ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings

BACKGROUND: ALG3-CDG is a rare autosomal recessive disease. It is characterized by deficiency of alpha-1,3-mannosyltransferase caused by pathogenic variants in the ALG3 gene. Patients manifest with severe neurologic, cardiac, musculoskeletal and ophthalmic phenotype in combination with dysmorphic features, and almost half of them die before or during the neonatal period. CASE PRESENTATION: A 23 months-old girl presented with severe developmental delay, epilepsy, cortical atrophy, cerebellar vermis hypoplasia and ocular impairment. Facial dysmorphism, clubfeet and multiple joint contractures were observed already at birth. Transferrin isoelectric focusing revealed a type 1 pattern. Funduscopy showed hypopigmentation and optic disc pallor. Profound retinal ganglion cell loss and inner retinal layer thinning was documented on spectral-domain optical coherence tomography imaging. The presence of optic nerve hypoplasia was also supported by magnetic resonance imaging. A gene panel based next-generation sequencing and subsequent Sanger sequencing identified compound heterozygosity for two novel variants c.116del p.(Pro39Argfs*40) and c.1060 C > T p.(Arg354Cys) in ALG3. CONCLUSIONS: Our study expands the spectrum of pathogenic variants identified in ALG3. Thirty-three variants in 43 subjects with ALG3-CDG have been reported. Literature review shows that visual impairment in ALG3-CDG is most commonly linked to optic nerve hypoplasia

Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation

Objective Mitochondrial disturbances of energy-generating systems in childhood are a heterogeneous group of disorders. The aim of this multi-site survey was to characterise the natural course of a novel mitochondrial disease with ATP synthase deficiency and mutation in the TMEM70 gene. Methods Retrospective clinical data and metabolic profiles were collected and evaluated in 25 patients (14 boys, 11 girls) from seven European countries with a c. 317-2A -> G mutation in the TMEM70 gene. Results Severe muscular hypotonia (in 92% of newborns), apnoic spells (92%), hypertrophic cardiomyopathy (HCMP; 76%) and profound lactic acidosis (lactate 5-36 mmol/l; 92%) with hyperammonaemia (100-520 mu mol/l; 86%) were present from birth. Ten patients died within the first 6 weeks of life. Most patients surviving the neonatal period had persisting muscular hypotonia and developed psychomotor delay. HCMP was non-progressive and even disappeared in some children. Hypospadia was present in 54% of the boys and cryptorchidism in 67%. Increased excretion of lactate and 3-methylglutaconic acid (3-MGC) was observed in all patients. In four surviving patients, life-threatening hyperammonaemia occurred during childhood, triggered by acute gastroenteritis and prolonged fasting. Conclusions ATP synthase deficiency with mutation in TMEM70 should be considered in the diagnosis and management of critically ill neonates with early neonatal onset of muscular hypotonia, HCMP and hypospadias in boys accompanied by lactic acidosis, hyperammonaemia and 3-MGC-uria. However, phenotype severity may vary significantly. The disease occurs frequently in the Roma population and molecular-genetic analysis of the TMEM70 gene is sufficient for diagnosis without need of muscle biopsy in affected children

Should patients with kearns-sayre syndrome and corneal endothelial failure be genotyped for a TCF4 trinucleotide repeat, commonly associated with fuchs endothelial corneal dystrophy?

The aim of this study was to describe the ocular phenotype in a case with Kearns-Sayre syndrome (KSS) spectrum and to determine if corneal endothelial cell dysfunction could be attributed to other known distinct genetic causes. Herein, genomic DNA was extracted from blood and exome sequencing was performed. Non-coding gene regions implicated in corneal endothelial dystrophies were screened by Sanger sequencing. In addition, a repeat expansion situated within an intron of TCF4 (termed CTG18.1) was genotyped using the short tandem repeat assay. The diagnosis of KSS spectrum was based on the presence of ptosis, chronic progressive external ophthalmoplegia, pigmentary retinopathy, hearing loss, and muscle weakness, which were further supported by the detection of ~6.5 kb mtDNA deletion. At the age of 33 years, the proband’s best corrected visual acuity was reduced to 0.04 in the right eye and 0.2 in the left eye. Rare ocular findings included marked corneal oedema with central corneal thickness of 824 and 844 µm in the right and left eye, respectively. No pathogenic variants in the genes, which are associated with corneal endothelial dystrophies, were identified. Furthermore, the CTG18.1 genotype was 12/33, which exceeds a previously determined critical threshold for toxic RNA foci appearance in corneal endothelial cells

The Phenotypic Spectrum of 47 Czech Patients with Single, Large-Scale Mitochondrial DNA Deletions

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 neede

Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies

Background: Tetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4 deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH4 deficiencies. Conclusion: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH4 deficient patients

Mitochondrial ATP synthase: architecture, function and pathology

Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F1, situated in the mitochondrial matrix, and Fo, located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. This review covers the architecture, function and assembly of complex V. The role of complex V di-and oligomerization and its relation with mitochondrial morphology is discussed. Finally, pathology related to complex V deficiency and current therapeutic strategies are highlighted. Despite the huge progress in this research field over the past decades, questions remain to be answered regarding the structure of subunits, the function of the rotary nanomotor at a molecular level, and the human complex V assembly process. The elucidation of more nuclear genetic defects will guide physio(patho)logical studies, paving the way for future therapeutic interventions

