Publications by authors named "Zita Krumina"

12 Publications

  • Page 1 of 1

Solar retinopathy: a new setting of red, green, and blue channels.

Eur J Ophthalmol 2021 May 23;31(3):1261-1266. Epub 2020 Mar 23.

St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, UK.

Purpose: To introduce a new color imaging technique using improved settings of red, green, and blue channels for improved delineation of retinal damage in patients with solar retinopathy.

Method: A retrospective case series of patients with poor vision secondary to solar retinopathy were analyzed. All patients underwent visual acuity, refraction, and dilated fundus examination. A spectral domain-optical coherence tomography of the macula and color fundus imaging using optimized red, green, and blue color setting was performed. Patients were reviewed over a 6-month period. The data were analyzed for statistical significance using an independent test and a receiver operating characteristic curve.

Results: In total, 20 eyes of 10 patients were included between 2009 and 2017. The mean age was 24.9 ± 18.1 years. Best corrected visual acuity at first consultation was 0.78 ± 0.11 and after 6 months was 0.83 ± 0.09. Spectral domain-optical coherence tomography demonstrated retinal abnormalities at the myoid zone, ellipsoid zone, and the outer segment of photoreceptors. Receiver operating characteristic curve analysis showed an improving effect (area under the curve = 0.62; 95% confidence interval = 0.42-0.79). The color channels parameters, which improve visualization of the lesions were found to be 67-0.98-255 for the R-guided setting, 19-0.63-121 for the B-guided setting, and 7-1.00-129 for the G-guided setting. The ideal red, green, and blue setting was in 24-0.82-229.

Conclusion: The use of a new setting of red, green, and blue channels could improve the diagnosis and monitoring of solar retinopathy, hence improving patient care.
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http://dx.doi.org/10.1177/1120672120914852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358560PMC
May 2021

Pathogenic Variants in Latvian Familial Adenomatous Polyposis Patients.

Medicina (Kaunas) 2019 Sep 20;55(10). Epub 2019 Sep 20.

Institute of Oncology, Riga Stradiņš University, LV-1007 Riga, Latvia.

Familial adenomatous polyposis is one of the -associated polyposis conditions described as genetically predetermined colorectal polyposis syndrome with a variety of symptoms. The purpose of this study was to determine sequence variants of the gene in patients with familial adenomatous polyposis (FAP) phenotype and positive or negative family history. Eight families with defined criteria of adenomatous polyposis underwent molecular genetic testing. Coding regions and flanking intron regions of the gene were analyzed by Sanger sequencing. Eight allelic variants of the gene coding sequence were detected. All allelic variants of the gene were predicted to be pathogenic based on criteria according to the "Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology" (2015), four of them c.1586_1587insAT, c.2336delT, c.3066_3067insGA, and c.4303_4304insC, were considered novel. The timely molecular genetic analysis of germline variants and standardized interpretation of the pathogenicity of novel allelic variants has a high impact on choice for treatment, cancer prevention, and family genetic counseling.
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http://dx.doi.org/10.3390/medicina55100612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843383PMC
September 2019

Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.

Am J Hum Genet 2019 08 27;105(2):384-394. Epub 2019 Jun 27.

Department of Paediatric Neurology, Leicester Royal Infirmary, Leicester LE1 5WW, UK.

Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698938PMC
August 2019

Complete mtDNA sequencing reveals mutations m.9185T>C and m.13513G>A in three patients with Leigh syndrome.

Mitochondrial DNA A DNA Mapp Seq Anal 2018 10 12;29(7):1115-1120. Epub 2017 Dec 12.

a Latvian Biomedical Research and Study Centre , Riga , Latvia.

