Publicação
Cobalamin C Deficiency - Experience of a Reference Center of Hereditary Metabolism Diseases
| Resumo: | The cobalamin C deficiency (CblCD) is the most common inborn error of the cobalamin metabolism. It is characterized by inability to convert dietary vitamin B12 into the coenzymes adenosylcobalamin and methylcobalamin, in cell. The former is crucial for the activity of methylmalonyl CoA mutase and the later for methionine synthase. Their deficit leads to accumulation of methylmalonic acid (MMA) and homocysteine, respectively. They have a toxic effect in various systems, including the nervous system and eye. Besides these products, disease can be detected by an increase of propionylcarnitine and diagnosed by identification of biallelic pathogenic variants in the MMACHC gene. Treatment consists in a combination of vitamin B12 and betaine. The benefits of folic acid supplementation and protein restricted diet are limited. Despite therapy, prognosis is poor, especially in the early onset phenotype.The goals of the present work were to describe the clinical presentation, diagnosis, treatment and disease progression of children (less than 18 years old) with an established diagnosis of CblCD, followed at Centro de Referência de Doenças Hereditárias do Metabolismo do Centro Hospitalar Universitário de Coimbra, between 2002 and 2021 (20 years).In the defined period, CblCD was diagnosed in five children, one of them presented symptoms before birth, while the other four were diagnosed by the Programa Nacional de Rastreio Neonatal. All presented the same mutation, (c.271dupA), in MMACHC gene.All the patients of our cohort presented clinic in the first weeks of life. The first manifestation of the disease was hypotonia in all patients. Some of them, also presented feeding difficulties, metabolic acidosis and seizures. With increasing age, all manifested ophthalmological and neurological features and three presented cardiovascular manifestations. All children presented global development delay, which is very common in this disorder. One child presented concomitant Type 1 Diabetes Mellitus, which to our knowledge, this association had never been reported. Two children have died. No correlation was found between MMA levels and date of onset or severity of the clinical manifestations. Methionine and homocysteine levels at presentation did not correlate with clinical severity. In spite of early treatment normal amino acids levels were never achieved, except for methionine.The current base of CblCD treatment is hydroxocobalamin and betaine. Folic acid and oral metronidazole were also used, despite the fact that their effectivity in CblCD is not consensual.Although the disease has progressed in all cases, the three living patients remain apparently stable. The youngest has a significant global development delay/intellectual disability. The others, who attend regular school with good performance, although needing visual aids, live a close to normal life. |
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| Autores principais: | Álvares, Maria Carolina de Mendanha Vaz |
| Assunto: | Vitamina B12 Acidémia Metilmalónica Homocistinúria Vitamin B12 Methylmalonic Acidemia Homocystinuria |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso embargado |
| Instituição associada: | Universidade de Coimbra |
| Idioma: | inglês |
| Origem: | Estudo Geral - Universidade de Coimbra |
| Resumo: | The cobalamin C deficiency (CblCD) is the most common inborn error of the cobalamin metabolism. It is characterized by inability to convert dietary vitamin B12 into the coenzymes adenosylcobalamin and methylcobalamin, in cell. The former is crucial for the activity of methylmalonyl CoA mutase and the later for methionine synthase. Their deficit leads to accumulation of methylmalonic acid (MMA) and homocysteine, respectively. They have a toxic effect in various systems, including the nervous system and eye. Besides these products, disease can be detected by an increase of propionylcarnitine and diagnosed by identification of biallelic pathogenic variants in the MMACHC gene. Treatment consists in a combination of vitamin B12 and betaine. The benefits of folic acid supplementation and protein restricted diet are limited. Despite therapy, prognosis is poor, especially in the early onset phenotype.The goals of the present work were to describe the clinical presentation, diagnosis, treatment and disease progression of children (less than 18 years old) with an established diagnosis of CblCD, followed at Centro de Referência de Doenças Hereditárias do Metabolismo do Centro Hospitalar Universitário de Coimbra, between 2002 and 2021 (20 years).In the defined period, CblCD was diagnosed in five children, one of them presented symptoms before birth, while the other four were diagnosed by the Programa Nacional de Rastreio Neonatal. All presented the same mutation, (c.271dupA), in MMACHC gene.All the patients of our cohort presented clinic in the first weeks of life. The first manifestation of the disease was hypotonia in all patients. Some of them, also presented feeding difficulties, metabolic acidosis and seizures. With increasing age, all manifested ophthalmological and neurological features and three presented cardiovascular manifestations. All children presented global development delay, which is very common in this disorder. One child presented concomitant Type 1 Diabetes Mellitus, which to our knowledge, this association had never been reported. Two children have died. No correlation was found between MMA levels and date of onset or severity of the clinical manifestations. Methionine and homocysteine levels at presentation did not correlate with clinical severity. In spite of early treatment normal amino acids levels were never achieved, except for methionine.The current base of CblCD treatment is hydroxocobalamin and betaine. Folic acid and oral metronidazole were also used, despite the fact that their effectivity in CblCD is not consensual.Although the disease has progressed in all cases, the three living patients remain apparently stable. The youngest has a significant global development delay/intellectual disability. The others, who attend regular school with good performance, although needing visual aids, live a close to normal life. |
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