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Moznost provést molekulárne genetické potvrzení dia shy;gnózy ACY1D má zásadní vyznam pro rodinu postizeného probanda. Vázená redakce, deficit aminoacylázy 1 (ACY1D) (MIM 609924) patrí mezi vzácné dedicné poruchy metabolizmu a je charakterizován zvysenym vylucováním N-acetylovanych aminokyselin do moci (serin, kyselina glutamová, alanin, methionin, glycin, leucin a valin). V Centru molekulární bio shy;logie a genetiky Interní hemato-onkologické kliniky FN Brno byla provedena analyza DNA genu I ACY1 i pomocí panelového sekvenování nové generace (target sequencing) s vyuzitím SeqCap EZ Choice Library (Roche Nimble-Gene, Madison, WI, USA) na platforme Illumina. [Extracted from the article]

Dominant optic atrophy (DOA) is an autosomal dominant disorder manifest--ing by slowly progres-sive painless bilateral visual acuity loss with variable degree of severity. DOA is caused by mutations in nuclear DNA encod--ing proteins as-sociated with the in-ner mitochondrial membrane. Most individuals with DOA harbour a dis-ease-caus--ing mutation in the OPA1 gene; however, other genes and loci as-sociated with DOA have also been identified. First symp-toms usual-ly manifest in the first two decades of life. The dis-ease mechanism lies in neurodegenerative damage of retinal ganglion cel-ls lead--ing to optic nerve atrophy. Decrease of visual acuity is as-sociated with colour vision alterations and central or paracentral visual field defects. On fundoscopic examination, optic head nerve pal-lor can be noticed, occasional-ly with excavation. Extraocular symp-toms are present in some patients, caus--ing so-cal-led DOA plus syndrome. Bilateral sensorineural hear--ing los-s, is the most common one; chronic progres-sive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like disorder, and spastic paraplegia of lower limbs are rare. Cur-rently, there is no ef-fective treatment available that would prevent the development of visual impairment. Genetic dia-gnostics and fol-low-up of patients with DOA are held in the Centre for Patients with Mitochondrial Optic Neuropathies, General University Hospital in Prague. The aim of this review is to increase awareness of the most com-mon genetical-ly determined optic neuropathy. [ABSTRACT FROM AUTHOR]

Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a severe metabolic disease manifesting as muscle hypotonia, developmental delay, cerebellar ataxia and ocular symptoms; typically, nystagmus and optic disc pallor. Recently, early onset retinal dystrophy has been reported as an additional feature. In this study, we summarize ocular phenotypes and SRD5A3 variants reported to be associated with SRD5A3-CDG. We also describe in detail the ophthalmic findings in a 12-year-old Czech child harbouring a novel homozygous variant, c.436G>A, p.(Glu146Lys) in SRD5A3. The patient was reviewed for congenital nystagmus and bilateral optic neuropathy diagnosed at 13 months of age. Examination by spectral domain optical coherence tomography and fundus autofluorescence imaging showed clear signs of retinal dystrophy not recognized until our investigation. Best corrected visual acuity was decreased to 0.15 and 0.16 in the right and left eye, respectively, with a myopic refractive error of -3.0 dioptre sphere (DS) / -2.5 dioptre cylinder (DC) in the right and -3.0 DS / -3.0 DC in the left eye. The proband also had optic head nerve drusen, which have not been previously observed in this syndrome. [ABSTRACT FROM AUTHOR]

Introduction: Inborn Errors of Metabolism (IEM) represent a group of >1000 rare genetic disorders that are caused by a defect of single/multiple enzymes or changes in structural, assembling and transporting proteins that participate in metabolic pathways. Since any system can be affected, variable clinical symptoms may occur, leading to a diagnostic delay. Aim: To provide clear overview of the main key clinical and laboratory findings of IEM encountered by both primary health care or hospital physicians – pediatricians. Results: Main clinical features of IEM are represented by developmental regression, pharmacoresistant epilepsy, cardiomyopathy, myopathic syndrome or muscle pain in rhabdomyolysis and hepato-/splenomegaly. As much as 70% of a childhood urolithiasis are caused by one of the IEM. Detailed ophthalmic examination may reveal corneal clouding or cataract, ophthalmoplegia, pigmentary retinopathy and optic neuropathy. Some of the symptoms may be helpful in making the right diagnosis faster at a glance, such as craniofacial dysmorphism, hypertrichosis, atypical structure of adnexa and some bone changes. The main laboratory abnormalities include hypoglycemia, hyperammonemia, dyslipidemia and (cholestatic) hepatopathy. Standardized cerebrospinal fluid examination is crucial for the diagnosis of some of the IEM that can be potentially treatable. Conclusion: Although individual IEM are considered rare, their estimated total prevalence is higher than 1:200. It is therefore very likely, that most physicians will experience at least one of the IEM in their lifetime. Setting up the correct diagnosis is of utmost importance for initiating therapy as for genetic and prenatal counselling. [ABSTRACT FROM AUTHOR]

