37
Carnitine transporter deficiency
Introduction 246
Clinical abnormalities 246
MAJOR PHENOTYPIC EXPRESSION
Hypoketotic hypoglycemia, seizures, vomiting, lethargy progressive to coma; cardiomyopathy; chronic muscle weakness;
carnitine deficiency in plasma and muscle and increased excretion of free-carnitine in urine; and defective transport of
carnitine into cultured fibroblasts.
INTRODUCTION
The inborn errors of fatty acid oxidation, including carnitine
transporter deficiency [1], represent a newly recognized area
of human disease. The rate of discovery of distinct disorders
has increased rapidly since the discovery of medium-chain
acyl CoA dehydrogenase (MCAD) deficiency in 1982 (Chapter
40). Deficiency of carnitine is common in these disorders
in which fatty acyl CoA compounds accumulate which
then form esters with carnitine and are preferentially excreted
in the urine. Carnitine deficiency may also be profound in
organic acidemias such as propionic acidemia for the same
reason. The transport of carnitine into fibroblasts is inhibited
by long and medium chain acylcarnitines [2], and this may be
an additional factor in carnitine deficiency in disorders of
fatty acid oxidation. Primary carnitine deficiency resulting
from an abnormality in the synthesis of carnitine from protein-
bound lysine has not yet been observed. Many of the patients
reported early as primary carnitine deficiency have turned
out to have MCAD deficiency. Deficiency of carnitine as a
result of abnormality in the transporter (Figure 37.1) that
facilitates its entry into certain cells has been referred to as
primary carnitine deficiency [1]. The gene for the carnitine
transporter SLC22A5 has been cloned, and a small number of
mol/L, slightly
mutations have been defined [3].
Genetics and pathogenesis 248
Treatment 250
CLINICAL ABNORMALITIES
The classic, and frequently the initial, presentation of carni-
tine transporter deficiency (CTD) is hypoketotic hypo-
glycemia, as in most disorders of fatty acid oxidation. The
first patient reported [1] (Figure 37.2) presented at 3 months
comatose, limp and unresponsive in the afternoon after a
prolonged overnight fast. She was acidotic; the serum bicar-
bonate was 16 mmol/L and the arterial pH 7.17. The blood
concentration of glucose was 0.39 mmol/L (7 mg/dL) and that
of the cerebrospinal fluid (CSF) was 0.2 mmol/L (4mg/dL).
Resuscitation required intubation, assisted ventilation and
parenteral glucose and saline. Acute episodes of hypoketotic
hypoglycemia are potentially fatal (Figure 37.3) [4] and may
be sudden and unexpected. An infant of a vegetarian mother
died at 5 days of life [5]. Episodes usually occur before 2 years
of age and follow fasting [2,6].
Modest hepatomegaly is characteristic of this condition.
Biopsy of the liver shows microvesicular lipid [7], a finding,
like the rest of this clinical picture, that might lead to a diag-
nosis of Reye syndrome.
Clinical chemistry is also consistent with Reye syndrome,
with hyperammonemia and increased levels of transaminases.
The initial patient had an ammonia of 338
prolonged prothrombin time, an aspartate transaminase

