RESUMO
Mucopolysaccharidosis (MPS) VI is an autosomal recessive lysosomal storage disorder arising from deficient activity of N-acetylgalactosamine-4-sulfatase (arylsulfatase B) and subsequent intracellular accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin-4-sulfate. Manifestations are multi-systemic and include skeletal abnormalities such as dysostosis multiplex and short stature. Reference height-for-age growth charts for treatment-naïve MPS VI patients have been published for both the slowly and rapidly progressing populations. Categorization of disease progression for these charts was based on urinary GAG (uGAG) level; high (>200µg/mg creatinine) levels identified subjects as rapidly progressing. Height data for 141 patients who began galsulfase treatment by the age of 18years were collected and stratified by baseline uGAG level and age at ERT initiation in 3-year increments. The reference MPS VI growth charts were used to calculate change in Z-score from pre-treatment baseline to last follow-up. Among patients with high baseline uGAG levels, galsulfase ERT was associated with an increase in Z-score for those beginning treatment at 0-3, >3-6, >6-9, >9-12, and >12-15years of age (p<0.05). Increases in Z-score were not detected for patients who began treatment between 15 and 18years of age, nor for patients with low (≤200µg/mg creatinine) baseline uGAG levels, regardless of age at treatment initiation. The largest positive deviation from untreated reference populations was seen in the high uGAG excretion groups who began treatment by 6years of age, suggesting an age- and severity-dependent impact of galsulfase ERT on growth.
Assuntos
Estatura/efeitos dos fármacos , Terapia de Reposição de Enzimas , Mucopolissacaridose VI/tratamento farmacológico , N-Acetilgalactosamina-4-Sulfatase/uso terapêutico , Adolescente , Fatores Etários , Criança , Pré-Escolar , Terapia de Reposição de Enzimas/efeitos adversos , Terapia de Reposição de Enzimas/métodos , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Mucopolissacaridose VI/fisiopatologia , N-Acetilgalactosamina-4-Sulfatase/administração & dosagem , N-Acetilgalactosamina-4-Sulfatase/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêuticoRESUMO
Propionic acidemia (PA) is a severe metabolic disorder with cardiac and neurologic complications and a poor quality of life. Liver transplantation (LT) was thus proposed in PA to increase enzyme activity. We studied retrospectively LT in PA in two European centers. Twelve patients underwent 17 LTs between 1991 and 2013. They developed severe, unusual and unexpected complications, with high mortality (58%). When present, the cardiomyopathy resolved and no acute metabolic decompensation occurred allowing dietary relaxation. Renal failure was present in half of the patients before LT and worsened in all of them. We suggest that cardiac and renal functions should be assessed before LT and monitored closely afterward. A renal sparing immunosuppression should be used. We speculate that some complications may be related to accumulated toxicity of the disease and that earlier LT could prevent some of these consequences. As kidney transplantation has been performed successfully in methylmalonic acidemia, a metabolic disease in the same biochemical pathway, the choice of the organ to transplant could be further discussed.
Assuntos
Transplante de Fígado/efeitos adversos , Acidemia Propiônica/cirurgia , Criança , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Acidemia Propiônica/fisiopatologiaRESUMO
Mitochondrial diseases are characterised by a broad clinical and genetic heterogeneity that makes diagnosis difficult. Owing to the wide pattern of symptoms in mitochondrial disorders and the constantly growing number of disease genes, their genetic diagnosis is difficult and genotype/phenotype correlations remain elusive. Brain MRI appears as a useful tool for genotype/phenotype correlations. Here, we summarise the various combinations of MRI lesions observed in the most frequent mitochondrial respiratory chain deficiencies so as to direct molecular genetic test in patients at risk of such diseases. We believe that the combination of brain MRI features is of value to support respiratory chain deficiency and direct molecular genetic tests.
