Degeneración combinada subaguda

Introducción: La degeneración combinada subaguda (DCS) es un trastorno caracterizado por la degeneración difusa de la sustancia blanca a nivel del SNC, que afecta específicamente los cordones posteriores y laterales de la médula espinal, con pérdida de la mielinización periférica y central. De manera frecuente, las manifestaciones clínicas son parestesias y debilidad generalizada causada por deficiencia de vitamina B12. Presentación del caso: Paciente masculino de 79 años, con cuadro clínico de 3 meses de evolución de limitación funcional para la marcha acompañado de desorientación. Al examen físico evidenció desorientación, cuadriparesia e hiporreflexia, con niveles séricos bajos de vitamina B12, RM cervical con focos hiperintensos en el segmento C3/C6 y endoscopia de vías digestivas altas con atrofia de la mucosa gástrica. Presentamos un caso clínico de DCS. Discusión: Este es un caso de DCS que se manifiesta por medio de una alteración neuropsiquiátrica, con una presentación inicial inespecífica que comprende deterioro de la marcha, movimientos anormales con afectación cognitiva y psiquiátrica dada por alucinaciones visuales y desorientación. Su sospecha es importante en pacientes con factores de riesgo por medio del conocimiento de la patología, para una adecuada sospecha diagnóstica y una instauración oportuna de reposición vitamínica, la cual presenta una excelente respuesta. Conclusión: La DCS es un trastorno en el que se evidencia anemia con deficiencia de vitamina B12, des-mielinización del tejido nervioso y en muchos casos signos sugestivos de atrofia gástrica, y para ello es crucial la detección temprana de esta enfermedad por medio de la determinación de niveles séricos de vitamina B12, asociado a síntomas neurológicos, para así lograr su adecuado diagnóstico y tratamiento.

Introduction: Subacute combined degeneration (DCS) is a disorder characterized by diffuse degeneration of white matter at the CNS level, specifically affecting the posterior and lateral cords of the spinal cord, also with loss of peripheral and central myelination, frequently the clinical manifestations are paresthesias and generalized weakness caused by vitamin B12 deficiency. Case presentation: A 79-year-old male patient with a 3-month history of functional limitation for walking accompanied by disorientation. On physical examination, he revealed disorientation, quadriparesis, and hyporeflexia, with low serum levels of vitamin B12, cervical MRI with hyperintense foci in segment C3/C6, and upper digestive tract endoscopy with atrophy of the gastric mucosa. We present a clinical case of DCS. Discussion: This is a case of DCS that manifests itself through neuropsychiatric alteration with a nonspecific initial presentation with gait impairment, abnormal movements with cognitive and psychiatric affectation given by visual hallucinations and disorientation. Its suspicion is important in patients with risk factors. risk through knowledge of the pathology for an adequate diagnostic suspicion and a timely establishment of vitamin replacement for which it presents an excellent response. Conclusion: DCS is a disorder where anemia with vitamin B12 deficiency, demyelination of the nervous tissue and in many cases signs suggestive of gastric atrophy are evident, for which early detection of this disease is crucial through the determination of serum levels of vitamin B12 associated with neurological symptoms, in order to achieve its proper diagnosis and treatment.

Usher syndrome with methylmalonic acidemia and homocysteine in an infant / 中华围产医学杂志

A case of Usher syndrome with methylmalonic acidemia and homocysteine is reported. The patient was a two-month-old and small for gestational age male infant hospitalized for "feeding difficulties" during the neonatal period. The baby boy presented hypotonia, microcephaly, and hearing loss after birth. Genetic test found compound heterozygous mutations of c.482G>A and c.567dup in MMACHC, and both were pathogenic mutations inherited from his parents. Moreover, the patient also had compound heterozygous variants at c.2802T>G and c.14017T>C of USH2A gene. The former was suspected to be pathogenic, and the latter was of unknown clinical significance. Both were from the parents. Usher syndrome and methylmalonic acidemia with homocysteine were clinically diagnosed. Followed up to the age of two, the child was found with moderate mental retardation, while the physical development was comparable to that of the same age group.

