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Objective:To observe the effect of Dredging Correcting Manipulation on cblC methylmalonic aciduria (MMA). Methods:From October, 2017 to October, 2018, 72 children with cblC MMA combined with growth retardation were divided into control group (n = 36) and experimental group (n = 36) according to the consent of their parents. The control group accepted routine medicine, and the experimental group received Dredging Correcting Manipulation in addition. The Griffiths Development Scale-Chinese version (GDS-C) was used to evaluate the two groups before and after treatment. At the same time, body length, body mass and head circumference were measured. Results:Six cases in the control group and five cases in the experimental group were dropped out. There was no significant difference in the development quotients of GDS-C in gross movement, personal and social, hearing and speech, hand-eye coordination, operation and total quotient between two groups before treatment (P > 0.05). After treatment, all the development quotients increased in both groups (t > 6.110, P < 0.001), and the development quotients of GDS-C in gross movement, personal and social, hand-eye coordination and total quotient were higher in the experimental group than in the control group (t > 2.154, P < 0.05), as well as the body length (t = 2.027, P < 0.05). Conclusion:Dredging Correcting Manipulation can promote the neuropsychological and physical development of children with cblC MMA combined with retardation.
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Abstract Genetic homocystinurias are a group of inborn errors of metabolism that result in the massive excretion of homocysteine (Hcy) in the urine due to Hcy accumulation in the body, usually causing neurological and cardiovascular complications. The three most frequent causes are classical homocystinuria [deficiency of cystathionine beta-synthase (CBS)], methylmalonic aciduria with homocystinuria, cblC type (cblC deficiency) and severe methylenetetrahydrofolate reductase (MTHFR) deficiency. In this review, we highlight the similarities and differences among these disorders. Briefly, their joint manifestation is the accumulation of tHcy, however, the other sulfur amino acids show various and even invers profiles. Vascular disease, developmental delay and seizures are found in all homocystinurias, nevertheless, the complications of CNS differ in a wide variety of presentations and severities and are apparently less pronounced in CBS deficiency. Moreover, patients with remethylation defects typically do not present ectopia lentis and bone disturbances, tall stature and osteoporosis. Whereas hematological alterations, such as megaloblastic anemia, thrombocytopenia neutropenia and life-threatening microangiopathy, are specific findings of cblC deficiency.
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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.
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Objective To summarize the experience of the ventriculoperitoneal shunt in treating children with methylmalonic aciduria combined with hydrocephalus,and to assess the clinical value.Methods From September 2012 to May 2016,a total of 12 patients with methylmalonic aciduria combined with hydrocephalus in Peking University First Hospital were enrolled,including 7 boys and 5 girls.All the 12 patients underwent ventriculoperitoneal shunt.Drug therapy was performed after surgery.The clinical manifestations and imaging findings were used as the basis for adjusting the pressure of the diverter valve appropriately.The clinical condition of patients were evaluated retrospectively.The patients' clinical symptoms,signs,imaging materials,surgical complications and postoperative prognosis were analyzed.Results All the cases were followed up for 3 to 36 months,no death case and no serious postoperative complications of hydrocephalus occurred.Clinical symptoms of intracranial hypertension were relieved or disappeared.The head circumference progressive enlargement stopped.The anterior fontanelle tension decreased significantly.Setting-sun sign of eyes disappeared.One out of 4 cases with convulsion and epilepsy was relieved after the operation.Seven cases of poor vision or vision loss,postoperative visual acuity were improved though not recover to normal eyesight.One case of the children with hearing loss,postoperative hearing recovered.During the follow-up period,the head CT showed that the ventricle was narrowed significantly,interstitial brain edema improved obviously.Conclusion Ventriculoperitoneal shunt is a effective method for treating children with methylmalonic aciduria combined with hydrocephalus,which is beneficial for patients with these diseases.
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Objective Mitochondrial DNA depletion syndrome is a rare autosomal recessive disorder characterized by complex genetic and clinical manifestations.This study aimed to investigate the clinical and laboratory features of a boy with mitochondrial encephalomyopathy caused by SUCLG1 mutation.Methods The clinical data and genetic test of a patient with mitochondrial DNA depletion syndrome were retrospectively analyzed.Result The proband presented with limb weakness at the 4th month after birth,and presented dystrophic appearance,muscular hypotonia,psychomotor retardation,failure to thrive,hearing impairment,scoliosis,thoracocyllosis and facial features at 9 months old.Laboratory tests showed blood lactic acid and pymvate increased,liver damage and abnormal myocardial enzymes.Plasma camitine ester profiling showed that amino acids decreased and C4-dicarboxylic-carnitine increased.Urinary organic acid analysis showed increased concentration of methylmalonic acid and its metabolites indicating methyl malonic aciduria.MRI showed bilateral T2 hyperintensities in bilateral caudate nuelei and lenticular and brain atrophy-like changes.Brainstem auditory evoked potential showed severe hearing loss.His development quotient was 35.Genetic sequencing of MUT,,MMAA,MMAB and other classic mitochondrial disease related genes of the proband revealed no mutation.Two heterozygous mutations,c.961C＞G and c.713T＞C,inherited from the phenotype of normal parents were detected in his SUCLG1 gene.The copy number of mitochondrial DNA was 244/cell in peripheral blood leukocytes,equivalent to 68.4％ of that in normal control.Conclusion In this study,an infant with muscular hypotonia,psychomotor retardation,deafness and slightly increased urine methyl malonic acid was diagnosed by genetic test.For patients with unexplained hypotonia,mental retardation,abnormal movements,hearing disorder together with increased blood pyruvic acid and lactic acid,mild methylmalonic acidemia and abnormal acylcarnitine,mitochondrial DNA depletion syndrome should be considered.Gene analysis is important for diagnosis and prenatal diagnosis of the next pregnancy.