Assuntos
Encéfalo/metabolismo , Complexo de Proteínas da Cadeia de Transporte de Elétrons/deficiência , Doenças Mitocondriais/patologia , Encéfalo/patologia , Estudos de Associação Genética , Humanos , Imageamento por Ressonância Magnética , Doenças Mitocondriais/metabolismo , Neuroimagem , Ubiquinona/deficiênciaRESUMO
Mitochondrial diseases are due to deficiency of the respiratory chain and are characterized by a broad clinical and genetic heterogeneity that makes diagnosis difficult. Some clinical presentations are highly suggestive of given gene mutations, allowing rapid genetic diagnosis. However, owing to the wide pattern of symptoms in mitochondrial disorders and the constantly growing number of disease genes, their genetic diagnosis is frequently difficult and genotype/phenotype correlations remain elusive. For this reason, brain MRI appears as a useful tool for genotype/phenotype correlations. Here, we report the most frequent neuroradiological signs in mitochondrial respiratory chain deficiency and we propose a diagnostic algorithm based on neuroimaging features, so as to direct molecular genetic tests in patients at risk of mitochondrial respiratory chain deficiency. This algorithm is based on the careful analysis of five areas on brain MRI: (1) basal ganglia (hyperintensities on T2 or calcifications); (2) cerebellum (hyperintensities on T2 or atrophy); (3) brainstem (hyperintensities on T2 or atrophy); (4) white matter (leukoencephalopathy); (5) cortex (sub-tentorial atrophy); (6) stroke-like episodes. We believe that the combination of brain MRI features is of value to support respiratory chain deficiency and direct molecular genetic tests.
Assuntos
Algoritmos , Transporte de Elétrons/genética , Imageamento por Ressonância Magnética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Neuroimagem/métodos , Encéfalo/patologia , Árvores de Decisões , Humanos , Doenças Mitocondriais/epidemiologia , MutaçãoRESUMO
INTRODUCTION: Patients with methylmalonic acidemia (MMA) may develop many complications despite medical treatment, in particular, severe central nervous system damage and chronic kidney disease (CKD). A kidney transplant may partially correct the metabolic dysfunctions. Liver, kidney and combined liver-kidney transplantations have been advocated but no guidelines are available to identify the most suitable organ to transplant. PATIENTS AND METHODS: Four patients with MMA (mut° phenotype) received a kidney graft because of repeated metabolic decompensations, with progression to CKD in 3 patients (end-stage kidney disease in two patients and CKD stage III in one patient with an estimated glomerular filtration rate [eGFR] of 40ml/min/1.73m(2)) but normal renal function in one (eGFR of 93ml/min/1.73m(2)) before transplantation. RESULTS: The medium age at transplantation was 7.9y (5-10.2) and the median follow-up was 2.8years (1.8-4.6). Renal transplantation improved the relevant metabolic parameters in 4/4 patients and renal function in the patients with CKD. Plasma and urinary MMA levels immediately decreased and remained normal or subnormal (mean values of plasma MMA before transplantation 1530µmol/L versus 240µmol/L after transplantation, and mean values of urine MMA before transplantation 4700mmol/mol creatinine versus 2300mmol/mol creatinine after transplantation). No further acute metabolic decompensation was observed and protein-intake was increased from 0.60 to 0.83g/Kg/day. One patient transplanted at age 9.7years developed a hepatoblastoma at age 11years with subsequent neurological complications and eventually died. The three other patients are alive. Two of them remained neurologically stable. The 3rd patient who displayed choreoathetosis transiently improved his neurological condition immediately after transplantation and then remained stable. CONCLUSION: Kidney transplantation represents an interesting alternative therapeutic option in methylmalonic aciduria, for renal complications but also as a "cellular therapy" that may significantly reduce metabolic decompensations and hospitalizations. However, further neurological impairment remains possible.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/terapia , Transplante de Rim , Transplante de Fígado , Doenças Metabólicas/terapia , Insuficiência Renal Crônica/terapia , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Erros Inatos do Metabolismo dos Aminoácidos/urina , Terapia Baseada em Transplante de Células e Tecidos , Criança , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Doenças Metabólicas/genética , Ácido Metilmalônico/sangue , Ácido Metilmalônico/urina , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologiaRESUMO
BACKGROUND: Acute decompensation of maple syrup urine disease (MSUD) is usually treated by enteral feeding with an amino-acid mixture without leucine (Leu), valine or isoleucine. However, its administration is ineffective in cases of gastric intolerance and some adult patients refuse enteral feeding via a nasogastric tube. We developed a new parenteral amino-acid mixture for patients with MSUD. METHODS: Seventeen decompensation episodes in four adult patients with MSUD treated with a parenteral amino-acid mixture (group P) were compared to 18 previous episodes in the same patients treated by enteral feeding (group E). RESULTS: The mean Leu concentration at presentation was similar in the groups P and E (1196.9 µmol/L and 1212.2 µmol/L, respectively). The mean decrease in the Leu concentration during the first 3 days of hospitalisation was significantly higher in group P than group E (p = 0.0026); there were no side effects. The mean duration of hospitalisation was similar (4 vs. 4.5 days, p = NS). No patient in group P deteriorated whereas one patient in group E required dialysis. CONCLUSION: This new parenteral amino-acid mixture is safe and allows efficient Leu concentration decrease during acute MSUD decompensation episodes in adults. Its use avoids the need for nasogastric tube insertion.
