CLINICO-PATHOLOGICAL CONFERENCE
A case of impairment of mitochondrial fatty acid b-oxidation
Tomonobu Hasegawa, Naoaki Hori and Wenlin Du1
Departments of Pediatrics and Pathology1, School of Medicine, Keio University, Tokyo, Japan(Received for publication on December 20, 2001)

Abstract. We describe a patient with impairment of mitochondrial fatty acid b-oxidation. A Japanese
baby boy was delivered in the 38th week of gestation by emergency cesarean section due to fetal asphyxia. His birth weight was 1,985 g (H10th percentile), length 44.8 cm (H10th percentile), and headcircumference 31.0 cm (10th percentile). His Apgar scores were 3 and 5 at 1 min and 5 min, respectively. Blood glucose was 12 mg/dl at 1 hour after birth, requiring glucose administration. On day 1 hisserum CK was 20,780 IU/ l, which was thought to be due to asphyxia. His serum CK levels graduallybegan to decrease. At 3 months of age, he sucked poorly, had poor body weight gain, and muscle
hypotonia was observed. On day 117 his general condition was impaired, and marked hepatomegaly
was observed. The blood glucose level was 43 mg/dl. The patient’s urine was negative for ketone bodies.
His serum triglyceride level was 3,670 mg/dl. Abdominal CT scan revealed a fatty liver. Serum levels ofacyl carnitine from very-long chain fatty acid increased. On day 118 he died due to ventricular ﬁbrillation. On necropsy, massive lipid deposition was observed in the liver, cardiac muscle, kidney, skeletal
muscle, and intestinal mucosa. The ratio of very-long chain acyl-CoA dehydrogenase (VLCAD) activity for C16/C8 fatty acid was 0.50 (normal control 1.29), suggesting abnormal VLCAD. He was diagnosed as having impairment of mitochondrial fatty acid b-oxidation, presumably due to the VLCAD
deﬁciency. (Keio J Med 51 (2): 100–106, June 2002)
Key words: mitochondria, fatty acid b-oxidation, very-long chain acyl-CoA dehydrogenase(VLCAD),
hypoglycemia

Dr. Hasegawa (Moderator): I now announce theopening of the 1040th Clinico-pathological Conference(CPC).
Today’s CPC is being conducted with two main goals
in mind. The ﬁrst is to understand the function of
mitochondrial fatty acid b-oxidation in terms of energy
production in the living body or cells. The second isto understand when, i.e., with what symptoms or laboratory data, clinicians must suspect the impairment of
mitochondrial fatty acid b-oxidation.
By way of introduction, I would like to mention
three points. The ﬁrst point is that, as we are all wellaware, glucose is the most important source of energy
production in the cells. Now, let me ask you, Mr.
Kanasaka – The energy, namely ATP, is critical for thecells to survive. The most important source of energy or
ATP production is glucose. Ingested carbohydrates arebroken down in the intestine, and absorbed in the formof glucose. Blood glucose is then taken up by the vari-

ous cells of the body to serve as the source of energy.
After prolonged fasting, i.e. when the supply of dietary
glucose stops, what would the cells obtain energy from?
Mr. Kanasaka (5th year student): Under such circumstances, fatty acids are b-oxidized to acetyl-CoA,and acetyl-CoA enters the TCA cycle to produce
energy.
Dr. Hasegawa: I shall ask you the same question
again, as you have perhaps not understood my question
clearly. If there is no supply of glucose from the diet,where can glucose be obtained from before the period
when energy is produced by mitochondrial fatty acidb-oxidation?
If the dietary supply of glucose is stopped, thecells still try to procure energy from glucose before
relying on mitochondrial fatty acid b-oxidation. This isbecause ATP production through the glycolytic pathway, the TCA cycle, and the electron transfer systemare extremely efﬁcient. Thus, the cells still attempt toThis is a record of the 1040th CPC of Keio University Hospital, held on November 14, 2001.
Reprint request to: Dr. Tomonobu Hasegawa, Department of Pediatrics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan100

