Mitochondrial Respiratory Chain Disorder CASE

CASE REPORT
REPORT

Heart Failure
Mitochondrial and Short
Respiratory ChainStature in ain
Disorder 43Two
year-old maleChildren
Filipino
Katerina
Katerina T.
T. leyritana
leyritana11,, Ma.
Ma. Czarlota
Czarlota M.
M. Acelajado-Valdenor
Acelajado-Valdenor11,, Amado
Amado o.
o. Tandoc
Tandoc III
III22 and
and Agnes
Agnes D.
D. Mejia
Mejia11
Mary Anne D. Chiong1,2 and Carmencita David-Padilla1,2
Department
Department of
11
of Medicine,
Medicine, College
College of
of Medicine
Medicine and
and Philippine
Philippine General
General Hospital,
Hospital, University
University of
of the
the Philippines
Philippines Manila
Manila
22
Department
Department of
of Pathology,
Pathology, College
College of
of Medicine,
Medicine, University
University of
of the
the Philippines
Philippines Manila
Manila
1Department of Pediatrics, College of Medicine and Philippine General Hospital, University of the Philippines Manila
2Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila

ABSTRACT and may result in one or more of the following: an increase

Mitochondrial respiratory chain disorders have very diverse of reducing equivalents in both mitochondria and cytosol, a
manifestations andPresentation Presentation
can presentof ofwith
the
the case
case
any symptom, in any require
require regular
decrease regular laxative
laxative use.
in mitochondrial use.ATP
There
Thereformation,
was
was also
also aaan report
report
increaseof
of two
twoin
organ at any time. Here we describe presenting
This
This is
is a
a case
case of
of a
a 43-year-old
43-year-old male
male presenting
two Filipino with
with short
short
children more
more syncopal
syncopal episodes.
episodes. He
He was
was
superoxide formation, and functional impairment of brought
brought to
to another
another doctor
doctor
stature
stature and
and heart
heart failure.
failure. The
The
confirmed to have a mitochondrial respiratory chain patient
patient was
was admitted
admitted at
at the
the in
in aa private
privatepathways
metabolic hospital
hospital wherewhere the
the assessment
requiring assessment
mitochondrial was
was still
still aa “heart
“heart
respiratory
medicine
medicine ward
ward of
of the
the Philippine
Philippine
disorder after presenting with non-specific neurologic General
General Hospital
Hospital (PGH)
(PGH) problem”.
problem”. The
The patient
patient was
was again
again
chain function such as Krebs cycle and beta oxidation. 2,4 prescribed
prescribed unrecalled
unrecalled
for
for dyspnea.
dyspnea. medications
medications and and again
again was was lostlost toto follow-up.
follow-up. This This time,
time,
symptoms. TheThis
This
first paper
paper
patientwill will investigate
investigate
had Otahara several
severaland
syndrome issues:
issues:
was
differentiating
differentiating congenitalcongenital from from acquired
acquired hypothyroidism,
hypothyroidism, however,
however, symptoms
symptoms were were persistent.
persistent. He He later
later consulted
consulted at at
later on found to have complex I deficiency. The second
the
the relationship
relationship between between hypothyroidism
hypothyroidism and and the the another
another local
local hospital,
hospital, where where he he was
was admitted
admitted and and managed
managed
patient had the m.8993T>G mtDNA mutation that was
cardiomyopathies,
cardiomyopathies, and and the the therapeutic
therapeutic options options in in patients
patients as
as aa case
case ofof anemia
anemia and and bronchial
bronchial asthma.
asthma. He He waswas discharged
discharged
consistent with a Leigh phenotype.
with
with cardiomyopathy
cardiomyopathy secondary secondary to to hypothyroidism.
hypothyroidism. slightly
slightly improved
improved after after fourfour days,
days, only
only to to have
have recurrent
recurrent heart
heart
The
The patient
patient had had beenbeen bornborn fullfull term
term to to aa then
then 31-year-
31-year- failure
failure symptoms,
symptoms, promptingprompting admissionadmission at at PGH.