Assuntos
Aminoácidos/administração & dosagem , Insuficiência Cardíaca/dietoterapia , Doença da Urina de Xarope de Bordo/dietoterapia , Nutrição Parenteral , Adulto , Feminino , Alimentos Formulados , Insuficiência Cardíaca/etiologia , Hospitalização , Humanos , Masculino , Doença da Urina de Xarope de Bordo/complicações , Aceitação pelo Paciente de Cuidados de Saúde , Adulto JovemRESUMO
OBJECTIVE: To identify a consistent pattern of brain MRI imaging in primary complex I deficiency. Complex I deficiency, a major cause of respiratory chain dysfunction, accounts for various clinical presentations, including Leigh syndrome. Human complex I comprises seven core subunits encoded by mitochondrial DNA (mtDNA) and 38 core subunits encoded by nuclear DNA (nDNA). Moreover, its assembly requires six known and many unknown assembly factors. To date, no correlation between genotypes and brain MRI phenotypes has been found in complex I deficiencies. DESIGN AND SUBJECTS: The brain MRIs of 30 patients carrying known mutation(s) in genes involved in complex I were retrospectively collected and compared with the brain MRIs of 11 patients carrying known mutations in genes involved in the pyruvate dehydrogenase (PDH) complex as well as 10 patients with MT-TL1 mutations. RESULTS: All complex I deficient patients showed bilateral brainstem lesions (30/30) and 77% (23/30) showed anomalies of the putamen. Supratentorial stroke-like lesions were only observed in complex I deficient patients carrying mtDNA mutations (8/19) and necrotising leucoencephalopathy in patients with nDNA mutations (4/5). Conversely, the isolated stroke-like images observed in patients with MT-TL1 mutations, or the corpus callosum malformations observed in PDH deficient patients, were never observed in complex I deficient patients. CONCLUSION: A common pattern of brain MRI imaging was identified with abnormal signal intensities in brainstem and subtentorial nuclei with lactate peak as a clue of complex I deficiency. Combining clinico-biochemical data with brain imaging may therefore help orient genetic studies in complex I deficiency.
Assuntos
Encéfalo/enzimologia , Encéfalo/patologia , Complexo I de Transporte de Elétrons/deficiência , Imageamento por Ressonância Magnética/métodos , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Complexo I de Transporte de Elétrons/genética , Feminino , Humanos , Lactente , Leucoencefalopatias/complicações , Leucoencefalopatias/patologia , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/genética , Mutação/genética , Complexo Piruvato Desidrogenase/genética , Radiografia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia , Adulto JovemRESUMO
BACKGROUND: Congenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic ß-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1 and KIR6.2 subunits of the ATP-sensitive potassium (K(ATP)) channel. CHI patients are classified according to their responsiveness to diazoxide and to their histopathological diagnosis (either focal, diffuse or atypical forms). Here, we raise the benefits/limits of the genetic diagnosis in the clinical management of CHI patients. METHODS: ABCC8/KCNJ11 mutational spectrum was established in 109 diazoxide-unresponsive CHI patients for whom an appropriate clinical management is essential to prevent brain damage. Relationships between genotype and radiopathological diagnosis were analysed. RESULTS: ABCC8 or KCNJ11 defects were found in 82% of the CHI cases. All patients with a focal form were associated with a single K(ATP) channel molecular event. In contrast, patients with diffuse forms were genetically more heterogeneous: 47% were associated with recessively inherited mutations, 34% carried a single heterozygous mutation and 19% had no mutation. There appeared to be a predominance of paternally inherited mutations in patients diagnosed with a diffuse form and carrying a sole K(ATP) channel mutation. CONCLUSIONS: The identification of recessively inherited mutations related to severe and diffuse forms of CHI provides an informative genetic diagnosis and allows prenatal diagnosis. In contrast, in patients carrying a single K(ATP) channel mutation, genetic analysis should be confronted with the PET imaging to categorise patients as focal or diffuse forms in order to get the appropriate therapeutic management.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Hiperinsulinismo Congênito/genética , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Droga/genética , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/tratamento farmacológico , Análise Mutacional de DNA , Diazóxido/uso terapêutico , Resistência a Medicamentos , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Receptores de Sulfonilureias , Vasodilatadores/uso terapêuticoRESUMO
Stem cell transplantation is not appropriate first-line treatment for attenuated phenotypes of mucopolysaccharidosis type I (MPS I). In three patients with attenuated MPSA I treated by laronidase, Patients 2 and 3 displayed significant cognitive improvement within 2years; Patients 1 and 3 displayed improvement on MRI scans of the brain.