Detection of urine metabolites in patients with inherited metabolic diseases by nuclear magnetic resonance spectroscopy / 中华检验医学杂志

Objective:Nuclear magnetic resonance spectroscopy (NMR) was used to detect the species and content of metabolites in urine of patients with inherited metabolic diseases, and to explore the application value of NMR technology in the diagnosis of inherited metabolic diseases.Methods:Urine samples were collected from 20 patients with inherited metabolic diseases diagnosed in Xinhua Hospital, Shanghai Jiaotong University School of Medicine from March to June 2019, including 9 cases of methylmalonic acidemia (MMA). NMR pulse length-based concentration determination and Gas chromatography mass spectrometry (GC/MS) semi-quantitative method were used to detect the composition of metabolites in urine samples of patients with inherited metabolic diseases, and the levels of abnormal metabolites in the two methods were analyzed.Results:NMR technology can detect the levels of characteristic metabolites significantly increased in the urine of patients with MMA, isovalerinemia, glutaric acidemia, propionic acidemia, 3-methylcrotonyl-CoA carboxylase deficiency, ornithine carbamyltransferase deficiency, Citrin deficiency, Canavan disease, tyrosinemia and lysinuria protein intolerance. The average is 8 times of the upper limit of the reference value, and the highest is 545 times. Compared to GC/MS, NMR technology can detect the levels of various metabolites such as organic acids, amino acids and sugars. In 9 cases of untreated MMA,the median levels of methylmalonic acid and 3-hydroxypropionic acid in NMR [1 800 (180-12 000) and 50 (0-270) mmol/mol Cr] were higher than the reference values (0-31, 0-35). The median levels of methylmalonic acid and methylmalonic acid in GC/MS [136.56 (43.79-518.67) and 4.87 (1.52-7.52)] were higher than the reference values (0-4 and 0-0.7).Conclusions:NMR and GC/MS technologies are specific for the diagnosis of organic acidemia. The primary component detected by GC/MS is organic acid. NMR technology can break through this limitation and measure the level of various metabolites in urine, which provides a more theoretical basis for the diagnosis and research of inherited metabolic disease.

Diagnóstico de aciduria metilmalónica en el periodo 2013-2018 / Diagnosis of Methyl Malonicaciduria from 2013 to 2018

RESUMEN Fundamento: la aciduria metilmalónica es una de las acidurias orgánicas más frecuentes y agrupa un conjunto de defectos genéticos caracterizados por la excreción de niveles elevados de ácido metilmalónico en la orina. La excreción de este metabolito puede ir acompañada o no de niveles elevados de homocisteína en dependencia de la ruta metabólica afectada. Objetivo describir la implementación de una metodología de laboratorio que combina el ácido metilmalónico y la homocisteína en el diagnóstico diferencial y seguimiento de la aciduria metilmalónica en el periodo de 2013 a 2018. Métodos: a los pacientes con incremento de ácido metilmalónico en el perfil de ácidos orgánicos, se les cuantificó homocisteína en plasma y orina. La identificación del ácido metilmalónico se realizó por cromatografía gaseosa/ espectrometría de masas, mientras que la cuantificación de homocisteína por cromatografía líquida de alta resolución. Resultados: los métodos cromatográficos permitieron la identificación y cuantificación del ácido metilmalónico y la homocisteína, respectivamente. La homocisteína se cuantificó en siete pacientes con niveles incrementados de aciduria metilmalónica. Los niveles de homocisteína en cuatro de ellos fueron superiores a los valores normales, sugiriendo una aciduria combinada con homocistinuria. Tres de los pacientes con aciduria metilmalónica combinada bajo tratamiento mostraron una disminución en los niveles de ambos metabolitos, correspondiendo con una satisfactoria evolución. Conclusiones: la metodología implementada con los análisis de la determinación simultánea de ambos marcadores permitió el diagnóstico diferencial y seguimiento bioquímico de la aciduria metilmalónica.