PGH.
Key Words: mitochondrial respiratory ththchain disorder, complex I
old
old Gravida
Gravida 44 Para Para 33 (G4P3),
(G4P3), the the 44 of of 99 siblings,
siblings, with
with an an Upon
Upon admission
admission the the patient
patient was was in in mild
mild respiratory
respiratory
deficiency, Otahara syndrome, m.8993T>G mutation, Leigh
apparently
apparently unremarkable
unremarkable delivery delivery at at home
home facilitated
facilitated by by distress,
distress, with
with stable
stable vital
vital signs
signs andand nono note
note of of fever.
fever. Pertinent
Pertinent
syndrome NARP phenotype
aa traditional
traditional birth birth attendant.
attendant. He He was was noted
noted to to be
be normal
normal physical
physical examexam findings
findings included
included shortshort stature,
stature, thickthick lips,
lips, non-
non-
at
at birth.
birth. The The patient
patient was was allegedly
allegedly at at par
par with
with ageage both
both pitting
pitting periorbital
periorbital edema,edema, dry dry skin,
skin, aa displaced
displaced apical apical impulse,
impulse,
Introduction
physically
physically and and mentally
mentally until until eight
eight years
years old old when
when he he was
was crackles
crackles on on both
both lung
lung fields,
fields, andand bilateral
bilateral non-pitting
non-pitting bipedal bipedal
The mitochondrion, being the powerhouse of the cell is
said
said to
to have
have stopped
stopped growinggrowing in in height.
height. He He was
was brought
brought to to edema.
edema. There
There was was also also aa 33 cm cm xx 33 cm cm reducible
reducible umbilical
umbilical
the organelle which supports aerobic respiration and
aa private
private doctor,
doctor, whosewhose diagnosis
diagnosis was was undisclosed,
undisclosed, and and he he hernia.
hernia. However,
However, there there was was no no pallor,
pallor, no no neck
neck veinvein distention,
distention,
provides energy for the metabolic pathways. Mitochondria
was
was given
given medications
medications to to increase
increase height,
height, which
which thethe patient
patient no
no apparent
apparent congenital
congenital malformations,
malformations, no no cardiac
cardiac murmurs
murmurs
are relics of independent bacterial intruders that took
took
took for
for only
only one one month
month with with no no improvement.
improvement. Through Through the the and
and nono clubbing.
clubbing. There There was was also
also nono note
note of of anan anterior
anterior neckneck
permanent residence in our cells over a billion years ago.
years,
years, thethe patient
patient was was apparently
apparently well, well, although
although still
still of
of short
short mass.
mass.
That is why mitochondria still possess their own circular
stature,
stature, withwith thickthick lips,
lips, coarse
coarse facial
facial features
features and and dry
dry skin.
skin. laboratory
laboratoryworkup workupshowed showedcardiomegaly
cardiomegalywith withpulmonary
pulmonary
DNA (mtDNA) which encodes 13 proteins of the
He
He was
was notably
notably slow slow in in ambulation.
ambulation. He He waswas said
said toto have
have congestion,
Figure 1. Complex I (NADH-ubiquinone reductase)aorta
congestion, thoracic
thoracic dextroscoliosis,
dextroscoliosis, and
and atheromatous
atheromatous aorta by
by
carries
approximately 90 proteins of the respiratory chain. All the
bronchial
bronchial asthmaasthma at at age
age 15 15 years,
years, and and since
since then
then hehe had
had been
been chest
chest radiograph,
radiograph, and
and left
left ventricular
ventricular
reducing equivalents from NADH to the ubiquinone pool, hypertrophy
hypertrophy by
by 12-lead
12-lead
other proteins of the respiratory chain needed for
taking
taking salbutamol
salbutamol tablets tablets occasionally
occasionally for for bouts
bouts of of dyspnea
dyspnea electrocardiogram
electrocardiogram
complex (12-l
(12-l ECG)
II (succinate-ubiquinoneECG) (Figures
(Figures 11reductase)
and
and 2), 2), normocytic
normocytic
carries
replication, repair, transcription, translation and proper
occurring
occurring one one to to two
two times
times annually.
