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During infancy or early childhood, patients with underlying
metabolic diseases may present with acute metabolic disturbance
simulating Reye's syndrome (RS). Just as several forms of
inherited organic acidemias and fatty acid oxidation disorders,
patients with primary systemic carnitine deficiency (SCD),
although rare, can also present with features like RS.(1,2)
L-Carnitine (3-hydroxy-4-N-trimethylaminobutyric acid) is
a quaternary amine which can either be biosynthesized from
its endogenous precursors, lysine and methionine, or be exogenously
derived from nutrient intake.(3) L-Carnitine plays a critical
role in fatty acid metabolism because it facilitates the transport
of long-chain fatty acids (LCFA), as acyl coenzyme A esters,
across the mitochondrial membrane, and is thus an essential
component of normal fatty acid b-oxidation in the mitochondrial
matrix.(3) Carnitine deficiency syndrome may occur when intracellular
free carnitine is not sufficient to accomplish the primary
functions of carnitine. I present a girl with primary SCD
with recurrent Reye-like syndrome and dilated cardiomyopathy.
The diagnosis of primary SCD was confirmed after extensive
metabolic studies, including urine organic acid profile and
plasma carnitine level.
CASE REPORT
A 6-year-old girl was admitted due to conscious disturbance
with convulsions. On initial examination at the emergency
department, she breathed rapidly (46/min) and deeply. Recent
history of cold sweats, abdominal pain and common colds were
also noted. Intravenous infusion with glucose solution was
given due to an earlier blood glucose level of 7 mg/dL. Her
vital signs became stable and her consciousness recovered
gradually (from E2V2M5 to E4V5M5). She is the second child
of healthy, non-consanguineous parents. No perinatal insult,
history of head trauma, or drug exposure was noted. However,
she was previously hospitalized 8 times due to the following:
(1) neonatal fever and metabolic acidosis of unknown cause
at 11 days old; (2) drowsiness and seizure with normal biochemical
and microbiological results at 2.1 years old; (3) pneumonia,
urinary tract infection, drowsiness, and dilated cardiomyopathy
at 2.3 years old, when digitalis and captopril were used;
(4-6) respiratory tract infections, cardiomyopathy, drowsiness,
and epilepsy at 2.5, 2.8 and 3.1 years old, respectively;
and (7,8) sepsis or pneumonia, drowsiness, and heart failure
at 4.9 and 5.7 years old, respectively.
The patient looked thin and short (body weight, 13.5 kg; body
height, 101 cm) without jaundice. No apparent craniofacial
dysmorphism were found. Her breathing sounds were clear and
there was no heart murmur. The liver was palpable 6 cm below
the right costal margin. No specific odor was smelled from
her urine or breath. The muscle power and reflexes were all
within reference ranges. The chest films showed marked cardiomegaly
with cardio-thoracic ratio of 80% (Fig. 1A). The plain abdomen
films showed no abnormalities. Laboratory results showed elevated
levels of serum aspartate aminotransferase, 75 U/L; alanine
aminotransferase, 45 U/L; ammonia (NH3), 391 mg/dL; urea nitrogen,
36 mg/dL; creatine kinase (CK), 302 U/L (15-130) with CK-MB:
73 (normal < 16); and normal serum levels of bilirubin,
sodium, potassium, calcium, creatinine, and chloride. Hemogram
showed a hemoglobin level of 11.6 g/dL, a leukocyte count
of 17200/mm3 (70% segmented, 4.5% banded, 7% monocytes, 17.5%
lymphocytes, and 1% atypical lymphocytes) and normal platelet
count. The serum level of C-reactive protein was 6.3 mg/L.
