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Objective:To investigate the incidence rate and gene variation of methylmalonic academia (MMA) in Ji′nan city by analyzing biochemical and genetic screening results, and to explore the carrier frequency of MMA-related pathogenic genes in the population in Ji′nan.Methods:The children diagnosed with MMA by tandem mass spectrometry screening in Ji′nan Neonatal Disease Screening Centre from May 2011 to May 2022 were enrolled in this study.Their genetic test results were retrospectively analyzed and summarized.The dried heel blood tablets collected from 6 800 newborns were tested for neonatal gene screening. MMAA, MMAB, MMACHC and MMUT genes in 4 800 cases were detected by high-throughput sequencing+ target area capture technology.Ultra-multiplex polymerase chain reaction+ target gene locus capture technology was used to detect 174 target loci of 8 genes related to MMA in 2 000 cases.The hotspot mutation and related gene carrier rate of MMA were analyzed. Results:A total of 367 452 newborns were screened by tandem mass spectrometry, and 103 cases (56 males and 47 females) were diagnosed with MMA by screening.The estimated incidence of MMA was 1∶3 567.Among the 103 MMA cases, 76 were genetically diagnosed, and 4 gene variants of MMA ( MMAHC, MMUT, MMAA, MMADHC) were identified.A total of 6 800 neonates underwent neonatal genetic screening.Three of them were diagnosed with MMA.About 318 infants carried pathogenic variants of MMA, with a total carrier rate of 4.68%.Specifically, the carrier rates of MMACHC and MMUT gene variants were 3.09%(210/6 800) and 1.43% (97/6 800), respectively. Conclusions:MMA is the most common organic acid metabolism disorder in our country.The incidence and carrier rate of this disease are high in Jinan city.Neonatal genetic screening is an important supplement to neonatal biochemical screening.Carrier screening for MMA-related pathogenic genes is recommended for couples of childbearing age in Jinan.
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Methylmalonic acidemia(MMA) is one of the common diseases in hereditary organic acid metabolism disorder. The disorder is mainly treated by using vitamin B12 which comes in various forms.The use of the methylcobalamin and adenosylcobalamin in China cannot meet the needs of children with MMA. Parenteral use of hydroxocobalamin of high concentration has significant advantages in the treatment of MMA. But, the accessibility to hydroxocobalamin is challenging now.Through the supervision and adjustment of hydroxocobalamin, we explored the strategy of using the drugs. Meanwhile, we are considering the oral use of the hydroxocobalamin as supplement to treatment. Solving the challenges of the hydrococobalamin is helpful to meet the treatment of MMA and to provide a new possibility for the use of medication for rare diseases. The improvement in policy and supervision measures will facilitate the development, involvement, and production of hydroxocobalamin, so that the patients will have a good chance of access to the treatment.
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Objective:To observe the clinical features of eyes in children with methylmalonic acidemia (MMA).Methods:A retrospective clinical case study. From June 2019 to June 2022, 13 children with MMA visited on the Department of Ophthalmology of Henan Children's Hospital were included in the study. The anterior segment and fundus were examined under surface or general anesthesia. Best corrected visual acuity (BCVA) and refraction were performed in 9 cases; fluorescein fundus angiography (FFA) was performed in 3 cases; flash electroretinogram (FERG) was performed in 6 cases; flash visual evoked potential (FVEP) was detected in 6 cases; optical coherence tomography (OCT) was performed in 3 cases.Results:Among the 13 pediatric patients with methylmalonic acidemia, 6 cases were male and 7 cases were female. The average age at first visit was 45 months. All cases suffered from hyperhomocysteinemia; 9 cases were with epilepsy; 2 cases were with infantile spasms; 11 cases were with stunting, 13 cases were with repeated pulmonary infection during growth period; 4 cases were with hydrocephalus; 1 cases was with hypertension and renal insufficiency. Genetic dectection results of 8 cases were recorded, MMACHC:c.609G>A:p.W203* mutation site was found in all cases. One case was accompanied by corneal ulcer. There were 10 cases with nystagmus, 4 cases with macular degeneration, 3 cases with hyperopic refractive error and esotropia. Nine cases underwent BCVA examination, BCVA was light perception-0.6. In OCT, 2 cases of 3 cases showed retinal thinning and photoreceptor cell layer atrophy in the macular area. In FFA, 2 cases of 3 cases showed circular transparent fluorescence in the macular area. Five cases of 6 cases who with FVEP had different degrees of P100 peak time delay and decreased amplitude, and 4 cases of 6 cases with FERG had decrease of a and b wave in light and dark adaptation. Conclusions:The clinical phenotypes of eyes in children with MMA are various and the severity was different; most of them are accompanied by nystagmus, and the fundus lesions are common in the characteristic bovine eye like macular region. Those with macular disease have severe visual impairment.