annually. normochromic
reducing equivalents from FADH2 to CoQ pool, complexand
normochromic anemia
anemia (Hgb
(Hgb 90
90 mg/dl),
mg/dl), dyslipidemia,
dyslipidemia, and
III
assembly
The
The patient’s
and function
patient’s symptoms
arestarted
symptoms started
encoded in
by nuclear
in 2001
2001 when
when he
DNA
he waswas pre-renal
pre-renal azotemia
azotemia (serum
(serum creatinine
creatinine 123
123 mmol).
mmol). Electrolytes
Electrolytes
(ubiquinol-cytochrome c reductase) carries electrons from
(nDNA).
reported
reported to
1,2 The
to have
mitochondrial
have sudden
sudden loss loss of
respiratory
of consciousness.
chain
consciousness. During
catalyzes
During this this on
on admission
admission showed
showed slight
slight c, hyponatremia,
hyponatremia, hypokalemia,
hypokalemia,
the CoQ pool to cytochrome complex IV (cytochrome c
the
time,oxidation patientof didfuel molecules by oxygen and the and
time, the
the patient did not
not have
have any
any symptoms
symptoms of
of heart
heart failure;
failure; oxidase, COX) catalyzes the transfer of reducing Blood
and hypochloremia
hypochloremia (serum
(serum Na
Na 136,
136, KK 3.35,
3.35, Cl
Cl 86).
86). Blood gases
gases
equivalents
concomitant energy transduction into ATP via five revealed
revealed partially
partially compensated
compensated metabolic
metabolic
no
no prior
prior seizures,
seizures, cyanotic
cyanotic episodes,
episodes, chestchest pain,
pain, headache,
headache, or or from cytochrome c to molecular oxygenalkalosis
alkalosis
producing with
withwater
mild
mild
complexes
blurring
blurring of (FigureHe
of vision.
vision. He1).
2 The consciousness
regained
regained transfer of protons
consciousness shortlycreates
shortly after
after and
and a hypoxemia.
hypoxemia. The
The patient
patient was
was noted
noted to
to be
be hypothyroid
hypothyroid based
based
and complex V (ATP synthase) allows proton to flow back
charge differential that leads to the production of ATP. 3
on
on elevated
elevated serum
serum thyroid-stimulating
thyroid-stimulating
was
was brought
brought to to aa private
private physician,
physician, whose whose assessment
assessment was was aa into the mitochondrial matrix and uses hormone hormone
the released (TSH)
(TSH) and
and
energy
Mitochondria
“heart
“heart problem”.
problem”. He also play
He was a role
was prescribed in cell
prescribed unrecalled signaling, and
unrecalled medications
medicationshost markedly
markedly decreased
decreased serum
serum free
free thyroxine
thyroxine (FT4).
(FT4). The
The exact
exact
to synthesize ATP. 2
several
taken
taken forforpathways
aa few
few monthssuch as
months and
and Krebs cycle, beta
eventually
eventually oxidationwhen
discontinued
discontinued and
when values
values areare shown
shown in in Tables
Tables 11 and and 2. 2.
lipid
the synthesis.
the syncopal
syncopal episode Given
episode did these
did not fundamental
not recur.
recur. functions, defects Upon
Upon admission
admission to
to the
the wards,
wards, the
the patient
patient was
was managed
managed
The first mitochondrial disorder was recognized in 1961.