ABSTRACT Foundation: methylmalonic aciduria is one of the most frequent organic acidurias and groups together a set of genetic defects, characterized by the excretion of elevated levels of urinemethyl malonic acid. The excretion of this metabolite may or may not be accompanied by elevated homocysteine ​​levels depending on the affected metabolic pathway. Objective: to describe the implementation of a laboratory methodology that combines methylmalonic acid and homocysteine ​​in the differential diagnosis and monitoring of methylmalonic aciduria in the period from 2013 to 2018. Methods: for patients with an increase in methylmalonic acid in the organic acid profile, homocysteine ​​was quantified in plasma and urine. The identification of methylmalonic acid was performed by gas chromatography / mass spectrometry, while the homocysteine ​​quantification by high performance liquid chromatography. Results: chromatographic methods allowed the identification and quantification of methylmalonic acid and homocysteine, respectively. Homocysteine ​​was quantified in seven patients with increased levels of methylmalonic aciduria. Homocysteine ​​levels in four of them were higher than normal values, suggesting aciduria combined with homocystinuria. Three of the patients with combined methylmalonic aciduria under treatment showed a decrease in the levels of both metabolites, corresponding to a satisfactory evolution. Conclusions: simultaneous determination of both markers allowed differential diagnosis and biochemical monitoring of this disease.

Vitamin B12 deficiency and involuntary movement / 中华神经科杂志

Vitamin B12 deficiency mainly leads to anemia and subacute combined degeneration of the spinal cord.These two manifestations can often be diagnosed early,treated in time and reversed.However,vitamin B12 deficiency can cause a variety of involuntary movements such as chorea,tremor,myoclonus,Parkinson-like symptoms,and dystonia,which are ignored by clinicians and cannot be treated early,resulting in irreversible damage.Therefore,in this paper,the characteristics of 33 cases of vitamin B12 deficiency with involuntary movement in recent 20 years are summarized and the possible mechanisms are reviewed to improve the understanding of clinicians.

Clinical value of liver transplantation in the treatment of methylmalonic acidemia / 中华实用儿科临床杂志

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.

Clinical analysis of methylmalonic acidemia and hyperhomocysteinemia with diffuse lung disease as an initial or main presentation / 中华儿科杂志

Objective@#To improve the awareness of methylmalonic acidemia and hyperhomocysteinemia with diffuse lung disease as an initial or main presentation.@*Methods@#A retrospective analysis of the clinical manifestations, radiological features, laboratory tests, genetic variations, treatments and prognoses was conducted in six children presented with diffuse lung disease and finally diagnosed with methylmalonic acidemia and hyperhomocysteinemia in Ward 2 of Department of Respiratory Diseases, Beijing Children′s Hospital, from August 2017 to November 2018.@*Results@#Six children were included in this study. Two children were male and four were female. The average age of onset was 28 months. The mean age at diagnosis was 34 months. The average interval from onset to diagnosis was 6 months. Four children who underwent genetic tests were found to have variants of gene MMACHC and diagnosed with CblC type. All children had respiratory symptoms and signs as initial or main presentation, which were tachypnea (5 cases), exercise intolerance (5 cases), cough (4 cases), cyanosis (4 cases), clubbing (4 cases), dyspnea (3 cases) and retractions (3 cases). Pulmonary arterial hypertension was found in all six children. Pericardial effusion (4 cases), kidney involvement (3 cases), nervous system involvement (3 cases), gastrointestinal system involvement (3 cases) and anemia (2 cases) also coexisted. The high resolution computed tomography (HRCT) features included dilated pulmonary artery (6 cases), ground-glass opacities (4 cases), diffuse poorly defined ground-glass centrilobular nodules (3 cases), pleural effusion (3 cases), thickening of interlobular septum (2 cases), etc. All children had an elevated concentration of methylmalonic acid in urine and homocysteine in plasma. Genetic tests were performed in four patients, and MMACHC genetic mutations were found in all of them. Clinical manifestations, HRCT features and pulmonary arterial hypertension turned better in five children after treatment. One patient who was not regularly followed-up died.@*Conclusions@#Pulmonary involvement including diffuse lung disease and pulmonary arterial hypertension could coexist with methylmalonic acidemia and hyperhomocysteinemia, which may have respiratory symptoms and signs as the initial or main presentation. Characteristic HRCT features were found in some patients. Plasma homocysteine test is a quick method for screening the disease in children with diffuse lung disease and (or) pulmonary arterial hypertension. Both diffuse lung disease and pulmonary arterial hypertension may turn better after treatment.