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Copyright of Czecho-Slovak Pediatrics / Česko-Slovenská Pediatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Czecho-Slovak Pediatrics / Česko-Slovenská Pediatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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Leber hereditary optic neuropathy (LHON) is maternal ly inherited disorder characterized by subacute loss of vision due to impairment of retinal ganglion cel ls eventual ly lead ing to optic atrophy. Three prevalent point mutations in mitochondrial DNA: m.11778G>A, m.3460G>A, and m.14484T>C, are causative in the majority (> 95%) of cases. All of these mutations aff ect one of the subunits of complex I, NADH-ubiquinone oxidoreductase, the fi rst enzyme of the mitochondrial respiratory chain. The presence of a mutation is neces sary but not suffi cient to cause visual los s. The penetrance is incomplete with only about 50% of men and 10% of women event. develop ing clinical signs of the dis ease. Recently, it was proven that early initiation of ther apy with idebenone in patients manifest ing LHON ameliorates visual functions and clinical trials test ing several other promis ing ther apies are underway. Incomplete penetrance, similarites with other disorders affect ing the optic nerve and a great variability of clinical features cause considerable dia gnostic diffi culties. Often there is a delay in ther apy initiation, as late as in the phase of the ir reversible optic nerve damage. In 2013, we established a multidisciplinary medical care centre dedicated to patients with mitochondrial optic neuropathies in General University Hospital in Prague to develop eff ective diagnostic and treatment algorithms and to study the underlying pathogenetic mechanisms. [ABSTRACT FROM AUTHOR]

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Mitochondrial morphology was studied in cultivated myoblasts obtained from patients with mitochondrial disorders, including CPEO, MELAS and TMEM70 deficiency. Mitochondrial networks and ultrastructure were visualized by fluorescence microscopy and transmission electron microscopy, respectively. A heterogeneous picture of abnormally sized and shaped mitochondria with fragmentation, shortening, and aberrant cristae, lower density of mitochondria and an increased number of “megamitochondria” were found in patient myoblasts. Morphometric Fiji analyses revealed different mitochondrial network properties in myoblasts from patients and controls. The small number of cultivated myoblasts required for semiautomatic morphometric image analysis makes this tool useful for estimating mitochondrial disturbances in patients with mitochondrial disorders. [ABSTRACT FROM PUBLISHER]

Copyright of Czecho-Slovak Pediatrics / Česko-Slovenská Pediatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Czecho-Slovak Pediatrics / Česko-Slovenská Pediatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Czecho-Slovak Pediatrics / Česko-Slovenská Pediatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Czecho-Slovak Pediatrics / Česko-Slovenská Pediatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Czecho-Slovak Pediatrics / Česko-Slovenská Pediatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Czecho-Slovak Pediatrics / Česko-Slovenská Pediatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Czecho-Slovak Pediatrics / Česko-Slovenská Pediatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The mitochondrial DNA (mtDNA) amount in cells as the basis for mitochondrial energy generating system, which produces ATP, plays an important role in the fetal development and postnatal morbidity. Isolated human cord blood leukocytes (HCBL) contribute very little to the overall metabolic turnover, but they may serve as easily available marker cells for the study of the mtDNA amount changes in cord blood during fetal development. The aim of our study was to analyze the mtDNA amount in HCBL. HCBL were isolated from cord blood samples of 107 neonates born between the 25th and 41st week of gestation. The mtDNA amount was analyzed by the real-time PCR method. The significant negative correlations were found between the relative mtDNA amount in HCBL and gestational age (r = -0.54, p<0.01) and birth weight (r = -0.43, p<0.01), respectively. The results revealed that the mtDNA content per cell decreases in HCBL with progressing fetal development. This may be explained by gradual shift of the hematopoiesis from fetal liver to bone marrow during the second half of pregnancy presumably accompanied by decreasing cell volume of HCBL as it was shown similarly in red blood cells. [ABSTRACT FROM AUTHOR]