of mitochondrial
In
In the the nextnext function
four
four years, can have
years, the disastrous
the patient
patient consequences
would
would develop
develop as
as having
having congestive
congestive heart
heart failure
failure from
from cardiomyopathy
cardiomyopathy
Pediatric cases were recognized rather later, but since the
intermittent,
intermittent,
_______________ progressive
progressive exertional
exertional dyspnea
dyspnea and
and bipedal
bipedal secondary
secondary
1980s, to
to acquired
acquiredofhypothyroidism.
presentations hypothyroidism.
pediatric mitochondrialoral
oral loop loop disorders
diuretics,
diuretics,
edema.
edema. laterlater on on this
this would
would be be accompanied
accompanied by by generalized
generalized angiotensin-converting
have been widely reported. The great varietybeta-
angiotensin-converting enzyme
enzyme (ACE)
(ACE) inhibitors,
inhibitors, beta-
of
body
body weakness,
weakness, anorexia,anorexia, and and constipation,
constipation, severe severe enough
enough to to blockers,
blockers, statins,
statins, and
and levothyroxine
levothyroxine
symptomatology and, in many of the cases, rapidly were
were started.
started. Electrolyte
Electrolyte
Corresponding author: Mary Anne D. Chiong, MD
Institute of Human Genetics
correction
correction was
progressive was instituted.
instituted.
course, are well The
The sections
sections
known becauseof
of Endocrinology
Endocrinology
of the major
National Institutes of Health and
and Cardiovascular
Cardiovascular Diseases
Diseases were
were
involvement of high rate aerobic metabolism in most co-managing
co-managing the
the organs,
patient
patient
Corresponding
Corresponding author:
author: Ma.
Ma. Czarlota
Czarlota Acelajado-Valdenor,
Acelajado-Valdenor, M.D.
M.D.
University of the Philippines Manila
Department
Department of of Medicine
Medicine together
together with
with the
the General
General Medicine
Medicine
specifically the brain, heart and skeletal muscles.2,5 service.
service.
625 Pedro Gil Street, Ermita, Manila 1000 Philippines
Philippine
Philippine General
General Hospital
Hospital He
He soon
soon developed
Mitochondrial developed
disorders respiratory
respiratory
are failure,
failure,
thus upon upon which
which the
a genetically, the
Telephone: +632 5261725
Taft
Taft Avenue,
Avenue, Manila,
Manila, 1000
1000 Philippines
Email: maryannechiong@gmail.com
Philippines considerations
considerations were
were acute
acute pulmonary
pulmonary
biochemically, and clinically heterogenous group of congestion,
congestion, nosocomial
nosocomial
Telephone:
Telephone: +632
+632 554-8488
554-8488 pneumonia,
pneumonia, to to rule
rule outout an an acute
acute coronary
coronary event.event. He He was
was later
later
Email:
Email: czarlota@yahoo.com
czarlota@yahoo.com

12
12 ACTA
76 ACTA
ACTAMEDICA
MEDICA
MEDICAPHILIPPINA
PHIlIPPINA
PHIlIPPINA Vol.
Vol.45
VOL. 43
43NO.
N0.
N0. 444 2009
2009
2011
 HeartMitochondrial
Failure and Short Stature in aChain
Respiratory 43 year-old male
Disorder

Table 1. Initial
disorders laboratory
involving Results phosphorylation.
