RESUMO
This case report describes a patient with early-onset cobalamin C deficiency who was started on treatment with high-dose parenteral hydroxocobalamin after diagnosis at 13 days of life. Prior to diagnosis, initial presenting symptoms included poor feeding, lethargy, apneic episodes, hypothermia, and hypotonia; these symptoms resolved after initiation of medication. Methylmalonic acid and homocysteine levels were trended and significantly improved with treatment. She was maintained on 2 mg/kg/day dosing of hydroxocobalamin. No adverse effects to treatment were observed. At the time of this report, the patient was 19 months of age; she had not manifested common findings of early-onset cobalamin C deficiency, including microcephaly, poor feeding, growth abnormalities, hypotonia, seizures, maculopathy, or neurodevelopmental delay. This report suggests that early initiation of high-dose hydroxocobalamin is safe and effective.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Deficiência de Vitamina B 12 , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Feminino , Humanos , Hidroxocobalamina/uso terapêutico , Recém-Nascido , Ácido Metilmalônico , Hipotonia Muscular/tratamento farmacológico , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina B 12/tratamento farmacológicoRESUMO
Mucopolysaccharidosis type I (MPSI) (OMIM #252800) is an autosomal recessive disorder caused by pathogenic variants in the IDUA gene encoding for the lysosomal alpha-L-iduronidase enzyme. The deficiency of this enzyme causes systemic accumulation of glycosaminoglycans (GAGs). Although disease manifestations are typically not apparent at birth, they can present early in life, are progressive, and include a wide spectrum of phenotypic findings. Among these, the storage of GAGs within the lysosomes disrupts cell function and metabolism in the cartilage, thus impairing normal bone development and ossification. Skeletal manifestations of MPSI are often refractory to treatment and severely affect patients' quality of life. This review discusses the pathological and molecular processes leading to impaired endochondral ossification in MPSI patients and the limitations of current therapeutic approaches. Understanding the underlying mechanisms responsible for the skeletal phenotype in MPSI patients is crucial, as it could lead to the development of new therapeutic strategies targeting the skeletal abnormalities of MPSI in the early stages of the disease.
Assuntos
Iduronidase , Mucopolissacaridose I , Glicosaminoglicanos/metabolismo , Humanos , Iduronidase/genética , Mucopolissacaridose I/genética , Fenótipo , Qualidade de VidaRESUMO
Mucopolysaccharidosis type IVA (OMIM 253000) is an autosomal recessive disorder caused by defective activity of the N-acetylgalactosamine 6-sulfatase (GALNS) enzyme. In 2014, enzyme replacement therapy (ERT) using recombinant human GALNS became available for affected patients. There is a limited number of studies to date that have explored the effect of ERT in infancy and there is also a lack of data assessing the effect of ERT in systems other than the skeletal. Here, we report on the effect of ERT in the youngest pair of siblings treated to date: Patient A, currently 4 years old, who started treatment at the age of 5 months; and Patient B, currently 3 years old, who started treatment at 58 days of life. Moreover, we investigate the effect of early ERT on the cardiovascular system. Our results show that, even when ERT is started before 2 months of age, it cannot fully prevent disease progression. As for the effect of ERT on the cardiovascular system, our preliminary results suggest that early treatment might play a role in preserving a normal left ventricular mass index in affected patients at least up to 1 year, but further observation over time will be required. Overall, this report shows that early diagnosis remains crucial and that prompt initiation of ERT has limited effect in slowing progression of the skeletal phenotype, thus confirming the need for new therapeutic approaches that target the skeletal system in affected patients.
Assuntos
Condroitina Sulfatases/genética , Terapia de Reposição de Enzimas , Mucopolissacaridose IV/tratamento farmacológico , Pré-Escolar , Humanos , Lactente , Masculino , Mucopolissacaridose IV/genética , Mucopolissacaridose IV/patologia , IrmãosRESUMO
Primary carnitine deficiency is caused by a defect in the OCTN2 carnitine transporter encoded by the SLC22A5 gene. It can cause hypoketotic hypoglycemia or cardiomyopathy in children, and sudden death in children and adults. Fibroblasts from affected patients have reduced carnitine transport. We evaluated carnitine transport in fibroblasts from 358 subjects referred for possible carnitine deficiency. Carnitine transport was reduced to 20% or less of normal in fibroblasts of 140 out of 358 subjects. Sequencing of the 10 exons and flanking regions of the SLC22A5 gene in 95 out of 140 subjects identified causative variants in 84% of the alleles. The missense variants identified in our patients and others previously reported (n = 92) were expressed in CHO cells. Carnitine transport was impaired by 73 out of 92 variants expressed. Prediction algorithms (Polyphen-2, SIFT) correctly predicted the functional effects of expressed variants in about 80% of cases. These results indicate that mutations in the coding region of the SLC22A5 gene cannot be identified in about 16% of the alleles causing primary carnitine deficiency. Prediction algorithms failed to determine the functional effects of amino acid substitutions in this transmembrane protein in about 20% of cases. Therefore, functional studies in fibroblasts remain the best strategy to confirm or exclude a diagnosis of primary carnitine deficiency.