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Resumen Los errores innatos del metabolismo intermediario (EIMi) son un grupo de enfermedades monogénicas que afectan alguna vía del metabolismo de las proteínas, los hidratos de carbono o los lípidos; cuando no son tratados a tiempo, se asocian con una elevada morbimortalidad. A la fecha, la piedra angular del tratamiento de los EIMi ha sido la terapia nutricional, cuyo propósito es evitar la acumulación de metabolitos tóxicos al restringir los sustratos que están involucrados en la vía afectada. El manejo nutricional en lactantes incluye una fórmula metabólica sin los nutrimentos involucrados en el EIMi más el aporte de alimentación al seno materno o fórmula infantil. Por el perfil de aminoácidos, la proporción de ácidos grasos esenciales y la protección contra enfermedades, la leche materna resulta un alimento ideal para los pacientes con EIMi. El objetivo de esta revisión de la literatura sobre la lactancia materna en algunos EIMi es servir de guía para el personal de salud involucrado en la atención médica de estos pacientes. La lactancia materna puede ser llevada a cabo de forma exitosa en pacientes con EIMi siempre que exista un seguimiento estrecho y continuo, de preferencia en centros especializados. El profesional de la nutrición y el pediatra deben individualizar las recomendaciones para proporcionar una lactancia a libre demanda en conjunto con una fórmula metabólica o una lactancia materna cuantificada, y con ello lograr una adecuada evolución en estos pacientes.
Abstract Inborn errors of intermediary metabolism (IEiM) are a group of monogenic disorders that affect a metabolic pathway of proteins, carbohidrates, or lipids; when not treated timely, IEiM are associated with high morbidity and mortality. To date, nutritional therapy is the cornerstone of treatment for patients with IEiM, which aims to prevent the accumulation of toxic metabolites by restricting the substrates involved in the affected pathway. Nutritional management in infants includes a metabolic formula free of the nutrients involved in IEiM and breastmilk or infant formula. Because of its amino acid profile, the content of essential fatty acids, and protection against disease, breast milk is an excellent food for patients with IEiM. This literature review on breastfeeding in some IEiM aims to serve as a guide for health care personnel involved in the medical care of these patients. Breastfeeding can be successfully carried out in patients with IEiM as long as there is a close and continuous follow-up, preferably in specialized centers. The nutrition professional and the pediatrician should individualize the recommendations to provide on-demand breastfeeding in conjunction with metabolic formula or quantified breastfeeding to achieve a good clinical evolution in this group of patients.
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Late onset methylmalonic acidemia (MMA) is a rare genetic metabolic disease.This case is a 46 year old adult patient with MMA complicated with hyperhomocysteinemia.It starts with progressive limb weakness and mental abnormality, and has dysuria and respiratory failure.Neurological examination showed decreased muscle strength of limbs and pyramidal tract sign.The levels of blood homocysteine and urinary methylmalonic acid increased significantly.Head, neck, thoracolumbar magnetic resonance imaging showed abnormal signals in the spinal cord from the level of foramen magnum to the level of lumbar 1 vertebral body.Two heterozygous variants of mmachc were found by gene detection: c: 609G>A, c: 349G>A, consistent with cobalamin C deficiency.Treat with L-carnitine, vitamin B12 and betaine.The patients′ mental symptoms, limb muscle strength and respiratory failure were improved, and the level of blood homocysteine also decreased significantly.
