ABSTRACT
Objective To improve the understanding of clinical phenotype and genotype of multiple acyl-CoA dehydrogenase deficiency (MADD) in neonates.Method The clinical data of a neonates with the diagnosis of MADD and treated in the Neonatal Department of Children's Hospital of Capital Institute of Pediatrics in December 2016 were analyzed.The literature collected from Wanfang database,CNKI and PubMed database from 1976 January to 2017 June was retrieved.Using "glutaric acidemia type Ⅱ ","multiple acyl CoA dehydrogenase deficiency","infant" and "neonate" as the key words.The phenotype and genotype characteristics were summarized.Result This boy was a full-term low birth weight infant with abnormal family history.He was admitted to hospital with recurrent episodes of poor response,respiratory distress and hyperlactacidemia.B-mode ultrasound abdominal examination suggested polycystic kidney disease.Laboratory tests revealed non-kenotic hypoglycemia,refractory metabolic acidosis,elevated lactate and muscle enzymes,hyperammonemia,abnormal coagulation function test.Mass spectrometry analysis showed that multiple acyl-carnitine increased.Urine gas chromatography-mass spectrometry showed significantly increased levels of lactic,glutaric,2-hydroxypentanedioic,dicarboxylic,and 4-hydroxybenzene lactic acids.The infant was given high doses of vitamin B2,L-carnitine,and other symptomatic treatments,but the condition did not improve.He died 5 days later.The gene test showed ETFDH gene compound heterozygous mutations,one missense mutations from the father with normal phenotype c.770A ＞ G (p.Y257C),a frameshift mutation from the mother with normal phenotype c.1281-1282 deletion mutation of AA (p.I428Rfs6).The protein structures of the mutations were predicted to be deleterious.Frameshift mutation c.1281-1282 deletion mutation of AA (p.I428Rfs6) were not included in the gene bank.A total of 21 cases with MADD were found from the literature.The clinical characteristics including:male (76.2％),dyspnea (52.4％),poor response (52.4％),hypoglycemia (47.6％),hepatomegaly (47.6％),elevated muscle enzymes (42.9％),immediate onset within 24 hour of birth (42.9％),abnormal family history (38.1％),malformation (38.1％),hyperammonemia (33.3％),metabolic acidosis (28.6％).81.0％of the patients were given vitamin B2 treatment,71.4％ of carnitine,28.6％ of coenzyme Q10,28.6％ of low fat,low protein and high carbohydrate feeding.However,the prognosis of these patients was poor,76.2％ died,and 42.9％ died within 1 week after birth,and 23.8％ survived.But all showed different degrees of mental retardation during follow-up periods.Conclusion Neonatal onset MADD can be characterized by dyspnea,poor response,hypoglycemia,hepatomegaly and elevated muscle enzymes.The disease is more common in early male neonates.It can be treated with vitamin B2 and L-carnitine,but with poor prognosis and high mortality.In this case,there were 2 sites in the ETFDH gene that formed complex heterozygous mutation:c.770A ＞ G (p.Y257C) and c.1281-1282 deletion mutation of AA (p.I428Rfs6),while the latter is a new mutation.
ABSTRACT
Objective To report the spectrum of electron transfer flavoprotein dehydrogenase (ETFDH)gene mutations in 20 Chinese RR-LsM families.Methods Twenty-four RR-LSM patients in the First Hospital of Peking University from January 2003 to May 2010 were collected and the clinical characteristics were analyzed.These patients came from 20 families in North Mainland China.Sixteen families had 1 patient each.and the other 4 families had 2 patients.ETFDH gene analysis was performed in all patients,11 family members and 100 healthy controls.Results The mean onset age was(27.9±9.9)years.The main symptoms were limb weakness(21,87.5%),dysmasesia(15,62.5%),neck weakness (14,58.3%)and myalgia(14,58.3%).Eighteen patients had high level of acyleamitine.Fifteen of 17patients had glutaric aciduria.Seventeen ETFDH mutations,including 13 missense mutations,2 splice mutations,and 2 nonsense mutations,were identified in 19 families:c.998A>G,c.1450T>C,c.1703T>C,c.1717C>T,c.821G>A,c.643G>A,c.251C>T,c.1763A>T,c.IVS7+2T>C and c.IVS6+1G>A were Hovel mutations which were not found in 100 healthy controls.Nine families had the mutation of c.770A>G(P.Y257C)and 5 families had the mutation of c.1227A>C(P.L409F).Conclusions The numerous novel mutations in ETFDH gene indicate that Chinese RR-LSM might have special mutation pattern.c.770A>G(P.Y257C)and c.1227A>C(p.L409F)may be hot spot mutations in North Mainland China.
ABSTRACT
Objective To investigate the clinical features and electron transfer flavoprotein dehydrogenase (ETFDH) gene mutations in 35 Chinese patients with lipid storage myopathy. Methods The clinical data of 35 cases with lipid storage myopathy confirmed by muscle biopsy were collected. The sequences of all 13 exons of ETFDH were analyzed. Results All 35 patients showed proximal weakness. Ten of them demonstrated masseter weakness and 28 of them showed weakness in neck flexion. Twenty-nine of 32 patients who were followed up showed improvement after treatment with VitB2 and CoQ10. Mutations of ETFDH were found in 30 of 35 patients,which included 8 homozygosises,20 compound heterozygosises and 2 single heterozygosises. Fourteen novel mutations were found, including 9 missense mutations ( c. 3G > C, c. 152G>A, c. 191G > A, c.349G>C, c.433G>C, c. 949C > A, c. 1454C > G, c. 1744A >T and c. 1763A>G), 1 nonsense mutation(c. 172G>T), 2 deletions(c. 1282_1283del and 1773_1774del) and 2 splice mutations (c. 405 + 1G > T and c. 1691 -3C > G). Nine of them showed c. 250G > A mutation and 6 of them showed c. 770A > G mutation. Conclusions Lipid storage myopathy is presented as proximal weakness. Multiple acyl-CoA dehydrogenase deficiency caused by mutations of ETFDH is the major cause of lipid storage disease in this group. ETFDH c. 250G > A and c. 770A > G mutations show a high frequency.