Keio J Med 2002; 51 (2): 100–106

use glucose rather than relying on mitochondrial fatty
acid b-oxidation.
Under conditions in which dietary glucose is nolonger supplied or after prolonged fasting, glucose isderived from the degradation of glycogen in the liver.
Glycogen is a storage form of glucose. The glucose thatis stored in the liver in the form of glycogen, like money
in a bank, is thus used during periods of starvation. At
these times of necessity, the glucose derived from thedegradation of glycogen is released into the blood, andused for energy production. When the glycogen in theliver is exhausted, just as when there is no money left inthe bank, then the source of energy is changed fromglucose to fatty acids.
Therefore, the liver can be compared to a bank,where money is deposited. When you have no income
today, but need money, you withdraw some moneyfrom the bank to cater to your needs of the day. Whenthe money in the bank is used up, you ask a moneylender for a loan. Fatty acids can be compared to moneylenders.
The second introductory point I would like to mention is, ‘‘when is the source of energy production ischanged from glucose to fatty acids’’. The source ofenergy production is changed from glucose to fatty
acids when there is no dietary glucose supply and theglycogen in the liver is also exhausted. In other words,
cells use fatty acids as the source of energy under thefollowing conditions: 1. prolonged fasting; 2. a newborn
whose glycogen in the liver is very poor; and, 3.
increased energy demands of the body for any reason.
During exercise or ill health, the energy demands of the
body is high. The source of energy, therefore, is changing from glucose to fatty acids.
The third introductory point I wish to mention is thatthe heart relies on fatty acids rather than glucose as its
source of energy. As I told you previously, most cells
produce ATP, initially using glucose as the source ofenergy. Fatty acids are not used until all of the glucose
is used up. However, as an exception, the heart overwhelmingly relies on fatty acids rather than glucose as
its source of energy. If there is some problem in the
production of energy from fatty acids, the heart may be
the ﬁrst organ to be affected when the energy source ischanged from glucose to fatty acids.
That was by way of introduction. Does anybody haveany questions?
So, now, Dr. Hori, the pediatrician-in-charge oftoday’s case, would you please present the case of theday?
Dr. Hori (Pediatrics): The patient was a 3-month-old
boy who presented with hypoglycemia. This boy wasdelivered by emergency caesarian section because of
fetal asphyxia at 38 weeks and 2 days of gestation. The
weight, length and head circumference at birth were101

1,985 g (below the 10th percentile), 44.8 cm (below the10th percentile), and 31.0 cm (10th percentile), respectively, indicative of intrauterine growth retardation.
The one-min and 5-min APGAR scores were 3 and 5,
respectively, indicative of neonatal asphyxia. The baby
was admitted to the NICU. Although the blood glucose level was 12 mg/dL 1 h after birth, it improved to
67 mg/dL following administration of 20% glucose.
The serum CK level was as high as 20,780 IU/L the
day after birth (Day 1), although it decreased to 214
IU/L on Day 6; the initial high CK level was thought to
be attributed to asphyxia. The body temperature was
35.5  C on Day 9, with abnormally high serum CK,
LDH, AST and ALT levels. The cause for these abnormal elevations, however, remained unclear. Thereafter, the serum CK level varied between 800 and 1,500
IU/L. Since the feeding status and weight gain werefavorable, the infant was discharged on Day 43. His
weight was 3,200 g at discharge.
The patient’s feeding status worsened gradually from
Day 90, and the boy was brought to the same hospitalon Day 111. Poor weight gain, hypotonia and hepatomegaly were found at that time. The feeding statusworsened further on Day 116, and the child wasadmitted to the hospital with vomiting on Day 117.
Physical examination on admission revealed low temperature (35.9  C), tachypnea, a decreased level of consciousness, generalized perspiration, and nasal ﬂaring.
The blood glucose level was 43 mg/dL, and urinary
ketone bodies were negative. Cardiac ultrasonography
revealed pericardial effusion, and abdominal CT
showed a prominent fatty liver. The patient was referred to our service for further evaluation on Day 118.
With regard to the developmental status, head control and eye contact were yet negative. The baby
laughed for the ﬁrst time at 3 months of age.
There was no family history of consanguineous marriage or muscular disease.
Are there any questions so far?
Mr. Kanasaka: Could you give us more details of thefamily history? For instance, was there any history of
SIDS, especially in the child’s siblings?
Dr. Hori: This patient was the ﬁrst child. There wereno siblings. There was no family history of sudden
death.
Mr. Kanasaka: Was the course of the pregnancy inthe mother normal?
Dr. Hori: Yes, absolutely normal.
Mr. Kamata (5th year student): The CK level varied
between 800 IU/L and 1,500 IU/L before the patient
was discharged on Day 43. Were the isozymes of CK
examined?
Dr. Hori: The MM isoenzyme from the skeletal
muscle was always the predominant.
Ms. Kawade (5th year student): Hepatomegaly was102