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Abstract Methylmalonic acidemia (MMA) should be diagnosed in early infancy and receive appropriate management promptly after the diagnosis to prevent severe complications leading to death. At present, a newborn screening (NBS) method using tandem mass spectrometry (MS/MS) identifies suspected patients with MMA by elevated propionylcarnitine. In addition, a liquid chromatography tandem mass spectrometry (LC/MS/MS) method using dried blood spot is effective to detect some metabolites as a second-tier test, and reduces the false-positive rate in NBS. However, these tests were only used in screening, and not applied as an examination for evaluating treatment. Herein, we describe a 57-day-old girl with MMA under treatment with cobalamin who had elevated urinary methylmalonic acid levels. We applied the LC/MS/MS method with a separation column to evaluate her cobalamin responsiveness, and discovered an insufficient cobalamin dose earlier than would have been possible using other methods. Based on the current data, this method seems to be applicable for the follow-up of the treatment of MMA patients. However, this should be confirmed with more experience with a larger number of cases and a wider spectrum of disorders.
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Cobalamin C (CblC) deficiency is an autosomal recessive disorder caused by mutations of the MMACHC gene that results in impaired synthesis of the methylcobalamin and adenosylcobalamin co-factors. This brings an impaired conversion of dietary cobalamin and therefore dysfunction of two key enzymes generating hyperhomocysteinemia, hypometionimemia and methylmalonic aciduria. It is the most common intracellular metabolism disorder of cobalamin. The early clinical form is the most frequent disorder and appears as a multisystemic disease with developmental delay, failure to thrive, and ocular, renal and hematological involvement during the first year of life. The thromboembolic events are associated with small vessel involvement, generating thrombotic microangiopathy responsible for renal involvement and pulmonary thromboembolism. The late-onset form is characterized by leukoencephalopathy, psychiatric disorders, subacute degeneration of the spinal cord, and thromboembolic events of medium to large vessels. The treatment currently available increases the survival of the patient and improves growth, neurological manifestations, biochemical, hematological profile and hydrocephalus. We present the neonatal debut of a case of CblC deficiency that appeared as a multisystem disease with initial neurological, ocular and hematological manifestations. The onset of symptoms was acute, a characteristic that is not frequent in CblC. The patient started treatment early, but in an unsatisfactory fashion, which led to increased neurological deterioration. Due to MRI images performed during the evolution of his condition, a superior and transverse sagittal sinus thrombosis, a rare manifestation of the disease, was observed.
La deficiencia de cobalamina C (CblC) es un defecto autosómico recesivo causado por la mutación del gen MMACHC, que resulta en la síntesis alterada de los cofactores metilcobalamina y adenosilcobalamina. Esto trae aparejado una disfunción de dos enzimas claves, lo cual genera hiperhomocisteinemia, hipometionimemia y aciduria metilmalónica. La presentación clínica de la deficiencia de CblC es heterogénea, y varía desde las formas de inicio temprano graves y potencialmente mortales, hasta los fenotipos más leves de inicio tardío. La forma clínica temprana es la más frecuente y se manifiesta como una enfermedad multisistémica, con restricción del desarrollo, restricción del crecimiento y alteraciones oculares, renales y hematológicas durante el primer año de vida. Las manifestaciones tromboembólicas están asociadas con el compromiso de pequeños vasos, lo que causa microangiopatía trombótica, responsable de compromiso renal y de tromboembolismo pulmonar. La forma tardía se caracteriza por leucoencefalopatía, trastornos psiquiátricos, degeneración subaguda de la médula espinal y eventos tromboembólicos de medianos o grandes vasos. El tratamiento disponible actualmente aumenta la supervivencia de la enfermedad y mejora el crecimiento, las manifestaciones neurológicas, el perfil bioquímico y hematológico y la hidrocefalia. Presentamos el debut neonatal de un caso de deficiencia de CblC que se manifestó con compromiso inicial neurológico, ocular y hematológico. El comienzo de los síntomas fue agudo, característica que no es frecuente en la deficiencia de CblC. El tratamiento se inició tempranamente, pero en forma insatisfactoria, con evolución de deterioro neurológico. En la evolución de su enfermedad en las imágenes de resonancia magnética, se puso de manifiesto trombosis de los senos sagital superior y transversos, una rara manifestación de la deficiencia de CblC.
