RESIDENT REVIEW SERIES
Carnitine Palmitoyltransferase II Deficiency: A
Clinical, Biochemical, and Molecular Review
Ellen Sigauke, Dinesh Rakheja, Kimberly Kitson, and Michael J. Bennett
Departments of Pathology (ES, DR), The University of Texas Southwestern Medical Center, and Departments of
Pathology and Pediatrics (MJB), Children’s Medical Center and The University of Texas Southwestern Medical
Center, Dallas, Texas; and The University of Illinois at Chicago (KK), College of Medicine at Peoria, Peoria, Illinois
SUMMARY: Congenital deficiency of carnitine palmitoyltransferase (CPT) II has been known for at least 30 years now, and its
phenotypic variability remains fascinating. Three distinct clinical entities have been described, the adult, the infantile, and the
perinatal, all with an autosomal recessive inheritance pattern. The adult CPT II clinical phenotype is somewhat benign and
requires additional external triggers such as high-intensity exercise before the predominantly myopathic symptoms are elicited.
The perinatal and infantile forms involve multiple organ systems. The perinatal disease is the most severe form and is invariably
fatal. The introduction of mass spectrometry to analyze blood acylcarnitine profiles has revolutionized the diagnosis of fatty acid
oxidation disorders including CPT II deficiency. Its use in expanded neonatal screening programs has made presymptomatic
diagnosis a reality. An increasing number of mutations are being identified in the CPT II gene with a distinct genotype-phenotype
correlation in most cases. However, clinical variability in some patients suggests additional genetic or environmental modifiers.
Herein, we present a new case of lethal perinatal CPT II deficiency with a rare missense mutation, R296Q (907G?A) associated
with a previously described 25-bp deletion on the second allele. We review the clinical features, the diagnostic protocol including
expanded neonatal screening, the treatment, and the biochemical and molecular basis of CPT II deficiency. (Lab Invest 2003,
(CoA) synthetase and the carnitine-acylcarnitine trans-
locase (CACT), plays an important role in the transfer
of long chain fatty acids (LCFA) from the cytosolic
compartment to the mitochondrial matrix, where
?-oxidation occurs (Bieber, 1988). Two genetically
distinct mitochondrial membrane-bound enzymes
make up the CPT system. CPT I is located on the inner
aspect of the outer mitochondrial membrane. This
enzyme is physiologically inhibited by the high levels
of malonyl-CoA that occur postprandially and thus
regulates the entry of LCFA into the mitochondria
(McGarry and Brown, 1997). CPT II, which is not
inhibited by malonyl-CoA, is situated on the inner
aspect of the inner mitochondrial membrane (Murthy
and Pande, 1987).
CPT II deficiency was first reported by DiMauro and
DiMauro (1973) in adults with exercise-induced rhab-
domyolysis. It is an autosomal recessive disorder
he carnitine palmitoyltransferase (CPT) enzyme
system, in association with acyl-coenzyme A
(Angelini et al, 1981; Meola et al, 1987) and is now
regarded as one of the most common inherited disor-
ders of lipid metabolism (Zierz, 1994). Isolated presen-
tation in two successive generations has been re-
ported, indicating a possible dominant inheritance
(Mongini et al, 1991). Partial CPT II deficiency with an
autosomal dominant inheritance pattern has also been
reported (Ionasescu et al, 1980). The molecular basis
for this presentation was not elucidated.
To date, three distinct CPT II-deficient phenotypes
have been described in the literature, for which geno-
typic information is now available. The adult form,
which was originally identified by DiMauro and Di-
Mauro (1973), is the most common and usually pre-
sents in young adults with recurrent myoglobinuria.