A new case of ALG8 deficiency (CDG Ih)

Congenital disorders of glycosylation (CDG) represent an expanding group of inherited diseases. One of them, ALG8 deficiency (CDG Ih), leads to protein N-glycosylation defects caused by malfunction of glucosyltransferase 2 (Dol-P-Glc:Glc1-Man(9)-GlcNAc(2)-P-P-Dol glucosyltransferase) resulting in inefficient addition of the second glucose residue onto lipid-linked oligosaccharides. So far, only five patients have been described with ALG8 deficiency. We present a new patient with neonatal onset. The girl was born at the 29th week of gestation complicated by oligohydramnios. Although the early postnatal adaptation was uneventful (Apgar score 8 and 9 at 5 and 10 min), generalized oedema, multifocal myoclonic seizures, and bleeding due to combined coagulopathy were present from the first day. Diarrhoea progressing to protein-losing enteropathy with ascites and pericardial effusion developed in the third week of life. Pharmacoresistant seizures and cortical, cerebellar and optic nerve atrophy indicated neurological involvement. No symptoms of liver disease except coagulopathy were observed; however, steatofibrosis with cholestasis was found at autopsy. The girl died at the age of 2 months owing to the progressive general oedema, bleeding and cardio-respiratory insufficiency. Molecular analysis revealed two heterozygous mutations in the ALG8 gene: c.139A>C (p.T47P) and the novel mutation c.1090C>T (p.R364X). Conclusion: The prognosis of patients with ALG8 deficiency is unfavourable. The majority of affected children have early onset of the disease with heterogeneous symptoms including multiple organ dysfunction, coagulopathy and protein-losing enteropathy. Neurological impairment is not a general clinical symptom, but it has to be taken into consideration when thinking about ALG8 deficiency

Assessment of selected properties of the humic industrial soil made of the brown coal blanket claystone (Chomutov, Czech Republik)

Badano glebę wytworzoną na zrekultywowanym składowisku nadkładu znad złoża węgla brunatnego. W warstwach na głębokościach: 0-5, 10-15, 20-25, 30-35, 40-45, 55-60 cm oznaczono: uziarnienie, wilgotność aktualną, gęstość objętościową szkieletu, opór ścinania i zwięzłość gleby. Stwierdzono, że wytworzony industrioziem próchniczny, zbudowany z utworów zwięzłych (glina, ił) o znacznej zawartości materii organicznej (od 10,2 do 20,1g·kg-1), zapewniał korzystne warunki rozwoju dla roślin uprawnych. Aktualny jego stan wskazywał na słabą do średniej podatność na ugniatanie. Obliczone wartości gęstości objętościowej szkieletu gleby wahały się w zakresie od 1,66 do 1,75 Mg·cm-3. Stwierdzono, że w warunkach silnego uwilgotnienia może być on podatny na pogorszenie właściwości fizycznych, na co wskazuje m.in. zawartość iłu łatwo dyspergującego (od 0,35 do 0,49g·100·g-1). Stwierdzono również, że zastosowanie maszyn uprawowych nie jest związane ze zwiększonym oporem ich pracy, zwłaszcza w warstwie ornej, ponieważ wartości oporu ścinania i zwięzłości nie przekraczały średnio odpowiednio wartości 163 i 970 kPa.The humic industrial soil, made of the brown coal blanket, was investigated. Soil was examined in layers located at the following depths: 0-5, 10-15, 20-25, 30-35, 40-45 and 55-60 cm. The following properties were examined: texture, water content, bulk density, shear strength and penetration resistance. It was proven that the industrial humic soil, created from heavy textured soil (loam, clay) with high organic matter content (10,2 - 20,1g·kg-1), provides good conditions for the plant growth. The results showed that the soil had rather low or medium susceptibility to further compaction – calculated value of the packing density ranged from 1,66 to 1,75 Mg·cm-3. Although at high water content it can be susceptible to deterioration of the investigated physical properties. This was due to, among others the content of readily-dispersible clay (0,35-0,49g·100·g-1). The use of tillage equipment should not be associated with increased working resistance, particularly in arable layer, because the values of shear strength and penetration resistance do not exceed on average respectively the values of 163 and 970 kPa

The International Working Group on Neurotransmitter related Disorders (iNTD): A worldwide research project focused on primary and secondary neurotransmitter disorders

Contains fulltext : 165803.pdf (publisher's version ) (Open Access)INTRODUCTION: Neurotransmitters are chemical messengers that enable communication between the neurons in the synaptic cleft. Inborn errors of neurotransmitter biosynthesis, breakdown and transport are a group of very rare neurometabolic diseases resulting in neurological impairment at any age from newborn to adulthood. METHODS AND RESULTS: The International Working Group on Neurotransmitter related Disorders (iNTD) is the first international network focusing on the study of primary and secondary neurotransmitter disorders. It was founded with the aim to foster exchange and improve knowledge in the field of these rare diseases. The newly established iNTD patient registry for neurotransmitter related diseases collects longitudinal data on the natural disease course, approach to diagnosis, therapeutic strategies, and quality of life of affected patients. The registry forms the evidence base for the development of consensus guidelines for patients with neurotransmitter related disorders. CONCLUSION: The iNTD network and registry will improve knowledge and strengthen research capacities in the field of inborn neurotransmitter disorders. The evidence-based guidelines will facilitate standardized diagnostic procedures and treatment approaches