Subject(s)
Humans , Infant, Newborn , Infant , Sinus Thrombosis, Intracranial , Vitamin B 12 , Vitamin B 12 Deficiency , Venous Thrombosis , Hyperhomocysteinemia , PediatricsABSTRACT
Methylmalonic acidemia (MMA) is a rare autosomal recessive disorder, with the manifestation of recurrent and severe episodes of acute metabolic decompensation or a variety of long-term complications that require timely treatment.As liver transplantation (LT) developing widely, it has become an effective treatment for patients with severe MCM deficiency.Although LT does not solve the fundamental problem of gene defect, it can prolong survival, improve the quality of life of patients and reduce recurrent hospitalization rate, as well as lower urine, plasma MMA and propionyl carnitine levels and prevent metabolic stroke.After LT, the metabolism-correcting medications are still partially needed.Neurological symptoms of some patients can be alleviated but renal damage may remain irreversible.The domestic liver transplantation in the treatment of methylmalonic acidemia is being carried out, but there is still a lack of research on the effect of LT on MMA.The paper is to make a review of the clinical value of liver transplantation in the treatment of methylmalonic acidemia in recent years in hope of sharing the information on this issue with more people.
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Objective@#To report on clinical characteristics and genetic findings in 15 Chinese patients with methylmalonic acidemia (MMA).@*Methods@#For the 15 MMA patients detected by tandem mass spectrometry, genetic analysis was carried out in twelve pedigrees. Clinical characteristics, genetic finding, treatment and outcomes were retrospectively analyzed.@*Results@#The main features of the patients included poor feeding, recurrent vomiting, lethargy, seizure and development retardation. Blood propionylcarnitine (except for 3 patients), its ratio with acetylcarnitine, and urine methylmalonic acid were increased in all patients. Twelve patients were diagnosed genetically, which included 7 with MUT variants, 4 with MMACHC variants, and 1 with MMAB variant. Nine MUT variants were detected, among which c. 1159A>C, 753+ 1delGinsTGGTTATTA and c. 504del were novel. Six known pathogenic MMACHC variants and two novel MMAB variants (c.289_290delGG, c. 566G>A) were also detected. Seven patients died of metabolic crises within a year, others had improved effectively following the treatment, but had mild to severe growth delay and/or developmental retardation.@*Conclusion@#The clinical manifestation of MMA are complex. Most patients have variants of the MUT and MMACHC genes. High mortality may occur before one year of age.
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Methylmalonic acidemia is the most common disease of congenital organic acid metabolic disorders,and it is an autosomal recessive disease.The clinical manifestations of methylmalonic acidemia are non-specific.It is characterized by the neurological symptoms.Cardiovascular diseases have little been associated with methylmalonic acidemia.But,cardiovascular diseases including structural heart disease,pulmonary hypertension,cardiomyopathy,hypertension,arrhythmias,may cause rapid deterioration,or even sudden death.This paper is a review of cardiovascular diseases of methylmalonic acidemia.
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Objective To explore the clinical manifestations, treatment and outcomes of patients with c. 482G>A ( p. R161Q ) variant of MMACHC gene in cblC type methylmalonic acidemia ( MMA ) . Methods The clinical manifestations, mass spectrometry results, genotypes, treatment and outcomes of 75 patients with cblC type MMAcarryingc.482G>A(p.R161Q)variantwereretrospectivelyanalyzed.Results Ofthe75patients,57(76％) were from newborn screening and one of them had an onset. Among the rest 18 unscreened patients, 2 were diagnosed after their full sisters' or brothers' diagnosis, the others were clinical patients. There were 17 clinical patients, with the medium age of onset 12 years old (10 days～26 years old). 12 late onset patients (70.6％) presented with poor academic performance, memory loss, poor expression, and decreased exercise capacity, while 5 early onset patients (29.4％) presented with convulsion and delay of development. All patients were vitamin B12-responsive. The levels of blood propionylcarnitine, the ratio of propionylcarnitine to acetylcarnitine, urinary methylmalonic acid and methyldecanoic acid, and plasma homocysteine were significantly decreased after treatment (P< 0.01). All patients diagnosed from newborn screening had normal development. However, only 3 clinical patients had a rather normal outcomes and the others remained different levels of intelligence and ( or ) motor dysfunction after treatment. Conclusion The c.482G>A ( p. R161Q) variant of MMACHC gene is associated with late onset cblC type MMA. Patients with this variant have a better response to hydroxycobalamin than other variants. The outcome of patients diagnosed from the newborn screening is good. When symptoms occur, the disability rate is often high. Therefore, newborn screening is a recommended method to prevent this disease.