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Objective To analyze the clinical features and gene mutation in mthylmalonic acidemia (MMA) accompanied by homocysteinemia (cblC), and review the relevant literatures. Methods The clinical features of 3 cases of MMA diagnosed by gene detection were retrospectively analyzed, and meanwhile the pertinent literatures of pathogenesis of MMA, especially combined with late-onset cblC and its gene detection, were reviewed. Results Patient 1 (26 days old) suffered from intermittent convulsions for 3 days, with isosuccinic acid 175.8 μmol/L, C3/C2 rate 1.363, homocysteine >?65 μmol/L and abnormal EEG. MMACHC gene detection found an exon deficiency (delEXON1), which has not been reported. Patient 2 ( 12 year old) was hospitalized for limb shaking, hyperspasmia and vomiting. His isosuccinic acid level was 334.3 μmol/L, C3/?C2 rate was 0.37, homocysteine >?65 μmol/L, and had abnormal EEG. MMACHC gene detection found the mutations of c.482G?>?A and c.609G?>?A. Patient 3 was hospitalized for intermittent convulsions for 20 days, whose isosuccinic acid, C3/?C2 rate, and homocysteine were increased. MMACHC gene detection found the mutations of c.394C?>?T and c.540del8 and c.540del8 had not been reported. Review of literatures discovered that MMA was combined with epileptic seizure in some patents, which further validate that the mutation in MMACHC gene c.482G?>?A may be related to the late-onset of cblC. Conclusions Gene detection contributes to the diagnosis of MMA; the mutation of MMACHC gene c.482G>A may be related to the late-onset of cblC; delEXON1 and c.540del8 are new mutations which have not been reported.
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Objective To explore the diagnosis and treatment of a rare case of methylmalonic aciduria combined with congenital adrenal hyperplasia. Methods The clinical and laboratory data of the first case of methylmalonyl CoA mutase deifcient methylmalonic aciduria combined with 21-hydroxylase deifciency in China were analyzed. Results The male patient with age of onset at 3 months presented with feeding dififculty, diarrhea, metabolic acidosis, and psychomotor retardation after polio vaccination or high protein diet. At one year and 8 months of age, methylmalonic aciduria was diagnosed, and the patient was clinically improved after treatment. At 5 years of age, precocious puberty was noticed, and virilizing form of 21-Hydroxylase deifciency was diagnosed. Genetic testing conifrmed 2 known mutations in MUT gene (c.866G?>?C, c.2179C?>?T) and 2 known mutations in CYP21A2 gene (c.188A?>?T, c.518T?>?A). Conclusions The clinical manifestations of inherited metabolic disorders and endocrine diseases are complex and it is rare that multiple disorders occurred simultaneously in one patient. This male patient has two rare diseases, methylmalonic aciduria and 21-hydroxylase deifciency.
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Objective To investigate the clinical,biochemical and genetic findings in patients with isolated methylmalonic aciduria. Methods From January 2001 to December 2014,a total of 126 patients with isolated methyl-malonic aciduria from Peking University First Hospital were enrolled in this study. In 60 patients,gene analysis was per-formed. The clinical characteristics,laboratory findings,treatment and outcomes were retrospectively analyzed. Results Among the 126 patients,only 3 cases(2. 4% )were detected through newborn screening and treated with dietary in-tervention,cobalamin and L - camitine. The age at onset of 123 cases(97. 6% )varied from a few hours after birth to 7 years and 11 months old. The common presentations were recurrent vomiting,mental retardation,poor feeding,lethargy, respiratory distress,coma,seizures,cutaneous lesion and jaundice with 11 patients(8. 73% )dead. Abnormal family his-tory was found in 27(21. 4% )patients. Metabolic acidosis and anemia were frequent laboratory findings. Basal ganglia damage and white matter changes were observed in most patients. Sixty patients got genetic analysis,and 58 cases of them had MUT gene mutations. One case had MMAA defect. One case had MMAB defect. In MUT gene,12 novel muta-tions were identified. After treatment,mild to severe psychomotor retardation was observed in 112 patients with isolated methylmalonic aciduria. Conclusions The clinical manifestation of patients with isolated methylmalonic aciduria is complex,and prone to appear metabolic crisis. MUT defect is the main cause. Early metabolic investigation is very im-portant to reach diagnosis. Newborn screening,early diagnosis and adequate therapy are key points to reduce the morta-lity and handicap.