noted when the patient was brought to the hospital on
Day 111. Was it found by palpation or by abdominal
ultrasonography?
Dr. Hori: By palpation.
Ms. Kawade: Poor weight gain was noted on Day
111. Do you have any precise data on the rate of weightgain?
Dr. Hori: No. I do not have any numerical data.
Mr. Gatayama (5th year student): Urinary ketone
bodies were negative when the blood glucose level was
43 mg/dL on Day 117. Is it common for infants under 1
year of age to be negative for urinary ketone bodies
even when the blood glucose level is so low, like 43 mg/
dL?
Dr. Hori: No. It is not common for even infants ofthis age to be negative for urinary ketone bodies when
the blood glucose level is low.
Now, I shall proceed with the presentation.
Physical examination on admission revealed the following ﬁndings: length, 59.5 cm; weight, 4,363 g; headcircumference, 38.5 cm; temperature, 36.2  C; heartrate, 150/min; respiratory rate, 46/min; systolic pressure,
96 mmHg. The child showed poor movement of theextremities, and cried weakly. Prominent edema of theeyelids and extremities was noted. The chest was clear
to auscultation, and there was no cardiac murmur.
There was abdominal distension, and the liver, with asharp edge, was palpable 9 cm below the right costal
margin. The spleen was not palpable. Moro’s reﬂex was
positive, with bilateral symmetry.
I shall now give the laboratory data on admission.
Peripheral blood examination revealed a total WBC
count of 5,600/mL, Hb of 10.4 g/dL, and platelet countof 30:8  10 4 /mL.
The serum was chylous. I will refer to some of thebiochemical data (Table 1). Serum UA was 12 mg/dL,
Na 120.8 mEq/L, Cl 85 mEq/L, Ca 7.6 mg/dL, AST 185
IU/L, ALT 69 IU/L, LDH 830 IU/L, CK 1,133 IU/L
(MM isoenzyme predominant), aldolase 13 IU/L, Glu
84 mg/dL, TC 371 mg/dL, TG 3,670 mg/dL, FFA 2.09
mEq/L, lactate 22.5 mg/dL, pyruvate 0.95 mg/dL, total
ketone bodies 521 mmol/L, acetoacetate 127 mmol/L,and 3-hydroxybutyrate 394 mmol/L.
Blood gas analysis did not reveal acidosis.
On chest X-ray, the cardiothoracic ratio was calculated to be 63%.
Electrocardiography showed non-speciﬁc T-wavechanges.
Cardiac ultrasonography revealed an ejection fraction of 64.1%, and there was a moderate pericardial
effusion from the lateral to posterior wall.
Head CT revealed no abnormalities.
Serum acyl carnitine analysis revealed that the levelof acyl carnitine derived from long chain fatty acids waselevated.