The symptoms are usually precipitated by heavy ex-
ercise, and to a lesser extent, by cold, infection,
emotional distress, and/or fasting. Renal failure may
be a complication in some cases (Demaugre et al,
1988). The infantile form, which usually presents in
early childhood with fasting-induced hypoketotic hy-
poglycemia, liver failure, cardiomyopathy, and periph-
eral neuropathy, is potentially fatal, although treatable
if diagnosed early (Hug et al, 1991; Taroni et al, 1992).
The perinatal form is the least common clinical pre-
sentation of CPT II deficiency and is almost universally
and rapidly fatal (Elpeleg et al, 2001; Gellera et al,
1992; North et al, 1995; Pierce et al, 1999; Taroni et al,
Received June 19, 2003.
Code 9073), The University of Texas Southwestern Medical Center, 5323
Copyright © 2003 by The United States and Canadian Academy of Pathology, Inc.
Vol. 83, No. 11, p. 1543, 2003
Printed in U.S.A.
Laboratory Investigation • November 2003 • Volume 83 • Number 11
1994; Vladutiu et al, 2002b). The phenotypic variability
of CPT II deficiency is fascinating. There is a signifi-
cant degree of genotype-phenotype correlation at the
severe and mild ends of the clinical spectrum. How-
ever, CPT II gene polymorphisms may modify the
expression of the mutated genes, giving rise to varied
clinical features in some cases.
We report a new case of perinatal CPT II deficiency
with a rare missense mutation and we review the
current and expanding literature on CPT II deficiency.
Biochemical Review of the Mitochondrial
The metabolic significance of the mitochondrial carni-
tine system in the pathway of ?-oxidation of LCFA is
well recognized. LCFA of chain lengths C14–C18 are
activated at the outer mitochondrial membrane to
acyl-CoA esters by long-chain acyl-CoA synthetase
(Kerner and Hoppel, 2000; Rinaldo et al, 2002). How-
ever, the inner mitochondrial membrane is imperme-
able to the acyl-CoA esters (Fig. 1). The so-called
“carnitine shuttle” regulates the flux of acyl-CoA es-
ters into the mitochondria. The shuttle requires the use
of three major proteins, namely, CPT I, CACT, and
CPT I catalyzes the rate-limiting step in ?-oxidation,
which is the conversion of the acyl-CoAs and free
carnitine to acylcarnitines and free CoAs. CPT I is
up-regulated when intracellular levels of malonyl-CoA
are low, as is seen with fasting. Its activity is physio-
logically inhibited by high levels of malonyl-CoA (Dai et
al, 2000; Declercq et al, 1987; Rinaldo et al, 2002).
CPT I is located in the outer mitochondrial membrane
(Fig. 1). Both the catalytic and the malonyl-CoA bind-
ing sites are exposed to the cytosol, where acyl-CoA
esters are initially formed. Alterations in the membrane
lipid environment can change the conformation of the
CPT I enzyme, exerting an effect on its long-chain
acyl-CoA binding site (Fraser et al, 2001; Zammit et al,
Two isoforms of CPT I have been described, a liver
isoform (CPT IA or L-CPT I) and a muscle isoform (CPT
IB or M-CPT I). L-CPT I is also found in lung, pancreas,
ovary, brain, spleen, intestine, kidney, and skin fibro-
blasts (McGarry and Brown, 1997). M-CPT I is found in
tissues with high-energy utilization such as heart and
skeletal muscle and is also present in adipose tissue.
The liver isoform has a lower affinity for malonyl-CoA
and a higher affinity for carnitine (Kerner and Hoppel,
2000). Full-length cDNA cloning of L-CPT I from rat
liver has predicted a protein of 773 amino acids with a
molecular mass of 88 kDa (Esser et al, 1993). There is
82% and 88% identity between the human and the rat
L-CPT I nucleotide sequence and the predicted pro-
tein primary structure, respectively. The human
M-CPT I gene has been mapped to chromosome
22q13.3, and the L-CPT I gene is located on chromo-
some 11q13 (Britton et al, 1995, 1997).