The most common mitochondrial disorder in children is Leigh syndrome, which is a progressive and genetically heterogeneous neurodegenerative disorder caused by mutations in nuclear genes or mitochondrial DNA (mtDNA). In the present study, a novel and robust method of complete mtDNA sequencing, which allows amplification of the whole mitochondrial genome, was tested. Complete mtDNA sequencing was performed in a cohort of patients with suspected mitochondrial mutations. Patients from Latvia and Lithuania (n = 92 and n = 57, respectively) referred by clinical geneticists were included. The de novo point mutations m.9185T>C and m.13513G>A, respectively, were detected in two patients with lactic acidosis and neurodegenerative lesions. In one patient with neurodegenerative lesions, the mutation m.9185T>C was identified. These mutations are associated with Leigh syndrome. The present data suggest that full-length mtDNA sequencing is recommended as a supplement to nuclear gene testing and enzymatic assays to enhance mitochondrial disease diagnostics.
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http://dx.doi.org/10.1080/24701394.2017.1413365DOI Listing
October 2018

Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.

Ann Neurol 2017 Dec;82(6):1004-1015

Pediatric Neurology, Brussels University Hospital, Brussels, Belgium.

Objective: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1.

Methods: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported.

Results: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills.

Interpretation: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.
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http://dx.doi.org/10.1002/ana.25110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847115PMC
December 2017

Importance of Axial Length and Functional Corneal Endothelial Cells in Descemet Membrane Endothelial Keratoplasty.

Cornea 2017 12;36(12):e35-e36

Departments of *Ophthalmology; and †Genetics, Riga Stradins University, Riga, Latvia ‡Faculty of Medicine, Riga Stradins University, Riga, Latvia §International Center for Ocular Physiopathology (ICOP), The Veneto Eye Bank Foundation, Venice, Italy.

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http://dx.doi.org/10.1097/ICO.0000000000001385DOI Listing
December 2017

Genetic variation spectrum in gene identified in Latvian patients with Wilson disease.

Mol Genet Genomic Med 2017 Jul 7;5(4):405-409. Epub 2017 Jun 7.

Scientific Laboratory of Molecular GeneticsRīga Stradiņš UniversityRigaLatvia.

Background: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by allelic variants in gene. More than 500 distinct variants have been reported, the most common WD causing allelic variant in the patients from Central, Eastern, and Northern Europe is H1069Q.

Methods: All Latvian patients with clinically confirmed WD were screened for the most common mutation p.H1069Q by PCR Bi-PASA method. Direct DNA sequencing of gene (all 21 exons) was performed for the patients with WD symptoms, being either heterozygous for H1069Q or without it on any allele.

Results: We identified 15 different allelic variants along with eight non-disease-causing allelic variants. Based on the gene molecular analysis and patients' clinical data variant p.His1069Gln was found in 66.9% of WD alleles. Wide clinical variability was observed among individuals with the same genotype. The results of our study confirm that neurological manifestations of WD are typically present later than the liver disease but no significant association between the presence/absence of the most common genetic variant and mode of initial WD presentation or age at presentation was identified.

Conclusions: (1) The most prevalent mutation in Latvian patients with Wilson disease was c.3207C>A (p.His1069Gln); (2) No significant phenotype-genotype correlation was found in Latvian patients with Wilson disease; (3) The estimated prevalence of Wilson disease in Latvia is 1 of 24,000 cases which is higher than frequently quoted prevalence of 1: 30,000.
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http://dx.doi.org/10.1002/mgg3.297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511797PMC
July 2017

Fabricated or Induced Illness Presenting as Recurrent Corneal Lesions, Cataracts, and Uveitis.

J Pediatr Ophthalmol Strabismus 2016 Feb 4;53 Online:e6-e11. Epub 2016 Feb 4.

Two siblings with ophthalmic findings, psychomotor retardation, somnolence, and seizures underwent diagnostic studies, genetic investigations, ultrasonography, biomicroscopy, and posterior and anterior optical coherence tomography. Both siblings experienced eye problems at different times from the age of 6 months to 12 years. The family pedigree and neurological problems (ie, hypotony, seizures, sleepiness, and speech and psychomotor delay) suggested a metabolic or mitochondrial pathology. After exclusion of multiple potential diseases, a fabricated or induced illness was suspected. Fabricated or induced illness can be a cause for unusual clinical findings and should be considered in the differential diagnosis when ocular and other abnormalities cannot be explained after a comprehensive evaluation. The diagnosis of fabricated or induced illness should not be based on exclusion alone but rather on positive findings.
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http://dx.doi.org/10.3928/01913913-20160122-01DOI Listing
February 2016

Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome.

