Diagnosis of mitochondrial trifunctional protein deficiency in a blood spot from the newborn screening card by tandem mass spectrometry and DNA analysis

被引:42
作者
Matern, D
Strauss, AW
Hillman, SL
Mayatepek, E
Millington, DS
Trefz, FK
机构
[1] Duke Univ, Med Ctr, Div Med Genet, Dept Pediat, Durham, NC 27710 USA
[2] Washington Univ, Dept Pediat, St Louis, MO 63130 USA
[3] Washington Univ, Dept Mol Biol & Pharmacol, St Louis, MO 63130 USA
[4] Univ Heidelberg, Dept Gen Pediat, D-6900 Heidelberg, Germany
[5] Childrens Hosp, Reutlingen, Germany
关键词
D O I
10.1203/00006450-199907000-00008
中图分类号
R72 [儿科学];
学科分类号
100202 ;
摘要
Trifunctional protein (TFP) plays a significant role in the mitochondrial beta-oxidation of long-chain fatty acids. Its deficiency impairs the energy generating function of this pathway and causes hypoketotic hypoglycemia once hepatic glycogen stores are depleted. A Reye-Like syndrome, cardiomyopathy, and sudden death may follow. The diagnosis is based on demonstration of significantly decreased enzyme activity of at least two of the three involved enzymes in fibroblasts. The possibility of prospective diagnosis of TFP deficiency by newborn screening using tandem mass spectrometry (MS/MS) has not been evaluated. We report the postmortem diagnosis of a male newborn, who suffered sudden death at 2 wk of age, and his younger sister,who died of cardiomyopathy complicated by acute heart failure at the age of 6 mo, after she had acquired a common viral infection. Blood spots from the original newborn screening cards were the only remaining material from the patients. Analysis by MS/MS revealed acylcarnitine profiles consistent with either TFP or long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency. To prove the diagnosis, the alpha- and beta-subunit genes coding for TFP were examined. The patients were compound heterozygous for a 4-bp-deletion and an a --> g missense mutation, both in the same exon 3 donor consensus splice site. This is the first report of the diagnosis of TFP deficiency using blood spots obtained for newborn screening and suggests that TFP deficiency may be detectable by prospective newborn screening using MS/MS.
引用
收藏
页码:45 / 49
页数:5
相关论文
共 28 条
[1]   2 ALPHA-SUBUNIT DONOR SPLICE-SITE MUTATIONS CAUSE HUMAN TRIFUNCTIONAL PROTEIN-DEFICIENCY [J].
BRACKETT, JC ;
SIMS, HF ;
RINALDO, P ;
SHAPIRO, S ;
POWELL, CK ;
BENNETT, MJ ;
STRAUSS, AW .
JOURNAL OF CLINICAL INVESTIGATION, 1995, 95 (05) :2076-2082
[2]   SIDS and disorders of fatty acid oxidation: Where do we go from here? [J].
Cederbaum, SD .
JOURNAL OF PEDIATRICS, 1998, 132 (06) :913-914
[3]  
Chace DH, 1996, CLIN CHEM, V42, P349
[4]  
CHACE DH, 1995, CLIN CHEM, V41, P62
[5]  
CHACE DH, 1993, CLIN CHEM, V39, P66
[6]  
Chace DH, 1997, CLIN CHEM, V43, P2106
[7]   Improved detection of the G1528C mutation in LCHAD deficiency [J].
Ding, JH ;
Yang, BZ ;
Nada, MA ;
Roe, CR .
BIOCHEMICAL AND MOLECULAR MEDICINE, 1996, 58 (01) :46-51
[8]   Neonatal lethal mitochondrial trifunctional protein deficiency mimicking a respiratory chain defect [J].
Grunewald, S ;
Bakkeren, J ;
Wanders, RA ;
Wendel, U .
JOURNAL OF INHERITED METABOLIC DISEASE, 1997, 20 (06) :835-836
[9]   MOLECULAR-BASIS OF LONG-CHAIN 3-HYDROXYACYL-COA DEHYDROGENASE-DEFICIENCY - IDENTIFICATION OF THE MAJOR DISEASE-CAUSING MUTATION IN THE ALPHA-SUBUNIT OF THE MITOCHONDRIAL TRIFUNCTIONAL PROTEIN [J].
IJLST, L ;
WANDERS, RJA ;
USHIKUBO, S ;
KAMIJO, T ;
HASHIMOTO, T .
BIOCHIMICA ET BIOPHYSICA ACTA-LIPIDS AND LIPID METABOLISM, 1994, 1215 (03) :347-350
[10]   Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency - Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene [J].
Ijlst, L ;
Ruiter, JPN ;
Hoovers, JMN ;
Jakobs, ME ;
Wanders, RJA .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 98 (04) :1028-1033