Hasegawa T, et al: A case of VLCAD deﬁciency
Table 1

Laboratory Data and Imaging Studies(Biochemistry) TP 4.2 g/dL, Alb 3.0 g/dL, BUN 31.3 mg/dL, Cr 0.4
mg/dL, UA 12.0 mg/dL, Na 120.8 mEq/L, K 4.7 mEq/L, Cl 85
mEq/L, Ca 7.6 mg/dL, IP 5.7 mg/dL, AST 185 IU/L, ALT 69 IU/
L, LDH 830 IU/L, CK 1,133 (MM 99%, MB 1%) IU/ L, Aldolase
13 IU/L, Glu 84 mg/dL, CRP 0.02 mg/dL, NH3 50 mmol/ L, TC 371
mg/dL, TG 3,670 mg/dL, HDL-C 23 mg/dL, FFA 2.09 mEq/L,
Lactate 22.5 mg/dL, Pyruvate 0.95 mg/dL, Total ketone body 521
mmol/ L (N ¼ 26–122), Acetoacetate 127 mmol/L (N ¼ 13–69), 3hydroxy lactate 394 mmol/ L (N ¼ 76 or less), Total carnitine 52.8
mmol/ L (N ¼ 45–91), Free carnitine 18.0 mmol/ L (N ¼ 36–74),
Acyl carnitine 34.8 mmol/ L (N ¼ 6–23).
(Venous blood gas analysis) pH 7.403, PCO2 44.5 Torr, HCO3 27.1
mEq/L, BE 2.0 mEq/L.
(Urinalysis) S.G. 1.015, Ketone body (), Protein (), Glucose (),Blood ().
(Chest X-ray) Cardiothoracic ratio 63%.
(Electrocardiography) Sinus rhythm, Axis þ10, nonspeciﬁc T wave
changes (þ).
(Cardiac ultrasonography) Ejection fraction 64.1%, prominent
pericardial effusion collection (þ) from the lateral to posterior
wall.
(Head CT) No abnormal ﬁndings such as bleeding, edema, orhydrocephalus.
(Urinary organic acid analysis) High level of non-ketone
dicarboxylate.
(Serum acyl carnitine analysis) High level of acyl carnitine derived
from long-chain fatty acids.

Abdominal CT ﬁndings were suggestive of a fatty
liver.
Mr. Kimura (6th year student): On physical examination, did he have any odd looking face or congenital
anomaly?
Dr. Hori: No. – there were no such abnormalities.
Now, I shall describe the clinical course of the patient after admission. On Day 119 (the second hospitalday), nystagmus was observed, which persisted for 1 h.
Soon after, hypoglycemia (48 mg/dL) was noted, but
the urinary ketone bodies were negative. The child thenabruptly developed ventricular ﬁbrillation with cardiopulmonary arrest, and eventually died, without any
response to resuscitation.
If you have any questions or comments about theclinical course of the patient, or any other questions sofar, I shall be happy to answer them.
Mr. Kanasaka: What race did the patient and his
family belong to?
Dr. Hori: The family is Japanese.
Mr. Kanasaka: So, they are not Caucasian.
Dr. Hori: No.
Mr. Oda (5th year student): The patient showed intrauterine growth retardation. What did that suggest?
Dr. Hori: Your point is well taken. I shall come tothat point later.
Dr. Hasegawa: No deﬁnite diagnosis has yet been
established at this moment. Now, I would like to ask

Keio J Med 2002; 51 (2): 100–106
Table 2

103

Postmortem Pathological Diagnosis

Congenital defects in fatty acid beta-oxidation[strongly suggesting very-long-chain-acyl-CoA dehydorogenase
deﬁciency]a. Weight at birth low (gestational age 38 weeks and 2 days, weight
1,985 g)At autopsy, length 58 cm, weight 4.6 kg, 3 month old
b. Decreased activity of very-long-chain-acyl-CoA dehydorogenase(Table 2)c. Severe fatty changes in systemic organs(heart, liver, kidney, stomach, systemic skeletal muscles)
d. Pericardial effusion (50 ml)

Dr. Hori to brieﬂy summarize the tentative diagnosis
from the clinical viewpoint.
Dr. Hori: I clinically suspected the impairment of
mitochondrial fatty acid b-oxidation because, 1) the
urinary ketone bodies were negative in association withhypoglycemia, 2) there was prominent hepatomegaly,3) the blood triglyceride level was high, and 4) CT suggested a fatty liver. However, since the patient died too
soon, no deﬁnitive diagnosis could be made.
Dr. Hasegawa: Then, I should ask the pathologist to
solve the riddle.
Dr. Du (pathology): The postmortem pathologicaldiagnosis is shown in Table 2. The weight of the patientat birth was low, but without any malformations. The
length of the patient (3 month old) was 58 cm which
was above the 10th percentile. The body weight was 4.6
kg that was below the 10th percentile. Mild-retardation of the body growth was observed. Marked hepatomegaly is shown in Fig. 1a and the weight of the liver(460 g) was over twice that of normal infants. The liver
was yellowish and histologically severe fatty changes
were revealed (Fig. 1b). The nuclei were located in the
peripheral spaces of liver cells and vacuoles were
stained with oil red-O (Fig. 1c). Hypertrophy of theheart (26 g) and a diffuse fatty degenerartion stainedwith the oil red-O, was revealed in the heart muscle(Fig. 2a and b). Positive staining with oil red-O in heart
muscle cells of normal infants should not be shown.
These fatty changes in systemic organs have been seen
in some disorders with lipid metabolism including theabnormality of fatty acid oxidation. The fat degeneration was also seen in the kidneys (in the cytoplasmof the uriniferous tubular epithlia), stomach (in the cytoplasm of the foveolar cells), intestine and systemic
skeletal muscles. Very-long-chain-acyl-CoA dehydrogenase activity was examined. Mitochondria fractions
were obtained from the liver specimens. Very-longchain-acyl-CoA dehydrogenase activity against C8, a
medium chain fatty acid, and C16, a very long chain
fatty acid, were examined by the ferrocemoium reduction assay (Table 3).

