Alternative titles; symbols
ORPHA: 157, 228308; DO: 0060235;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p32.3 | CPT II deficiency, lethal neonatal | 608836 | Autosomal recessive | 3 | CPT2 | 600650 |
A number sign (#) is used with this entry because the lethal neonatal form of carnitine palmitoyltransferase II (CPT2) deficiency is caused by homozygous or compound heterozygous mutation in the CPT2 gene (600650) on chromosome 1p32.
Carnitine palmitoyltransferase II deficiency is an inherited disorder of mitochondrial long-chain fatty acid oxidation. The neonatal form presents shortly after birth with respiratory distress, seizures, altered mental status, hepatomegaly, cardiomegaly, cardiac arrhythmia, and, in many cases, dysmorphic features, renal dysgenesis, and migration defects. This form is rapidly fatal (summary by Longo et al., 2006).
See also the infantile (600649) and adult-onset (255110) forms of the disorder, which are also caused by mutation in the CPT2 gene.
The lethal neonatal form was recognized by Hug et al. (1989, 1991) and Zinn et al. (1991), who described infants who died in the first days of life. The patient reported by Hug et al. (1989, 1991), who presented on day 2 of life with hypothermia and lethargy, was found to have hepatomegaly, cardiomegaly, and hypoglycemia. Neurologic signs developed, including seizures, hypotonia, and hyperreflexia, as did cardiac arrhythmias. The patient died suddenly at age 5 days. Laboratory analysis showed decreased serum and tissue total and free carnitine and increased serum and tissue long-chain acylcarnitines. CPT II activity was severely decreased (less than 10%) in multiple tissues and in cultured fibroblasts.
Taroni et al. (1994) reported a premature Haitian infant who presented at birth with respiratory distress, cardiac arrhythmia, and heart failure, and died on day 4 of life. Postmortem examination showed a hypertrophied, dilated heart and lipid accumulation in liver, heart, and kidney. The brain showed polymicrogyria in the occipital lobe and evidence of intracerebral hemorrhage. CPT II residual activity was measured at less than 15% of normal control values.
North et al. (1995) reported a similar patient who died at day 10 of life. Associated dysmorphic features were noted, including microcephaly, a high sloping forehead, overfolded helices, long and tapered fingers and toes, contractures, and hypoplastic toenails. Postmortem examination showed lipid accumulation in multiple tissues, including liver, kidney, and skeletal muscle. In the brain, the cingulate gyrus was abnormal and several cysts were identified. The kidneys were markedly enlarged with multiple cysts and dysplastic parenchyma. There was an increase in long-chain fatty acids in the serum and urine, and an increase in long-chain acylcarnitines in all tissues examined. The patient also showed hyperammonemia. A profound decrease in CPT II activity (average less than 10% of normal) was detected in several tissues.
Land et al. (1995) described a female infant with CPT II deficiency who developed respiratory difficulty at 1 hour of age and died at 34 days of age. The child had a normal fasting ketotic response, and liver mitochondria contained appreciable amounts of total CPT activity, a substantial portion of which was insensitive to the addition of malonyl-CoA, and thus likely to be CPT2. Although there was negligible CPT2 activity in skeletal muscle, the amount detected by immunoblot from the skeletal muscle was considerable. The authors suggested that this reflected a lethal functional but conservative structural mutation of the enzyme protein.
Pierce et al. (1999) reported an infant with neonatal lethal CPT II deficiency. He presented on the first day of life with nonketotic hypoglycemia, seizures, hepatomegaly, cardiomegaly with biventricular hypertrophy, and ventricular arrhythmias. Cranial ultrasound showed cystic dysplasia with several foci of hyperechogenicity within the right basal ganglia. Free carnitine was markedly decreased in the urine and plasma with a pronounced elevation of plasma long-chain acylcarnitines. Fibroblast CPT II activity was reduced to 26% and 38% in the father and mother, respectively. The infant died on day 5 from malignant ventricular tachyarrhythmias. Postmortem examination showed diffuse lipid accumulation in the liver, heart, kidney, adrenal cortex, skeletal muscle, and lungs.
Elpeleg et al. (2001) reported 2 Ashkenazi Jewish sibs with the antenatal form of CPT II deficiency. The first sib was a male in whom fetal screening at 23 weeks revealed absence of the corpus callosum, ventriculomegaly, intracerebral periventricular calcifications, markedly enlarged polycystic kidneys, and cardiomegaly with a thickened myocardium. At birth, he showed a high-arched narrow palate, mild generalized hypotonia, and decreased responsiveness. He developed renal insufficiency, hepatomegaly with diffuse macrovesicular steatosis, feeding difficulties, metabolic acidosis, increased serum creatine kinase, and decreased serum carnitine. Urinary organic acid analysis showed severe nonketotic dicarboxylic aciduria. He died at age 43 days. Activity of CPT II in lymphocytes was undetectable. A younger affected sib was identified by fetal ultrasound screening.