In the second step of the carnitine shuttle, acylcar-
nitines enter the mitochondrial matrix in exchange for
free carnitine, using CACT, an integral inner mitochon-
drial membrane protein (Fig. 1). CACT differs from
other mitochondrial metabolite transporters in that its
action is bidirectional (Indiveri et al, 1994; Palmieri et
al, 1996) (Fig. 1). In addition to its function in the
mitochondrial fatty acid oxidation (FAO), this enzyme
is also thought to be involved in the membrane trans-
port of acyl groups of different chain lengths. This
multifunctionality may be the reason why deficiency of
this protein tends to be more severe than most other
FAO disorders (Kerner and Hoppel, 1998). The human
CACT gene has been mapped to chromosome
3p21.31. The protein is composed of 301 amino acids
and has a molecular mass of 33 kDa (Huizing et al,
1997; Indiveri et al, 1997; Palmieri et al, 1996; Viggiano
et al, 1997).
The last step of the carnitine system is catalyzed by
CPT II, an enzyme located on the matrix side of the
inner mitochondrial membrane (Hoppel and Tomec,
1972). This step involves reconverting the acylcarni-
tine esters to their respective acyl-CoAs, which are
now primed substrates for the ?-oxidation process
(Kerner and Hoppel, 2000). The transcribed CPT II
protein with a molecular mass of approximately 71
kDa is composed of 658 amino acids, which includes
an N-terminal 25 amino acid mitochondrial targeting
sequence that is cleaved upon import into the mito-
chondria (Brown et al, 1991; McGarry and Brown,
1997; Woeltje et al, 1990b). The CPT II gene is located
on chromosome 1p32, and the enzyme is ubiquitously
expressed in all tissues that require FAO as an energy-
The carnitine pathway. PM ? plasma membrane; OMM ? outer mitochondrial
membrane; IMM ? inner mitochondrial membrane.
Sigauke et al
1544 Laboratory Investigation • November 2003 • Volume 83 • Number 11
Taggart RT, Smail D, Apolito C, and Vladutiu GD (1999).
Novel mutations associated with carnitine palmitoyltrans-
ferase II deficiency. Hum Mut 13:210–220.
Taroni F, Gellera C, Cavadini P, Baratta S, Lamantea E,
Dethlefs S, DiDonato S, Reik RA, and Benke PJ (1994). Lethal
carnitine palmitoyltransferase (CPT) II deficiency in
newborns: A molecular genetic study (Abstract). Am J Hum
Taroni F, Verderio E, Dworzak F, Willems PJ, Cavadini P, and
DiDonato S (1993). Identification of a common mutation in
the carnitine palmitoyltransferase II gene in familial recurrent
myoglobinuria patients. Nat Genet 4:314–320.
Taroni F, Verderio E, Fiorucci S, Cavadini P, Finocchiaro G,
Uziel G, Lamantea E, Gellera C, and DiDonato S (1992).
Molecular characterization of inherited carnitine palmitoyl-
transferase II deficiency. Proc Natl Acad Sci USA 89:8429–
Tein I, Christodoulou J, Donner E, and McInnes RR (1994).
Carnitine palmitoyltransferase II deficiency: A new cause of
recurrent pancreatitis. J Pediatr 124:938–940.
Thuillier L, Rostane H, Droin V, Demaugre F, Brivet M,
Kadhom N, Prip-Buus C, Gobin S, Saudubray JM, and
Bonnefont JP (2003). Correlation between genotype, meta-
bolic data, and clinical presentation in carnitine palmitoyl-
transferase 2 (CPT2) deficiency. Hum Mutat 21:493–501.
Thuillier L, Sevin C, Demaugre F, Brivet M, Rabier D, Droin V,
Aupetit J, Abadi N, Kamoun P, Saudubray JM, and Bonne-
font JP (2000). Genotype/phenotype correlation in carnitine
palmitoyltransferase II deficiency: Lessons from a compound
heterozygous patient. Neuromuscul Disord 10:200–205.
