Alternative titles; symbols
ORPHA: 157, 228305; DO: 0060235;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p32.3 | CPT II deficiency, infantile | 600649 | Autosomal recessive | 3 | CPT2 | 600650 |
A number sign (#) is used with this entry because the infantile form of carnitine palmitoyltransferase II 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 infantile form usually presents between 6 and 24 months of age with recurrent attacks of hypoketotic hypoglycemia causing loss of consciousness and seizures, liver failure, and transient hepatomegaly. Some children also have heart involvement with cardiomyopathy and arrhythmia. Episodes are triggered by infections, fever, or fasting. Laboratory studies usually indicate hyperammonemia, metabolic acidosis, and hypoketotic hypoglycemia with elevated levels of creatine kinase (summary by Longo et al., 2006).
See also the lethal neonatal (608836) and adult-onset (255110) forms of the disorder, which are also caused by mutation in the CPT2 gene.
Demaugre et al. (1991) reported a male infant, born of first-cousin parents, who presented at 3 months of age with lethargy, respiratory arrest, and seizures following a febrile illness. He had mild hepatomegaly and cardiomegaly, as well as multiple cardiac arrhythmias. Laboratory analysis showed hypoketotic hypoglycemia, elevated liver enzymes, increased plasma creatine kinase, and low plasma carnitine. The patient's plasma ketones rose after medium-chain triglyceride loading, but did not increase after long-chain triglyceride loading, indicating impaired oxidation of long-chain fatty acids in the liver. CPT II activity was 10% of normal in the patient's fibroblasts, and approximately 50% of normal in lymphocytes of the parents and 1 unaffected sib. Protein analysis showed decreased levels of a normal-sized CPT II protein in the patient's fibroblasts. The child died suddenly after an overnight fast at the age of 17 months.
Taroni et al. (1992) reported a 5-year-old boy, born of first cousin parents, who had recurrent episodes of vomiting, sweating, and lethargy from infancy. At age 23 months, he had an acute episode of seizures, coma, and respiratory distress, which ultimately led to severe brain damage. Physical examination showed hepatomegaly and mild dilated cardiomyopathy. After fasting, he developed hypoketotic hypoglycemia. Laboratory analysis showed that CPT II activity was reduced to 16.4%, 8.8%, and 6.6% of normal controls in the patient's fibroblasts, lymphoblasts, and skeletal muscle, respectively. Fibroblast CPT II activity was reduced by 40% and 35% in the father and mother, respectively.
Yamamoto et al. (1996) reported a previously healthy Japanese infant who became lethargic at the age of 9 months after a 2-day febrile illness. She had hypoketotic hypoglycemia, metabolic acidosis, hyperammonemia, elevated liver enzymes, and hepatomegaly with macrovesicular steatosis. Palmitate oxidation and CPT II activity in lymphoblasts were 46% and 3% of normal control rates, respectively. Her younger brother had a similar illness and laboratory results.
Isackson et al. (2008) reported a patient with infantile CPT II deficiency who presented at age 15 months following a febrile episode with hypoglycemic encephalopathy and hepatomegaly. He had elevated liver function tests and fatty infiltration of the liver. Echocardiogram showed ventricular hypertrophy with normal function. He had complete neurologic recovery and did well with proper treatment, although he had a few episodes of myolysis when stressed. CPT2 activity was 2.5% of control values. Genetic analysis revealed a homozygous mutation in the CPT2 gene (Y120C; 600650.0017).
Clinical Variability
Illsinger et al. (2008) reported an infant with CPT2 deficiency identified by newborn screening of a dried blood spot; acylcarnitines were increased. However, acylcarnitine profile in blood taken on day 9 was normal with breast milk feeding, and there was no dicarboxylic aciduria. CPT2 activity was decreased to 25% in fibroblasts, and overall oxidation of the long-chain fatty acids was reduced to 10% of control values. The patient was found to be compound heterozygous for 2 mutations in the CPT2 gene. At age 2.5 years, he had no clinical symptoms associated with the marked impairment of long-chain fatty acid oxidation. Illsinger et al. (2008) noted that the phenotype of CPT2 deficiency can range from normal to early death in infancy, but concluded that all patients with abnormal neonatal screening should be followed for possible decompensation under certain circumstances.
