly428Asp) in EGFR. They presented with thin, translucent, fragile skin (14/15), skin desquamation (10/17), ichthyosis (9/17), recurrent skin infections and sepsis (9/12), nephromegaly (10/16) and congenital heart defects (7/17). Their prognosis was poor, and all died before the age of 6 months except one 13-year-old boy with a severe skin disorder, dentinogenesis imperfecta, Fanconi-like syndrome and secondary hyperaldosteronism. Management of ion and water imbalances and extremely demanding skin care may improve the unfavorable outcome of such patients.

Dentinogenesis Imperfecta/mortality , Heart Defects, Congenital/mortality , Ichthyosis/mortality , Kidney Diseases/mortality , Roma/genetics , Adolescent , Child , Child, Preschool , Czech Republic/epidemiology , Dentinogenesis Imperfecta/diagnosis , Dentinogenesis Imperfecta/genetics , ErbB Receptors/deficiency , ErbB Receptors/genetics , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/genetics , Homozygote , Humans , Ichthyosis/diagnosis , Ichthyosis/genetics , Infant , Infant, Newborn , Infant, Premature , Infant, Very Low Birth Weight , Kidney Diseases/congenital , Kidney Diseases/diagnosis , Kidney Diseases/genetics , Loss of Function Mutation , Severity of Illness Index , Slovakia/epidemiology , Syndrome , Whole Exome Sequencing
Nutr Diet ; 77(3): 310-314, 2020 07.
Article En | MEDLINE | ID: mdl-31012243

AIM: Evidence has demonstrated that breastfeeding is the optimal nutrition for infants. The present study aims to report possible associations of the duration of full or partial breastfeeding with selected health outcomes during infancy. METHODS: Data from 2304 mothers were obtained by online mother-reported questionnaires at the age of 1 year of the child, providing information on full and partial breastfeeding durations, the frequency of infant upper respiratory tract infections and possible antibiotics use, and the occurrence of allergic diseases. RESULTS: Overall breastfeeding initiation rates (i.e. including both partial and full breastfeeding rates counted together) were 97.8%, declined to 95.1% at the age of 3 months, and remained as high as 90.0% at 6 months. At 1 year, 74.7% of children were still partially breastfed. There was no significant benefit of either full or partial breastfeeding over formula feeding for upper respiratory tract infection rates. Fully breastfed children had a significantly lower risk of early exposure to antibiotics when compared with either partially breastfed (odds ratio, OR: 0.74; 95% CI: 0.56, 1.00, P = 0.048) or formula-fed (OR: 0.67; 95% CI: 0.46, 1.0, P = 0.047) children. We found a neutral effect of breastfeeding on the development of allergies. CONCLUSIONS: Although no significant association between either full or partial breastfeeding versus formula feeding and the occurrence of respiratory infections during infancy was found, we demonstrated a significantly lower risk of early exposure to antibiotics in fully breastfed children when compared with those either partially breastfed or formula-fed.

Breast Feeding , Health Status , Infant Health , Adult , Anti-Bacterial Agents/administration & dosage , Cross-Sectional Studies , Czech Republic , Female , Humans , Hypersensitivity/epidemiology , Infant , Male , Mothers , Respiratory Tract Infections/epidemiology , Self Report
J Neurol ; 266(8): 1953-1959, 2019 Aug.
Article En | MEDLINE | ID: mdl-31076878

BACKGROUND: Tay-Sachs disease (TSD) is an inherited neurodegenerative disorder caused by a lysosomal ß-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 ß-hexosaminidase A in serum/plasma is a rapid and reliable tool to verify clinical suspicions.

Cerebellum/diagnostic imaging , Mental Disorders/diagnostic imaging , Muscular Atrophy/diagnostic imaging , Tay-Sachs Disease/diagnostic imaging , Adolescent , Adult , Age of Onset , Cohort Studies , Czech Republic/epidemiology , Female , Humans , Male , Mental Disorders/epidemiology , Mental Disorders/psychology , Middle Aged , Muscular Atrophy/epidemiology , Muscular Atrophy/psychology , Tay-Sachs Disease/epidemiology , Tay-Sachs Disease/psychology , Young Adult
Pediatr Blood Cancer ; 66(4): e27591, 2019 04.
Article En | MEDLINE | ID: mdl-30588737

BACKGROUND: Sideroblastic anemia represents a heterogeneous group of inherited or acquired diseases with disrupted erythroblast iron utilization, ineffective erythropoiesis, and variable systemic iron overload. In a cohort of 421 patients with multisystem mitochondrial diseases, refractory anemia was found in 8 children. RESULTS: Five children had sideroblastic anemia with increased numbers of ring sideroblasts >15%. Two of the children had a fatal course of MLASA1 syndrome (mitochondrial myopathy, lactic acidosis, and sideroblastic anemia [SA]) due to a homozygous, 6-kb deletion in the PUS1 gene, part of the six-member family of pseudouridine synthases (pseudouridylases). Large homozygous deletions represent a novel cause of presumed PUS1-loss-of-function phenotype. The other three children with SA had Pearson syndrome (PS) due to mtDNA deletions of 4 to 8 kb; two of these children showed early onset of PS and died due to repeated sepsis; the other child had later onset of PS and survived as the hematological parameters normalized and the disease transitioned to Kearns-Sayre syndrome. In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the heterozygous mutations c.610A>G (p.Asn204Asp) and c.674C>T (p.Pro225Leu) in the COX10 gene encoding the cytochrome c oxidase assembly factor. CONCLUSIONS: Sideroblastic anemia was found in fewer than 1.2% of patients with multisystem mitochondrial disease, and it was usually associated with an unfavorable prognosis.

Acyl-CoA Dehydrogenase, Long-Chain/deficiency , Anemia, Sideroblastic , Iron Overload , Lipid Metabolism, Inborn Errors , MELAS Syndrome , Mitochondrial Diseases , Muscular Diseases , Acyl-CoA Dehydrogenase, Long-Chain/genetics , Acyl-CoA Dehydrogenase, Long-Chain/metabolism , Anemia, Sideroblastic/genetics , Anemia, Sideroblastic/metabolism , Anemia, Sideroblastic/pathology , Child , Child, Preschool , Congenital Bone Marrow Failure Syndromes , Female , Humans , Iron Overload/genetics , Iron Overload/metabolism , Iron Overload/pathology , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/metabolism , Lipid Metabolism, Inborn Errors/pathology , MELAS Syndrome/genetics , MELAS Syndrome/metabolism , Male , Mitochondrial Diseases/genetics , Mitochondrial Diseases/metabolism , Mitochondrial Diseases/pathology , Muscular Diseases/genetics , Muscular Diseases/metabolism , Muscular Diseases/pathology