Neuropediatrics 2015 Apr 2;46(2):98-103. Epub 2015 Feb 2.

Department of Neurology, Radboudumc, Nijmegen, The Netherlands.

Pediatric movement disorders are still a diagnostic challenge, as many patients remain without a (genetic) diagnosis. Magnetic resonance imaging (MRI) pattern recognition can lead to the diagnosis. MEGDEL syndrome (3-MethylGlutaconic aciduria, Deafness, Encephalopathy, Leigh-like syndrome MIM #614739) is a clinically and biochemically highly distinctive dystonia deafness syndrome accompanied by 3-methylglutaconic aciduria, severe developmental delay, and progressive spasticity. Mutations are found in SERAC1, encoding a phosphatidylglycerol remodeling enzyme essential for both mitochondrial function and intracellular cholesterol trafficking. Based on the homogenous phenotype, we hypothesized an accordingly characteristic MRI pattern. A total of 43 complete MRI studies of 30 patients were systematically reevaluated. All patients presented a distinctive brain MRI pattern with five characteristic disease stages affecting the basal ganglia, especially the putamen. In stage 1, T2 signal changes of the pallidum are present. In stage 2, swelling of the putamen and caudate nucleus is seen. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease. It later increases, reflecting progressive putaminal involvement. This "eye" was found in all patients with MEGDEL syndrome during a specific age range, and has not been reported in other disorders, making it pathognomonic for MEDGEL and allowing diagnosis based on MRI findings.
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http://dx.doi.org/10.1055/s-0034-1399755DOI Listing
April 2015

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.

Hum Mol Genet 2014 Jun 8;23(11):2888-900. Epub 2014 Jan 8.

Sektion für Funktionelle Genetik am Institut für Humangenetik, Universität zu Lübeck, Lübeck 23538, Germany.

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.
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http://dx.doi.org/10.1093/hmg/ddu002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014191PMC
June 2014

Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.

Nat Genet 2012 Jun 10;44(7):797-802. Epub 2012 Jun 10.

Department of Pediatrics, Radboud University Nijmegen Medical Centre (RUNMC), Nijmegen, The Netherlands.

Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-methylglutaconic aciduria. We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange. A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1 (where the species nomenclature denotes the number of carbon atoms in the two acyl chains:number of double bonds in the two acyl groups) and decreased concentrations of phosphatidylglycerol-36:1 species, resulting in an altered cardiolipin subspecies composition. We also detected low concentrations of bis(monoacyl-glycerol)-phosphate, leading to the accumulation of free cholesterol, as shown by abnormal filipin staining. Complementation of patient fibroblasts with wild-type human SERAC1 by lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1. Our data identify SERAC1 as a key player in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking.
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http://dx.doi.org/10.1038/ng.2325DOI Listing
June 2012

Mucopolysaccharidosis type II in females and response to enzyme replacement therapy.

Am J Med Genet A 2012 Feb 13;158A(2):450-4. Epub 2012 Jan 13.

Department of Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Polandd.

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked lysosomal storage disease caused by a deficiency of iduronate-2-sulfatase (IDS). Two affected girls with moderate and severe forms of MPS II with normal karyotypes and increased urinary dermatan sulphate and heparin sulphate excretion and marked deficiencies of IDS activity are reported. Molecular studies showed that case 1 has a heterozygous mutation c.1568A > G (p.Y523C) associated with almost totally skewed inactivation of the normal maternal X chromosome, and case 2 has a heterozygous deletion that includes exons 1-4 of IDS (minimal deletion range c.1-103_184del). The multi-exon deletion correlated with early onset of the disease and severe phenotype with intellectual disability, whereas the missense mutation was associated with moderate developmental delay. Although genotype-phenotype correlation in MPS II is difficult, gene deletions seem to correlate with more severe clinical manifestation of the disease. Enzyme replacement therapy (ERT) in these two females resulted in disease stabilization in both.
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http://dx.doi.org/10.1002/ajmg.a.34415DOI Listing
February 2012
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