oxidative The the patient was started on a vitamin cocktail consisting of L-
estimated incidence is 1:7000-10,000 live births.6,7,8,9 Here we carnitine (100 mg/kg/day), Coenzyme Q (5 mg/kg/day),
CBC Blood chem. Urinalysis ABG
report the first two confirmed cases of mitochondrial Vitamin K (1 mg/kg/day), Vitamin C (60 mg/kg), Thiamine
Reference
Reference
respiratory chain Result
disorder in two Filipino infants. (37Result
mg/kg/day),Color Riboflavinstraw pH
(18 mg/kg/day), 7.408
Biotin (5
Value Value
WBC 5-10 4.5 RBS 3.9-6.1 mg/day),
6.3 Folic acid (5
Transp mg/day), alpha
Clear lipoic
pCo2acid (25 mg/day)
49.1
RBC 4-6 Clinical Reports HGBA1C 4.27-6.07 and6.4Pyridoxine Sp (150
Gravity mg/day). 1.010She initially
po2 improved 70 and
HGB 1
Patient 120-150 90 BUN 2.6-6.4 5.0
seizures were noted pH to decrease 8.0 in frequency
HCo3 and duration 31.3
HCTThis patient
0.38-0.48 0.27
was a 3-month-old CREA born to 53-115
female non- with123topiramate,Sugar levetiracetam NEG o2 sat
and clonazepam. 93.6
However,
MCV 80-100 Fl AlB 34-50 32 Protein NEG Fio2 21%
consanguineous parents of Chinese descent. She was she subsequently developed nosocomial gram negative
MCH 27-31 PG TAG 0.34-1.7 0.82 RBC 0-1 Temp 36.9
delivered
MCHC full term
320-360 G/l after a pregnancy HDl complicated by
0.91-1.56 sepsis
0.67 and candidiasis,
WBC upper0-2 gastrointestinal bleeding,
urinary
RDW tract 11.5-15.5%
infection and bronchial asthma lDl during the1.1-3.8
first pulmonary
4.21 hemorrhage
Cast and hemothorax. CTPBS scan of the
PlT
trimester and200-400 Inc
premature contractions ToTAl
at CHol age
33 weeks 4.2-5.2
of 5.25
abdomen Epith cellhepatomegaly
showed Rare with
Slight poikilocytosis,fatty
diffuse
RETIC
gestation. The pregnancy was carried AST
0.005-0.015 on to term, with15-37a 95
replacement andBacteria
splenomegaly. occ’l She died at 5 months
acanthocytes, of
ovalocytes,
SEG 50-70% 48 AlT 30-65 91 Mucus th Rare slight toxic Laboratory,
granulation,
normal
lYMPH
spontaneous delivery and a birth weight of 2.4 kg,
Alk po4
age.184
Respiratory chain
Crystals
enzymes Rare
(Mitochondrial
20-44% 50
length
MoNoof 47 cm2-9%and with good 2 Apgar scores.
NA The neonatal
140-148 Victorian
136.9 Clinical Genetics Services andslight
Am urates
anisocytosis
Murdoch Childrens
course
Eo was complicated
0-4% by 0jitteriness Kduring the first 24
3.6-5.2 Research
3.35 Institute) in skeletal muscle homogenate were low
BASo of life
hours 0-2%that persisted 0 Cl
even after 100-108
correction of for86complex I relative to protein (21% of control mean) and
BlAST
hypocalcemia 0%and treatment 0for sepsis.CA++ 2.12-2.52
Cranial ultrasound 2.37
borderline low for other enzymes (38-60%). Complex I was
P 2.27
showed non-specific right thalamus
MG++ mineralizing0.74-1 borderline
0.83 low relative to citrate synthase and complex II
angiopathy with bilateral grade 1 germinal matrix (36% and 35% of control means). In the liver homogenate,
hemorrhage and a right subependymal cyst. EEG was respiratory chain enzymes were borderline low for complex
normal. Expanded newborn screening (NSW Newborn I (39%). Complex I was low relative to citrate synthase and
Screening Program, the Children’s Hospital at Westmead) fat pad. Cardiac
relative to complex enzymes
II (15% wereand not21%,
consistent with an acute
respectively). In
Table 2. Thyroid Function Tests
was also normal. A heart murmur was likewise noted which coronary
conjunction with the clinical features, (IV)metabolic
event (Table 3), however, intravenous heparin
Reference Value Result (overlapping
onFree2D-echocardiography
T4 (0.8-2.0)
revealed a 0.02 patent
ng/dl
ductus investigationswith andoral warfarin)
with was stillmuscle
the skeletal given toand coverliver
for
arteriousus, mild to moderate the presence of a possible lV thrombus as demonstrated
TSH (0.4-6.0) tricuspid regurgitation
24.75 Uiu/ml and enzymology, the above results were diagnostic of a
right ventricular and right atrial hypertension. She was by rheologic
respiratory stasis
chain complexon cardiac ultrasound. Medications
I deficiency.
discharged asymptomatic on the second week of life. were shifted to IV diuretics and inotropes; oral digoxin was
At 25 days of life, she was noted to have seizure started.