Sharma et al. (2003) reported a term male newborn who developed hypothermia, cardiac dysarrhythmia, and hyperkalemia within 24 hours of birth. Cystic renal dysplasia had been identified prenatally. Other features included hypotonia, poor feeding, renal insufficiency, and respiratory failure. Death occurred on day 12 of life, and postmortem examination confirmed lethal neonatal CPT II deficiency.
Isackson et al. (2008) reported an African American patient with lethal neonatal CPT II deficiency. The infant appeared normal at birth but developed hypoglycemia and hyperammonemia in the nursery. She also had heart block, polycystic kidneys, and seizures, and she died at age 14 days. Laboratory studies showed significantly increased plasma carnitine species. Genetic analysis revealed a homozygous mutation in the CPT2 gene (P227L; 600650.0013).
Prenatal Diagnosis
Witt et al. (1991) performed prenatal diagnosis using fetal ultrasound, which detected polycystic kidneys, and oxidation studies on amniocytes, which showed less that 5% CPT II activity. In addition, long-chain acylcarnitine levels in fetal tissues were elevated.
Elpeleg et al. (2001) achieved successful prenatal diagnosis of antenatal CPT II deficiency by ultrasound in an Ashkenazi Jewish fetus.
Albers et al. (2001) reported an infant with lethal neonatal CPT II deficiency who was detected by newborn screening with tandem mass spectrometry.
Vekemans et al. (2003) developed a CPT2 activity assay using 10 mg chorionic villus sampling. Combined with haplotype analysis using markers linked to the CPT2 gene, they carried out prenatal diagnosis of CPT II deficiency in 2 unrelated families at the eleventh week of gestation.
The transmission pattern of CPT II in the family reported by Witt et al. (1991) and Gellera et al. (1992) and the family reported by Elpeleg et al. (2001) was consistent with autosomal recessive inheritance.
In 2 sibs with lethal neonatal CPT II deficiency originally reported by Witt et al. (1991), Gellera et al. (1992) identified a heterozygous 11-bp duplication in the CPT2 gene (600650.0012). The asymptomatic mother was heterozygous for the mutation, but the father had only wildtype alleles, and Gellera et al. (1992) concluded that an additional unidentified CPT2 mutation was present in the affected sibs.
In 2 Ashkenazi Jewish sibs with antenatal CPT II deficiency, Elpeleg et al. (2001) identified homozygosity for 2 mutations in exon 4 of the CPT2 gene, a 2-bp deletion and a missense mutation (see 600650.0009). Since compound heterozygosity for the same allele carrying both of these mutations with an S113L mutation on the other allele was identified in several Ashkenazi patients with the adult form of CPT II deficiency (Taggart et al., 1999), Elpeleg et al. (2001) suggested that genotype determination be performed in all Ashkenazi patients with CPT II deficiency regardless of disease severity.
Vladutiu et al. (2002) described a male infant of Ashkenazi Jewish descent with the lethal neonatal form of CPT II who had 2 truncating mutations in the CPT2 gene (600650.0009; 600650.0014). The infant died on the third day of life; CPT II activity was 6% and 18% of normal in fibroblasts and skeletal muscle, respectively.
Albers, S., Marsden, D., Quackenbush, E., Stark, A. R., Levy, H. L., Irons, M. Detection of neonatal carnitine palmitoyltransferase II deficiency by expanded newborn screening with tandem mass spectrometry. Pediatrics 107: E103, 2001. Note: Electronic Article. [PubMed: 11389301] [Full Text: https://doi.org/10.1542/peds.107.6.e103]
Elpeleg, O. N., Hammerman, C., Saada, A., Shaag, A., Golzand, E., Hochner-Celnikier, D., Berger, I., Nadjari, M. Antenatal presentation of carnitine palmitoyltransferase II deficiency. Am. J. Med. Genet. 102: 183-187, 2001. [PubMed: 11477613] [Full Text: https://doi.org/10.1002/ajmg.1457]
Gellera, C., Witt, D. R., Verderio, E., Cavadini, P., DiDonato, S., Taroni, F. Molecular study of lethal neonatal carnitine palmitoyltransferase II (CPT II) deficiency. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A168 only, 1992.
Hug, G., Bove, K. E., Soukup, S. Lethal neonatal multiorgan deficiency of carnitine palmitoyltransferase II. New Eng. J. Med. 325: 1862-1864, 1991. [PubMed: 1961225] [Full Text: https://doi.org/10.1056/NEJM199112263252607]
Hug, G., Soukup, S., Berry, H., Bove, K. Carnitine palmityl transferase (CPT): deficiency of CPT II but not of CPT I with reduced total and free carnitine but increased acylcarnitine. (Abstract) Pediat. Res. 25 (suppl.): 115A only, 1989.