Guffon et al. (2021) described clinical response to treatment with triheptanoin in 18 patients with disorders of long chain fatty acid oxidation, including 5 with VLCAD deficiency (201475), 5 with LCHAD deficiency (609016), 3 with CACT deficiency (212138), 3 with CPT II deficiency, and 2 with MTP deficiency (609015). Treatment duration was for an average of 22 months, with a range of 9 to 228 months. Ten of 12 pediatric patients and 4 of 6 adult patients reported reduction in fatigue and weakness. Eight of 12 pediatric patients and 3 of 6 adult patients experienced reduced intensity of myalgia. Episodes of rhabdomyolysis decreased in 8 of 12 pediatric patients and 3 of 6 adult patients. Of 3 patients who had severe hypoglycemic events in the year prior to starting triheptanoin, none had these events in the year following initiation of therapy. On average, emergency hospital care visits and days of emergency home care were also reduced.
In a patient with infantile CPT II deficiency, Taroni et al. (1992) identified a homozygous mutation in the CPT2 gene (600650.0001).
In the patient with infantile CPT II deficiency reported by Demaugre et al. (1991), Bonnefont et al. (1996) identified a homozygous mutation in the CPT2 gene (600650.0005). In 2 Japanese sibs with infantile CPT II deficiency, Yamamoto et al. (1996) identified compound heterozygosity for 2 mutations in the CPT2 gene (600650.0006; 600650.0007).
Vladutiu et al. (2002) reported an 11-month-old male infant of mixed heritage presenting with episodic hypoglycemia who was compound heterozygous for 2 mutations in the CPT2 gene (600650.0003; 600650.0009).
Bonnefont, J.-P., Taroni, F., Cavadini, P., Cepanec, C., Brivet, M., Saudubray, J.-M., Leroux, J.-P., Demaugre, F. Molecular analysis of carnitine palmitoyltransferase II deficiency with hepatocardiomuscular expression. Am. J. Hum. Genet. 58: 971-978, 1996. [PubMed: 8651281]
Demaugre, F., Bonnefont, J.-P., Colonna, M., Cepanec, C., Leroux, J.-P., Saudubray, J.-M. Infantile form of carnitine palmitoyltransferase II deficiency with hepatomuscular symptoms and sudden death: physiopathological approach to carnitine palmitoyltransferase II deficiencies. J. Clin. Invest. 87: 859-864, 1991. [PubMed: 1999498] [Full Text: https://doi.org/10.1172/JCI115090]
Guffon, N., Mochel, F., Schiff, M., De Lonlay, P., Douillard, C., Vianey-Saban, C. Clinical outcomes in a series of 18 patients with long chain fatty acids oxidation disorders treated with triheptanoin for a median duration of 22 months. Molec. Genet. Metab. 132: 227-233, 2021. [PubMed: 33610471] [Full Text: https://doi.org/10.1016/j.ymgme.2021.02.003]
Illsinger, S., Lucke, T., Peter, M., Ruiter, J. P. N., Wanders, R. J. A., Deschauer, M., Handig, I., Wuyts, W., Das, A. M. Carnitine-palmitoyltransferase 2 deficiency: novel mutations and relevance of newborn screening. Am. J. Med. Genet. 146A: 2925-2928, 2008. [PubMed: 18925671] [Full Text: https://doi.org/10.1002/ajmg.a.32545]
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]
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]
Taroni, F., Verderio, E., Fiorucci, S., Cavadini, P., Finocchiaro, G., Uziel, G., Lamantea, E., Gellera, C., DiDonato, S. Molecular characterization of inherited carnitine palmitoyltransferase II deficiency. Proc. Nat. Acad. Sci. 89: 8429-8433, 1992. [PubMed: 1528846] [Full Text: https://doi.org/10.1073/pnas.89.18.8429]
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]
Yamamoto, S., Abe, H., Kohgo, T., Ogawa, A., Ohtake, A., Hayashibe, H., Sakuraba, H., Suzuki, Y., Aramaki, S., Takayanagi, M., Hasegawa, S., Niimi, H. Two novel gene mutations (glu174-to-lys, phe383-to-tyr) causing the 'hepatic' form of carnitine palmitoyltransferase II deficiency. Hum. Genet. 98: 116-118, 1996. [PubMed: 8682496] [Full Text: https://doi.org/10.1007/s004390050170]