Phenylketonuria screening and management in southeastern Europe – survey results from 11 for the ... more Phenylketonuria screening and management in southeastern Europe – survey results from 11 for the patients. Dietitian was a member of PKU team in only 4 of 11 countries, while regular psychological assessments
The results from a pilot prospective study--second trimester Down syndrome [DS] serum screening b... more The results from a pilot prospective study--second trimester Down syndrome [DS] serum screening between 15 and 21 w.g. with two markers (alpha-fetoprotein and free bb-hCG)--were summarised. Sensitivity, false-positive rate [FPR], positive predictive value [PPV] of the screen positive and negative predictive value [NPV] of the screen negative result for the sbgroups II and below 35 years of age were analysed. The uptake for invasive prenatal testing in screen positive patients and the percentage of terminated pregnancies with prenatally diagnosed DS fetuses as well as the ratio "lost unaffected pregnancies/1 DS fetus diagnosed antenatally" were also calculated. High sensitivity of the DS serum screening was achieved--75% and 87.5% in the subgroups below and II the age of 35 respectively with 6.6 and 31.7% FPR. With higher DS age risk the PPV of the screen positive test was higher and the NPV of the screen negative result--lower. The percentage of invasive prenatal testing in screen positive patients was high (average 83.4%) without significant differences in the two age subgroups. Pregnancy was terminated in all cases with antenatally diagnosed DS fetuses. The ratio "lost unaffected pregnancies/1 DS fetus diagnosed antenatally" for serum screening was lower compared to the same ratio when screening by age. The results from our pilot study (serum screening sensitivity and FPR, uptake for invasive testing in screen-positive cases) are comparable to the ones reported in literature. This is an important prerequisite for introduction of mass DS screening for our population.
Ambroxol hydrochloride is an oral mucolytic drug available over‐the‐counter for many years as cou... more Ambroxol hydrochloride is an oral mucolytic drug available over‐the‐counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several‐fold higher dose. Unfortunately, there have been no pharma‐driven clinical trials to establish its use. Thus, real‐world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA‐Parkinson disease (GBA‐PD). Clinicians treating patients with ambroxol for GD and GBA‐PD were approached to collaborate in an investigator‐initiated registry. Anonymized data were collected, including demographics, GD type, GD‐specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5–74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with...
Introduction: Precocious puberty is defined as the onset of pubertal signs in girls younger than ... more Introduction: Precocious puberty is defined as the onset of pubertal signs in girls younger than 8 years of age and in boys younger than 9 years of age. Central precocious puberty (CPP) is due to an early activation of the hypothalamic-pituitary-gonadal axis. It is 20 times more common in girls and 90% of the female cases are considered to be idiopathic (ICPP) (1). Different genes have been proposed as candidate genes in ICPP, but there is not enough evidence for their role in the etiology. In 2013 Abreu et al. first described the role of the MKRN3 gene in pubertal initiation. They detected three frameshift and a missense mutation in five families with familial CPP (2). A year later, Macedo et al. reported five novel mutations four frameshift variants and one missense variant (3). Following studies in patients with ICPP detected different defects in the MKRN3 gene (4, 5, 6, 7, 8) The MKRN3 gene is an intronless gene located on chromosome 15q11.2. Only the paternal allele of the gene...
AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 s... more AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can caus...
Ten girls with sporadic central precocious puberty were screened for mutations in the maternally ... more Ten girls with sporadic central precocious puberty were screened for mutations in the maternally imprinted gene MKRN3. We detected 1 novel frameshift mutation (p.Arg351Serfs*44) and a previously described mutation (p.Pro161Argfs*10). In the course of investigating the family, genetic analysis found 2 asymptomatic males with paternally inherited MKRN3 mutations, which has not been reported in previous studies.
Background: CH could be associated with other diseases or congenital malformations,incl. chromoso... more Background: CH could be associated with other diseases or congenital malformations,incl. chromosomal aberrations.Objective and hypotheses: Description of the complex phenotype in a patient with CH and underlying new aberration in chromosome 2.Methods: Hormonal investigations by Delfia®, Cytogenetics: G banding, genomic hybridization on microarrays; Auxological and complex clinical follow up until 8yrs of age. Results: Primary CH (TSH screening and serum confirmation), associated with SGA status, eutopic thyroid gland, congenital heart malformation (ASD,VSD spontaneously closed, stenotic left A. pulmonalis), dysmorphic features,muscle hypotonia, profound skeletal, developmental and growth delay despite early and sufficient L-Thyroxine therapy was evident in a boy from the Bulgarian CH cohort picked up by neonatal thyroid screening. This complex, syndromic phenotype was accompanied by a deletion in chromosome 2 (G banding): 46,XY,del(2) (q13-q21). Comparative genomic hybridization on ...
