Browsing by Author "Valongo, Carla"
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- Atraso mental: denominador comum dos défices do metabolismo da creatinaPublication . Valongo, CarlaO atraso mental (AM) afeta cerca de 3% da população dos países ocidentais. Na grande maioria dos casos as causas genéticas inerentes ao AM ainda não se encontram esclarecidas. Os doentes com défice do metabolismo da creatina têm como denominador comum o AM/atraso de desenvolvimento bem como atraso de linguagem, epilepsia e autismo. Estes défices englobam um grupo de doenças tratáveis: défices da biossíntese da creatina (envolve as enzimas arginina:glicina amidinotransferase e guanidinoacetato metiltransferase) e do transportador de creatina cerebral (défice em SLC6A8/CT1). Desde 2002 estudamos 6761 urinas de indivíduos com AM e identificamos 23 indivíduos com défices do metabolismo da creatina: oito com défice em guanidinoacetato metiltransferase (GAMT) e 15 com défice em SLC6A8. A análise molecular permitiu identificar a mesma mutação em todos os doentes com défice em GAMT, o que sugere que podemos estar perante um efeito fundador na nossa população. Os doentes com défice no SLC6A8 apresentaram uma grande heterogeneidade molecular. Sendo a prevalência destas patologias de 1:294, na nossa casuística, devemos ter em consideração estes défices quando estamos perante indivíduos com AM de etiologia desconhecida, epilepsia e atraso de linguagem. O défice em SLC6A8, sendo uma patologia ligada ao X, também deve ser tido em conta em todos os indivíduos do sexo masculino com AM e X-frágil negativo.
- Biochemical data as important clues for diagnosis of SUCLA2 defectsPublication . Nogueira, Célia; Garcia, Paula; Diogo, Luisa; Valongo, Carla; Santorelli, Filippo; Vilarinho, Laura
- Creatine deficiency syndromes: biochemical and molecular aspectsPublication . Valongo, Carla; Almeida, Lígia; Ramos, Altina; Salomons, Gajja; Jacobs, Cornelis; Vilarinho, LauraIntroduction: Creatine deficiency syndromes (CDS) represent a group of inborn errors of creatine biosynthesis: L-arginine-glycine amidinotransferase - AGAT and guanidinoacetate methyltransferase - GAMT deficiencies and transport (creatine transporter - SLC6A8 deficiency). Patients with CDS may present with mental retardation (MR), expressive speech and language delay, and epilepsy. Patients with GAMT deficiency or SLC6A8 deficiency may also exhibit autistic-like behavior. The common denominator of these disorders is the depletion of the brain creatine pool, as demonstrated by in vivo 1H-MRS. Patients and Methods: The authors studied 6,600 urine samples from Portuguese autistic children and young adults for defects in creatine metabolism. We started with the determination of guanidinoacetate and creatine in urine by GC-MS-SIM. Based on these findings, enzyme assays or DNA mutation analysis may be performed. Molecular genetic analysis for GAMT deficiency and creatine transporter deficiency is also available in our laboratory. Results: A marked excretion of guanidinoacetate in urine compatible with GAMT deficiency was observed in seven cases. Furthermore, other 15 patients showed high urinary levels of creatine/creatinine ratio what suggests a defect of SLC6A8. All GAMT deficient patients show the same mutation (c.59G>C) which suggests a founder effect in our population. Molecular genetic analysis of the SLC6A8 deficiency patients revealed a large spectrum of mutations. Discussion: So far, 22 patients with CDS were identified in our laboratory (1:300). We believe these defects are still under diagnosed, so the possibility should be considered in all children affected by unexplained MR, seizures, and speech delay. SLC6A8 defect should also be considered in males with MR and negative fragile-X testing. GAMT deficiency is treatable with oral creatine monohydrate and ornithine supplementation with arginine dietary restriction.