Abstract Background To strengthen research and differential diagnostics of mitochondrial disorders, we constructed and validated an oligonucleotide microarray (h-MitoArray) allowing expression analysis of 1632 human genes involved in mitochondrial biology, cell cycle regulation, signal transduction and apoptosis. Using h-MitoArray we analyzed gene expression profiles in 9 control and 13 fibroblast cell lines from patients with F1Fo ATP synthase deficiency consisting of 2 patients with mt9205ΔTA microdeletion and a genetically heterogeneous group of 11 patients with not yet characterized nuclear defects. Analysing gene expression profiles, we attempted to classify patients into expected defect specific subgroups, and subsequently reveal group specific compensatory changes, identify potential phenotype causing pathways and define candidate disease causing genes. Results Molecular studies, in combination with unsupervised clustering methods, defined three subgroups of patient cell lines – M group with mtDNA mutation and N1 and N2 groups with nuclear defect. Comparison of expression profiles and functional annotation, gene enrichment and pathway analyses of differentially expressed genes revealed in the M group a transcription profile suggestive of synchronized suppression of mitochondrial biogenesis and G1/S arrest. The N1 group showed elevated expression of complex I and reduced expression of complexes III, V, and V-type ATP synthase subunit genes, reduced expression of genes involved in phosphorylation dependent signaling along MAPK, Jak-STAT, JNK, and p38 MAP kinase pathways, signs of activated apoptosis and oxidative stress resembling phenotype of premature senescent fibroblasts. No specific functionally meaningful changes, except of signs of activated apoptosis, were detected in the N2 group. Evaluation of individual gene expression profiles confirmed already known ATP6/ATP8 defect in patients from the M group and indicated several candidate disease causing genes for nuclear defects. Conclusion Our analysis showed that deficiency in the ATP synthase protein complex amount is generally accompanied by only minor changes in expression of ATP synthase related genes. It also suggested that the site (mtDNA vs nuclear DNA) and the severity (ATP synthase content) of the underlying defect have diverse effects on cellular gene expression phenotypes, which warrants further investigation of cell cycle regulatory and signal transduction pathways in other OXPHOS disorders and related pharmacological models.

Je prezentován případ chlapce, u kterého v devíti letech byla diagnostikována hypertrofická kardiomyopatie. Kromě srdečního postižení byla přítomna psychomotorická retardace. Přes vyšetření na specializovaném pracovišti však v této fázi nebyla stanovena etiologická podstata onemocnění. V dalším průběhu se ve věku 15 let objevuje život ohrožující synkopální stav, který byl spojen s výraznou metabolickou acidózou (pH 6,803; pCO2 2,13; BE -23,6) a elevací laktátu. Současně byla zjištěna porucha systolické funkce levé komory, která se s odstupem času a při léčbě betablokátorem a inhibitorem ACE upravila. Elevace laktátu přetrvávala i po uvedené epizodě a byla důvodem k podrobnému vyšetření metabolismu. Při vyšetření v Ústavu dědičných metabolických poruch byla provedena svalová biopsie a v mitochondriích svalové tkáně bylo detekováno snížení aktivity IV a I komplexu respiračního řetězce. Sekvenace celé molekuly mitochondriální DNA však neprokazuje maternální přenosné mitochondriální onemocnění, jako např. MELAS aj. Přesto při vyšetření mozku MRI byly v difuzně vážených obrazech detekovány hypersignální změny v mozkové kůře podobné těm jako u MELAS. Doposud u pacienta nebyla stanovena konkrétní klinická jednotka (kromě jiného i pro obtížnou spolupráci). Kazuistika upozorňuje na poměrně širokou diferenciální diagnostiku hypertrofické kardiomyopatie a také na nebezpečí metabolického selhání u pacientů s poruchou energetického metabolismu. [ABSTRACT FROM AUTHOR]

