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TMEM70 deficiency is a panethnic, multisystemic disease with variable outcome depending mainly on adequate management of hyperammonaemic crises in the neonatal period and early childhood.

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.

Cardiomyopathy is a common manifestation in neonates and infants with mitochondrial disorders. In this study, we report two cases manifesting with fatal mitochondrial hypertrophic cardiomyopathy, which include the third known patient with thymidine kinase 2 deficiency and the ninth patient with alanyl-tRNA synthetase 2 deficiency. The girl with thymidine kinase 2 deficiency had hypertrophic cardiomyopathy together with regression of gross motor development at the age of 13 months. Neurological symptoms and cardiac involvement progressed into severe myopathy, psychomotor arrest, and cardiorespiratory failure at the age of 22 months. The imaging methods and autoptic studies proved that she suffered from unique findings of leucoencephalopathy, severe, mainly cerebellar neuronal degeneration, and hepatic steatosis. The girl with alanyl-tRNA synthetase 2 deficiency presented with cardiac failure and underlying hypertrophic cardiomyopathy within 12 hours of life and subsequently died at 9 weeks of age. Muscle biopsy analyses demonstrated respiratory chain complex I and IV deficiencies, and histological evaluation revealed massive mitochondrial accumulation and cytochrome c oxidase-negative fibres in both cases. Exome sequencing in the first case revealed compound heterozygozity for one novel c.209T>C and one previously published c.416C>T mutation in the TK2 gene, whereas in the second case homozygozity for the previously described mutation c.1774C>T in the AARS2 gene was determined. The thymidine kinase 2 mutations resulted in severe mitochondrial DNA depletion (to 12% of controls) in the muscle. We present, for the first time, severe leucoencephalopathy and hepatic steatosis in a patient with thymidine kinase 2 deficiency and the finding of a ragged red fibre-like image in the muscle biopsy in a patient with alanyl-tRNA synthetase 2 deficiency.

Marfan syndrome (MFS) is an autosomal dominant disorder caused by mutations in the fibrillin 1 gene (FBN1). Neonatal form of MFS is rare and is associated with severe phenotype and a poor prognosis. We report on a newborn girl with neonatal MFS who displayed cyanosis and dyspnea on the first day of life. The main clinical features included mitral and tricuspid valve insufficiency, aortic root dilatation, arachnodactyly, and loose skin. Despite the presence of severe and inoperable heart anomalies, the girl was quite stable on symptomatic treatment and lived up to the 7th month of age when she died due to cardiorespiratory failure. Molecular-genetic studies revealed a novel intronic c.4211-32_-13del mutation in the FBN1 gene. Subsequent in vitro splicing analysis showed this mutation led to exon 35 skipping, presumably resulting in a deletion of 42 amino acids (p.Leu1405_Asp1446del). Interestingly, this mutation is localized outside the region of exons 24-32, whose mutation is responsible for the substantial majority of cases of neonatal MFS. Although the family history of MFS was negative, the subsequent molecular genetic examination documented a mosaicism of the same mutation in the maternal blood cells (10-25% of genomic DNA) and the detailed clinical examination showed unilateral lens ectopy.

Barth syndrome is an X-linked recessive disorder that is caused by mutations in Taffazin gene (TAZ), leading to severe cardiolipin deficiency which results in respiratory chain dysfunction. Barth syndrome is characterized by cardiomyopathy, neutropenia, skeletal myopathy, growth deficiency and 3-methylglutaconic aciduria. In this paper, we present clinical, biochemical and molecular data of the first four Czech patients from four unrelated families diagnosed with this rare disease. The mean age of onset was 5.5 ± 3.8 months. One child suffered from sudden cardiac death at the age of 2 years, the age of living patients is between 3 and 13 years. Muscle hypotonia was present in all four patients; cardiomyopathy and growth retardation in three and neutropenia in two of them. Two patients manifested a dilated and one patient a hypertrophic cardiomyopathy. A characteristic laboratory abnormality was the intermittently increased excretion of 3-methylglutaconic acid. Three novel hemizygous mutations in the TAZ gene were found (c.584G>T; c.109+6T>C; c.86G>A). We conclude that Barth syndrome should be included in differential diagnosis of cardiomyopathy in childhood, especially in the cooccurrence of dilated cardiomyopathy and 3-methylglutaconic aciduria.

Fabry disease (FD) is a rare X-linked disorder of glycosphingolipid metabolism caused by pathogenic variants within the alpha-galactosidase A (GLA) gene, often leading to neurological manifestations including stroke. Multiple screening programs seeking GLA variants among stroke survivors lacked detailed phenotype description, making the interpretation of the detected variant’s pathogenicity difficult. Here, we describe detailed clinical characteristics of GLA variant carriers identified by a nationwide stroke screening program in the Czech Republic. A total of 23 individuals with 8 different GLA variants were included in the study. A comprehensive diagnostic workup was performed by a team of FD specialists. The investigation led to the suggestion of phenotype reclassification for the G325S mutation from late-onset to classical. A novel variant R30K was found and was classified as a variant of unknown significance (VUS). The typical manifestation in our FD patients was a stroke occurring in the posterior circulation with an accompanying pathological finding in the cerebrospinal fluid. Moreover, we confirmed that cornea verticillata is typically associated with classical variants. Our findings underline the importance of detailed phenotype description and data sharing in the correct identification of pathogenicity of gene variants detected by high-risk-population screening programs.

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