abcFig. 1 Fatty liver. (a) Gross appearance showing marked hepatomegaly (460 g) with a yellow colour. (b) HE staining. Hepatocyteswith vacuolar degeneration are shown. The hepatocyte nuclei arelocated in the peripheral spaces. (c) Oil-red O staining. The vacuoles
in the cytoplasm are stained orange-red.

Normal infant liver and human skin ﬁbroblasts
derived from a normal donor were used as negative
controls. The enzymatic activity, which was expressed

104

Hasegawa T, et al: A case of VLCAD deﬁciencyabFig. 2 Heart muscle specimens with fatty changes. (a) HE staining.
(b) Oil-red O staining. Small fatty droplets stained with oil-red O exist
diffusely in the heart muscle.
Table 3 Very-long-chain-acyl-CoA Dehydrogenase Activity (Ferricenium Reduction Assay)

Patient liver

exp-1
exp-2
Normal infant liver
Human ﬁbroblastProtein(mg/ml)C8*

C16*

C16/C8

13.7

35.6
35.6
11.3
1.67

17.8
19.7
14.5
2.15

0.50
0.56
1.29
1.29

16.8
14.2

C8: octanoyl-CoA,
C16: palmitoyl-CoA,*: nmol reduction of ferricenium/min/mg protein.
exp-1: the ﬁrst experiment.
exp-2: the second experiment using the same specimen.

as the C16/C8 ratio, was 0.5–0.56 in this patient’s livertissue compared with the control ratio of 1.29. This result showed decreased activity of the very long chain
acyl-CoA dehydrogenase. As a result, it was suggested
that the disorder in this case was caused by the impairment of beta-fatty acid oxidation.

Mr. Kanasaka: Did you observe any changes in thebrain?
Dr. Du: Autopsy of the brain was not permitted by
the bereaved family.
Dr. Hori: I shall now speak a little about the signiﬁcance and mechanism of mitochondrial fatty acid boxidation. The living body normally uses glucose as theenergy source. Under conditions in which no glucose
is available, energy is produced by mitochondrial fatty
acid b-oxidation.
Fatty acids cannot enter the mitochondria without
undergoing biochemical changes. First, they are converted to acyl-CoA, and later to acyl carnitine, whichthen enters the mitochondria, where it is reconverted toacyl-CoA. I shall not discuss in detail the mechanismsof entry of fatty acids into the mitochondria.
In the mitochondria, acyl-CoA is subjected to boxidation. b-oxidation is a reaction in which two carbons are removed in each step. The ﬁrst enzyme in boxidation is acyl-CoA dehydrogenase, which consistsof three types: acyl-CoA dehydrogenase for very-longchain fatty acids (VLCAD), acyl-CoA dehydrogenase
for medium-chain fatty acids (MCAD), and acyl-CoA
dehydrogenase for short-chain fatty acids (SCAD).
I will come back the question about the race of thechild. Most of reported patients with MCAD deﬁciency
are Caucasians. When the impairment of mitochondrial
fatty acid b-oxidation is suspected, it is important to
conﬁrm the race of the patient.
Only seven cases of VLCAD deﬁxiency have beenreported so far in Japanese patients. In fact, only about
60 cases have been reported world-wide.
Based on the clinical ﬁndings and the enzyme activity
in the liver, a diagnosis of VLCAD deﬁciency was suspected, as mentioned by Dr. Du.
At present, a mutation analysis of the VLCAD geneis under way to reach a deﬁnitive diagnosis.
Does anyone have any questions?
Mr. Hasegawa (6th year student): Does VLCAD
deﬁciency fall under the category of peroxisomal diseases, because it is a disorder of very-long-chain fatty
acid metabolism?
Dr. Hori: No. VLCAD deﬁciency does not belong
to the category of peroxisomal diseases. VLCAD is an
enzyme localized in the mitochondria, and it mainly
catalyzes the b-oxidation of 18-carbon fatty acids. On
the other hand, oxidation of fatty acids in peroxisomes
usually involves 24- or 26-carbon fatty acid substrates.
Mr. Hasegawa: The patient did not have peroxisomal
disease. Didn’t he exhibit peroxisomal-disease-speciﬁc
symptoms, such as central nervous system symptoms?
Dr. Hori: No. A question was asked some time ago
regarding intrauterine growth retardation (IUGR) in
this child; to tell you the truth, I can’t explain why thepatient had intrauterine growth retardation. IUGR canKeio J Med 2002; 51 (2): 100–106