Assuntos
Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Iduronidase/uso terapêutico , Mucopolissacaridose I/tratamento farmacológico , Adolescente , Encéfalo/patologia , Criança , Pré-Escolar , Humanos , Inteligência/efeitos dos fármacos , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIFS: To propose a MRI cerebellar algorithm that may be applied to guide genetic/malformative or biochemical investigations for patients with cerebellar ataxia. PATIENTS AND METHODS: Cerebral MRI of 158 patients with cerebellar ataxia and no supratentorial abnormality were examined according to a new categorization system based on posterior fossa imaging. The clinical and radiological findings were confronted to biochemical and/or genetic results using the MR cerebellar algorithm. Seven groups of cerebellar MRI pattern were described: vermian dysgenesis (n=27), cerebellar hypoplasia (n=15), hemispheric cerebellar dysgenesis (n=6), unilateral hemispheric atrophy (n=5), global cerebellar atrophy (n=84), signal abnormalities (n=11) and normal MRI (n=10). Cerebellar hypoplasia, vermian dysgenesis and hemispheric cerebellar dysgenesis groups were classified as malformative disorders. Global atrophy and signal abnormality groups were classified as metabolic disorders. RESULTS: In the vermian dysgenesis group, a specific genetic diagnosis was obtained in eight children (8/27) and all of the mutated genes (AHI1 (JBS3), CEP290 (JBS5), TMEM67 (JBS6), and RPGRIP1L (JBS7)) are involved in primary cilia function. In the group of pontocerebellar hypoplasia specific genetic diagnosis was obtained in one patient (PCH2) (1/15). Thus, nine of 42 children classified as malformative disorder had a molecular diagnosis. Global atrophy and signal abnormality groups were classified as metabolic disorders, specific biochemical was obtained in 46/95 children. In global atrophy group, respiratory chain deficiency was diagnosed in 18 children (18/84). In 21 children a congenital disorders of glycosylation type 1a (CDG Ia) was diagnosed (21/84) and infantile neuroaxonale dystrophy (INAD) was diagnosed in one child. In signal abnormalities group, specific biochemical diagnosis was obtained in six out of 11 children, five children with respiratory chain deficiency and one child with sulphite oxidase deficiency. In hemispheric cerebellar dysgenesis and normal MRI groups, no biological diagnosis was found for any of the patients. In the group of unilateral hemispheric atrophy, we hypothesized a clastic prenatal injury. CONCLUSION: The proposed MR cerebellar algorithm was useful to guide genetic/malformative or biochemical investigations, allowing an etiological diagnosis in 55 children.