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Objective@#To analyz the current situation of the diagnosis, treatment and prevention of methylmalonic acidemia, the phenotypes, biochemical features and genotypes of the patients in the mainland of China, were investigated.@*Methods@#Tottally 1 003 patients of methylmalonic acidemia from 26 provinces and municipalities of the mainland of China were enrolled. The clinical data, biochemical features and gene mutations were studied. Blood aminoacids and acylcarnitines, urine organic acids, and plasma total homocysteine were determined for the biochemical diagnosis. Gene analyses were performed for the genetic study of 661 patients. The patients were treated with individual intervention and long-term follow up. Prenatal diagnoses were carried out for 165 fetuses of the families.@*Results@#Among 1 003 patients (580 boys and 423 girls), 296 cases (29.5%) had isolated methylmalonic acidemia; 707 cases (70.5%) had combined homocysteinemia; 59 patients (5.9%) were detected by newborn screening; 944 patients (94.1%) had the onset at the ages from several minutes after birth to 25 years and diagnosed at 3 days to 25 years of age. The main clinical presentations were psychomotor retardation and metabolic crisis. Multi-organ damage, including hematological abnormalities, pulmonary hypertension, kidney damage, were found. MMACHC, MUT, MMAA, MMAB, HCFC1, SUCLG1, SUCLA2 mutations were found in 631 patients (96.6%) out of 661 patients who accepted gene analysis. MMACHC mutations were detected in 460 patients (94.7%) out of 486 cases of methylmalonic acidemia combined with homocysteinemia. MUT mutations were found in 158 (90.3%) out of 169 cases of isolated methylmalonic acidemia. The development of 59 patients detected by newborn screening were normal; 918 cases (97.2%) were diagnosed after onset accepted the treatment. Forty-five of them completely recovered with normal development. Twenty-six patients (2.7%) died; 873 (92.5%) patients had mild to severe psychomotor retardation. Methylmalonic acidemia were found in 35 out of 165 fetuses by metabolites assay of amniotic fluid and amniocytes gene analysis.@*Conclusion@#Combined methylmalonic acidemia and homocysteinemia is the common type of methylmalonic acidemia in the mainland of China. CblC defect due to MMACHC mutations is the most common type of methylmalonic acidemia combined with homocysteinemia. MUT gene mutations are frequent in the patients with isolated methylmalonic acidemia. Newborn screening is key for the early diagnosis and the better outcome. Combined diagnosis of biochemical assays and gene analysis are reliable for the prenatal diagnosis of methylmalonic acidemia.
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Objective To investigate the combined application value of tandem mass spectrometry ( MS/MS) and high performance liquid chromatogram-tandem mass spectrometry ( LC-MS/MS ) in the newborn screening of children with methylmalonic acidemia ( MMA ) . Methods The dried blood spot samples from the newborn with abnormal propionylcarnitine ( C3) or C3/acetylcarnitine ( C2) or C3/free carnitine ( C0) levels in the preliminary screening of MS/MS were collected, and the concentrations of MMA, methylcitric acid ( MCA) and homocysteine ( Hcy) in these samples were detected with LC-MS/MS. The neonates with increased MMA, MCA or Hcy levels were recalled, and their urinary organic acids were analyzed with gas chromatographic mass spectrometry (GC/MS). Last, gene mutation anal-ysis was performed to make a definite diagnosis.Results A total of 423 samples with abnormal C3 or C3/C2 or C3/C0 levels in the new-born screening were collected, and the positive rate of preliminary screening was about 1％. The LC-MS/MS results showed that 8 neo-nates had higher MMA and tHcy levels. The GC/MS results further showed that the level of MMA increased slightly. Conclusion The combined application of MS/MS and LC-MS/MS may increase the positive predictive value and decrease the false positive rate of MMA screening in the newborn, which may have an important clinical significane in the screening of inherited metabolic disorders.