Case-control study of vitamin B12 and metabolite MMA and transporter TCN2 in children with ASD / 中国学校卫生

Objective@#To investigate the level of vitamin B12 in children with autism spectrum disorder(ASD), and provide a theoretical basis for early detection and drug treatment of ASD.@*Methods@#A total of 89 ASD cases and 89 matched controls were collected. The levels of urinary methylmalonic acid (MMA) and serum vitamin B12, Transcobalamin Ⅱ (TCN2) were determined by enzyme-linked immunosorbent assay (ELISA). TCN2 gene rs1801198 was genotyped by SNaPshot.@*Results@#The serum levels of vitamin B12 and TCN2 in children with ASD [(369.08±131.88)pmol/L, (1.56±0.16)ng/mL] were significantly lower than those in the control group[(485.16±200.33)pmol/L, (1.71±0.17)ng/mL](t=-5.47, -5.92, P<0.05). The level of MMA in urine of ASD children [(758.97±106.96) ng/mL] was significantly higher than that in the control group[(693.66±121.72)ng/mL](t=3.94, P<0.05); The genetic polymorphism of rs1801198 locus was not associated with the risk of ASD(P>0.05), and there was no significant correlation with serum TCN2 level(F=1.16, P>0.05).@*Conclusion@#ASD children are at a potential deficiency of vitamin B12 and should strengthen their nutritional interventions while conducting ASD interventions.

Clinical analysis and outcome of patients with c. 482G >A variant of MMACHC gene in cblC type methylmalonic acidemia / 中华内分泌代谢杂志

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.

Degeneración combinada subaguda en un paciente sin anemia y con hipertensión severa / Subacute combined degeneration in a patient without anemia but with severe hypertension

RESUMEN La degeneración combinada subaguda, es una patología de tipo neuropsiquiatrica asociada al déficit de vitamina B12. Se manifiesta clínicamente por ataxia sensorial, neuropatía periférica, disfunción cognitiva y neuropatía óptica; estas manifestaciones generalmente son atribuidas a la síntesis anormal de mielina. Puede tener una presentación clínica inespecífica, pero la medición de los niveles de vitamina B12, algunos metabolitos séricos, y el uso de métodos de neuroimagen, ayudan a confirmar el diagnóstico ante su sospecha. A continuación se describe el caso de un paciente con un cuadro de degeneración combinada subaguda, quien consultó por síntomas neurológicos e hipertensión severa, quien luego del tratamiento presentó mejoría de su sintomatologia neurológica y vascular.

SUMMARY Sub-acute combined degeneration is a neuropsychiatrical pathology associated with vitamin B12 deficiency It is clinically manifested through sensorial ataxia, peripheral neuropathy, cognitive dysfunction and optical neuropathy; these manifestations are generally attributed to the abnormal synthesis of myelin. It can have a nonspecific clinical presentation but the measurement of the levels of vitamin B12, some serum metabolites, and the use of neuroimaging methods help to confirm the diagnose when suspected. The case of a patient with sub-acute combined degeneration is described below. The patient was attended because of neurological symptoms and severe hypertension, and after the treatment, the patient's neurological and vascular symptomatology improved.

Combined application of MS/MS and LC-MS/MS in the newborn screening of children with methylmalonic acidemia / 临床检验杂志

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.

A case of cerebral hemorrhage in patients with methylmalonic aciduria with hyperhomocystinuria / 中华神经科杂志

A case of late-onset methylmalonic aciduria combined with hyperhomocysteinemia (cblC type) is reported. The main manifestations were the reduction of intelligence,the instability of walking,and the inability to take care of oneself,with secondary cerebral hemorrhage. The effect of treatment was good. MMACHC gene mutation detection showed exon1 deletion, indicating that delExon1 is one of the causes of late onset methylmalonic aciduria, cblC type.