- Doenças do metabolismo do colesterol: cromatografia de esteróis no diagnóstico de 25 casos em PortugalPublication . Valongo, Carla; Dias, Aureliano Jorge; Leite, Mónica Sofia; Vilarinho, LauraOs esteróis desempenham um papel fundamental nos processos fisiológicos de praticamente todos os organismos vivos. O esterol mais abundante nos seres humanos é o colesterol, o qual desempenha uma multiplicidade de funções desde a estrutural à sinalização. A extração e análise de esteróis no plasma é complexa devido à sua insolubilidade, sequestração dentro das lipoproteínas e à grande diferença entre cada tipo de esterol. Os autores apresentam a casuística referentes à análise de 13 esteróis e fitosteróis em plasma e líquido amniótico.
- Identification of novel L2HGDH gene mutations and update of the pathological spectrumPublication . Vilarinho, Laura; Tafulo, Sandra; Sibilio, Michelina; Kok, Fernando; Fontana, Federica; Diogo, Luisa; Venâncio, Margarida; Ferreira, Mariana; Nogueira, Celia; Valongo, Carla; Parenti, Giancarlo; Amorim, António; Azevedo, LuisaL-2-hydroxyglutaric aciduria (L-2-HGA, MIM 236792) is a neurometabolic disorder caused by the toxic accumulation of high concentration of L-2-hydroxyglutaric acid in plasma and cerebrospinal fluid. Distinct mutations on the L2HGDH gene have been associated with the clinical and biochemical phenotype. Here we present three novel mutations (Gln197X, Gly211Val and c.540+1 G4A), which increase the present deleterious collection of L2HGDH gene up to 35 mutations that we have compiled in this study. In addition, we used the haplotypic information based on polymorphic markers to demonstrate the common origin of Gly57Arg harboring chromosomes.
- Mental retardation: a common clinical hallmark of creatine deficiency disordersPublication . Valongo, Carla; Almeida, Lígia; Ramos, Altina; Santos, Raquel Andreia; Vilarinho, LauraIntroduction: In Western countries, mental retardation (MR) affects about 3% of the general population. For the majority of the cases of inherited MR, the genetic causes are not yet elucidated. Patients with creatine deficiency disorders (CDD) may present with MR/developmental delay as well as expressive speech and language delay, autism and epilepsy. They represent a group of treatable inborn errors of creatine biosynthesis and transport (SLC6A8) across the blood brain barrier. Patients and Methods: A group of children and young adults with MR were studied for defects in creatine metabolism. We started with the determination of guanidinoacetate and creatine in 6,600 urine samples by GC-MS-SIM. DNA mutation analysis was performed in all suspected cases. Results: Urine biochemical analysis revealed seven cases compatible with GAMT deficiency and 15 patients suggestive of a defect in SLC6A8. All GAMT deficient patients show the same mutation which suggests a founder effect in our population. SLC6A8 deficiency patients revealed a large spectrum of mutations. Discussion: So far, 22 patients with CDD were identified in our laboratory (1:300). We believe these defects are still under diagnosed, so the possibility should be considered in all children affected by unexplained MR, seizures, and speech delay.