Assuntos
Cardiomiopatias/genética , Carnitina/deficiência , Carnitina/metabolismo , Variação Genética , Hiperamonemia/genética , Hipoglicemia/genética , Doenças Musculares/genética , Membro 5 da Família 22 de Carreadores de Soluto/genética , Substituição de Aminoácidos , Animais , Transporte Biológico , Células CHO , Cardiomiopatias/diagnóstico , Carnitina/genética , Cricetinae , Cricetulus , Análise Mutacional de DNA , Éxons/genética , Fibroblastos/metabolismo , Frequência do Gene , Humanos , Hiperamonemia/diagnóstico , Hipoglicemia/diagnóstico , Doenças Musculares/diagnóstico , Mutação , Mutação de Sentido Incorreto , Membro 5 da Família 22 de Carreadores de Soluto/metabolismoRESUMO
Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent ß-oxidation. It can be synthesized by the body or assumed with the diet from meat and dairy products. Defects in carnitine biosynthesis do not routinely result in low plasma carnitine levels. Carnitine is accumulated by the cells and retained by kidneys using OCTN2, a high affinity organic cation transporter specific for carnitine. Defects in the OCTN2 carnitine transporter results in autosomal recessive primary carnitine deficiency characterized by decreased intracellular carnitine accumulation, increased losses of carnitine in the urine, and low serum carnitine levels. Patients can present early in life with hypoketotic hypoglycemia and hepatic encephalopathy, or later in life with skeletal and cardiac myopathy or sudden death from cardiac arrhythmia, usually triggered by fasting or catabolic state. This disease responds to oral carnitine that, in pharmacological doses, enters cells using the amino acid transporter B(0,+). Primary carnitine deficiency can be suspected from the clinical presentation or identified by low levels of free carnitine (C0) in the newborn screening. Some adult patients have been diagnosed following the birth of an unaffected child with very low carnitine levels in the newborn screening. The diagnosis is confirmed by measuring low carnitine uptake in the patients' fibroblasts or by DNA sequencing of the SLC22A5 gene encoding the OCTN2 carnitine transporter. Some mutations are specific for certain ethnic backgrounds, but the majority are private and identified only in individual families. Although the genotype usually does not correlate with metabolic or cardiac involvement in primary carnitine deficiency, patients presenting as adults tend to have at least one missense mutation retaining residual activity. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.
Assuntos
Carnitina/metabolismo , Ácidos Graxos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Adulto , Idade de Início , Transporte Biológico , Carnitina/deficiência , Carnitina/uso terapêutico , Caveolinas/metabolismo , Metabolismo Energético , Jejum/fisiologia , Proteínas de Transporte de Ácido Graxo/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Recém-Nascido , Rim/metabolismo , Mutação , Triagem Neonatal , Especificidade de Órgãos , Proteínas de Transporte de Cátions Orgânicos/deficiência , Proteínas de Transporte de Cátions Orgânicos/genética , Oxirredução , Membro 5 da Família 22 de Carreadores de SolutoRESUMO
BACKGROUND: Organic cation transporters transfer solutes with a positive charge across the plasma membrane. The novel organic cation transporter 1 (OCTN1) and 2 (OCTN2) transport ergothioneine and carnitine, respectively. Mutations in the SLC22A5 gene encoding OCTN2 cause primary carnitine deficiency, a recessive disorders resulting in low carnitine levels and defective fatty acid oxidation. Variations in the SLC22A4 gene encoding OCTN1 are associated with rheumatoid arthritis and Crohn disease. METHODS: Here we evaluate the functional properties of the OCTN1 transporter using chimeric transporters constructed by fusing different portion of the OCTN1 and OCTN2 cDNAs. Their relative abundance and subcellular distribution was evaluated through western blot analysis and confocal microscopy. RESULTS: Substitutions of the C-terminal portion of OCTN1 with the correspondent residues of OCTN2 generated chimeric OCTN transporters more active than wild-type OCTN1 in transporting ergothioneine. Additional single amino acid substitutions introduced in chimeric OCTN transporters further increased ergothioneine transport activity. Kinetic analysis indicated that increased transport activity was due to an increased V(max), with modest changes in K(m) toward ergothioneine. CONCLUSIONS: Our results indicate that the OCTN1 transporter is tolerant to extensive amino acid substitutions. This is in sharp contrast to the OCTN2 carnitine transporter that has been selected for high functional activity through evolution, with almost all substitutions reducing carnitine transport activity. GENERAL SIGNIFICANCE: The widespread tolerance of OCTN1 to amino acid substitutions suggests that the corresponding SLC22A4 gene may have derived from a recent duplication of the SLC22A5 gene and might not yet have a defined physiological role.