Patient 2 IV antibiotics were given for possible pulmonary
occurring mostly in sleep with initial eye version to the left infection.
This Thewaspatient later on showed
a 4-month-old femaleimprovement,
patient born and was
to non-
eventually weaned off from ventilatory support, extubated,
and subsequent head and eye version to the right. Repeat consanguineous parents after a pregnancy complicated by
EEG at 2 months of age showed a burst-suppression pattern UTI during the first trimester. She was delivered full term by
with considerations of either early infantile epileptic Table
repeat3.cesarean
Cardiac section
Enzymes with a birth weight of 2.95 kg and
encephalopathy (EIEE/ Otahara syndrome) or early good Apgar scores.Reference Her perinatal
Range (mmoL)and neonatal course were
Result
myoclonic encephalopathy (EME). Clonazepam and unremarkable.
Qualitative Developmentally, she was PoSITIVEto have
noted
Valproic acid were started. MRI at this time showed an slower motor
Troponin I development compared to her older sister. At
increased signal intensity on white matter symmetrically. CK-MB of age, she turned
4 months 0-6.0to her side occasionally, 1.14 brought
She was readmitted at 3 months of age due to persistence of herCK-ToTAl
hands to her mouth,21-232 had a social smile and543could focus
seizures. A video EEG showed frequent electrographic and track but had prominent head lag and could not lift her
seizures with onset independently from the right or left head while on prone. At the same age, she was rushed to a
posterior, temporal and parietal regions with evolution to local emergency room because of difficulty of breathing.
the other hemisphere in alternating fashion, each lasted 60- Chest x-ray and otorhinolaryngology consult showed
Figure 1. Electrocardiogram
120 seconds with a minimum upon admission
of 12 seizures in a 30 minute normal findings. Blood gas showed metabolic acidosis with
period. She was then transferred to PICU where the seizures an increased anion gap of 22. Plasma lactate levels were 9.6
remained intractable despite intravenous midazolam. and 7.7 umol/L. She also had elevated LDH, CK-MB and
transferred to the intensive care unit (ICU) for ventilatory
Ophthalmologic evaluation showed optic nerve hypoplasia LFT’s. Urine organic acid analysis indicated gross lactic
support and closer monitoring. on bedside cardiac ultrasound,
on the left. Her clinical course was complicated by liver acidosis, ketosis and Kreb’s cycle metabolites. A
there was a finding of eccentric left ventricular hypertrophy,
problems, splenomegaly, hypothyroidism and drug allergy. mitochondrial respiratory chain disorder was then
global hypokinesia with depressed overall systolic function
Investigations included a urine amino acid screen which suspected. On physical examination, she was lethargic with
with concomitant spontaneous echo contrast on left ventricular
showed increase in alanine, urine organic acid screen which weight, height and head circumference that were
(lV) cavity suggestive of rheologic stasis, the ejection fraction
showed
was 25%,grossly
with increased
moderate lactate,
mitral slightly increased
regurgitation, Kreb’s
moderate appropriate for age. Liver was palpable 4 cm below the
cycle metabolites and presence of compounds that
aortic regurgitation with aortic sclerosis, severe tricuspid were right costal margin. The rest of the physical examination
suggestive of ketosis. Plasma lactate was 2.8
regurgitation with mild pulmonary hypertension, pulmonary umol/L. A was normal. Neurologic examination showed head lag and
mitochondrial respiratory chain disorder was suspected
regurgitation, and minimal pericardial effusion or pericardial and truncal 2.hypotonia,
Figure Chest radiographnormalon deep tendon reflexes, bilateral
admission

Vol. 45
VOL. 43 NO.