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Methylmalonic aciduria (MMA) is a common inherited autosomal recessive disorder resulting from defects in the enzyme methylmalonyl CoA mutase (MCM,mut complementation group) or in the synthesis of the MCM cofactor adenosylcobalamin (cbl complementation groups).The defects in the mut complementation group accounts for the largest number of patients with isolated MMA.At least 200 mutations in the MUT gene on chromosome 6p12 have been identified in MMA patients until now.This study aimed to investigate the clinical characteristics of MMA and genomic variations in the MUT gene of Chinese patients.Genomic DNA was extracted from 18 patients who were diagnosed as having isolated MMA by gas chromatography/mass spectrometry (GC-MS),and from some of their parents as well.Amplification and direct sequencing of the MUT coding regions (exon 2-13) and their adjacent intronic consensus splice sites were performed in order to identify the disease causing mutations.In this group,six novel mutations in the MUT gene,c.424A＞G (p.T142A),c.786T＞G (p.S262R),c.808G＞C(p.G270R),c.1323_1324insA,c.1445-1G＞A and c.1676+77A＞C were identified.p.T142A and p.G270R were respectively detected at a heterozygous level in one patient.Two previously reported mutations,c.682C＞T (p.R228X) and c.323G＞A (p.R108H) were also found in this study.In addition,six previously described single nucleotide polymorphism (SNP),c.636A＞G (p.K212K),c.1495G＞A(p.A499T),c.1595A＞G (p.H532R),c.1992G＞A (p.A664A),c.2011G＞A (p.V671I) and c.1677-53A＞Gwere identified.In this study,we updated the spectrum of MUT mutations and identified the main MMA-causing mutations in Chinese MMA patients.
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PURPOSE: Methylmalonic aciduria (MMA) and propionic aciduria (PA) are inborn errors in the catabolism of branched-chain amino acids. The study was undertaken to investigate the genotypes and clinical features of Korean patients with MMA and PA. METHODS: This study examined 12 patients with MMA and eight with PA. We analyzed various clinical features, laboratory findings, treatments, and neuro-developmental outcomes. Diagnoses were based on the presence of characteristic compounds detected by amino acid analysis in serum and organic acid analysis in urine. Mutation analysis was performed in the genes of MUT, MMAA, MMAB, and MMACHC for MMA and PCCA and PCCB for PA. RESULTS: Among the 20 patients, six patients were diagnosed before one month of age and nine patients were diagnosed after the newborn period. Five patients were diagnosed via a neonatal screening test. Patients with early-onset forms had more severe illness at presentation and generally poor outcomes. A favorable outcome was obtained in 55% patients; most of them were of a late-onset type or diagnosed by neonatal mass screening test without symptoms. Genotypes were confirmed in all patients with MMA. We detected 11 different mutations by MUT gene analysis in 10 patients, and three different mutations in MMACHC genes in two patients. PCCA and PCCB gene mutations were identified in 14 of the 16 alleles, in eight patients with PA. CONCLUSION: Organic aciduria is a fatal disease; however, better outcomes are expected whenever early diagnosis and prompt management are made possible. Mutation analysis is useful for confirming diagnoses and planning management strategies.
Subject(s)
Humans , Infant, Newborn , Alleles , Amino Acids, Branched-Chain , Chromones , Diethylpropion , Early Diagnosis , Genotype , Mass Screening , Neonatal Screening , Propionic AcidemiaABSTRACT
PURPOSE: Methylmalonic aciduria (MMA) and propionic aciduria (PA) are inborn errors in the catabolism of branched-chain amino acids. The study was undertaken to investigate the genotypes and clinical features of Korean patients with MMA and PA. METHODS: This study examined 12 patients with MMA and eight with PA. We analyzed various clinical features, laboratory findings, treatments, and neuro-developmental outcomes. Diagnoses were based on the presence of characteristic compounds detected by amino acid analysis in serum and organic acid analysis in urine. Mutation analysis was performed in the genes of MUT, MMAA, MMAB, and MMACHC for MMA and PCCA and PCCB for PA. RESULTS: Among the 20 patients, six patients were diagnosed before one month of age and nine patients were diagnosed after the newborn period. Five patients were diagnosed via a neonatal screening test. Patients with early-onset forms had more severe illness at presentation and generally poor outcomes. A favorable outcome was obtained in 55% patients; most of them were of a late-onset type or diagnosed by neonatal mass screening test without symptoms. Genotypes were confirmed in all patients with MMA. We detected 11 different mutations by MUT gene analysis in 10 patients, and three different mutations in MMACHC genes in two patients. PCCA and PCCB gene mutations were identified in 14 of the 16 alleles, in eight patients with PA. CONCLUSION: Organic aciduria is a fatal disease; however, better outcomes are expected whenever early diagnosis and prompt management are made possible. Mutation analysis is useful for confirming diagnoses and planning management strategies.