Urinalysis revealed only trace ketones. Cerebrospinal fluid
(CSF) examination results were negative. The blood gas was
pH of 7.390, PCO2 of 26.3 mmHg, PO2 of 149.7 mmHg, HCO3 of
15.9 mEq/L, and base excess of -7.4 mEq/L (under 30% oxygen)
with increased anion gap (23 mEq/L). The levels of lactate/pyruvate
were 8.0/0.85 mg/dL, and her plasma amino acid pattern was
normal. The results of microbiological studies of urine, blood,
and CSF were all negative. The computed tomographic scan of
the head showed mild brain edema. Electrocardiography showed
left ventricular hypertrophy and echocardiogram revealed dilated
cardiomyopathy with ejection fraction (EF) of 31%. The plasma
carnitine level (free form/total) was below 5/5 mmol/L (reference
range, 27-49/ 36-58 mmol/L). The urine gas chromatography/mass
spectrometry (GC/MS) study for organic acids profile showed
mildly increased adipic, methylcitric, and d-glucuronic acids
(Fig. 2). The diagnosis of primary systemic carnitine deficiency,
complicated with epilepsy, hypoglycemia, dilated cardiomyopathy,
Reye-like syndrome, failure to thrive, and short stature was
established. After treatment with oral L-carnitine (50 mg/kg/day)
for 3 months, she was much improved clinically with carnitine
level of 22.5/32.5 mmol/L. Sequential chest radiographs demonstrated
decreased cardiomegaly (Fig. 1B), and the echocardiographic
studies documented increases in the EF (61%) and reduction
of the end diastolic volume. At the 9th month of treatment,
the dosage was raised to 100 mg/kg/day due to relatively low
levels of carnitine (9.93/14.56). No more hypoglycemia, hyperammonemia,
or conscious disturbance occurred. Her appetite became better
with appropriate weight gain and growth. The carnitine levels
in her mother and father were 18.53/22.76 mmol/L and 15.15/23.56
mmol/L, respectively.
DISCUSSION
Reye's syndrome is an acute noninflammatory encephalopathy
associated with evidence of hepatic dysfunction. It has been
noted to be associated with the use of aspirin following various
viral infections, and numerous other disease states including
liver necrosis, drug intoxication and several inherited metabolic
diseases (IMD) which may produce symptoms and signs mimicking
RS.(1,2) The diagnosis of SCD is difficult. In this case,
the initial features including epilepsy and dilated cardiomyopathy
did not show specific clues to alert the doctors. Finally,
according to her complicated medical history and after extensive
metabolic studies (urine GC/MS, plasma amino acids, and carnitine
levels), a certain IMD such as SCD was highly possible. The
clinical course of this patient was consistent with the diagnosis
of primary SCD including features similar to RS (encephalopathy,
elevation of serum transaminase values, hypoglycemia and hyperammonemia),
dilated cardiomyopathy, very low concentrations of free and
total carnitine in plasma, and an excellent response to carnitine
therapy. Other metabolic etiologies that may lead to RS (urea
cycle defects, and organic acidurias) or RS/ cardiomyopathy
(fatty acid oxidation disorders, respiratory chain disorders,
and glycogenosis) were excluded using the laboratory findings.(1,2)
Carnitine is synthesized from lysine and methionine, however,
the greater part is derived from the diet.(3) Cellular carnitine
acts as an obligatory cofactor for b-oxidation of fatty acid
by facilitating the transport of LCFA across the mitochondrial
inner membrane as acylcarnitine-esters and also modulates
the intramitochondrial Coenzyme A (CoA)/acly-Co-A ratio.(4)
Impairment of LCFA transport into the mitochondria results
in failure of energy production and accumulation of triglycerides
in tissues dependent on oxidative metabolism, such as skeletal
and cardiac muscle.(3,4) Failure to modulate the CoA/acyl-CoA
ratio also impairs energy production and allows the accumulation
of toxic acyl-CoA compounds. These aberrations in the metabolism
may cause a variety of potentially fatal symptom complexes
during infancy and childhood, including neonatal death, hepatic
encephalopathy, dilated cardiomyopathy and progressive skeletal
myopathy.(3,4) In addition, the accumulation of toxic fatty