Assuntos
Ataxia Cerebelar/patologia , Cerebelo/patologia , Fossa Craniana Posterior/patologia , Adolescente , Algoritmos , Cerebelo/anormalidades , Criança , Pré-Escolar , Fossa Craniana Posterior/anormalidades , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Seleção de PacientesRESUMO
AIMS: Ornithine delta-aminotransferase (OAT) deficiency causes gyrate atrophy (GA) of the retina, as a consequence of high plasma ornithine concentrations. Because creatine synthesis requires the conversion of arginine and glycine into ornithine and guanidinoacetate, high ornithine concentration inhibits this reaction thus causing secondary creatine deficiency. The aim of this study was to evaluate the neuropsychological features and creatine metabolism in patients with GA. METHODS: The study involved 7 GA patients, aged from 11 to 27 years who underwent neuropsychological evaluation and cerebral proton magnetic resonance spectroscopy (MRS). RESULTS: Neurocognitive impairment was found in 5/7 patients, including mental retardation (3/7), school failure (1/7), major visuospatial dyspraxia (1/7), aggressive behavior (3/7) and epilepsy (2/7). Two patients had normal neuropsychological evaluation. Cerebral proton magnetic resonance spectroscopy revealed a profound creatine deficiency in all patients. MRS data were confirmed by decreased levels of creatine and/or guanidinoacetate in plasma and urine in all patients. CONCLUSIONS: In our group of patients with GA, we found a high prevalence of neurological impairment, not reported so far, and possibly related to secondary creatine deficiency and hyperornithinemia. We propose to treat mentally retarded GA patients with high doses of creatine, as it may normalize brain creatine levels and help to reduce ornithine levels.
Assuntos
Creatina/deficiência , Atrofia Girata/complicações , Atrofia Girata/fisiopatologia , Ornitina-Oxo-Ácido Transaminase/deficiência , Adolescente , Adulto , Agressão , Apraxias/etiologia , Apraxias/metabolismo , Encéfalo/metabolismo , Criança , Epilepsia/etiologia , Epilepsia/metabolismo , Feminino , Atrofia Girata/metabolismo , Humanos , Deficiência Intelectual/etiologia , Deficiência Intelectual/metabolismo , Imageamento por Ressonância Magnética , Masculino , Ornitina-Oxo-Ácido Transaminase/antagonistas & inibidores , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: To better delineate the natural history of patients with methylmalonic aciduria (MMA). STUDY DESIGN: Thirty patients with vitamin-B12-unresponsive MMA (25 aged 1.5 to 22.0 years (y) at the end of the study and 5 who died during a metabolic crisis) were managed following standardized guidelines and studied retrospectively. The median follow-up was 8.3 y (range: 1.4-19.5). Patients were investigated with neuropsychological testing, brain MRIs, inulin clearances, biochemical and genetic studies. RESULTS: Fifteen patients had a neonatal onset. Thirteen patients (43%) had significant neurological impairment. Chronic renal disease (CRD) occurred in 14 patients (47%) with a median age of onset of 6.5 y (range 1.5-18.6). Renal function further deteriorated in 4 patients within a median period of 5.8 y (range 2-7.4). Of 25 patients investigated at the enzymatic level, 17 were classified mut(o), 3 mut- and 5 cblA. Mortality, number of acute decompensations (p=0.031), median MMA urinary excretion (p=0.006) and neurological impairment (p<0.0001) were higher in mut degrees patients compared to mut-/cblA patients. Concerning the CRD, no difference incidence was found although the onset of CRD occurred earlier in mut(o) patients and was more severe. CONCLUSIONS: Our study provides unique data concerning the progression of renal disease in MMA. Patients with mut(o) phenotype have a more severe phenotype and probably an earlier and more severe CRD than patients with mut-/cblA phenotype.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/terapia , População Branca , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/urina , Criança , Pré-Escolar , Progressão da Doença , Feminino , França , Humanos , Lactente , Rim/patologia , Falência Renal Crônica/complicações , Falência Renal Crônica/patologia , Masculino , Ácido Metilmalônico/urina , Doenças do Sistema Nervoso/complicações , Fenótipo , Fatores de Tempo , Resultado do TratamentoRESUMO