Fatty acyl CoA
Carnitine Carnitine Acylcarnitine
CPT I
Transporter
Fatty acyl CoA
-Oxidation
Figure 37.2 A 17-month-old who was the initial reported patient [1]
with transporter defect. She presented at 3 months with hypoglycemic
coma precipitated by an intercurrent illness and prolonged fasting.
This episode left her with severe brain damage reflected in her vacant
expression. She died shortly after the picture was taken because of
complications of a gastrostomy. (Illustration was kindly provided by
Dr. Charles Stanley of the Children’s Hospital of Philadelphia.)
(AST) of 248 and alanine transaminase (ALT) of 149 IU/L [1].
Uric acid concentrations are also elevated at the time of the
episode. This, along with the elevation of creatine phosphok-
inase (CK) [2] should strongly suggest a disorder of fatty acid
oxidation.
Examination of the urine may reveal no ketonuria [1,2],
and this should strongly suggest the diagnosis. However, in
Clinical abnormalities 247
Acylcarnitine
Carnitine
Figure 37.1 The carnitine transporter
and its role in fatty acid metabolism.
the height of the hypoglycemic illness, there may be mis-
leading ketonuria in any disorder of fatty acid oxidation.
Quantification of the plasma concentration of 3-hydroxy-
butyric acid or of acetoacetic and 3-hydroxybutyric acids at
this time will provide definitive evidence of impaired ketoge-
nesis, but this information is not usually available to the clini-
cian. Dicarboxylic aciduria is usually notably absent [1,4].
Cardiomyopathy is the other classic way in which this dis-
order presents [2,7] and may be expected in any patient not
given the benefit of diagnosis and treatment with carnitine [4].
It was the most common presenting complaint in 15 patients
[3] and present in 100 percent of 20 reported patients. The
patient of Waber and colleagues [7] reported with progressive
cardiomyopathy and cardiac failure successfully treated with
carnitine has been shown to have the transporter defect. The
median age of onset of cardiac symptoms was 3 years [2].
Onset may be with rapidly progressive heart failure [2] or a
murmur, and cardiomegaly may be found on routine physi-
cal examination or examination at the time of hypoglycemia.
Roentgenograms and echocardiography reveal cardiac enlarge-
ment and increased thickness of the left ventricular wall.
Electrocardiogram (EKG) reveals left ventricular hypertrophy.
Nevertheless, the cardiomyopathy has been described as char-
acteristically dilated [8], and this has repeatedly been confirmed
by cardiac catheterization. This may be expected to be a lethal
disease in which patients without carnitine supplementation
display cardiac failure progressive to death. Death in a sibling
has been recorded in 8 families [2]. A 12-year-old boy who died
suddenly of cardiomyopathy following a routine surgical proce-
dure was found to have a low concentration of carnitine in
plasma and defective transport of carnitine in fibroblasts [9].
Muscle weakness or hypotonia is the third major manifes-
tation of disease. It may be present along with other features,
particularly those of the heart, but in two patients it was the
only manifestation [2]. The picture may be that of a progressive
proximal myopathy [8]. Biopsy of muscle reveals lipid storage
myopathy [1].
248 Carnitine transporter deficiency

Delay in diagnosis has been another characteristic of this

disease. In nine patients, the delay was 1–6 years after the onset
of symptoms [2], and in this time all developed cardiomyopa-
thy, and all but one had muscle weakness. In some patients
mild muscle weakness may not have been noted because of the
attention devoted to the major cardiac manifestations.

GENETICS AND PATHOGENESIS

Transmission of the disorder is autosomal recessive. Affected

siblings of both sexes have been observed, and consanguinity
has been present in at least five families [2]. Concentrations
of carnitine in plasma were low in 11 mothers studied and 10
of 11 fathers [6]. Prevalence is unknown, but there were 10
patients in the series of 107 with disorders of fatty acid oxida-
tion in the Saudubray Paris experience [8]. Among 313 patients
with an autopsy diagnosis of sudden infant death syndrome
(SIDS), 3 were designated as transporter defects on the basis
of hepatic steatosis and very low hepatic carnitine along with
Figure 37.3 J.S., a12-year-old boy with carnitine transporter
low esterified carnitine [10].
deficiency. The disease is exquisitely responsive to carnitine. His death
The diagnosis is usually suspected initially on the basis of
at 13 years highlights the dangerous nature of the disease and the
a low concentration of free-carnitine in plasma. In the first
importance of close follow-up of carnitine status and expert
patient, the total plasma carnitine ranged from 0 to 2.2
mol/L
management.
and no free-carnitine could be detected. In 20 patients [2]
total plasma carnitine ranged from 0 to 9
mol/L, with 18
having values less than 4.2
mol/L. In controls total carnitine 1
mol/L uptake was negligible. Uptake in patients at high
was 40–60
mol/L. The acylcarnitine profile reveals a decrease concentrations, such as 10 or 20
mol/L reflect a second low-
in free and esterfied carnitines. affinity transporter [11] or passive diffusion [12]. Transport of
Concentrations of carnitine in muscle are also quite low. carnitine in control fibroblasts is sodium-dependent [1]. The
In 13 patients studied, the range for total carnitine was from uptake of carnitine by fibroblasts at 5
mol/L showed no over-
0.05 to 17 percent of the normal mean. In liver, the total was lap among patients, parents and controls with the exception of
five percent of normal. The excretion of carnitine in the urine one father. The velocity of carnitine uptake can be measured in
is inappropriately high, consistent with defective renal tubu- lymphoblasts as well as fibroblasts [13]. Patients display rates
lar reabsorption [7]. At a time when the plasma carnitine below 10 percent of control. Heterozygosity can be demon-
approximated zero, the renal excretion was 121
mol/g crea- strated in some patients by rates below 40 percent of control.
tinine (normal 17–425) [1], and following a dose of 100 mg/kg Low uptake of carnitine has also been demonstrated in cul-
of oral carnitine the plasma carnitine rose only to 21
mol/L, tured myocytes derived from patients [14]. Prenatal diagnosis
but urinary excretion increased to 2911 mol/g creatinine. has been accomplished by demonstration of defective uptake
After four months of carnitine treatment, the plasma concen- of carnitine from aminocytes of an affected fetus [15].
trations reached the low normal range, while urinary excre- In response to the administration of carnitine, levels in
tion was four to five times normal. The fractional excretion liver return to normal, while those in muscle respond poorly,
rate for free-carnitine was nearly 100 percent of the filtered indicating that the transport defect includes muscle and kid-
load. On withdrawal of treatment the fractional excretion ney, but not liver. Consistent with this, the low Km and prefer-
exceeded the filtered load. ence for L-isomer that characterize the uptake of carnitine by
The nature of the defect has been demonstrated by study fibroblasts is shared by heart and muscle [11,12,16], but not
of the uptake of carnitine in vitro by cultured fibroblasts [1,2] by liver [17].
(Figure 37.3). In control cells the uptake of 14C-labeled carni- The gene for the carnitine transporter, SLC22A5, has
tine was via a high-affinity, carrier-mediated transport process been mapped to chromosome 5q31, the locus for carnitine
with an apparent Km of 3.24  0.5 and a Vmax of 1.67  0.19 transporter deficiency in a large Japanese kindred. It codes
[1] consistent with previous reports [11]. Fibroblasts from for an organic cation transporter OCTN2 [18,19]. This is one
patients have shown little uptake of carnitine; at a concentra- of a family of organic cation (OCTN) sodium ion dependent
tion of carnitine of 5
mol/L, control uptake was 0.94 and transporters. The protein contains 557 amino acids and has
a patient uptake was 0.1 pmol/min/mg protein [1]. High- the properties of a high affinity transporter. A number of
affinity transport is best shown at lower concentrations; up to mutations have now been identified in patients with this disease