Copyright of Czecho-Slovak Pediatrics / Česko-Slovenská Pediatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Czecho-Slovak Pediatrics / Česko-Slovenská Pediatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Czecho-Slovak Pediatrics / Česko-Slovenská Pediatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Transport protein particle (TRAPP) is a multiprotein complex that functions in localising proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in diseases affecting muscle, brain, eye and to some extent liver. We present three patients who are compound heterozygotes for a missense variant and a structural variant in the TRAPPC11 gene. TRAPPC11 structural variants have not yet been described in association with a disease. In order to reveal the estimated genesis of identified structural variants, we performed sequencing of individual breakpoint junctions and analysed the extent of homology and the presence of repetitive elements in and around the breakpoints., Methods: Biochemical methods including isoelectric focusing on serum transferrin and apolipoprotein C-III, as well as mitochondrial respiratory chain complex activity measurements, were used. Muscle biopsy samples underwent histochemical analysis. Next-generation sequencing was employed for identifying sequence variants associated with neuromuscular disorders, and Sanger sequencing was used to confirm findings., Results: We suppose that non-homologous end joining is a possible mechanism of deletion origin in two patients and non-allelic homologous recombination in one patient. Analyses of mitochondrial function performed in patients' skeletal muscles revealed an imbalance of mitochondrial metabolism, which worsens with age and disease progression., Conclusion: Our results contribute to further knowledge in the field of neuromuscular diseases and mutational mechanisms. This knowledge is important for understanding the molecular nature of human diseases and allows us to improve strategies for identifying disease-causing mutations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Limb girdle muscular dystrophies (LGMD) are a genetically heterogeneous group of muscular dystrophies. The study presents an overview of molecular characteristics of a large cohort of LGMD patients who are representative of the Czech LGMD population. We present 226 LGMD probands in which 433 mutant alleles carrying 157 different variants with a supposed pathogenic effect were identified. Fifty-four variants have been described only in the Czech LGMD population so far. LGMD R1 caplain3-related is the most frequent subtype of LGMD involving 53.1% of patients with genetically confirmed LGMD, followed by LGMD R9 FKRP-related (11.1%), and LGMD R12 anoctamin5-related (7.1%). If we consider identified variants, then all but five were small-scale variants. One large gene deletion was identified in the LAMA2 gene and two deletions in each of CAPN3 and SGCG. We performed comparison our result with other published studies. The results obtained in the Czech LGMD population clearly differ from the outcome of other LGMD populations in two aspects-we have a more significant proportion of patients with LGMD R1 calpain3-related and a smaller proportion of LGMD R2 dysferlin-related., (© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Regulation of H 2 S homeostasis in humans is poorly understood. Therefore, we assessed the importance of individual enzymes in synthesis and catabolism of H 2 S by studying patients with respective genetic defects. We analyzed sulfur compounds (including bioavailable sulfide) in 37 untreated or insufficiently treated patients with seven ultrarare enzyme deficiencies and compared them to 63 controls. Surprisingly, we observed that patients with severe deficiency in cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE) - the enzymes primarily responsible for H 2 S synthesis - exhibited increased and normal levels of bioavailable sulfide, respectively. However, an approximately 21-fold increase of urinary homolanthionine in CBS deficiency strongly suggests that lacking CBS activity is compensated for by an increase in CSE-dependent H 2 S synthesis from accumulating homocysteine, which suggests a control of H 2 S homeostasis in vivo. In deficiency of sulfide:quinone oxidoreductase - the first enzyme in mitochondrial H 2 S oxidation - we found normal H 2 S concentrations in a symptomatic patient and his asymptomatic sibling, and elevated levels in an asymptomatic sibling, challenging the requirement for this enzyme in catabolizing H 2 S under physiological conditions. Patients with ethylmalonic encephalopathy and sulfite oxidase/molybdenum cofactor deficiencies exhibited massive accumulation of thiosulfate and sulfite with formation of large amounts of S-sulfocysteine and S-sulfohomocysteine, increased renal losses of sulfur compounds and concomitant strong reduction in plasma total cysteine. Our results demonstrate the value of a comprehensive assessment of sulfur compounds in severe disorders of homocysteine/cysteine metabolism and provide evidence for redundancy and compensatory mechanisms in the maintenance of H 2 S homeostasis., Competing Interests: Declaration of competing interest GS declares that he serves as CEO of Colbourne Pharmaceuticals consulting Origin Biosciences in the developments of treatments for MoCD type A, BS is investigator in clinical trials to develop a treatment for MoCD-A sponsored by Origin Biosciences Inc. The other authors do not declare any competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inherited neurometabolic disorder with variable clinical course and severity, ranging from infantile epileptic encephalopathy to psychiatric disorders. A precise phenotypic characterization and an evaluation of predictive approaches are needed., Methods: Longitudinal clinical and biochemical data of 25 individuals with NKH from the patient registry of the International Working Group on Neurotransmitter Related Disorders were studied with in silico analyses, pathogenicity scores, and molecular modeling of GLDC and AMT variants., Results: Symptom onset (p < 0.01) and diagnosis occur earlier in life in severe NKH (p < 0.01). Presenting symptoms affect the age at diagnosis. Psychiatric problems occur predominantly in attenuated NKH. Onset age ≥ 3 months (66% specificity, 100% sensitivity, area under the curve [AUC] = 0.87) and cerebrospinal fluid (CSF)/plasma glycine ratio ≤ 0.09 (57% specificity, 100% sensitivity, AUC = 0.88) are sensitive indicators for attenuated NKH, whereas CSF glycine concentration ≥ 116.5μmol/l (100% specificity, 93% sensitivity, AUC = 0.97) and CSF/plasma glycine ratio ≥ 0.15 (100% specificity, 64% sensitivity, AUC = 0.88) are specific for severe forms. A ratio threshold of 0.128 discriminates the overlapping range. We present 10 new GLDC variants. Two mild variants resulted in attenuated, whereas 2 severe variants or 1 mild and 1 severe variant led to severe phenotype. Based on clinical, biochemical, and genetic parameters, we propose a severity prediction model., Interpretation: This study widens the phenotypic spectrum of attenuated NKH and expands the number of pathogenic variants. The multiparametric approach provides a promising tool to predict disease severity, helping to improve clinical management strategies. ANN NEUROL 2022;92:292-303., (© 2022 American Neurological Association.)