Assuntos
Ergotioneína/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/fisiologia , Substituição de Aminoácidos , Animais , Transporte Biológico , Western Blotting , Células CHO , Cricetulus , Humanos , Microscopia Confocal , Proteínas de Transporte de Cátions Orgânicos/química , Relação Estrutura-Atividade , SimportadoresRESUMO
The paper-and-pencil Rey-Osterrieth Complex Figure (ROCF) copy task has been extensively used to assess visuo-constructional skills in children and adults. The scoring systems utilized in clinical practice provide an integrated evaluation of the drawing process, without differentiating between its visuo-constructional, organizational, and motor components. Here, a tablet-based ROCF copy task capable of providing a quantitative assessment of the drawing process, differentiating between visuo-constructional, organizational, and motor skills, is trialed in 94 healthy children, between 7 and 11 years of age. Through previously validated algorithms, 12 indices of performance in the ROCF copy task were obtained for each child. Principal component analysis of the 12 indices identified spatial, procedural, and kinematic components as distinct dimensions of the drawing process. A composite score for each dimension was determined, and correlation analysis between composite scores and conventional paper-and-pencil measures of visuo-constructional, procedural, and motor skills performed. The results obtained confirmed that the constructional, organizational, and motor dimensions underlie complex figure drawing in children; and that each dimension can be measured by a unique composite score. In addition, the composite scores here obtained from children were compared with previsions results from adults, offering a novel insight into how the interplay between the three dimensions of drawing evolves with age.
Assuntos
Destreza Motora , Humanos , Criança , Feminino , Masculino , Fenômenos Biomecânicos , Destreza Motora/fisiologia , Desempenho Psicomotor/fisiologia , Computadores de Mão , Análise de Componente PrincipalRESUMO
Creatine transporter deficiency (CTD) is a metabolic disorder resulting in cognitive, motor, and behavioral deficits. Cyclocreatine (cCr), a creatine analog, has been explored as a therapeutic strategy for the treatment of CTD. We developed a rapid, selective, and accurate HILIC ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to simultaneously quantify the intracellular concentrations of cCr, creatine (Cr), creatine-d3 (Cr-d3), phosphocyclocreatine (pcCr), and phosphocreatine (pCr). Using HILIC-UPLC-MS/MS, we measured cCr and Cr-d3 uptake and their conversion to the phosphorylated forms in primary human control and CTD fibroblasts. Altogether, the data demonstrate that cCr enters cells and its dominant intracellular form is pcCr in both control and CTD patient cells. Therefore, cCr may replace creatine as a therapeutic strategy for the treatment of CTD.
Assuntos
Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Creatina/deficiência , Creatinina/análogos & derivados , Fibroblastos/metabolismo , Imidazolidinas/metabolismo , Deficiência Intelectual Ligada ao Cromossomo X/tratamento farmacológico , Fosfocreatina/análogos & derivados , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Encefalopatias Metabólicas Congênitas/metabolismo , Células Cultivadas , Cromatografia Líquida de Alta Pressão/métodos , Creatina/metabolismo , Creatinina/farmacocinética , Creatinina/uso terapêutico , Humanos , Imidazolidinas/análise , Deficiência Intelectual Ligada ao Cromossomo X/metabolismo , Fosfocreatina/análise , Fosfocreatina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo , Cultura Primária de Células , Espectrometria de Massas em Tandem/métodosRESUMO
IMPORTANCE: Facial paralysis is a life-altering condition that significantly impairs function, appearance, and communication. Facial rehabilitation via closed-loop pacing represents a potential but as yet theoretical approach to reanimation. A first critical step toward closed-loop facial pacing in cases of unilateral paralysis is the detection of healthy movements to use as a trigger to prosthetically elicit automatic artificial movements on the contralateral side of the face. OBJECTIVES: To test and to maximize the performance of an electromyography (EMG)-based blink detection system for applications in closed-loop facial pacing. DESIGN, SETTING, AND PARTICIPANTS: Blinking was detected across the periocular region by means of multichannel surface EMG at an academic neuroengineering and medical robotics laboratory among 15 healthy volunteers. MAIN OUTCOMES AND MEASURES: Real-time blink detection was accomplished by mapping the surface of the orbicularis oculi muscle on one side of the face with a multichannel surface EMG. The biosignal from each channel was independently processed; custom software registered a blink when an amplitude-based or slope-based suprathreshold activity was detected. The experiments were performed when participants were relaxed and during the production of particular orofacial movements. An F1 score metric was used to analyze software performance in detecting blinks. RESULTS: The maximal software performance was achieved when a blink was recorded from the superomedial orbit quadrant. At this recording location, the median F1 scores were 0.89 during spontaneous blinking, 0.82 when chewing gum, 0.80 when raising the eyebrows, and 0.70 when smiling. The overall performance of blink detection was significantly better at the superomedial quadrant (F1 score, 0.75) than at the traditionally used inferolateral quadrant (F1 score, 0.40) (P < .05). CONCLUSIONS AND RELEVANCE: Electromyographic recording represents an accurate tool to detect spontaneous blinks as part of closed-loop facial pacing systems. The early detection of blink activity may allow real-time pacing via rapid triggering of contralateral muscles. Moreover, an EMG detection system can be integrated in external devices and in implanted neuroprostheses. A potential downside to this approach involves cross talk from adjacent muscles, which can be notably reduced by recording from the superomedial quadrant of the orbicularis oculi muscle and by applying proper signal processing. LEVEL OF EVIDENCE: NA.