An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA) responsive to vitamin B(12) presented suddenly with severe visual impairment ascribed to optic atrophy followed by a fatal multiorgan failure and lactic acidosis but low methylmalonic acid in plasma and urine. Multiple deficiency of oxidative phosphorylation was found in the patient's liver. We suggest that patients with B(12)-sensitive methylmalonic aciduria who have a milder clinical course should be carefully monitored for long-term complications.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Fígado/metabolismo , Ácido Metilmalônico/urina , Fosforilação Oxidativa , Vitamina B 12/uso terapêutico , Vitamina B 12/urina , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/genética , Ciclo do Ácido Cítrico/fisiologia , DNA Mitocondrial/química , DNA Mitocondrial/genética , Transporte de Elétrons/fisiologia , Evolução Fatal , Humanos , Fígado/patologia , Masculino , Músculo Esquelético/patologiaRESUMO
BACKGROUND: The cerebro-oculo-facio-skeletal syndrome (COFS syndrome) is an autosomal recessive disorder which was initially described in a specific aboriginal population from Manitoba. In recent years, COFS syndrome has been linked in this original population to a defective DNA repair pathway and to a homozygous mutation in the major gene underlying Cockayne syndrome (CSB). However, most reports of suspected COFS syndrome outside this population have not been confirmed at the molecular level, leading to considerable heterogeneity within the syndrome and confusing overlaps between COFS syndrome and other eye and brain disorders. OBJECTIVE: To refine the delineation of the syndrome on genetically proven COFS cases. METHODS: We report the exhaustive clinical, cellular and molecular data of three unrelated COFS patients with mutations in the CSB gene. RESULTS: All three patients present the cardinal features of COFS syndrome including extreme microcephaly, congenital cataracts, facial dysmorphism and arthrogryposis. They also exhibit a predominantly postnatal growth failure, a severe psychomotor retardation, with axial hypotonia and peripheral hypertonia and neonatal feeding difficulties. Fibroblasts from the patients show the same DNA repair defect which can be complemented by transfection of the CSB wild-type cDNA. Five new mutations in the CSB gene have been identified in these patients. CONCLUSIONS: Our data indicate that COFS syndrome represents the most severe end of the Cockayne spectrum. New diagnostic criteria for COFS syndrome are proposed, based on our findings and on the few genetically proven COFS cases from the literature.
Assuntos
Artrogripose/diagnóstico , Catarata/congênito , DNA Helicases/genética , Enzimas Reparadoras do DNA/genética , Microcefalia/diagnóstico , Sequência de Aminoácidos , Artrogripose/genética , Artrogripose/patologia , Western Blotting , Catarata/diagnóstico , Catarata/genética , Sobrevivência Celular , Células Cultivadas , DNA Helicases/análise , Análise Mutacional de DNA , Reparo do DNA , Enzimas Reparadoras do DNA/análise , Fácies , Feminino , Teste de Complementação Genética , Humanos , Recém-Nascido , Masculino , Microcefalia/genética , Microcefalia/patologia , Dados de Sequência Molecular , Proteínas de Ligação a Poli-ADP-Ribose , Alinhamento de Sequência , SíndromeRESUMO
Genetic defects of oxidative phosphorylation (OXPHOS) are known to account for a variety of neuromuscular and non-neuromuscular symptoms in childhood, including growth hormone (GH) deficiency. However GH administration for GH deficiency is controversial in OXPHOS deficiencies as GH is a mitosis-stimulator which may increase energy demand for cell proliferation. Here, we report the observation of four unrelated children with OXPHOS deficiency or bearing a mitochondrial DNA rearrangement and growth retardation, who required GH therapy. The first patient had no GH deficiency while the other three had low GH response to test stimulations. The condition of the first two patients quickly deteriorated under GH administration, GH was then stopped and subsequent clinical improvement was noted. In the other two patients, no adverse event was noted but various additional organs were involved following GH administration. In all patients, no benefit was observed concerning growth response as growth speed remained unchanged. These observations question the use of GH as a treatment of growth retardation for patients with OXPHOS deficiency.
Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Doenças Mitocondriais/tratamento farmacológico , Adolescente , Criança , DNA Mitocondrial/genética , Feminino , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/enzimologia , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Mutação , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , SegurançaRESUMO
The congenital disorder of glycosylation type Ia (CDG-Ia) presents a broad clinical spectrum. Some patients suffer from acute vascular events (thrombosis and bleeding) and stroke-like events. No correlations have been made between the marked hemostasis abnormalities of CDG-Ia and the occurrence of acute vascular events. We report on 6 patients with CDG-Ia presenting vascular events, then we analyze the clinical and hemostasis data of 39 CDG-Ia patients described in the literature, 17 with vascular events (E) and 21 unscathed from any event (EF), to determine the risk factors for acute vascular events in CDG-Ia. Acute vascular events occurred in patients younger than 15 years, especially with fever and prolonged immobilization. Hemostasis and liver cytolysis were statistically abnormal in patients younger than 5 years whatever the occurrence of vascular events and they normalized with time. Higher factors VIII and IX activities were statistically observed in the E cluster (p=0.03) compared to the EF cluster. The activity/antigenicity ratio for protein C (p=0.02) was also higher in the E group. CDG-Ia patients younger than 15 years old are at risk of acute vascular events. The paradoxical results-abnormal VIII and IX factors in EF patients and normal results in E patients, while XI, antithrombin, protein C, ASAT and ALAT are abnormal in both groups, could suggest a disequilibrium between prothrombotic and antithrombotic factors in the E group. Vascular events may also occur in patients where glycoproteins are proportionally more hypoglycosylated, particularly protein C.
Assuntos
Defeitos Congênitos da Glicosilação/complicações , Fosfotransferases (Fosfomutases)/genética , Acidente Vascular Cerebral/etiologia , Adolescente , Criança , Pré-Escolar , Feminino , Glicosilação , Hemostasia , Humanos , Lactente , Recém-Nascido , Masculino , Fosfotransferases (Fosfomutases)/deficiência , Medição de Risco , Trombose/etiologiaRESUMO
In a series of 137 patients with methylmalonic acidaemia (MMA) and propionic acidaemia (PA) diagnosed since the early 1970s, we report in more detail 81 patients (51 MMA and 30 PA) diagnosed between 1988 and 2005. In this series, 14% of patients died at initial access revealing the disease before or despite treatment, 18% died later, and the remainder (68%) are still alive. All patients were treated with the same protocol of enteral feeds with a low-protein diet adjusted to individual tolerance, carnitine, antibiotics, and only occasional use of an amino acid (AA) mixture. There was intensive follow-up and monitoring using measurements of urinary urea. Thirty-nine patients with severe forms, followed for more than 3 years, are analysed in particular detail. Of the 17 PA patients, 6 had moderate disability (all neonatal-onset forms), whereas 11 were normal or slightly delayed in their mental development. Four presented with cardiomyopathy, of whom 2 died. Of the 22 MMA patients, 13 presented in the neonatal period, of whom 3 died later, 2 are in renal failure and only 5 are still alive and have a normal or slightly delayed mental development. In the 9 patients with late-onset forms, there were no deaths and all patients but one have normal mental development. Among the 39 patients, only 40% were given an AA supplement at 3 years, and 50% between 6 and 11 years. The actual intake of natural protein was 0.92, 0.78 and 0.77 g/kg per day at 3, 6 and 11 years, respectively, in patients without AA supplementation, whereas it was 0.75, 0.74 and 0.54 g/kg per day in the group who received small quantities of AA (0.4-0.6 g/kg per day). In both groups, feeding disorders were frequent: 55% at 3 years, 35% at 6 years and 12% at 11 years. Many patients were given a food supplement by tube overnight or were even exclusively tube fed: 60% at 3 years, 48% at 6 years and still 27% at 11 years. Growth velocity was near the normal values. Plasma valine and isoleucine were low to very low, as were leucine and phenylalanine but to a lesser extent. Albumin, vitamins, trace elements and markers of bone metabolism were within the normal values. IGF1, 24-hour urine calcium and body mass density were low. Body composition showed a normal to low lean mass and a normal to high fat mass.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/terapia , Aminoácidos/uso terapêutico , Dieta com Restrição de Proteínas , Suplementos Nutricionais , Nutrição Enteral , Ácido Metilmalônico/urina , Propionatos/urina , Erros Inatos do Metabolismo dos Aminoácidos/dietoterapia , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Erros Inatos do Metabolismo dos Aminoácidos/urina , Aminoácidos/sangue , Estatura , Peso Corporal , Química Farmacêutica , Criança , Pré-Escolar , Proteínas Alimentares/metabolismo , Ingestão de Alimentos , Feminino , Seguimentos , Hospitalização , Humanos , Ácido Láctico/análogos & derivados , Ácido Láctico/urina , Masculino , Avaliação Nutricional , Resultado do TratamentoRESUMO