Characteristics of clinical manifestations and molecular genetics of late-onset cobalamin C deficiency / 中华神经科杂志

Objective To investigate the characteristics of clinical manifestations and genetics of late-onset cobalamin (cbl) C deficiency,also named as combined methylmalonic acidemia and homocystinemia, cblC type. Methods We reviewed 26 late-onset cblC deficiency patients diagnosed in Qilu Hospital, Shandong University from 2012 to 2017 and analysed the clinical, biochemistry, neuroimaging, follow-up and MMACHC gene data. Results Among the 26 patients, male:female ratio is 11:15, with the age of diagnosis from 4 to 39 years and sibling comorbidity in 4 families. The clinical manifestaions of nervous system included spastic paraplegia,mental and behavior disorder,intelectual decline,epilepsy,ataxia,dystonia and peripheral neuropathy. There were four cases with proteinuria at onset. At first visit, the levels of serum total homocystinuria of all patients were elevated, from 61.4 to 193.4μmol/Lwith methylmalonic acidemia. The neuroimaging data of the 26 cases showed 11 with cerebral atrophy, 10 with thoracic spinal cord atrophy, five with brain parenchymal lesions, three with longitudinal myelopathy which were reversible in follow-up, one with syringomyelia, one with multiple cerebral artery stenosis. In all the cases, cobalamins were supplied parenterally and folate, betaine, L-carnitine, vitamin B6 were supplied orally during acute metabolic crisis, and the symptoms of acute encephalopathy disappeared but symptoms of spastic paraplegia had little improvement. In chronic stage, frequency of intramuscular injection of hydroxocobalamine could be decreased while the index can still be improved. All the 26 cases had definite mutations in MMACHC gene, the most common mutations of which were found to be c.482G>A(15/52) and c. 609G>A(13/52). Conclusions Homocystine is the important biomarker for cblC deficiency. Once diagnosed, parenteral hydroxocobalamin and oral betaine should be supplied for a lifetime with good prognosis. The most common mutations of MMACHC gene in our cases are c. 482G>A and c. 609G>A missense mutations.

Pulmonary arterial hypertension as leading manifestation of methylmalonic aciduria: clinical characteristics and gene testing in 15 cases / 北京大学学报(医学版)

