Analysis The Gene Types And Clinical Feature Of50Newborns With Primary Carnitine Deficiency

Objective:To explore the incidence, gene types and clinical feature of primary carnitine deficiency （PCD）, and provide the support for early diagnosis of PCD.Methods:We found all the neonates who were screened by tandem mass spectrometry technology during the period January2009to December2014in the Children’s Hospital, Zhejiang University School of Medicine, and recalled the cases who had PCD or were the carriers. And recorded the data of sex, gestational weeks, birth weight, the first screen of plasma free carnitine concentration, the dose of drugs, the time when plasma free carnitine concentration back to normal, mother’s age and plasma free carnitine level, family history, clinical manifestation, physical and laboratory examination, ECG and Imaging, gene tests’ result, follow-up time, prognosis and so on.Results:1. During the period,1,119,198neonates were screened, and50neonates were diagnosed of PCD, the incidence is about1:22,384. Among50PCD neonates, there are48term infants and2premature infants, the male female ratio is about1:1.38, average gestational weeks is38+weeks, average birth weight is3270g, average age of drawing blood is3.7days, and mothers’ average age is28.1years. Among27 carriers, all of them are term infants, the male female ratio is1:1.07, average gestational weeks is39+weeks, average birth weight is3300g, average age of drawing blood is3.6days, and mothers’ average age is28.5years.2. There are33PCD neonates finished the gene tests, and find23different mutation types,67different mutant sites, almostly in exon1/4/8. There are11known pathogenic mutations, c.1400C> G（p.S467C）, c.760C> T（p.R254X）, c.51C> G（p.F17L）, c.865C<T（p.R289X）, c.1195C>T（p.R399W）, c.338G> A（p.C113Y）, c.845G> A（p.R282Q）, c.428C> T（p.P143L）, c.1433C> T（p.P478L）, c.505C> T（p.R169W） and c.652+1G>A, and12new mutations, c.308T> G（p.V103G）, c.1505C> A（p.T502K）, c.1445A> G（p.Y482C）, c.538C> G（p.Q180E）, c.1427T> C（p.L476P）, c.40T>A（p.W14R）, c.1362T> G（p.Y454X）, c.1252C>T（p.Q418X）, c.42G> A（p.W14X）, c.498-2A> G, c.507de1G（p.R169RfsX5）, c.252₂65dup14（p.189TfsX46）. Among them, c.1400C> G（p.S467C） has the highest mutation frequency34.3%, and then the c.760C> T（p.R254X）（19.4%） and c.51C> G（p.F17L）（11.9%）.3. There are6carriers and their mothers finished the gene tests. Among mothers,4different mutation types,12different mutant sites have been found. Besides one new mutation （c.497+1G> T）, there are3known pathogenic mutations, c.1400C> G（p.S467C）, c.760C> T（p.R254X） and c.51C> G（p.F17L）. Among them, c.1400C> G（p.S467C） is the most common mutation （75%）. Among6carriers,4of them have c.1400C> G（p.S467C）, the other2have c.51C> G（p.F17L） or c.760C> T（p.R254X）. The most common mutation is also c.1400C> G（p.S467C）（66.7%）.4. The average of first screen plasma free carnitine concentration is [（7.70±2.70）μmol/L] in PCD group, and carrier group is [（6.43±2.33）μmol/L], both of them are below the normal. The concentration of plasma free carnitine before treatment in PCD group is progressively declined, while the carrier group is gradually rising （p=0.000）. And the recover time of PCD group is significantly longer than carrier group（p=0.000）.5. Except8failure to follow-up and2therapy discontinued, PCD group have no symptoms. However,16carriers’ mothers complained about leg pain, fatigue or hypoglycemia.6. The average follow-up time in PCD group is about19.7m. There’re2infants failed to follow doctors’advice and therapy discontinued, one of them died suddenly, the other died of Reye syndrome like encephalopathy after infection.7. Homozygote and heterozygote have no significant difference between first screen plasma free carnitine level, recover time and clinical features.Conclusion:1. PCD is one of most common fatty acid metabolic disorder diseases. In our province, the neonates’incidence of PCD is higher than other similar studys.2. The most common mutations of PCD neonates are c.1400C> G（p.S467C）, c.760C>T（p.R254X） and c.51C>G（p.F17L）. The majority is in exonl/4/8. And the most common mutation of PCD mothers is c.1400C> G（p.S467C）.3. We couldn’t distinguish PCD and carriers only by first screen of lower plasma free carnitine concentration. However, the normal or slightly less than normal of mothers’plasma free carnitine concentration, progressively declined plasma free carnitine before treatment and longer recover time may refer to PCD.4. Early diagnosis, regularly treatment and longtime follow-up means well prognosis. Therapy discontinued may induce severe clinical issues.5. There’s no definite relation between the genotype and phenotype.