OBJECTIVE AND PATIENTS: We report on two new cases of serine deficiency due respectively to 3-phosphoglycerate dehydrogenase (PHGDH) deficiency (Patient 1) and phosphoserine aminotransferase (PSAT1) deficiency (Patient 2), presenting with congenital microcephaly (<3rd centile at birth) and encephalopathy with spasticity. Patient 1 had also intractable seizures. A treatment with oral l-serine was started at age 4.5 years and 3 months respectively. RESULTS: Serine levels were low in plasma and CSF relative to the reference population, for which we confirm recently redefined intervals based on a larger number of samples. l-Serine treatment led in patient 1 to a significant reduction of seizures after one week of treatment and decrease of electroencephalographic abnormalities within one year. In patient 2 treatment with l-serine led to an improvement of spasticity. However for both patients, l-serine failed to improve substantially head circumference (HC) and neurocognitive development. In a couple related to patient's 2 family, dosage of serine was performed on fetal cord blood when the fetus presented severe microcephaly, showing reduced serine levels at 30 weeks of pregnancy. CONCLUSIONS: l-Serine treatment in patients with 2 different serine synthesis defects, led to a significant reduction of seizures and an improvement of spasticity, but failed to improve substantially neurocognitive impairment. Therefore, CSF and plasma serine levels should be measured in all cases of severe microcephaly at birth to screen for serine deficiency, as prompt treatment with l-serine may significantly impact the outcome of the disease. Reduced serine levels in fetal cord blood may also be diagnostic as early as 30 weeks of pregnancy.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Erros Inatos do Metabolismo dos Carboidratos/tratamento farmacológico , Microcefalia/tratamento farmacológico , Fosfoglicerato Desidrogenase/deficiência , Transtornos Psicomotores/tratamento farmacológico , Convulsões/tratamento farmacológico , Serina/deficiência , Serina/uso terapêutico , Transaminases/deficiência , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/genética , Aminoácidos/líquido cefalorraquidiano , Erros Inatos do Metabolismo dos Carboidratos/genética , Pré-Escolar , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Epilepsia Resistente a Medicamentos/etiologia , Eletroencefalografia , Feminino , Cabeça/crescimento & desenvolvimento , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/etiologia , Microcefalia/genética , Espasticidade Muscular/etiologia , Fosfoglicerato Desidrogenase/genética , Gravidez , Transtornos Psicomotores/genética , Convulsões/etiologia , Convulsões/genética , Serina/sangue , Transaminases/genética , Resultado do TratamentoRESUMO
BACKGROUND: Type I congenital disorders of glycosylation (CDG-I) are mostly complex multisystemic diseases associated with hypoglycosylated serum glycoproteins. A subgroup harbour mutations in genes necessary for the biosynthesis of the dolichol-linked oligosaccharide (DLO) precursor that is essential for protein N-glycosylation. Here, our objective was to identify the molecular origins of disease in such a CDG-Ix patient presenting with axial hypotonia, peripheral hypertonia, enlarged liver, micropenis, cryptorchidism and sensorineural deafness associated with hypo glycosylated serum glycoproteins. RESULTS: Targeted sequencing of DNA revealed a splice site mutation in intron 5 and a non-sense mutation in exon 4 of the dehydrodolichol diphosphate synthase gene (DHDDS). Skin biopsy fibroblasts derived from the patient revealed ~20 % residual DHDDS mRNA, ~35 % residual DHDDS activity, reduced dolichol-phosphate, truncated DLO and N-glycans, and an increased ratio of [2-(3)H]mannose labeled glycoprotein to [2-(3)H]mannose labeled DLO. Predicted truncated DHDDS transcripts did not complement rer2-deficient yeast. SiRNA-mediated down-regulation of DHDDS in human hepatocellular carcinoma HepG2 cells largely mirrored the biochemical phenotype of cells from the patient. The patient also harboured the homozygous ALG6(F304S) variant, which does not cause CDG but has been reported to be more frequent in PMM2-CDG patients with severe/fatal disease than in those with moderate presentations. WES did not reveal other strong candidate causal genes. CONCLUSIONS: We describe a patient presenting with severe multisystem disease associated with DHDDS deficiency. As retinitis pigmentosa is the only clinical sign in previously reported cases, this report broadens the spectrum of phenotypes associated with this condition.