Toscano A, Baratta S, Rodolico C, Aguennouz M, Autunno
M, Vita G, Messina C, Invernizzi F, and Taroni F (1996).
Carnitine palmitoyltransferase II (CPT II) deficiency: Occur-
rence of the adult-onset muscular phenotype in a family with
the infant-type Arg-631-Cys CPT II mutation (Abstract).
J Neurol 243(Suppl 2):A159.
Tsao CY and Mendell JR (2002). Combined partial deficien-
cies of carnitine palmitoyltransferase II and mitochondrial
complex I presenting as increased serum creatine kinase
level. J Child Neurol 17:304–306.
Verderio E, Cavadini P, Montermini L, Wang H, Lamantea E,
Finocchiaro G, DiDonato S, Gellera C, and Taroni F (1995).
Carnitine palmitoyltransferase II deficiency: Structure of the
gene and characterization of two novel disease-causing
mutations. Hum Mol Genet 4:19–29.
Verderio E, Cavadini P, Pandolfo M, DiDonato S, and Taroni
F (1993). Two novel sequence polymorphisms of the human
carnitine palmitoyltransferase II (CPT 1) gene. Hum Mol
Vianey-Saban C, Stremler N, Paut O, Buttin T, Divry P, Zabot
MT, Camboulives J, Mathieu M, and Mousson B (1995).
Infantile form of carnitine palmitoyltransferase II deficiency in
a girl with rapid fatal onset. J Inherit Metab Dis 18:362–363.
Videen JS, Haseler LJ, Karpinski NC, and Terkeltaub RA
(1999). Noninvasive evaluation of adult onset myopathy from
carnitine palmitoyltransferase II deficiency using proton mag-
netic resonance spectroscopy. J Rheumatol 26:1757–1763.
Viggiano L, Iacobazzi V, Marzella R, Cassano C, Rocchi M,
and Palmieri F (1997). Assignment of the carnitine/
acylcarnitine translocase gene (CACT) to human chromo-
some band 3p21.31 by in situ hybridization. Cytogenet Cell
Villard J, Fischer A, Mandon G, Collombet JM, Taroni F, and
Mousson B (1996). Recurrent myoglobinuria due to carnitine
palmitoyltransferase II deficiency: Expression of the molecu-
lar phenotype in cultured muscle cells. J Neurol Sci 136:178–
Vladutiu GD, Bennett MJ, Fisher NM, Smail D, Boriack R,
Leddy J, and Pendergast DR (2002a). Phenotypic variability
among first-degree relatives with carnitine palmitoyltrans-
ferase II deficiency. Muscle Nerve 26:492–498.
Vladutiu GD, Bennett MJ, Smail D, Wong LJ, Taggart RT, and
Lindsey HB (2000). A variable myopathy associated with
heterozygosity for the R503C mutation in the carnitine palmi-
toyltransferase II gene. Mol Genet Metab 70:134–141.
Vladutiu GD, Quackenbush EJ, Hainline BE, Albers S, Smail
DS, and Bennett MJ (2002b). Lethal neonatal and severe late
infantile forms of carnitine palmitoyltransferase II deficiency
associated with compound heterozygosity for different pro-
tein truncation mutations. J Pediatr 141:734–736.
Wallace RA, Klestov AC, and Kubler PA (2001). Emotional
distress induced rhabdomyolysis in an individual with carni-
tine palmitoyltransferase deficiency. Clin Exp Rheumatol
Wataya K, Akanuma J, Cavadini P, Aoki Y, Kure S, Invernizzi
F, Yoshida I, Kira J, Taroni F, Matsubara Y, and Narisawa K
(1998). Two CPT2 mutations in three Japanese patients with
carnitine palmitoyltransferase II deficiency: Functional analy-
sis and association with polymorphic haplotypes and two
clinical phenotypes. Hum Mutat 11:377–386.
