Browsing by Author "Maver, A. (22135394900)"

Deficiency of lysosomal acid lipase (LAL-D) is caused by biallelic pathogenic variants in the LIPA gene. Spectrum of LAL-D ranges from early onset of hepatosplenomegaly and psychomotor regression (Wolman disease) to a more chronic course (cholesteryl ester storage disease - CESD). The diagnosis is based on lipid and biomarker profiles, specific liver histopathology, enzyme deficiency, and identification of causative genetic variants. Biomarker findings are a useful for diagnostics of LAL-D, including high plasma concentration of chitotriosidase as well as elevated oxysterols. Current treatment options include enzyme replacement therapy (sebelipase-alpha), statins, liver transplantation, and stem cell transplantation. We present two pairs of siblings from Serbia with a distinctive phenotype resembling LAL-D with a novel variant of unknown significance (VUS) detected in the LIPA gene and residual LAL activity. All patients presented with hepatosplenomegaly at early childhood. In siblings from family 1, compound heterozygosity for a pathogenic c.419G>A (p.Trp140Ter) variant and a novel VUS c.851C>T (p.Ser284Phe) was detected. Patients from family 2 were homozygous for c.851C>T VUS and both have typical histopathologic findings for LAL-D in the liver. Enzyme activity of LAL was tested in three patients and reported as sufficient, and therefore enzyme replacement therapy could not be approved. When confronted with a challenge of diagnosing an inherited metabolic disorder, several aspects are taken into consideration: clinical manifestations, specific biomarkers, enzyme assay results, and molecular genetic findings. This report brings cases to light which have a considerable discrepancy between those aspects, namely the preserved LAL enzyme activity in presence of clinical manifestations and rare variants in the LIPA gene. © 2022 Sarajlija A., Armengol L., Maver A., Kitic I., Prokic D., Cehic M., Djuricic M.S., Peterlin B., published by Sciendo.

Deficiency of lysosomal acid lipase (LAL-D) is caused by biallelic pathogenic variants in the LIPA gene. Spectrum of LAL-D ranges from early onset of hepatosplenomegaly and psychomotor regression (Wolman disease) to a more chronic course (cholesteryl ester storage disease - CESD). The diagnosis is based on lipid and biomarker profiles, specific liver histopathology, enzyme deficiency, and identification of causative genetic variants. Biomarker findings are a useful for diagnostics of LAL-D, including high plasma concentration of chitotriosidase as well as elevated oxysterols. Current treatment options include enzyme replacement therapy (sebelipase-alpha), statins, liver transplantation, and stem cell transplantation. We present two pairs of siblings from Serbia with a distinctive phenotype resembling LAL-D with a novel variant of unknown significance (VUS) detected in the LIPA gene and residual LAL activity. All patients presented with hepatosplenomegaly at early childhood. In siblings from family 1, compound heterozygosity for a pathogenic c.419G>A (p.Trp140Ter) variant and a novel VUS c.851C>T (p.Ser284Phe) was detected. Patients from family 2 were homozygous for c.851C>T VUS and both have typical histopathologic findings for LAL-D in the liver. Enzyme activity of LAL was tested in three patients and reported as sufficient, and therefore enzyme replacement therapy could not be approved. When confronted with a challenge of diagnosing an inherited metabolic disorder, several aspects are taken into consideration: clinical manifestations, specific biomarkers, enzyme assay results, and molecular genetic findings. This report brings cases to light which have a considerable discrepancy between those aspects, namely the preserved LAL enzyme activity in presence of clinical manifestations and rare variants in the LIPA gene. © 2022 Sarajlija A., Armengol L., Maver A., Kitic I., Prokic D., Cehic M., Djuricic M.S., Peterlin B., published by Sciendo.

Microcephaly is characterized by significant clinical and genetic heterogeneity, therefore reaching the genetic diagnosis remains challenging in this group of disorders. We describe a case of a girl with secondary microcephaly, associated with severe developmental delay, intellectual disability, growth retardation and dysmorphic features. For purposes of clinical genetic diagnostic testing, we performed trio whole exome sequencing in the proband and unaffected parents. We found a heterozygous de novo missense variant in the H3F3A gene in the proband (NM-002107.4: c.185T>G), which is absent from the gnomAD and from the Slovenian Genome databases. The identified variant affects a highly conserved leucine residue at position 62 of the histone H3 protein (H3.3) and is predicted to affect the physicochemical properties of the affected protein. Mouse models, which demonstrated involvement of H3.3 protein in the control of neuronal-and glial-specific gene expression patterns that control synaptic connectivity and behavioral plasticity. Additionally, we also identified similar cases reported in the ClinVar database. These arguments support the possible pathogenic role of the reported genetic variant and thus suggest a novel molecular mechanism for this syndromic form of microcephaly. © 2019 Maver A, Čuturilo G, Ruml Stojanović J, Peterlin B, published by Sciendo.

Microcephaly is characterized by significant clinical and genetic heterogeneity, therefore reaching the genetic diagnosis remains challenging in this group of disorders. We describe a case of a girl with secondary microcephaly, associated with severe developmental delay, intellectual disability, growth retardation and dysmorphic features. For purposes of clinical genetic diagnostic testing, we performed trio whole exome sequencing in the proband and unaffected parents. We found a heterozygous de novo missense variant in the H3F3A gene in the proband (NM-002107.4: c.185T>G), which is absent from the gnomAD and from the Slovenian Genome databases. The identified variant affects a highly conserved leucine residue at position 62 of the histone H3 protein (H3.3) and is predicted to affect the physicochemical properties of the affected protein. Mouse models, which demonstrated involvement of H3.3 protein in the control of neuronal-and glial-specific gene expression patterns that control synaptic connectivity and behavioral plasticity. Additionally, we also identified similar cases reported in the ClinVar database. These arguments support the possible pathogenic role of the reported genetic variant and thus suggest a novel molecular mechanism for this syndromic form of microcephaly. © 2019 Maver A, Čuturilo G, Ruml Stojanović J, Peterlin B, published by Sciendo.