Many studies have supported a genetic aetiology for autism. Neuroligins are postsynaptically loca... more Many studies have supported a genetic aetiology for autism. Neuroligins are postsynaptically located cell-adhesion molecules. Mutations in two X-linked neuroligin genes, NLGN3 and NLGN4, have been implicated in pathogenesis of autism. In order to confirm these causative mutations in our autistic population and to determine their frequency we screened 20 individuals affected with autism. We identified one patient with a point mutation in NLGN4 gene that substituted a Met for Thr 787 - c.2360C > T, p.(Thr787Met) and three patients with identical polymorphisms in the same gene: c.933C > T, p.(Thr311Thr) in combination with c.[1777C > T+1779C > G, p.(Leu593Leu)]. All patients tested for NLGN3 mutations were negative. These results indicate that mutations in these genes are responsible for at most a small fraction of autism cases.
The results from a pilot prospective study--second trimester Down syndrome [DS] serum screening b... more The results from a pilot prospective study--second trimester Down syndrome [DS] serum screening between 15 and 21 w.g. with two markers (alpha-fetoprotein and free bb-hCG)--were summarised. Sensitivity, false-positive rate [FPR], positive predictive value [PPV] of the screen positive and negative predictive value [NPV] of the screen negative result for the sbgroups II and below 35 years of age were analysed. The uptake for invasive prenatal testing in screen positive patients and the percentage of terminated pregnancies with prenatally diagnosed DS fetuses as well as the ratio "lost unaffected pregnancies/1 DS fetus diagnosed antenatally" were also calculated. High sensitivity of the DS serum screening was achieved--75% and 87.5% in the subgroups below and II the age of 35 respectively with 6.6 and 31.7% FPR. With higher DS age risk the PPV of the screen positive test was higher and the NPV of the screen negative result--lower. The percentage of invasive prenatal testing i...
The aim of our study was to assess the current state of newborn screening (NBS) in the region of ... more The aim of our study was to assess the current state of newborn screening (NBS) in the region of southeastern Europe, as an example of a developing region, focusing also on future plans. Responses were obtained from 11 countries. Phenylketonuria screening was not introduced in four of 11 countries, while congenital hypothyroidism screening was not introduced in three of them; extended NBS programs were non-existent. The primary challenges were identified. Implementation of NBS to developing countries worldwide should be considered as a priority.
Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a progressive, multisystemic disease... more Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a progressive, multisystemic disease caused by a deficiency of iduronate-2-sulfatase. Patients with the severe form of the disease have cognitive impairment and typically die in the second decade of life. Patients with the less severe form do not experience significant cognitive involvement and may survive until the fifth or sixth decade of life. We studied the relationship of both severity of MPS II and the time period in which patients died with age at death in 129 patients for whom data were entered retrospectively into HOS (Hunter Outcome Survey), the only large-scale, multinational observational study of patients with MPS II. Median age at death was significantly lower in patients with cognitive involvement compared with those without cognitive involvement (11.7 versus 14.1 years; p = 0.024). These data indicate that cognitive involvement is indicative of more severe disease and lower life expectancy in patients with MPS II. Median age at death was significantly lower in patients who died in or before 1985 compared with those who died after 1985 (11.3 versus 14.1 years; p alpha 0.001). The difference in age at death between patients dying in or before, relative to after, the selected cut-off date of 1985 may reflect improvements in patient identification, care and management over the past two decades. Data from patients who died after 1985 could serve as a control in analyses of the effects of enzyme replacement therapy with idursulfase on mortality in patients with MPS II.