Objective:To deepen our understanding of Methylmalonic aciduria (MMA) associated pulmonary hypertension (PH) by analyzing the characteristics of clinical presentation,pulmonary high resolusion CT(HRCT),treatment response and gene mutation.Methods:This study includes 15 cases of pediatric patients with MMA associated PH diagnosed and treated in Peking University First Hospital pediatric department between May 2012 and May 2016 with symptoms of PH as their leading presentation.Clinical symptoms and signs were recorded,Routine blood laboratory examinations was done including arterial blood gas analysis.Plasma total homocysteine (Hcy) and brain natriuretic peptide (BNP) level were measured.MMA gene mutation was analyzed.Chest HRCT was done in most of the patients.Standard treatment strategy to MMA and PH was given and follow up study was done,and the related literature was reviewed.Statistical analysis was done.The diagnosis of MMA was made by methylmalonic acid level ＞ 100 times the normal value in the urine.The diagnosis of PH was made by pulmonary arterial systolic pressure (PASP) ＞ 40 mmHg,which was estimated by the measurement of tricuspid regurgitation velocity through Doppler Echocardiography.Results:(1) Patient characteristics:There were 10 male and 5 female patients diagnosed as MMA associated PH,aged 0.5 to 13.8 years,with an average of (5.0 ± 4.3) years.The age of onset of PH was (3.7 ± 3.5) years,with an early onset type MMA in 5 cases and late-onset type in 10 cases.(2) Clinical presentation:Among the 15 cases of MMA,the first symptoms were associated with PH in 10 cases,so PH and MMA were diagnosed at the same time,and PH was diagnosed 3 to 72 months post MMA presentation in the other 5 cases.The main presentations of PH were techypnea/dyspnea and cyanosis in 11 cases each,weakness and fatigue on exertion in 6 cases,and edema in 4 cases.PH WHO functional classification (WHO FC) was Class Ⅱ in 4,Class Ⅲ in 5 and Class Ⅵ in 6 cases,with an average of Class 3.1 ± 0.8.Multi-system involvements were common with the highest frequency in the kidney (14 cases).Macrocytic anemia was present in 8 cases and subclinical hypothyroidism in 5 cases,and mild to moderate mental retardation in 4 cases.(3) Laboratory examination:PASP of the 15 patients was from 49 to 135 mmHg,with an average of (90.3 ±23.9) mm Hg.Total blood Hcy level was severely elevated to (121.2 ± 48.2) μmol/L (range:35.0-221.0 μmol/L),and Hcy ＞ 100 μmoL/L within 11 cases.Plasma BNP level was also elevated,median 794 ng/ L (range:21.0-4 995.0 ng/L) with 12 cases ＞ 300 ng/L.Blood gas analysis showed low arterial blood oxygen saturation between 70％ and 94％,with an average of 81.4％ ±8.4％.(4) Chest HRCT:chest HRCT showed a diffuse ground-glass centrilobular nodular opacities with septal line thickening in the lungs in 9 cases,and with associated mediastinal lymph node enlargement in 1 case,which indicated pulmonary veno-occlusive disease (PVOD),a rare type of pulmonary arterial hypertension (PAH).There was lung infection or edema in 3 cases,and interstitial infiltration and mesh-like feature in other 3 cases,which was inferred to interstitial lung disease.(5) Gene mutation:Genetic testing was done in 10 cases,totally 5 reported disease-causing mutations were found.There were 100％ presence of MMACHC c.80A ＞ G mutation in all the 10 patients tested,with the allelic genes of c.609G ＞ A mutation in 6 patients,including a sister and a brother from the same parents.(6).Treatment and follow up:Intramus cular hydroxocobalamin or vitamin B12 was given to all of the patients,together with betaine,levocarnidtine,folinic acid and vitamin B6.According to the severity of PH,single or combined PAH targeted drugs was given to 11 cases.By an average of (20.0 ± 13.5) days of in-hospital treatment in 13 patients (excepting 1 case treated as outpatient),symptoms remarkably resolved,WHO FC reduced to an average of Class 2.4 ±0.9,PASP dropped to (69.4 ±21.3) mmHg,and plasma Hcy and BNP level were decreased to (74.9 ± 25.9) μmol/L and (341.6 ± 180.2) ng/L,respectively.The above values all reached statistical significance (P ＜ 0.05) compared with each related value before treatment.Therewere 2 patients who expired during hospitalization despite of treatment.At the end of 3 months' follow up,all of the 13 patients disposed oxygen,and PASP significantly dropped to 38.7 ± 7.9 mmHg,and plasma BNP returned to normal,but plasma Hcy level showed no further decline.At the last follow up of 27.5 ± 19.0 (range:11-64) months,all the patients' PASP remained normal except for the 13.8-year-old boy with 6 years-long history of MMA and almost 3.6 years' history of PH still having PASP 58 mmHg.Conclusion:PH is a severe complication of MMA combined type,especially cblC type,it is more often happens in late-onset type of male patients and can be the first and leading manifestations of MMA.Its clinical symptoms are urgent and severe,characterized by tachypnea/dyspnea and cyanosis,and sometimes right heart failure,hypoxemia is usually present,chest HRCT is often indicative of PVOD,lung edema and interstitial lung disease may occur.Rapid diagnosis and targeted treatment of MMA with appropriate anti-PAH mcdication can reverse PH and save life.MMACHC gene c.80A ＞ G mutation may be the hot point of MMA cblC type associated PH.