Weiser T, Deschauer M, Olek K, Hermann T, and Zierz S
(2003). Carnitine palmitoyltransferase II deficiency: Molecular
and biochemical analysis of 32 patients. Neurology 60:1351–
Weiser T, Deschauer M, and Zierz S (1997). Carnitine palmi-
toyltransferase II deficiency: Three novel mutations. Ann
Wiley V, Carpenter K, and Wilcken B (1999). Newborn
screening with tandem mass spectrometry: 12 months ex-
perience in NSW Australia. Acta Pediatr 432(Suppl): 48–51.
Witt DR, Theobald M, Santa-Maria M, Packman S, Townsend
S, Sweetman L, Goodman S, Rhead W, and Hoppel C (1991).
Carnitine palmitoyltransferase-type 2 deficiency: Two new
cases and successful prenatal diagnosis. Am J Hum Genet
Woeltje KF, Esser V, Weis BC, Cox WF, Schroeder JG, Liao
ST, Foster DW, and McGarry JD (1990b). Inter-tissue and
inter-species characteristics of the mitochondrial carnitine
palmitoyltransferase enzyme system. J Biol Chem 265:
Woeltje KF, Esser V, Weis BC, Sen A, Cox WF, McPhaul MJ,
Slaughter CA, Foster DW, and McGarry JD (1990a). Cloning,
sequencing, and expression of a cDNA encoding rat liver
mitochondrial carnitine palmitoyltransferase II. J Biol Chem
Yamamoto S, Abe H, Kohgo T, Ogawa A, Ohtake A, Hayash-
ibe H, Sakuraba H, Suzuki Y, Aramaki S, Takayanagi M,
Hasegawa S, and Niimi H (1996). Two novel mutations
(Glu1743Lys, Phe3833Tyr) causing the “hepatic” form of
carnitine palmitoyltransferase II deficiency. Hum Genet 98:
CPT II Deficiency
Laboratory Investigation • November 2003 • Volume 83 • Number 11
Yang BZ, Ding JH, Dewese T, Roe D, He G, Wilkinson J, Day
DW, Demaugre F, Rabier D, Brivet M, and Roe CR (1998b).
Identification of four novel mutations in patients with carnitine
palmitoyltransferase II deficiency. Mol Genet Metab 64:229–
Yang BZ, Ding JH, Roe D, Demaugre F, Brivet M, and Roe CR
(1997). Carnitine palmitoyltransferase II deficiency: Clinical
forms and mutations. Proceeding, Seventh International
Congress of Inborn Errors of Metabolism, Vienna, Austria,
May 21 to 25, 1997, P202 (Abstract).
Yang BZ, Ding JH, Roe D, Dewese T, Day DW, and Roe CR
(1998a). A novel mutation identified in carnitine palmitoyl-
transferase II deficiency. Mol Genet Metab 63:110–115.
Zammit VA, Fraser F, and Corstorphine CG (1997). Regula-
tion of mitochondrial outer-membrane carnitine palmitoyl-
transferase (CPT I): Role of membrane topology. Adv Enzyme
Zierz S (1994). Carnitine palmitoyltransferase deficiency. In:
Engel AG and Franzini-Armstrong C, editors. Mycology. New
York: McGraw-Hill, 1577–1586.
Zierz S, Engel AG, and Olek K (1994). The Ser 113 Leu
mutation in the carnitine palmitoyltransferase II gene in
patients with muscle carnitine palmitoyltransferase defi-
ciency. Muscle Nerve Suppl 1:S129.
Zinn AB, Zurcher VL, Kraus F, Strohl C, Walsh-Sukys MC,
and Hoppel CL (1991). Carnitine palmitoyltransferase B (CPT
B) deficiency: A heritable cause of neonatal cardiomyopathy
and dysgenesis of the kidney. Pediatr Res 29:73A.
Sigauke et al
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