Lysosomal storage diseases (LSD) comprise a group of more than 40 different disorders, most of th... more Lysosomal storage diseases (LSD) comprise a group of more than 40 different disorders, most of them resulting from a specific enzyme deficiency. The diagnosis of these disorders is often complicated due to their clinical and biochemical heterogeneity. Definitive diagnosis as well as prenatal diagnosis of LSD is based on specific enzyme assays. Analysis of urinary metabolites facilitates differential diagnosis of LSD, pointing to the probable enzyme defect. A flowchart for biochemical diagnosis is described. The goal of our work was to detect rapidly and reliably most of the known LSD. The results obtained in an 8-year period using this combined clinical/biochemical approach for 528 patients suspected of having LSD are presented. The diagnoses of 36 patients with different enzyme deficiencies show unambiguously the usefulness of the diagnostic algorithm.
Barth syndrome (BTHS) is an X-linked recessive disease caused by mutations in tafazzin gene (TAZ)... more Barth syndrome (BTHS) is an X-linked recessive disease caused by mutations in tafazzin gene (TAZ) which lead to cardiolipin deficiency and mitochondrial dysfunction. Male patients have variable clinical findings, including cardiomyopathy, skeletal myopathy, prepubertal short stature, neutropenia and 3-methylglutaconic aciduria. Female carriers are usually asymptomatic. We report a novel TAZ gene mutation in male and female siblings with left ventricular noncompaction and hypotonia. Additionally, the brother presented an intermittent neutropenia and increased urinary levels of 3-methylglutaconic and 3-methylglutaric acid. The molecular genetic testing showed that both siblings carry the mutation: c.253insC, p.(Arg85Profs*54) in exon 3 of the TAZ gene. This article presents the first case of BTHS in a heterozygous female patient with normal karyotype.
This article has been accepted for publication and undergone full peer review but has not been th... more This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as
Congenital malformations present at delivery of an infant are due to genetic or non genetic facto... more Congenital malformations present at delivery of an infant are due to genetic or non genetic factors and occur in 15-20% of stillborn children. Most can be diagnosed prenatally by ultrasound examination, but some can only be diagnosed after birth. Seven to 10% of infants with abnormal phenotype have numerical or structural chromosomal abnormalities that require identification for accurate diagnosis and genetic counseling. Molecular-cytogenetic and array-based techniques have enabled screening at higher resolution for congenital anomalies that result from genomic imbalances. We have examined four children with congenital anomalies, with or without mental retardation, of unclear etiology. In one child, we detected a deletion (about 28 Mb) of the region 18q21.1-18q23, in mosaic form. This abnormality was missed in a routine cyto genetic examination. We detected different polymorphic copy number variations (CNVs) in the other children. We conclude that array-based comparative genomic hybridization (CGH) is a powerful diagnostic tool for the detection of low level mosaicism.
Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene and... more Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene and has three phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in newborns, failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) in older children, and recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2) in adults. NICCD presents in the first few weeks of life with cholestatic hepatitis syndrome, multiple aminoacidemia and hypergalactosemia. To date almost all reported patients were from East Asia and only few cases from Caucasian origin have been described. We report the first Bulgarian case of NICCD. Mutation screening of the SLC25A13 gene revealed the compound heterozygous mutations c.1081C>T (p.R361*) and c.74C>A (p. A25E) which confirmed the diagnosis of NICCD. The nonsense mutation c.1081C>T (p.R361*) is novel.
Hunter syndrome (Mucopolysaccharidosis type II, MPS II) is a rare X-linked disease caused by a de... more Hunter syndrome (Mucopolysaccharidosis type II, MPS II) is a rare X-linked disease caused by a deficiency of the enzyme iduronate-2-sulphatase (IDS), which results in the lysosomal accumulation of the undegraded glycosaminoglycans (GAGs) dermatan and heparan sulfate in various tissues and organs. Enzyme replacement therapy (ERT) with recombinant iduronate-2-sulphatase is the first disease-specific treatment for Hunter syndrome. Clinical trial data for the use of idursulfase to treat severe Hunter patients are limited and controversial. Our study analyzes therapeutic responses after ERT over 42 months of five Hunter patients and further expanding the knowledge of benefits and disadvantages of such therapy. Five boys with the severe form of MPS II (age range, 5−17 years) were treated with idursulfase for a minimum period of 8 months to a maximum period of 42 months. ERT with idursulfase in patients with the severe form of MPS II was associated with improvements in urinary GAG excretion and spleen size, stabilization of cardiac disease, and not effective on joint contractures, and on liver volume. MPS II is a progressive disease and response to ERT is influenced by the severity of the phenotype at treatment initiation.