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Objective To explore the clinical features of methylmalonic acidemia (MMA) in children admitted to the pediatric intensive care unit, to help improve our understanding of MMA. Methods The clinical data of 21 patients with MMA admitted to our PICU from December 2012 to August 2016 were analyzed. Diagnosis were confirmed by gas chromatography-mass spectrometry, GC/MS. Results twenty-four of 158 suspected cases were confirmed as having organic acidemia diseases including 21 cases of MMA, one case of propionic acidemia, one case of urea cycle disorders, and one case of glutaric acidemia. The main clinical manifestations were feeding difficulty, malnutrition (13 cases), developmental retardation (12 cases), lethargy (10 cases), tricuspid severe reflux and pulmonary hypertension (1 case), hydrocephaly (5 cases), muscular dystonia (three cases with hypertonia, and four with hypotonia), convulsion (7 cases), apnea, sobbing respiration (10 cases), chromatosis (6 cases), anemia (13 cases), edema (6 cases), thrombocytopenia (6 cases), hematuria and proteinuria (2 cases). Five cases gave up therapy before diagnosis was made. Sixteen cases received the treatment with Vitamin B12 and supplementation of L-carnitine. Seven cases gave up after treatment without effect or deterioration of condition. Eight cases were vitamin B12-responsive, and one case was vitamin B12-nonresponsive. The follow-up for a period ranging from three months to two years, among eight vitamin B12-responsive cases, 6 cases showed a favorable outcome with apparent improvement, one case had no symptom and one patient died from severe pneumonia. Vitamin B12-nonresponsive case was still alive. Conclusions The clinical manifestations of MMA are non-specific. Urine organic acid analysis is critical to early diagnosis of MMA in high-risk patients. Timely diagnosis and appropriate long-term treatment are essential to improve the prognosis of the disease.
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Methylmalonic acidemia (MMA) is an autosomal recessive metabolic disorder characterized by an abnormal accumulation of methylmalonyl-CoA and methylmalonate in body fluids without hyperhomocysteinemia. Cardiac disease is a rarely known lethal complication of MMA, herein, we report a Korean neonate diagnosed with MMA on the basis of biochemical and genetic findings, who developed cardiomyopathy, resulting in sudden death. The patient presented vomiting and lethargy at 3 days of age. Initially, the patient had an increased plasma propionylcarnitine/acetylcarnitine concentration ratio of 0.49 in a tandem mass spectrometry analysis and an elevated ammonia level of 537 µmol/L. Urine organic acid analysis showed increased excretion of methylmalonate. Subsequent sequence analysis of the methylmalonyl-CoA mutase (MUT) gene revealed compound heterozygous mutations c.323G>A (p.Arg108His) in exon 1 and c.1033_1034del (p. Leu345Serfs*15) in exon 4, the latter being a novel mutation. In summary, this is the first case of MMA and cardiomyopathy in Korea that was confirmed by genetic analysis to involve a novel MUT mutation.
Subject(s)
Humans , Infant, Newborn , Ammonia , Body Fluids , Cardiomyopathies , Death, Sudden , Exons , Frameshift Mutation , Heart Diseases , Hyperhomocysteinemia , Korea , Lethargy , Methylmalonyl-CoA Mutase , Plasma , Sequence Analysis , Tandem Mass Spectrometry , VomitingABSTRACT
Objective To explore the clinical and genetic features in the pedigree of Cb1X type X-linked methylmalonic aciduria. Methods Clinical data of one child with X-linked methylmalonic aciduria diagnosed by blood and urine analysis were analyzed retrospectively. Targeted next-generation sequencing has been performed to detect the mutation of methylmalonic aciduria-related genes. Results The boy started presenting with seizures and severe mental retardation at 2 months of age. At 5 months of age, he had the manifestations of seizures, severe mental retardation, increased methylmalonic acid in urinary, increased propionylcarnitine in blood and increased plasma homocysteine, and met the requirements for the diagnosis of methylmalonic aciduria complicated with hyperhomocysteinemia. No mutation was detected in his MMA-related autosomal genes. However, a hemizygote mutation c.344C?>?T (p.Ala115Val) was identiifed in exon 3 of HCFC1 in X chromosome, which conifrmed the CblX type methylmalonic aciduria. His parents were healthy. His elder brother also manifested severe psychomotor retardation with intractable epilepsy, and died at 6 months of age with unknown cause. His mother carried the same mutation and had slightly elevated urine methylmalonic acid and plasma total homocysteine. His father did not carry the mutation. Conclusion A pedigree of a rare Cb1X type X-linked methylmalonic acidemia is ifrstly diagnosed in China by the new generation sequencing technology.
