Case reports
Carnitine palmitoyltransferase II deficiency due to a novel gene variant in a patient with rhabdomyolysis and ARF

Presented in abstract form at the American Society of Nephrology Annual Meeting, St Louis, MO, October 31, 2004.
https://doi.org/10.1053/j.ajkd.2004.12.006Get rights and content

Adult patients deficient in carnitine palmitoyltransferase II (CPT II) cannot generate sufficient amounts of energy, which results in rhabdomyolysis and acute renal failure (ARF). Its genetic basis has been recognized; but histopathologic changes, especially electron microscopic changes, have scarcely been described. The study subject is a patient with ARF caused by repetitive nontraumatic rhabdomyolysis. The acylcarnitine profile of serum and enzyme assay on skin fibroblasts confirmed the diagnosis of CPT II deficiency. Renal biopsy specimens were examined microscopically and immunohistochemically. The histological diagnosis was interstitial nephritis with acute tubular necrosis caused by rhabdomyolysis. Myoglobin in tubules was detected by means of immunohistochemistry and electron microscopy. The genetic structure of CPT II was analyzed in the patient and his family. Eight pairs of polymerase chain reaction (PCR) primers were designed to cover the coding region. Each PCR-amplified gene product was subjected to DNA sequencing, which unveiled heterozygosity at the CPT II locus consisting of a deletion of cytosine and thymine at codon 408, resulting in a stop signal at 420, as well as a mutation of arginine to cysteine at codon 631. The frame shift at 408 has never been described before. DNA sequencing of the family showed the deletion mutation from the mother and the point mutation from the father. We describe renopathological findings in a patient with CPT II deficiency associated with rhabdomyolysis, which suggested the pathological role of myoglobin casts in the development of tubular necrosis. Genetic analysis of the patient identified a novel variant of the CPT II gene.

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Case report

A 24-year-old Japanese man was transferred to the emergency department of Fukuoka University Hospital and Clinic (Fukuoka, Japan) because of ARF. Three years before presentation, he developed an illness characterized by high fever, myalgia, respiratory symptoms, and dark-colored urine. After hospitalization, he was found to have markedly elevated levels of serum muscle enzymes and urine myoglobin, and a diagnosis of rhabdomyolysis, probably caused by a viral infection or drugs prescribed for a

Discussion

Nontraumatic or non–drug-induced rhabdomyolysis is seen after exhaustive exercise and after severe infection, evidenced by dark-colored urine, recognized as one of the frequent causes of ARF, and, in rare cases, presents repeatedly and among family members.9, 10, 11, 12, 13 Familial rhabdomyolysis often is attributed to deficiency of enzymes related to the metabolism of long-chain fatty acids. CPT II mutation is the most common disorder affecting mitochondrial β-oxidation. Genetic analyses have

Acknowledgment

The authors thank Kaoru Kojima for excellent technical and secretarial assistance.

References (25)

  • L. Thuillier et al.

    Correlation between genotype, metabolic data, and clinical presentation in carnitine palmitoyltransferase 2 (CPT2) deficiency

    Hum Mutat

    (2003)
  • F. Demaugre et al.

    Infantile form of carnitine palmitoyltransferase II deficiency with hepatomuscular symptoms and sudden deathPhysiopathological approach to carnitine palmitoyltransferase II deficiencies

    J Clin Invest

    (1991)
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    Originally published online as doi:10.1053/j.ajkd.2004.12.006 on January 27, 2005.

    Supported in part by fund no. 026006 from the Central Research Institute of Fukuoka University and a grant for Progressive Renal Diseases from the Ministry of Health, Labor, and Welfare, Japan.

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