Phenylketonuria screening and management in southeastern Europe – survey results from 11 for the ... more Phenylketonuria screening and management in southeastern Europe – survey results from 11 for the patients. Dietitian was a member of PKU team in only 4 of 11 countries, while regular psychological assessments
The results from a pilot prospective study--second trimester Down syndrome [DS] serum screening b... more The results from a pilot prospective study--second trimester Down syndrome [DS] serum screening between 15 and 21 w.g. with two markers (alpha-fetoprotein and free bb-hCG)--were summarised. Sensitivity, false-positive rate [FPR], positive predictive value [PPV] of the screen positive and negative predictive value [NPV] of the screen negative result for the sbgroups II and below 35 years of age were analysed. The uptake for invasive prenatal testing in screen positive patients and the percentage of terminated pregnancies with prenatally diagnosed DS fetuses as well as the ratio "lost unaffected pregnancies/1 DS fetus diagnosed antenatally" were also calculated. High sensitivity of the DS serum screening was achieved--75% and 87.5% in the subgroups below and II the age of 35 respectively with 6.6 and 31.7% FPR. With higher DS age risk the PPV of the screen positive test was higher and the NPV of the screen negative result--lower. The percentage of invasive prenatal testing in screen positive patients was high (average 83.4%) without significant differences in the two age subgroups. Pregnancy was terminated in all cases with antenatally diagnosed DS fetuses. The ratio "lost unaffected pregnancies/1 DS fetus diagnosed antenatally" for serum screening was lower compared to the same ratio when screening by age. The results from our pilot study (serum screening sensitivity and FPR, uptake for invasive testing in screen-positive cases) are comparable to the ones reported in literature. This is an important prerequisite for introduction of mass DS screening for our population.
Ambroxol hydrochloride is an oral mucolytic drug available over‐the‐counter for many years as cou... more Ambroxol hydrochloride is an oral mucolytic drug available over‐the‐counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several‐fold higher dose. Unfortunately, there have been no pharma‐driven clinical trials to establish its use. Thus, real‐world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA‐Parkinson disease (GBA‐PD). Clinicians treating patients with ambroxol for GD and GBA‐PD were approached to collaborate in an investigator‐initiated registry. Anonymized data were collected, including demographics, GD type, GD‐specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5–74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with...
Introduction: Precocious puberty is defined as the onset of pubertal signs in girls younger than ... more Introduction: Precocious puberty is defined as the onset of pubertal signs in girls younger than 8 years of age and in boys younger than 9 years of age. Central precocious puberty (CPP) is due to an early activation of the hypothalamic-pituitary-gonadal axis. It is 20 times more common in girls and 90% of the female cases are considered to be idiopathic (ICPP) (1). Different genes have been proposed as candidate genes in ICPP, but there is not enough evidence for their role in the etiology. In 2013 Abreu et al. first described the role of the MKRN3 gene in pubertal initiation. They detected three frameshift and a missense mutation in five families with familial CPP (2). A year later, Macedo et al. reported five novel mutations four frameshift variants and one missense variant (3). Following studies in patients with ICPP detected different defects in the MKRN3 gene (4, 5, 6, 7, 8) The MKRN3 gene is an intronless gene located on chromosome 15q11.2. Only the paternal allele of the gene...
AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 s... more AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can caus...
Ten girls with sporadic central precocious puberty were screened for mutations in the maternally ... more Ten girls with sporadic central precocious puberty were screened for mutations in the maternally imprinted gene MKRN3. We detected 1 novel frameshift mutation (p.Arg351Serfs*44) and a previously described mutation (p.Pro161Argfs*10). In the course of investigating the family, genetic analysis found 2 asymptomatic males with paternally inherited MKRN3 mutations, which has not been reported in previous studies.
Background: CH could be associated with other diseases or congenital malformations,incl. chromoso... more Background: CH could be associated with other diseases or congenital malformations,incl. chromosomal aberrations.Objective and hypotheses: Description of the complex phenotype in a patient with CH and underlying new aberration in chromosome 2.Methods: Hormonal investigations by Delfia®, Cytogenetics: G banding, genomic hybridization on microarrays; Auxological and complex clinical follow up until 8yrs of age. Results: Primary CH (TSH screening and serum confirmation), associated with SGA status, eutopic thyroid gland, congenital heart malformation (ASD,VSD spontaneously closed, stenotic left A. pulmonalis), dysmorphic features,muscle hypotonia, profound skeletal, developmental and growth delay despite early and sufficient L-Thyroxine therapy was evident in a boy from the Bulgarian CH cohort picked up by neonatal thyroid screening. This complex, syndromic phenotype was accompanied by a deletion in chromosome 2 (G banding): 46,XY,del(2) (q13-q21). Comparative genomic hybridization on ...