Slow weight gain and unremarkably increased urine methylmalonic acid / 中华实用儿科临床杂志

A 2-month-and-20-day-old girl was hospitalized because of slow weight gain for 20 days.The patient was diagnosed as anemia,pneumonia and neutrophils firstly,and showed no improvement during anti-infective therapy,blood transfusion,and leukopenia drugs.The urinary organic acid spectrum of the patient showed increased methylmalonic acid slightly,but the normal value was found by 4 tests,which was inconsistent with the typical methylmalonic aciduria.By analyzing clinical manifestations and plasma homocysteine,folic acid and vitamin B12 levels,she was considered to have intracellular cobalamin metabolic disorder.Then,normal diet,intramuscular injection of vitamin B12,and feeding calcium,betaine,and L-carnitine were given,and the girl's symptoms were improved significantly.Latter gene analysis further showed that the patient had methylmalonic aciduria CblC type.Clinical manifestations of methylmalonic aciduria are complex and individually various,different therapies showed be applied to different causes.The value of urinary methylmalonic acid level alone cannot judge etiology;diagnosis should be based on blood amino acids and carnitine spectrum,homocysteine level and vitamin B12 level.

Hampered Vitamin B12 Metabolism in Gaucher Disease?

Abstract Untreated vitamin B12 deficiency manifests clinically with hematological abnormalities and combined degeneration of the spinal cord and polyneuropathy and biochemically with elevated homocysteine (Hcy) and methylmalonic acid (MMA). Vitamin B12 metabolism involves various cellular compartments including the lysosome, and a disruption in the lysosomal and endocytic pathways induces functional deficiency of this micronutrient. Gaucher disease (GD) is characterized by dysfunctional lysosomal metabolism brought about by mutations in the enzyme beta-glucocerebrosidase (Online Mendelian Inheritance in Man (OMIM): 606463; Enzyme Commission (EC) 3.2.1.45, gene: GBA1). In this study, we collected and examined available literature on the associations between GD, the second most prevalent lysosomal storage disorder in humans, and hampered vitamin B12 metabolism. Results from independent cohorts of patients show elevated circulating holotranscobalamin without changes in vitamin B12 levels in serum. Gaucher disease patients under enzyme replacement therapy present normal levels of Hcy and MMA. Although within the normal range, a significant increase in Hcy and MMA with normal serum vitamin B12 was documented in treated GD patients with polyneuropathy versus treated GD patients without polyneuropathy. Thus, a functional deficiency of vitamin B12 caused by disrupted lysosomal metabolism in GD is a plausible mechanism, contributing to the neurological form of the disorder but this awaits confirmation. Observational studies suggest that an assessment of vitamin B12 status prior to the initiation of enzyme replacement therapy may shed light on the role of vitamin B12 in the pathogenesis and progression of GD.

Subacute Combined Degeneration Caused by Chronic Atrophic Gastritis with Spurious Elevation of Vitamin B12 Level

We report a patient who was diagnosed as subacute combined degeneration (SCD) with elevated homocysteine and methylmalonic acid levels in the situation of a spurious elevation of the vitamin B12 concentration. A false-positive elevation of the vitamin B12 level could lead to a delayed diagnosis and cause irreversible changes in the nervous systems. We therefore suggest that the homocysteine and methylmalonic acid levels should be checked in patients with a normal or elevated vitamin B12 level for whom there is a high clinical suspicion for vitamin B12 deficiency, as a further evaluation for SCD.

Preparation and biodistribution of 2-(5-[18F] fluoro-pentyl)-2-methyl-malonic acid and its clinical application / 中华核医学与分子影像杂志

Objective To synthesize 2-(5-[18 F] fluoro-pentyl)-2-methyl-malonic acid (18 F-ML-10) and to investigate the biodistribution in mice and the primary clinical application.Methods 18F-ML-10 was synthesized by domestic synthesis module MF-2V-IT-1.Quality control of the probe was performed after automated synthesis.The biological characteristics of 18F-ML-10 were assessed by biodistribution assay on male Kunming mice and microPET imaging on a male SD rat.Six patients with brain metastasis (4males,2 females,and age 21-68 years) were enrolled in this study.18F-ML-10 PET images were acquired before and at 48 h after radiotherapy.SUVmean and SUVmax of ROI were calculated.GTV changes were measured by MRI before and 3 months after radiotherapy.Response of brain metastasis to radiotherapy was assessed by PET imaging with 18F-ML-10.Two-sample t test was used.Results The non-corrected radiochemical yield of 18F-ML-10 was (26.5±7.3)％ with acceptable quality.The radiochemical purity exceeded 99％.18F-ML-10 was excreted through the kidneys,and the radiouptake in the blood was declined rapidly.The radiotracer accumulation was low in most of other organs.The testis showed a significant uptake.The SUVmean and SUVmax after radiotherapy (5.54±2.72 and 7.29±3.09) were significantly higher than the baseline values(3.81±1.13 and 4.97±1.05;t=2.670,2.663,both P＜0.05).The GTV after radiotherapy was significantly lower than the baseline value:(13.14±9.39) cm3 vs (23.34± 18.13) cm3;t =3.002,P＜0.05.Conclusions 18F-ML-10 could be synthesized reliably and repeatedly by domestic synthesis module.It has satisfactory properties in vivo and is probably suitable for early assessment of the response to radiotherapy in patients with brain metastasis.