In this study, we report on a novel heteroplasmic pathogenic variant in mitochondrial DNA (mtDNA). The studied patient had myoclonus, epilepsy, muscle weakness, and hearing impairment and harbored a heteroplasmic m.8315A>C variant in the MTTK gene with a mutation load ranging from 71% to >96% in tested tissues. In muscle mitochondria, markedly decreased activities of respiratory chain complex I + III and complex IV were observed together with mildly reduced amounts of complex I and complex V (with the detection of V*- and free F1-subcomplexes) and a diminished level of complex IV holoenzyme. This pattern was previously seen in other MTTK pathogenic variants. The novel variant was not present in internal and publicly available control databases. Our report further expands the spectrum of MTTK variants associated with mitochondrial encephalopathies in adults.

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.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH 4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH 4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH 4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits., (© 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Inherited disorders of neurotransmitter metabolism are rare neurodevelopmental diseases presenting with movement disorders and global developmental delay. This study presents the results of the first standardized deep phenotyping approach and describes the clinical and biochemical presentation at disease onset as well as diagnostic approaches of 275 patients from the registry of the International Working Group on Neurotransmitter related Disorders. The results reveal an increased rate of prematurity, a high risk for being small for gestational age and for congenital microcephaly in some disorders. Age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms. The timepoint of investigation was also a significant factor: delay to diagnosis has decreased in recent years, possibly due to novel diagnostic approaches or raised awareness. Although each disorder has a specific biochemical pattern, we observed confounding exceptions to the rule. The data provide comprehensive insights into the phenotypic spectrum of neurotransmitter disorders., (© 2021. The Author(s).)

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.

PMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 μg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction., (© 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Leber hereditary optic neuropathy and Dominant optic atrophy are associated with a selective loss of retinal ganglion cells (RGC). A subtype of RGC is responsible for light-dependent physiological processes. The aim of our study was to evaluate both subjective and objective sleep parameters in 36 (18 males; mean age 33.8 ± 16.7) symptomatic/asymptomatic subjects with Leber hereditary optic neuropathy and dominant optic atrophy. The Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS) and nocturnal polysomnography were used to assess sleep disturbances and sleep quality. The questionnaires indicated significantly worse sleep quality (PSQI > 5; average 7.7 ± 3.8) in 21 (70%) and excessive daytime sleepiness (ESS > 10; average 6.3 ± 5.8) in six (20%) individuals. Nocturnal polysomnography has not revealed any significant changes of sleep structure. Rapid eye movement (REM) sleep without atonia was observed in two patients with Leber hereditary optic neuropathy. Obstructive sleep apnea was noted in eight cases. No correlation between subjective and polysomnographic data and no differences between symptomatic and asymptomatic groups were observed. None of the subjects fulfilled criteria for a circadian sleep disorder. In both symptomatic and asymptomatic individuals, a subjective decrease of the quality of sleep and wakefulness was noted without any correlation on polysomnography., (© 2020 European Sleep Research Society.)

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.

An amendment to this paper has been published and can be accessed via the original article.

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) deficiency is a rare subtype of congenital disorders of protein N-glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI-CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence-based data and experts' opinions. Those guidelines also reveal more questions about MPI-CDG which need to be further studied., (© 2020 SSIEM.)