be symmetrical or asymmetrical. In symmetrical IUGR,
length, weight, and head circumference were appropriately small. Conversely, in asymmetrical IUGR, while
the length and weight are small, the head is relatively
normal in size. When the mother herself or the placenta
is under stress, the fetus tries to protect the most important part of the body, namely, the head. That is,blood ﬂow to the head is maintained, so that the headgrows normally, while the length and weight are small;this is asymmetrical IUGR. On the other hand, in thecase of symmetrical IUGR, as in our case, fetal factors
must exist without (or in addition to) maternal andplacental factors. The patient showed symmetrical
IUGR, which could be due to the inborn error of fatty
acid metabolism.
Mr. Sato (6th year student): I have two questions; 1)
The child had nystagmus. Why did that happen? 2)
What are the reasons for the clinical differences between VLCAD deﬁciency and peroxisomal diseases. In
my understanding, the difference between the two is thenumber of carbons in the substrate, while both are ultimately defective of fatty acid metabolism? Clinicallymalformations are characteristic of peroxisomal diseases. Does that suggest that organogenesis is inﬂuenced differently according to the number of carbons in
the fatty acid chain?
Dr. Hori: In response to your ﬁrst question, I should
admit that the cause of the nystagmus remains unclear.
Dr. Hasegawa: I will answer the second question.
Peroxisomal diseases comprise several different types.
In the representative form, the peroxisomes themselves
are absent. Each cell in our body is composed of various factories. The absence of peroxisomes means theabsence of one entire factory. On the other hand, in
VLCAD deﬁciency, in which an abnormality of fatty
acid b-oxidation occurs, the mitochondria (one of thefactories) are normal in structure, however, the processof b-oxidation, i.e., one of the various processes in thefactory, is out of order. In other words, the factory itself
is present, but a part of the machinery is unserviceable.
Thus, in VLCAD deﬁciency, all machines other than
VLCAD are in working condition. On the other hand,in peroxisomal diseases, the factory itself is absent, sothat not only fatty acid b-oxidation but also all the otherreactions in the peroxisomes are defective. These features may explain why there are marked clinical differences between the two conditions.
Mr. Sato: Is there any disease in which only the metabolism of fatty acids that takes place in the peroxisomes is defective?
Dr. Hasegawa: Yes. Other than the representative
form of peroxisomal diseases which I told you, there
are some forms with peroxisome being present but
functionally defective. For instance, 3-ketothiolase deﬁciency has defective fatty acid metabolism that takes