Many studies have supported a genetic aetiology for autism. Neuroligins are postsynaptically loca... more Many studies have supported a genetic aetiology for autism. Neuroligins are postsynaptically located cell-adhesion molecules. Mutations in two X-linked neuroligin genes, NLGN3 and NLGN4, have been implicated in pathogenesis of autism. In order to confirm these causative mutations in our autistic population and to determine their frequency we screened 20 individuals affected with autism. We identified one patient with a point mutation in NLGN4 gene that substituted a Met for Thr 787 - c.2360C > T, p.(Thr787Met) and three patients with identical polymorphisms in the same gene: c.933C > T, p.(Thr311Thr) in combination with c.[1777C > T+1779C > G, p.(Leu593Leu)]. All patients tested for NLGN3 mutations were negative. These results indicate that mutations in these genes are responsible for at most a small fraction of autism cases.
The results from a pilot prospective study--second trimester Down syndrome [DS] serum screening b... more The results from a pilot prospective study--second trimester Down syndrome [DS] serum screening between 15 and 21 w.g. with two markers (alpha-fetoprotein and free bb-hCG)--were summarised. Sensitivity, false-positive rate [FPR], positive predictive value [PPV] of the screen positive and negative predictive value [NPV] of the screen negative result for the sbgroups II and below 35 years of age were analysed. The uptake for invasive prenatal testing in screen positive patients and the percentage of terminated pregnancies with prenatally diagnosed DS fetuses as well as the ratio "lost unaffected pregnancies/1 DS fetus diagnosed antenatally" were also calculated. High sensitivity of the DS serum screening was achieved--75% and 87.5% in the subgroups below and II the age of 35 respectively with 6.6 and 31.7% FPR. With higher DS age risk the PPV of the screen positive test was higher and the NPV of the screen negative result--lower. The percentage of invasive prenatal testing i...
The aim of our study was to assess the current state of newborn screening (NBS) in the region of ... more The aim of our study was to assess the current state of newborn screening (NBS) in the region of southeastern Europe, as an example of a developing region, focusing also on future plans. Responses were obtained from 11 countries. Phenylketonuria screening was not introduced in four of 11 countries, while congenital hypothyroidism screening was not introduced in three of them; extended NBS programs were non-existent. The primary challenges were identified. Implementation of NBS to developing countries worldwide should be considered as a priority.
Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a progressive, multisystemic disease... more Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a progressive, multisystemic disease caused by a deficiency of iduronate-2-sulfatase. Patients with the severe form of the disease have cognitive impairment and typically die in the second decade of life. Patients with the less severe form do not experience significant cognitive involvement and may survive until the fifth or sixth decade of life. We studied the relationship of both severity of MPS II and the time period in which patients died with age at death in 129 patients for whom data were entered retrospectively into HOS (Hunter Outcome Survey), the only large-scale, multinational observational study of patients with MPS II. Median age at death was significantly lower in patients with cognitive involvement compared with those without cognitive involvement (11.7 versus 14.1 years; p = 0.024). These data indicate that cognitive involvement is indicative of more severe disease and lower life expectancy in patients with MPS II. Median age at death was significantly lower in patients who died in or before 1985 compared with those who died after 1985 (11.3 versus 14.1 years; p alpha 0.001). The difference in age at death between patients dying in or before, relative to after, the selected cut-off date of 1985 may reflect improvements in patient identification, care and management over the past two decades. Data from patients who died after 1985 could serve as a control in analyses of the effects of enzyme replacement therapy with idursulfase on mortality in patients with MPS II.