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Objective To understand the clinical characteristics, treatment effect and prognosis of children with methylmalonic acidemia (MMA) combined with renal damage, and to provide experiences about how to improve the level of diagnosis and treatment.Methods The medical records of children with MMA were collected from January of 2007 to December of 2013 in Beijing Children's Hospital Affiliated to Capital University of Medical Sciences,while the clinical manifestations,laboratory findings, imaging material, inspection results were analyzed, and the renal pathological gene analysis, treatment effect, and prognosis of MMA children with renal damage were studied, and follow-up was carried out for 3 months up to 7 years.Results Among the two hundred and ninety-six cases of MMA,28 cases (9.5％) with renal damage,including 19 boys and 9 girls, 18 patients with hyperhomocysteinemia.Their ages varied from 2 days to 13 years old when confirmed.The first symptoms of 16 cases were proteinuria, hematuria, and edema, 9 cases were complicated with acute renal failure,5 cases were diagnosed as hemolytic uremic syndrome,6 patients were diagnosed as nephrotic syndrome, receiving enough glucocorticoids treatment without improvement.The routine examination of the urine showed that proteinuria (241-3 060 mg/d), methylmalonic acid levels and urinary protein were positively correlated (r =0.982, P =0.003), as urinary β2-microglobulin [(360.386 ± 231.496) μg/L], retinol binding protein [(338.537 ± 243.293) μg/L] increased.Extrarenal clinical manifestations were the spiritual, mental and physical development retardations, seizures, anemia etc.Two cases had a positive family history.Renal pathology showed mesangial cells and mesangial matrix proliferation broadening, no electron dense deposits in mesangial area, renal tubular epithelial cell swelling degeneration, and immunofluorescence was negative.Gene analysis of 3 cases showed exon1:c.80A ＞ G,p.Q27R and exon1 :c.365A ＞ T,p.H122L/c.609 G ＞ A,p.W203X.Children with MMA were treated with vitamin B12 treatment.Two cases of multiple organ failure died during hospitalization, and 2 cases died after leaving hospital.After treatment, the level of urinary methylmalonic acid was significantly decreased, while nervous system symptoms improved significantly, and the mental state and the renal function were improved.Conclusions MMA may be associated with kidney damage,usually with severe renal tubular and glomerular impairment.Early diagnosis is the key,and timely treatment can effectively control the disease, improve the prognosis.
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Methylmalonic acidemia (MMA) is an autosomal recessive metabolic disease. MMA results from a deficiency of L-methylmalonyl-CoA mutase (encoded by MUT), its cofactor 5-deoxyadenosylcobalamin (MMAA, MMAB, and MMADHC), or a deficiency of methylmalonyl CoA-epimerase (MCEE). We report the case of a 5-day-old infant with MMA in which a missense and a novel nonsense mutation in MUT were present. Direct sequencing analysis of MUT revealed a heterozygous c.1106G>A (p.Arg369His) mutation in exon 6 and a heterozygous c.362_368dupAGTTCTA (p.Tyr123*) mutation in exon 2; the latter results in a premature stop codon.
Subject(s)
Female , Humans , Infant , Codon, Nonsense , Exons , Metabolic DiseasesABSTRACT
La acidemia metilmalónica es un desorden causado por anormalidad en la enzima metil malonil CoA mutasa o su cofactor Adenosilcobalamina. Esta holoenzima se encuentra implicada en el catabolismo de varios aminoácidos entre los que se incluyen dos de cadena ramificada (isoleucina y valina). Puede presentarse como una forma severa de inicio neonatal hasta formas con síntomas lentamente progresivos como hipotonía y retardo en el desarrollo. El diagnóstico y tratamiento oportuno, pueden modificar el curso y desenlace de la enfermedad, mejorando la calidad de vida del paciente. Reportamos el caso de un lactante de 3 meses, con pancitopenia, hipotonía, retardo en desarrollo y convulsiones. Se diagnosticó acidemia metilmalónica mediante cromatografía de ácidos orgánicos en orina. El paciente fue tratado con Cianocobalamina, restricción dietaria y levetiracetam con respuesta clínica favorable. Actualmente permanece libre de crisis, los índices de desarrollo son normales y la pancitopenia resolvió. Este caso muestra como el diagnóstico y tratamiento temprano en un paciente con acidemia metilmalónica, aun cuando se origine por déficit de cofactor, puede favorecer el pronóstico neurológico y funcional.