The aim of this study was to examine whether there is an association among genetic variability in leptin (LEP) and leptin receptor (LEPR) genes and male infertility. We performed a case–control study and were searching for an association between polymorphisms of LEP and LEPR genes and male infertility. The study group consisted of 317 patients with idiopathic infertility and a control group of 241 fertile men from Slovenia. Four single nucleotide polymorphisms (SNPs) in LEP gene and four single nucleotide polymorphisms (SNPs) in LEPR gene were chosen and genotyped. Statistically significant SNP was further validated in additional 255 infertile patients and 168 controls from Serbia and Macedonia. In the Slovenian population, we found a statistically significant difference in genotype distribution for rs10244329 polymorphism in LEP gene (recessive genotype model, p value = 0.048). The trend toward statistically significant difference in genotype distribution for rs10244329 polymorphism was confirmed in the Serbian and Macedonian populations (p value = 0.07). Our data suggest that genetic variability in the LEP gene might be associated with male infertility warranting further confirmation and mechanistic investigations. © 2016 American Society of Andrology and European Academy of Andrology

The aim of this study was to examine whether there is an association among genetic variability in leptin (LEP) and leptin receptor (LEPR) genes and male infertility. We performed a case–control study and were searching for an association between polymorphisms of LEP and LEPR genes and male infertility. The study group consisted of 317 patients with idiopathic infertility and a control group of 241 fertile men from Slovenia. Four single nucleotide polymorphisms (SNPs) in LEP gene and four single nucleotide polymorphisms (SNPs) in LEPR gene were chosen and genotyped. Statistically significant SNP was further validated in additional 255 infertile patients and 168 controls from Serbia and Macedonia. In the Slovenian population, we found a statistically significant difference in genotype distribution for rs10244329 polymorphism in LEP gene (recessive genotype model, p value = 0.048). The trend toward statistically significant difference in genotype distribution for rs10244329 polymorphism was confirmed in the Serbian and Macedonian populations (p value = 0.07). Our data suggest that genetic variability in the LEP gene might be associated with male infertility warranting further confirmation and mechanistic investigations. © 2016 American Society of Andrology and European Academy of Andrology

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal-recessive disorder of gamma-aminobutyric acid (GABA) metabolism, resulting in accumulation of GABA and gamma-hydroxybutyric acid (GHB) in physiological fluids. Approximately 450 patients have been diagnosed worldwide with this inherited neurotransmitter disorder. We report on a five-year-old male patient, homozygous for the pathogenic variant (NM_170740:c.1265G>A) in ALDH5A1 presenting with an unexpected association of typical SSADH deficiency manifestations with bilateral sensorineural hearing loss (SNHL). Brainstem evoked response audiometry (BERA) testing showed mid-frequency sensorineural hearing damage that suggested a hereditary component to SNHL. Whole exome sequencing (WES) failed to discern other genetic causes of deafness. Several variants of uncertain significance (VUS) detected in genes known for their role in hearing physiology could not be verified as the cause for the SNHL. It is known that central auditory processing depends on a delicate balance between excitatory and inhibitory neurotransmission, and GABA is known to play a significant role in this process. Additionally, excessive concentrations of accumulated GABA and GBH are known to cause a down-regulation of GABA receptors, which could have an adverse influence on hearing function. However, these mechanisms are very speculative in context of SNHL in a patient with inherited disorder of GABA metabolism. Injury of the globi pallidi, one of hallmarks of SSADH deficiency, could also be a contributory factor to SNHL, as was suspected in some other inborn errors in metabolism. We hope that this case will contribute to the understanding of phenotypic complexity of SSADH deficiency. © 2023 M Parezanović et al., published by Sciendo.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal-recessive disorder of gamma-aminobutyric acid (GABA) metabolism, resulting in accumulation of GABA and gamma-hydroxybutyric acid (GHB) in physiological fluids. Approximately 450 patients have been diagnosed worldwide with this inherited neurotransmitter disorder. We report on a five-year-old male patient, homozygous for the pathogenic variant (NM_170740:c.1265G>A) in ALDH5A1 presenting with an unexpected association of typical SSADH deficiency manifestations with bilateral sensorineural hearing loss (SNHL). Brainstem evoked response audiometry (BERA) testing showed mid-frequency sensorineural hearing damage that suggested a hereditary component to SNHL. Whole exome sequencing (WES) failed to discern other genetic causes of deafness. Several variants of uncertain significance (VUS) detected in genes known for their role in hearing physiology could not be verified as the cause for the SNHL. It is known that central auditory processing depends on a delicate balance between excitatory and inhibitory neurotransmission, and GABA is known to play a significant role in this process. Additionally, excessive concentrations of accumulated GABA and GBH are known to cause a down-regulation of GABA receptors, which could have an adverse influence on hearing function. However, these mechanisms are very speculative in context of SNHL in a patient with inherited disorder of GABA metabolism. Injury of the globi pallidi, one of hallmarks of SSADH deficiency, could also be a contributory factor to SNHL, as was suspected in some other inborn errors in metabolism. We hope that this case will contribute to the understanding of phenotypic complexity of SSADH deficiency. © 2023 M Parezanović et al., published by Sciendo.