Table 37.1 Differential diagnosis of disorders involving carnitine
Control
Carnitine transporter deficiency
Carnitine palmitoyl transferase (CPT) I deficiency
Carnitine translocase deficiency
Carnitine palmitoyl transferase (CPT) II deficiency
Defects in -oxidation
3-Hydroxy-3-methylglutaryl CoA lyase deficiency
[2,20–30]. Most individual families have had unique muta-
tions. There have been a few instances of the same mutation
in unrelated patients [22,24,25,28]. A few stop codons and
frame shifts have been defined [2,20]. A lack of correlation
between genotype and phenotype has been discussed [2,28].
However, decisions as to severity of phenotype often rest on
whether or not hypoglycemia once occurred early in life, as in
the case of one of two sibs with the R399Q missense mutation.
The episode followed gastroenteritis at 2 years of age [2].
Because of her diagnosis an older sib who had proximal limb
mol/L (51 mg/dL) at which time
girdle weakness and mild developmental delay at 4 years-of-
age was tested and found to have the mutation. Differences of
mol/L, but the level of
this nature appear to reflect the chance occurrence of an illness
mol/L. Blood con-
that led to fasting.
Among ethnic differences an 11 bp deletion was found in
unrelated patients from Switzerland and neighboring north-
ern Italy [2], and R169W was found in two unrelated families
in Italy [28]. In Japan, where the disease appears relatively
frequent, most families have had a few mutations [31]. In a
survey of 973 unrelated Japanese [31], 14 were found to have
low levels of carnitine, and of these, six had mutations in the
gene for OCTN2: W132X, S467C, W283C and M179L. These
data gave a carrier frequency of one percent in Japan. Echo-
cardiographic study indicated asymptomatic cardiac hyper-
trophy in these heterozygotes.
An animal model of the carnitine transporter defect, the
juvenile visceral steatosis (jvs) mouse [32], has autosomal
recessive fatty infiltration of the liver, hypoglycemia and
hyperammonemia two weeks after birth, and very low levels
of carnitine in blood and muscle, along with defective renal
reabsorption of free carnitine. The hyperammonemia results
from decreased expression of genes for enzymes of the urea
cycle; low levels of mRNA are associated with low levels of all
of the hepatic enzymes of the urea cycle [33]. Treatment with
carnitine corrects the abnormal expression and urea cycle
enzyme activity [34]. The jvs gene has been mapped to
mouse chromosome 11, which is syntenic with the SLC22A5
locus on human chromosome 5 [35].
Analysis of the organic acids of the urine of these patients
is usually normal. The absence of dicarboxylic aciduria, espe-
cially at times of acute illness and hypoglycemia, contrasts
sharply with findings in patients with defects in -oxidation
such as MCAD deficiency. Patients with deficiency of carnitine
Genetics and pathogenesis 249
Plasma total Carnitine esterfied Urinary
␮mol/L % of total carnitine
40–60 30 Normal
5 30 Paradoxically high free
60–100 20 Normal or high
5–30 80–100 High ester
10–40 40–80 Normal or high ester
10–30 30–60 High ester
10–30 30–60 High ester
palmitoyl-transferase I (Chapter 39) also develop hypoketotic
hypoglycemia without dicarboxylic aciduria [36]. Comparisons
of alterations of plasma carnitine in various disorders is
shown in Table 37.1. Low free and total carnitine in plasma
along with urinary free carnitine that is paradoxically main-
tained is suggestive of a transporter defect.
The response to fasting in a patient with defective carnitine
transporter showed hypoketosis throughout and hypoglycemia
by 12 hours (Figure 37.4) [1]. The fast was stopped when the
plasma glucose reached 2.8
the patient remained asymptomatic. Levels of free-fatty acids
in plasma rose sharply to 2.22
3-hydroxybutyrate remained flat at 0.27
centrations of ammonia rose. Treatment with carnitine cor-
rected this patient’s impaired hepatic oxidation of fatty acids;
and she was able to fast for 24 hours without hypoglycemia.
Levels of 3-hydroxybutyrate rose to 2 mmol/L, higher than
the free-fatty acids (1.25 mmol/L).
Diet may contribute to the pathogenesis of symptoms in
this disease. A 12-year old who died suddenly following sur-
gery [9] had been exposed to an essentially vegetarian diet
for some time. The 3-month-old initial patient [1] had been
changed from a cow’s milk protein containing formulation to
a soy protein preparation that contained no carnitine, four
weeks prior to the episode of hypoketotic hypoglycemia.
The pathogenesis of symptoms of hypoketotic hypo-
glycemia reflects the role of fat in energy metabolism. Hypo-
glycemia after short periods of fasting usually represent
disorders of carbohydrate metabolism. The oxidation of fatty
acids is not a major source of energy until relatively late in
fasting. It usually takes 15 to 24 hours of fasting to induce
hypoglycemia in a patient with a disorder of fatty acid oxida-
tion. An individual who never fasted beyond 12 hours would
usually be protected against this manifestation.
The metabolism of fat begins with lipolysis; those patients
with defective fatty acid oxidation have high ratios of free
fatty acids to 3-hydroxybutyrate in blood after fasting. Once
transported into cells carnitine is esterified with acyl CoA esters
including those of fatty acids resulting from lipolysis. The
esterifications are catalyzed by carnitine acyl transferases such
as carnitine palmitoyl transferase (CPT) I. Carnitine translo-
case then catalyzes the transfer of the fatty acylcarnitines across
the membrane into the mitochondrion, where hydrolysis to
250 Carnitine transporter deficiency