Isackson, P. J., Bennett, M. J., Lichter-Konecki, U., Willis, M., Nyhan, W. L., Sutton, V. R., Tein, I., Vladutiu, G. D. CPT2 gene mutations resulting in lethal neonatal or severe infantile carnitine palmitoyltransferase II deficiency. Molec. Genet. Metab. 94: 422-427, 2008. [PubMed: 18550408] [Full Text: https://doi.org/10.1016/j.ymgme.2008.05.002]
Land, J. M., Mistry, S., Squier, M., Hope, P., Ghadiminejad, I., Orford, M., Saggerson, D. Neonatal carnitine palmitoyltransferase-2 deficiency: a case presenting with myopathy. Neuromusc. Disord. 5: 129-137, 1995. [PubMed: 7767092] [Full Text: https://doi.org/10.1016/0960-8966(94)00037-a]
Longo, N., Amat di San Filippo, C., Pasquali, M. Disorders of carnitine transport and the carnitine cycle. Am. J. Med. Genet. 142C: 77-85, 2006. [PubMed: 16602102] [Full Text: https://doi.org/10.1002/ajmg.c.30087]
North, K. N., Hoppel, C. L., De Girolami, U., Kozakewich, H. P. W., Korson, M. S. Lethal neonatal deficiency of carnitine palmitoyltransferase II associated with dysgenesis of the brain and kidneys. J. Pediat. 127: 414-420, 1995. [PubMed: 7658272] [Full Text: https://doi.org/10.1016/s0022-3476(95)70073-0]
Pierce, M. R., Pridjian, G., Morrison, S., Pickoff, A. S. Fatal carnitine palmitoyltransferase II deficiency in a newborn: new phenotypic features. Clin. Pediat. 38: 13-20, 1999. [PubMed: 9924637] [Full Text: https://doi.org/10.1177/000992289903800102]
Sharma, R., Perszyk, A. A., Marangi, D., Monteiro, C., Raja, S. Lethal neonatal carnitine palmitoyltransferase II deficiency: an unusual presentation of a rare disorder. Am. J. Perinatol. 20: 25-32, 2003. [PubMed: 12638078] [Full Text: https://doi.org/10.1055/s-2003-37952]
Taggart, R. T., Smail, D., Apolito, C., Vladutiu, G. D. Novel mutations associated with carnitine palmitoyltransferase II deficiency. Hum. Mutat. 13: 210-220, 1999. [PubMed: 10090476] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)13:3<210::AID-HUMU5>3.0.CO;2-0]
Taroni, F., Gellera, C., Cavadini, P., Baratta, S., Lamantea, E., Dethlefs, S., DiDonato, S., Reik, R. A., Benke, P. J. Lethal carnitine palmitoyltransferase (CPT) II deficiency in newborns: a molecular-genetic study. (Abstract) Am. J. Hum. Genet. 55 (suppl.): A245 only, 1994.
Vekemans, B. C., Bonnefont, J.-P., Aupetit, J., Royer, G., Droin, V., Attie-Bitach, T., Saudubray, J.-M., Thuillier, L. Prenatal diagnosis of carnitine palmitoyltransferase 2 deficiency in chorionic villi: a novel approach. Prenatal Diag. 23: 884-887, 2003. [PubMed: 14634971] [Full Text: https://doi.org/10.1002/pd.713]
Vladutiu, G. D., Quackenbush, E. J., Hainline, B. E., Albers, S., Smail, D. S., Bennett, M. J. Lethal neonatal and severe late infantile forms of carnitine palmitoyltransferase II deficiency associated with compound heterozygosity for different protein truncation mutations. J. Pediat. 141: 734-736, 2002. [PubMed: 12410208] [Full Text: https://doi.org/10.1067/mpd.2002.128545]
Witt, D. R., Theobald, M., Santa-Maria, M., Packman, S., Townsend, S., Sweetman, L., Goodman, S., Rhead, W., Hoppel, C. Carnitine palmitoyl transferase-type 2 deficiency: two new cases and successful prenatal diagnosis. (Abstract) Am. J. Hum. Genet. 49 (suppl.): A109 only, 1991.
Zinn, A. B., Zurcher, V. L., Kraus, F., Strohl, C., Walsh-Sukys, M. C., Hoppel, C. L. Carnitine palmitoyltransferase B (CPT B) deficiency: a heritable cause of neonatal cardiomyopathy and dysgenesis of the kidney. (Abstract) Pediat. Res. 29 (suppl.): 73A only, 1991.