Predictors of Survival in Children With Methymalonic Acidemia With Homocystinuria in Beijing, China: A Prospective Cohort Study.

Objective: (i) To determine whether clinical features and biochemical parameters help to predict survival of methylmalonic acidemia with homocystinuria; (ii) To find the cutoff values of biochemical parameters for predicting survival of methylmalonic acidemia with homocystinuria. Design: A prospective cohort study. Setting: A pediatric tertiary hospital in Beijing; all patients were followed until death or June 2013. Subjects: 45 pediatric patients diagnosed with methylmalonic acidemia with homocystinuria between 2006 and 2012. Outcome measures: The data of clinical characteristics and pretreatment biochemical parameters were collected. The Cox regression analysis was performed to identify independent risk factors for survival of patients with methylmalonic acidemia and homocystinuria. The best cutoff values for these independent factors were determined by the receiver characteristic curve. Results: Newborn onset (OR=6.856, 95%CI=2.241-20.976, P=0.001), high level of methylmalonic acid in urine (OR=1.022, 95%CI=1.011-1.033, P<0.001), and high level of urea in serum (OR=1.083, 95%CI=1.027-1.141, P=0.003) were independent negative risk factors for survival of patients with methylmalonic acidemia and homocystinuria. The cutoff values of maximum predictive accuracy of methylmalonic acid in urine and urea in serum were respectively 5.41 mmol/mmol creatinine and 7.80 mmol/L by receiver operating characteristic curve analysis. Conclusion: The patients of methylmalonic acidemia with homocystinuria tend to have an adverse outcome if they have newborn onsets. Elevated urea and urinary methylmalonic acid are predictors of adverse outcomes for the patients. They show similar effect for predicting severe adverse prognosis. The combination of methylmalonic acid in urine concentration and urea in serum concentration provided the most accurate predictive tool.

Clinical characteristics of 12 cases with methylmalonic acidemia / 中国基层医药

Objective To investigate the clinical characteristics of methylmalonic acidemia.Methods Methylmalonic acidemia diagnosis and treatment of 12 cases of clinical data were collected,the clinical manifestations,laboratory examinations,gas chromatography/tandem mass spectrometry analysis of the measurement results of urine organic acids,blood gas analysis,glucose,lactic acid,ammonia and other characteristics were sumarized,and the clinical features and outcome of the situation were also sumarized.Results 1 year old first visit eight cases,12 cases,8 cases from rural areas;12 cases of major treatment complained of anorexia,poor spirit hospitalized one case;respiratory infection hospitalized five cases; seizure hospitalized three cases;weight gain admission,one case;vomiting admitted three cases,three cases of drowsiness,coma admitted one case,the movement behind the main complaint admitted two cases.After hospitalization check urine organic acid analysis found significantly increased methylmalonic acid,respectively,while ammonia,lactic acid increased,high blood sugar,high uric acid,low albumin,urine protein abnormalities,abnormal urine ketone bodies,abnormal increased anion gap,video science and abnormal electrophysiological examination.Diagnosed with methylmalonic acidemia,according to the case were given VitB12,betaine,folic acid,L-carnitine,limiting protein intake and other treatment.Symptomatic treatment improved in seven patients,two patients were lost;automatically discharged one case,two cases of death.Conclusion Methylmalonic acidemia based on clinical characteristics,so early detection,early diagnosis,early treatment will help to improve prognosis.