80 120 160 4.0 NH3

(A) (B)

60 90 120 3.0

Plasma BOB, FFA (mmol/L)

Plasma carnitine (
mol/L)

Blood ammonia (
mol/L)

Plasma glucose (mg/dL)

Glu
FFA Carn
40 60 80 2.0
NH3

Glu
20 30 40 1.0

FFA

BOB
Carn BOB
0 0 0 0
0 6 12 18 24 0 6 12 18 24

Duration of fast (hours)

Figure 37.4 The response to fasting in a patient with the carnitine transporter defect. (A) In the control state hypoglycemia(glu) was
prominent at 12 hours, and there was no evident ketogenesis (3-hydroxybutyrate [BOB]) despite elevation of free-fatty acids (FFA). (B) Following
treatment with carnitine, fasting for 24 hours was without hypoglycemia, and ketogenesis was evident in the rising BOB. (Reprinted with
permission from the New England Journal of Medicine [1].)

fatty acyl CoA and free or recycled carnitine is catalyzed function may be unaffected until the intracellular muscle
by CPT II. Fatty acyl CoA compounds then undergo - concentration of carnitine falls below 30–50
mol/L or two to
oxidation in which there is successive shortening by two carbon four percent of normal. Biopsied muscle revealed a decrease
atoms releasing acetyl CoA. In muscle, this is largely oxidized of stored lipid with treatment, but not a disappearance [1].
via the citric acid cycle, while in liver ketogenesis proceeds via
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