105

place in the peroxisomes, while other metabolic processes in the peroxisome are normal. Needless to say,
3-ketothiolase deﬁciency has normal mitochondrial
fatty acid b-oxidation.
Mr. Hasegawa: I can understand why pathologicalabnormalities in the impairment of mitochondrial fatty
acid b-oxidation are prominent in organs such as theliver, myocardium, and skeletal muscle, where mitochondria are abundant. On the other hand, I guess thatthe pathological abnormalities in peroxisomal diseases
are systemic. Is that right?
Dr. Hasegawa: As you have pointed out, in diseases
like VLCAD deﬁciency, which are associated withmitochondrial failure, lesions are mainly found inorgans which originally have abundant mitochondria.
On the other hand, in peroxisomal diseases, the organ
showing the most severe pathological abnormalities
varies according to the type of the disease.
Mr. Kiuchi (5th year student): I would like to ask
about the laboratory ﬁndings on admission. What is thereason for the rather high total ketone body levels inthe blood?
Dr. Hori: I will change your question as follows. Why
was the blood ketone body level increased, while urinary ketone bodies were negative? In VLCAD deﬁciency, b-oxidation by MCAD and SCAD are normal.
Even in VLCAD deﬁciency, mitochondrial fatty acid boxidation by MCAD and SCAD occurs leading to the
production of ketone bodies. The blood ketone bodylevel in the child was rather high, although it was nothigh enough to be excreted into the urine.
Mr. Kiuchi: I have a question regarding the enzyme
activity. You mentioned that the ratio of C16/C8 boxidation activity was low. It appeared like there wasan increase in the oxidation activity of C8, rather than adecrease in that of C16. Was there an increased oxidation of short- and middle-chain fatty acids?
Dr. Hasegawa: You misunderstood the experiment
to measure the enzyme activity. I would like to pointout that the enzyme activity measured was the activityof VLCAD. The activity of VLCAD was measured by
two different substrates, C16- and C8-fatty acid. The
activity of MCAD and SCAD was not measured. The
normal VLCAD mainly oxidizes C16-fatty acid, while
it acts little on C8, because the enzyme is substratespeciﬁc. In this patient, the data show that the substratespeciﬁcity of VLCAD may be altered.
Since we are running out of time, I would like tobrieﬂy summarize the discussion. Under conditions inwhich the body or cells cannot use glucose as the energy source, fatty acids are oxidized to produce ATPfor survival. This is the essence of mitochondrial fatty
acid b-oxidation. The patient with the impairment of
mitochondrial fatty acid b-oxidation showed signs andsymptoms in the organ in which the cells depend more

106

on fatty acids rather than glucose, when the source ofenergy is changing from glucose to fatty acid.
Are there any questions or comments?
Ms. Kim (5th year student): I have two questions.
1) How did you tell the results of the autopsy to theparents? 2) Is prenatal diagnosis of VLCAD deﬁciency
possible?
Dr. Hasegawa: We told the parents that the child had
an impairment of mitochondrial fatty acid b-oxidation.
We did not tell them that the diagnosis of VLCAD deﬁciency was convincing.
Prenatal diagnosis of VLCAD deﬁciency is theoretically possible once the gene mutation is identiﬁed. We,
however, should bear in mind that prenatal diagnosis
includes a lot of ethical issues.
Mr. Kanasaka: What is the prognosis of children with
VLCAD deﬁciency? Has any case of VLCAD deﬁciency
been reported to survive into childhood or adult?
Dr. Hasegawa: All patients with VLCAD deﬁciency
do not have a poor prognosis. Let us think about thetreatment of a patient with VLCAD deﬁciency if an
early diagnosis has been established. Glucose dependency as the source of energy is critical such as 1)
taking meals frequently to avoid fasting, 2) intake ofHasegawa T, et al: A case of VLCAD deﬁciency

a diet that promotes accumulation of glycogen in theliver, and 3) glucose supplementation when the energy
demands are increased, e.g., during exercise or illness.
Mr. Kanasaka: Some patients with VLCAD deﬁciency have a poor prognosis, while others survive for along period. What is the reason for this difference?
Dr. Hasegawa: The clinical picture varies from very
mild to very severe in patients with VLCAD deﬁciency.
One of the reasons for the varied clinical picture is thedifferences in the residual enzymatic activity. Patientswith VLCAD deﬁciency who have some residual enzymatic activity may not have any symptoms at all until
they reach adulthood – some may not have any symptoms until they have run a marathon.
Mr. Kamata: Patients with VLCAD deﬁciency
have skeletal muscle symptoms, while MCAD-deﬁcientpatients have no such symptoms. How can you explain
this difference?
Dr. Hasegawa: That is because in skeletal muscles,
mainly VLCAD is functional, i.e., fatty acids that havelong carbon chains are oxidized to provide energy.
I would now like to thank the participants for the
lively question-answer session and discussions. I now
declare today’s CPC closed.