acyl derivatives impedes gluconeogenesis and urea cycle function
and, in turn, causes hypoketotic hypoglycemia, elevations
in transaminase, and hyperammonemia.(1,4)
Primary systemic carnitine deficiency is an autosomal recessive
disorder. Two different clinical presentations have been described.(3)
Some young patients (< 2 years of age) may first have episodes
of fasting hypoketotic hypoglycemia or a Reye-like syndrome,
but the majority of patients are diagnosed later in their
childhood when progressive cardiomyopathy with or without
skeletal muscle weakness developed. In some patients, endocardial
fibroelastosis also occurred. Several sudden and unexpected
deaths have been reported.(5) Clinical detection is often
possible when significant symptoms diagnostic of SCD are accompanied
by extremely reduced carnitine levels in plasma and muscles
to 1-2% of normal. Heterozygote parents may have plasma carnitine
levels below the reference range (The parents had approximately
50% of normal in this report). Acute crises produced by carnitine
deficiency are treated with generous intravenous glucose supplementation
to correct or prevent hypoglycemia.(1) When hyperammonemia
is present, protein intake must be restricted. Fluid deficits
and acid/base abnormalities must be corrected. Avoidance of
fasting, supplying frequent meals of high-carbohydrate content
and low-fat diet are advisable in all patients with SCD. Maintenance
therapy with L-carnitine 100 mg/kg daily is suggested. Cardiomyopathy
often responds well to carnitine supplementation.(3,4)
There is an active transporter system across membranes in
the small intestine, renal tubules, skeletal muscle, and skin
fibroblasts.(6,7) In membrane-physiological studies, researchers
have discovered a defect in the carnitine transporter system
of the plasma membrane in SCD patients. The carnitine transporter
defects impair the uptake of carnitine in the kidney, heart,
muscle, and skin fibroblasts but not in the liver.(6,7) Because
of the failure of muscle uptake and renal conservation of
carnitine, affected patients cannot maintain adequate plasma
and tissue levels of carnitine, leading to impairment of mitochondrial
fatty acid oxidation. Fasting ketogenesis may be normal, because
the liver carnitine transporter is normal, but may be impaired
if dietary carnitine intake is interrupted.(6-8) The fasting
urinary organic acid profile may show hypoketotic dicarboxylic
aciduria if hepatic fatty acids oxidation is impaired, but
is otherwise unremarkable. Oxidation of accumulated fatty
acid through an alternative pathway, w-oxidation, produces
dicarboxylic aciduria.(3,4)
Systemic carnitine deficiency is the only genetic defect in
which carnitine deficiency is the cause, rather than the consequence,
of impaired fatty acid oxidation. Its genetic defect is in
a sodium ion-dependent carnitine transporter that has been
mapped at 5q31.1.(9) This transporter protein, termed OCTN2,
is responsible for maintaining intracellular carnitine 20~50-fold
higher than plasma concentrations and for renal conservation
of carnitine.(8,9) OCTN2 has the ability to transport carnitine
in a sodium-gradient dependent manner. Biochemical analysis
revealed that this mutation abrogates carnitine transport.
The mutation studies (homozygous deletion, compound heterozygote,
and homozygous splice-site mutations) have shown evidence
that loss of OCTN2 function causes SCD.(8,9)
Reye-like IMDs may result in early neonatal death with the
misdiagnosis of neonatal sepsis. In the cases of positive
family history of RS, unexplained encephalopathy, sudden infant
death, recurrent encephalopathy or metabolic acidosis since
a young age, early sampling of the body fluid or tissue is
recommended to elucidate the underlying IMDs.(1,2) This would
help prevent the recurrence of symptoms using diet control
and medications, and help with genetic counseling. I presented
carnitine deficiency syndrome, which is one of the many rare
but treatable disorders, in a 6-year-old girl. It is necessary
to detect and treat this disease early to decrease the morbidity
and mortality rates.
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