Lysosomal storage diseases (LSD) comprise a group of more than 40 different disorders, most of th... more Lysosomal storage diseases (LSD) comprise a group of more than 40 different disorders, most of them resulting from a specific enzyme deficiency. The diagnosis of these disorders is often complicated due to their clinical and biochemical heterogeneity. Definitive diagnosis as well as prenatal diagnosis of LSD is based on specific enzyme assays. Analysis of urinary metabolites facilitates differential diagnosis of LSD, pointing to the probable enzyme defect. A flowchart for biochemical diagnosis is described. The goal of our work was to detect rapidly and reliably most of the known LSD. The results obtained in an 8-year period using this combined clinical/biochemical approach for 528 patients suspected of having LSD are presented. The diagnoses of 36 patients with different enzyme deficiencies show unambiguously the usefulness of the diagnostic algorithm.
Barth syndrome (BTHS) is an X-linked recessive disease caused by mutations in tafazzin gene (TAZ)... more Barth syndrome (BTHS) is an X-linked recessive disease caused by mutations in tafazzin gene (TAZ) which lead to cardiolipin deficiency and mitochondrial dysfunction. Male patients have variable clinical findings, including cardiomyopathy, skeletal myopathy, prepubertal short stature, neutropenia and 3-methylglutaconic aciduria. Female carriers are usually asymptomatic. We report a novel TAZ gene mutation in male and female siblings with left ventricular noncompaction and hypotonia. Additionally, the brother presented an intermittent neutropenia and increased urinary levels of 3-methylglutaconic and 3-methylglutaric acid. The molecular genetic testing showed that both siblings carry the mutation: c.253insC, p.(Arg85Profs*54) in exon 3 of the TAZ gene. This article presents the first case of BTHS in a heterozygous female patient with normal karyotype.
This article has been accepted for publication and undergone full peer review but has not been th... more This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as
Congenital malformations present at delivery of an infant are due to genetic or non genetic facto... more Congenital malformations present at delivery of an infant are due to genetic or non genetic factors and occur in 15-20% of stillborn children. Most can be diagnosed prenatally by ultrasound examination, but some can only be diagnosed after birth. Seven to 10% of infants with abnormal phenotype have numerical or structural chromosomal abnormalities that require identification for accurate diagnosis and genetic counseling. Molecular-cytogenetic and array-based techniques have enabled screening at higher resolution for congenital anomalies that result from genomic imbalances. We have examined four children with congenital anomalies, with or without mental retardation, of unclear etiology. In one child, we detected a deletion (about 28 Mb) of the region 18q21.1-18q23, in mosaic form. This abnormality was missed in a routine cyto genetic examination. We detected different polymorphic copy number variations (CNVs) in the other children. We conclude that array-based comparative genomic hybridization (CGH) is a powerful diagnostic tool for the detection of low level mosaicism.
Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene and... more Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene and has three phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in newborns, failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) in older children, and recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2) in adults. NICCD presents in the first few weeks of life with cholestatic hepatitis syndrome, multiple aminoacidemia and hypergalactosemia. To date almost all reported patients were from East Asia and only few cases from Caucasian origin have been described. We report the first Bulgarian case of NICCD. Mutation screening of the SLC25A13 gene revealed the compound heterozygous mutations c.1081C>T (p.R361*) and c.74C>A (p. A25E) which confirmed the diagnosis of NICCD. The nonsense mutation c.1081C>T (p.R361*) is novel.
Hunter syndrome (Mucopolysaccharidosis type II, MPS II) is a rare X-linked disease caused by a de... more Hunter syndrome (Mucopolysaccharidosis type II, MPS II) is a rare X-linked disease caused by a deficiency of the enzyme iduronate-2-sulphatase (IDS), which results in the lysosomal accumulation of the undegraded glycosaminoglycans (GAGs) dermatan and heparan sulfate in various tissues and organs. Enzyme replacement therapy (ERT) with recombinant iduronate-2-sulphatase is the first disease-specific treatment for Hunter syndrome. Clinical trial data for the use of idursulfase to treat severe Hunter patients are limited and controversial. Our study analyzes therapeutic responses after ERT over 42 months of five Hunter patients and further expanding the knowledge of benefits and disadvantages of such therapy. Five boys with the severe form of MPS II (age range, 5−17 years) were treated with idursulfase for a minimum period of 8 months to a maximum period of 42 months. ERT with idursulfase in patients with the severe form of MPS II was associated with improvements in urinary GAG excretion and spleen size, stabilization of cardiac disease, and not effective on joint contractures, and on liver volume. MPS II is a progressive disease and response to ERT is influenced by the severity of the phenotype at treatment initiation.
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