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SLC19A3 related disorder: Treatment implication and clinical outcome of 2 new patients.
Tonduti, D, Invernizzi, F, Panteghini, C, Pinelli, L, Battaglia, S, Fazzi, E, Zorzi, G, Moroni, I, Garavaglia, B, Chiapparini, L, et al
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2018;(2):332-335
Abstract
Encephalopathies with neostriatal involvement constitute a heterogeneous group of acquired and genetically inherited conditions that include Bilateral Striatal Necrosis (BSN) and other Striatal Lesions (SL) (Tonduti et al). We describe two new patients suffering from BSN due to biallelic SLC19A3 mutations. In the first patient vitamin supplementation was started early on, resulting in the remission of the clinical picture, and an almost complete normalization of the neuroradiological findings. In the second one treatment was started late, compliance was irregular and the resulting clinical outcome was poor. The clinical outcome of our two patients confirms and further stresses the importance of the early administration of vitamin supplementation in all patients presenting with neostriatal lesions, or clear bilateral striatal necrosis. Patient 2 didn't present any additional episode of acute decompensation after the age of 20 years despite having completely stopped treatment. This suggests the existence of an age dependency of thiamin requirement in humans.
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2.
Teaching NeuroImages: Subacute encephalopathy in a young woman with THTR2 gene mutation.
Sechi, E, Addis, A, Fadda, G, Minafra, L, Bravatà, V, Sechi, G
Neurology. 2015;(14):e108-9
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Identification of PENDRIN (SLC26A4) mutations in patients with congenital hypothyroidism and "apparent" thyroid dysgenesis.
Kühnen, P, Turan, S, Fröhler, S, Güran, T, Abali, S, Biebermann, H, Bereket, A, Grüters, A, Chen, W, Krude, H
The Journal of clinical endocrinology and metabolism. 2014;(1):E169-76
Abstract
CONTEXT Congenital hypothyroidism, the most frequent endocrine congenital disease, can occur either based on a thyroid hormone biosynthesis defect or can predominantly be due to thyroid dysgenesis. However, a genetic cause could so far only be identified in less than 10% of patients with a thyroid dysgenesis. OBJECTIVES Exome sequencing was used for the first time to find additional genetic defects in thyroid dysgenesis. PATIENTS AND METHODS In a consanguineous family with thyroid dysgenesis, exome sequencing was applied, and findings were further validated by Sanger sequencing in a cohort of 94 patients with thyroid dysgenesis. RESULTS By exome sequencing we identified a homozygous missense mutation (p.Leu597Ser) in the SLC26A4 gene of a patient with hypoplastic thyroid tissue, who was otherwise healthy. In the cohort of patients with thyroid dysgenesis, we observed a second case with a homozygous missense mutation (p.Gln413Arg) in the SLC26A4 gene, who was additionally affected by severe hearing problems. Both mutations were previously described as loss-of-function mutations in patients with Pendred syndrome and nonsyndromic enlarged vestibular aqueduct. CONCLUSION We unexpectedly identified SLC26A4 mutations that were hitherto diagnosed in thyroid dyshormonogenesis patients, now for the first time in patients with structural thyroid defects. This result resembles the historic description of thyroid atrophy in patients with the so-called myxedematous form of cretinism after severe iodine deficiency. Most likely the thyroid defect of the two homozygous SLC26A4 gene mutation carriers represents a kind of secondary thyroid atrophy, rather than a primary defect of thyroid development in the sense of thyroid agenesis. Our study extends the variable clinical spectrum of patients with SLC26A4 mutations and points out the necessity to analyze the SLC26A4 gene in patients with apparent thyroid dysgenesis in addition to the known candidate genes TSHR, PAX8, NKX2.1, NKX2.5, and FOXE1.
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Recessive SLC19A2 mutations are a cause of neonatal diabetes mellitus in thiamine-responsive megaloblastic anaemia.
Shaw-Smith, C, Flanagan, SE, Patch, AM, Grulich-Henn, J, Habeb, AM, Hussain, K, Pomahacova, R, Matyka, K, Abdullah, M, Hattersley, AT, et al
Pediatric diabetes. 2012;(4):314-21
Abstract
Permanent neonatal diabetes mellitus (PNDM) is diagnosed within the first 6 months of life, and is usually monogenic in origin. Heterozygous mutations in ABCC8, KCNJ11, and INS genes account for around half of cases of PNDM; mutations in 10 further genes account for a further 10%, and the remaining 40% of cases are currently without a molecular genetic diagnosis. Thiamine-responsive megaloblastic anaemia (TRMA), due to mutations in the thiamine transporter SLC19A2, is associated with the classical clinical triad of diabetes, deafness, and megaloblastic anaemia. Diabetes in this condition is well described in infancy but has only very rarely been reported in association with neonatal diabetes. We used a combination of homozygosity mapping and evaluation of clinical information to identify cases of TRMA from our cohort of patients with PNDM. Homozygous mutations in SLC19A2 were identified in three cases in which diabetes presented in the first 6 months of life, and a further two cases in which diabetes presented between 6 and 12 months of age. We noted the presence of a significant neurological disorder in four of the five cases in our series, prompting us to examine the incidence of these and other non-classical clinical features in TRMA. From 30 cases reported in the literature, we found significant neurological deficit (stroke, focal, or generalized epilepsy) in 27%, visual system disturbance in 43%, and cardiac abnormalities in 27% of cases. TRMA should be considered in the differential diagnosis of diabetes presenting in the neonatal period.
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5.
[Pharmacokinetic problems in clinical practice: role of drug transporters].
Rosskopf, D, Kroemer, HK, Siegmund, W
Deutsche medizinische Wochenschrift (1946). 2009;(8):345-56; quiz 357-60
Abstract
Drug disposition is controlled by drug metabolism and drug transport. In the last decade numerous drug transporters have been identified and characterized in the context of drug uptake, efflux and interactions. This article reviews major advancements in this field. Efflux pumps like the multidrug resistance protein 1 (MDR1, ABCB1) are expressed in the intestine where they secrete drugs back into the intestinal lumen. Inhibitors of ABCB1 can increase the bioavailability of such drugs due to an increased absorption. Inducers of metabolism (rifampicin, carbamazepine, St. John's Wort) also induce the expression of drug transporters like ABCB1. Subsequently, an increased intestinal secretion in addition to an increased metabolism can diminish plasma levels of drugs, for example ciclosporin. The relevance of uptake transporters is increasingly recognized. SLCO1B1 is a hepatic uptake transporter involved in the absorption of statins. Inhibition of SLCO1B1 as well as common genetic variants can lead to increased bioavailability and to adverse reactions, ultimately culminating in rhabdomyolysis.