Faculty of Medicine

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Author: search.filters.author.Plaseska-Karanfilska D

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    Heterotopic ossifications and Charcot joints: Congenital insensitivity to pain with anhidrosis (CIPA) and a novel NTRK1 gene mutation
    (Elsevier BV, 2020-01)
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    Bogevska I
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    Laban N
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    Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN-IV), is a rare and severe autosomal recessive disorder. We report on an adult female patient whose clinical findings during childhood were not recognized as CIPA. There was neither complete anhidrosis nor a recognizable sensitivity to heat. Tumorlike swellings of many joints and skeletal signs of Charcot neuropathy developed in adolescence which, together with a history of self-mutilation, led to a clinical suspicion of CIPA confirmed by identification of a novel homozygous variant c.1795G > T in the NTRK1 gene in blood lymphocytes. Both parents were heterozygous for the mutation. The variant predicts a premature stop codon (p.Gly599Ter) and thus represents a pathogenic variant; the first reported in the Southeastern European population.
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    Characteristic Diagnostic Clues of Metatropic Dysplasia: The Lumbothoracic Humpback with Dumbbell Appearance of the Long Bones
    (Walter de Gruyter GmbH, 2018-12)
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    Kalcev G
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    Laban N
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    Popovski N
    Metatropic dysplasia (MD) is a rare skeletal dysplasia associated with heterozygous mutations in the TRPV4 gene. We describe a 28-month-old boy with knock-knees referred for metabolic investigation suspected of carrying vitamin D-resistant rickets. He has received regular vitamin D prophylaxis at the usual dose. Laboratory investigations revealed normal values for calcium, phosphorus and alkaline phosphatase. He was short (-3.5 SDS), his mental development was normal, and he started to walk at the age of 22 months. The diagnostic clue for the diagnosis of metatropic dysplasia was the presence of the hump back in the upper lumbar and lower thoracic vertebrae, in addition to a long and narrow chest. An X-ray survey of the skeleton revealed platyspondyly, dysplastic metaphyses with dumbbell appearance of the long bones, kyphoscoliosis, and narrow and elongated thorax with short ribs. This is the first patient with MD in the Republic of Macedonia. Knock-knees were the cause of his referral, as a peculiarity of his phenotype. The very presence of the hump back, and the dumbbell appearance of the long bones distinguished the MD from other bone dysplasias with similar characteristics. We believe that the presence of those two features can shorten the path to accurate diagnosis in the crowded field of overlapping skeletal dysplasias. The diagnosis of MD in this patient was further confirmed by the discovery of the mutation c.2396C>T; p.Pro799Leu (P799L) of the TRPV4 gene.
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    CYSTIC FIBROSIS MUTATION SPECTRUM IN NORTH MACEDONIA: A STEP TOWARD PERSONALIZED THERAPY
    (Macedonian Academy of Sciences and Arts / Sciendo, 2019)
    Terzic M
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    Jakimovska M
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    Sukarova-Stefanovska E
    The most prevalent “rare” disease worldwide, cystic fibrosis (CF), is an autosomal recessive multisystem dis ease, caused by mutations in the CFTR gene. The knowledge of CFTR mutations present in certain population is important for designing a simple, fast and cost-effective genetic testing approach, also for better management of CF patients, including the administration of novel targeted therapies. Here, we present genetic results of 158 unrelated CF patients from the National CF Registry of the Republic of North Macedonia. Initially, patients were screened for the 11 most common CF mutations. Additional CF muta tions and large deletions/duplications in the CFTR gene were analyzed using commercial kits. If the genotype was undetermined, all CFTR exons were analyzed using Sanger DNA sequencing or next generation sequencing (NGS) (since 2014). The most common CF mutation, c.1521_ 1523del (legacy name F508del), was found with an over all incidence of 75.9%. Additionally, 26 other pathogenic variants and three large deletions were identified in the CFTR gene as a genetic cause of CF. Two of these, c.1070 C>T (p.Ala357Val) and c.2779_2788dup CTTGCTATGG (p.Gly930AlafsTer48), were novel. According to the distri bution and prevalence of the pathogenic variants detected in our patients, a fast and cost-effective method, based on a single base extension was designed as a first-line CF genetic test with a 90.0% detection rate within our population. Furthermore, the knowledge of CFTR mutation classes in our CF patients represents the first step toward personalized therapy for CF in our country.
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    Two Years of Newborn Screening for Cystic Fibrosis in North Macedonia: First Experience
    (Macedonian Academy of Sciences and Arts / Sciendo, 2021-07)
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    Plaseska-Karanfilska D
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    Stamatova A
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    Spirevska L
    There is a widely accepted consensus on the benefits of newborn screening (NBS) for cystic fibrosis (CF) in terms of reduced disease severity, improved quality of life, lower treatment burden, and reduced costs. More and more countries in the world are introducing NBS for CF as a national preventive health program. Newborn screening for CF was introduced in the Republic of North Macedonia (RNM) in April, 2019, after a pilot study of 6 months in 2018. A two-step immunoreactive trysinogen (IRT-IRT) algorithm is performed, and then a sweat test for confirmation/exclusion of the CF diagnosis when the IRT values were both over the cutoff (70.0 and 45.0 ng/mL, respectively). In cases with confirmed diagnosis of CF (a sweat chloride concentration >60.0 mmol/L) or with intermediate sweat test results (a sweat chloride concentration of between 30.0 and 59.0 mmol/L), CF transmembrane conductance regulator (CFTR) mutation analysis is performed. By the end of 2020, over a period of 27 months, including the pilot study period, a total number of 43,139 newborns were screened for CF. Seventeen (0.039%) newborns were diagnosed with CF. In all newly discovered CF cases by screening, the diagnosis was confirmed by determination of the CFTR mutations. The most common CFTR mutation, F508del, was found with an overall incidence of 70.6%. Other more frequent mutations were G542X (11.8%) and N1303K (5.9%). Four mutations were found in one CFTR allele each: G1349D, G126D, 457TAT>G and CFTRdupexon22, with the last one being newly discovered with unknown consequences. An incredibly large difference was found in the incidence of the disease between the Macedonian and Albanian neonatal population, with almost four time higher prevalence among Albanians (1:4530 vs. 1:1284).