Methylmalonic Acidemia is a disorder caused by an abnormality of methylmalonyl-CoA mutase or a deficiency of adenosylcobalamin as cofactor. This holoenzyme is involved in the catabolism of branched chain amino acids. It can present clinically either as a severe neonatal-onset form, or some progressive symptoms as hypotonia and developmental delay. Early diagnosis and treatment can alter the course and outcome. We report the case of a 3- month- old boy, with pancytopenia, hypotonia, developmental delay and seizures. Methylmalonic Acidemia was diagnosed by urinary organic acid chromatography. Patient was treated with Cyanocobalamin, dietary restriction and levetiracetam with favorable response. He is currently seizure free, development indexes are normal and pancytopenia has resolved. This case shows how early diagnosis and treatment in a patient with Methylmalonic Acidemia caused by cofactor deficiency may favor functional and neurologic outcomes.
A acidémia metilmalónica é uma desordem causada pela anormalidade na enzima l-metil malonil- coa mutase o no seu cofator adenosilcobalamina. Esta holoenzima está envolvida no catabolismo de vários aminoácidos, entre os quais encontrasse os de cadeia ramificada (isoleucina e valina). Sua apresentação clínica pode ser uma forma grave em neonatos com sintomas lentamente progressivos, como hipotonia e atraso no desenvolvimento. O diagnóstico e tratamento precoce podem alterar a história natural da doença, melhorando a qualidade de vida dos pacientes. Relata-se o caso de uma criança de colo de três meses, com pancitopenia, hipotonia, atraso no desenvolvimento e convulsões. O diagnóstico de acidémia metilmalónica foi feito com cromatografia. O paciente foi tratado com Cianocobalamina, regime de dieta e levetiracetam, com resposta clínica favorável. Atualmente o paciente está sem crises, o desenvolvimento é normal para idade e a pancitopenia foi resolvida. Na acidémica metilmalónica, a despeito, da sua origem por déficit de cofator com diagnóstico e tratamento precoce, pode ter uma evolução neurológica e funcional.
Subject(s)
Humans , Pancytopenia , Peroxisomal DisordersABSTRACT
Objective To assess the efficiency and reliability of clinical genetic diagnosis of methylmalonic acidemia(MMA) using new generation sequencing platform (HiSeq2000).Methods 1.Nine patients diagnosed with clinical signs of MMA were recruited.DNA library from the patients were mixed with designed gene capture probe.The whole exons region of 48 genes related to organic acid metabolism were screened using the gene capture combined with high-throughput sequencing.2.The joints were removed and the low quality data were filtered,the data were analyzed by means of SNP and InDel.To avoid the false positive,the abnormal sites were verified using the Sanger sequencing method.3.The detection of the organic acid in the urine was performed through gas chromatography-mass spectrometry and other auxiliary examinations.Results 1.Gene mutation:7 gene mutations of MMACHC were identified in 7 patients.Seven mutations:c.482G ＞ A,c.567_568insT,c.609G ＞ A,c.440_441del,c.80A ＞ G,c.315C ＞ G,c.90G ＞ Awere screened.The mutation c.440_441del had not been reported before,and others were all related to the disease.Two gene mutations of mutase apoenzyme(MUT) were identified in 1 case,all of which were introns:.c.754-1G ＞ C,c.1677-1G ＞ A.The novel mutation was c.754-1G ＞ C.No gene mutation was identified in 1 patient.2.Clinical manifestation:all of the patients were development delay,but the degrees were different;3 patients with convulsion; 1 patient with headache and central facial paralysis;1 patient with repeated intractable metabolic acidosis;1 patient with repeated hemolysis.Electroencephalogram of the all patients were abnormal;the result of cranial MRI of the 8 patients were abnormal;In all patients,urine level of methylmalonic acid significantly increased (273.4-146 022.8 times).Blood homo cysteine of 8 patients were significantly increased(27.13-396.84 μmol/L,normal ＜ 20 μmol/L).3.Sanger sequencing:there were no false positive exists.Conclusions 1.There were not a correlation between the clinical manifestation and gene mutation of the patients with MMA.The c.609G ＞ A was the hotspot mutation of MMACHC gene in Chinese patients with MMA and homocysteinemia.2.The mutations c.440_441del and c.754-1G ＞ C were presumed to be novel mutations.3.Gene capture technology combined with next-generation sequencing technology could be used to interrogate the wealth of data available in the human genome and lay the foundations for counseling of gene.This platform can be readily and timely adopted by clinical molecular diagnosis of MMA and represents a high throughput,high sensitivity,high efficiency and other characteristics approach for screening common genetic diseases.