- A novel missense mutation in SUCLA2 associated with mild methylmalonic aciduriaPublication . Nogueira, Célia; Garcia, Paula; Diogo, Luisa; Valongo, Carla; Santorelli, Filippo; Vilarinho, LauraIntroduction Succinyl CoA synthase is a mitochondrial matrix enzyme that catalyzes the reversible synthesis of succinate and ATP or GTP from succinyl-CoA and ADP in the tricarboxylic acid cycle (TCA). This enzyme is made up of two subunits, α and β, encoded by SUCLG1 and SUCLA2, respectively. The clinical features of patients with mutations in SUCLA2 include early childhood hypotonia, developmental delay, and almost invariably, progressive dystonia and sensorineural deafness. Mutations in SUCLA2 and SUCLG1 cause an encephalomyopathic form of infantile mtDNA depletion syndrome. A useful diagnostic clue in succinyl CoA synthase disorders is a ‘‘mildly’’ elevated urinary methylmalonic acid (MMA), and presence of TCA intermediates. To date, two patients with SUCLG1 mutations have been reported, whereas mutations in SUCLA2 have been reported in 17 patients. We here present an additional patient with a novel SUCLA2 mutation. Methods We report a 17-month-old-boy, who presented severe muscular hypotonia, failure to thrive, developmental delay, weight loss during a gastroenteritis crises, dysmorphisms and muscular atrophy. A clinical investigation disclosed hyperlactacidemia together with moderate excretion of MMA and elevated C4-dicarboxylic carnitine. Sequencing analysis of SUCLA2 and SUCLG1 was performed using standard methods. Results Mutation analysis of SUCLA2 revealed a homozygous c.985A>G mutation in exon 8 (p.M329V). This missense mutation affects an amino acid that is highly conserved in different species and was not found in controls. The analysis by bioinformatics tools also confirmed a pathogenic mutation. Discussion The clinical and biochemical phenotype of our patient is strikingly similar to other reported patients with SUCLA2 mutations. In addition, the mildly elevated levels of methylmalonate and lactate raised the suspicion of this disease. Our study contributed to expand the spectrum of patients with SUCLA2 mutations, and will be important for an accurate genetic counseling and a prenatal diagnosis to the affected family.
- A novel SUCLA2 mutation in a Portuguese patientPublication . Nogueira, Célia; Garcia, Paula; Diogo, Luísa; Valongo, Carla; Santorelli, Filippo; Vilarinho, Laura
- Primary hyperoxaluria Type 1: organic aciduria diagnosed in plasmaPublication . Valongo, Carla; Rodrigues, Marilia; Dias, Aureliano; Vilarinho, LauraBackground: Primary hyperoxaluria Type 1 (PH1) is a rare autosomal recessive inborn error of glyoxylate metabolism, caused by a deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase. The disorder results in overproduction and excessive urinary excretion of oxalate, causing recurrent urolithiasis and nephrocalcinosis. Patient and methods: The patient, a 38 year-old-woman, was referred to our lab with severe arthritis in the hips and knees, calcinosis and stage V chronic renal failure under hemodialysis. No urine samples were available to perform organic acids analysis so we studied patient plasma. Samples were extracted with ethylacetate and analyzed by GC-MS. Results: Plasmatic organic acids profile in two different samples revealed a marked excretion of oxalate (131 and 125 µmol/L; controls: 0-5) and glycolate (362 and 338 µmol/L; controls: 9-42). Glicerate concentration was normal (17 and 15 µmol/L; controls: 0-24). Conclusions: The usual biochemical indicator of PH1 is a persistently and markedly elevated urine oxalate. In the absence of urine samples, this biochemical diagnosis can also be done in plasma samples. PH1 is a treatable organic aciduria and an early and accurate diagnosis preserves renal function. So, it is important to screen for PH1 in patients with recurrent urolithiasis or unexplained renal insufficiency.
- Síndromes de deficiência em creatina cerebral: 13 anos de experiência em PortugalPublication . Valongo, Carla; Lopes, Altina; Vilarinho, LauraOs síndromes da deficiência em creatina cerebral são um grupo de erros inatos do metabolismo da creatina que incluem as deficiências de síntese da creatina: arginina:glicina amidinotransferase (AGAT) e S-adenosil- L-metionina:guanidinoacetato metiltransferase (GAMT) e a deficiência no transportador transmembranar (CT1/SLC6A8). O diagnóstico destas patologias pode ser efetuado através da determinação do ácido guanidinoacético e creatina urinária e plasmática e do estudo molecular. Desde 2003 que a Unidade de Rastreio Neonatal, Metabolismo e Genética (URN) disponibiliza este tipo de diagnóstico que permitiu a identificação de nove doentes com deficiência em GAMT e 20 doentes com deficiência em CT1. O rastreio bioquímico das deficiências em creatina cerebral deve ser realizado em todos os doentes que apresentem encefalopatia epiléptica de causa desconhecida, doença do movimento, alterações cognitivas e comportamento tipo autista.