N0. 442009
2011 ACTA MEDICA
ACTA MEDICA PHILIPPINA
PHIlIPPINA 77
13
Mitochondrial Respiratory Chain Disorder CASE REPORT

Babinski and 1-2 beatsHeart clonus. FailureCranial MRI and Short

showed signalStatureof bloodinlactate.
a 433 year-old
Elevated lactate male was seen in both patients.
abnormality within the bilateral putamen and caudate Likewise, their urine organic acid analysis showed gross
nucleusKaterina T. leyritana
with associated lactate , Ma. Czarlota M. Acelajado-Valdenor
1 peak on spectroscopy. Vision
, Amadoand
lactic 1acidosis o. Tandoc
ketosis III with
2
andelevated
Agnes D. Mejia
levels of1 TCA
and hearing evaluation were normal as well as 2D metabolites. These findings heightened the likelihood of a
echocardiography. 1
Department
Renalofevaluation
Medicine, College
wasofconsistent
Medicine andwithPhilippinemitochondrial
General Hospital, respiratory
University of the Philippines
chain disorder Manila
in the two patients
renal tubular acidosis. Mutation
2
Department of Pathology,
analysis of DNA College of Medicine,
sample in University
concurrence of thewith
Philippines
their Manila
clinical findings. It must be noted
from skin fibroblasts (Baylor College of Medicine, Medical however, that absence of lactic acidosis does not rule out a
Genetics Laboratory) showed a m.8993T>G mutation in the respiratory chain defect, especially in somewhat later
ATPase6 gene of the mitochondria. She was found to have presentations.
93% heteroplasmy for the m.8993T>G mutation in her blood Enzyme analysis in intact mitochondria and molecular
and 33% heteroplasmy in her skin. She had a couple of analysis of nuclear or mitochondrial DNA mutations are two
metabolic decompensations Presentation of the case by acidosis and
characterized require regulartools
of the major laxative
that use.
willThere
help was in thealsoestablishment
a report of two of
This is a case ofduring
hyperlactacidemia a 43-year-old
a bout of male
viralpresenting
infection with
that short
were more syncopal
diagnosis for aepisodes. He was
mitochondrial brought tochain
respiratory another doctor8
disorder.
stature and heart failure.
easily corrected The patient
by bicarbonate was admitted
correction, fluidsat andthe in a private
Patient hospital
1 showed lowwhere the of
activity assessment
respiratory was stillenzymes
chain a “heart
medicine
supportiveward of the Philippine
management. At the timeGeneral Hospital
of this report(PGH)
at 10 problem”.
in complexThe I of patient
both thewas againand
skeletal prescribed unrecalled
liver homogenates.
for dyspnea.
months of age, Thisherpaper will investigate
development several steadily
is progressing issues: medications
Patient 2 on the andother
againhand washad losta to follow-up.
confirmed This time,
mitochondrial
differentiating
albeit slowly as congenital
she undergoesfrom acquired
physical hypothyroidism,
therapy and is however,
DNA mutation symptoms were fibroblasts
in skin persistent. He which laterharbored
consultedthe at
the relationship
maintained on thiamine, between
coenzyme hypothyroidism
Q, carnitine and andvitaminthe another
mtDNA local hospital,
m.8993T>G where he was admitted and managed
mutation.
cardiomyopathies,
E. and the therapeutic options in patients as a case of anemia
Complex and bronchial
I deficiency is the asthma. He was discharged
most commonly observed
with cardiomyopathy secondary to hypothyroidism. slightly improved after four
mitochondrial respiratory chain defect.days, only to have
5,10 Arecurrent
diversity heart
of
The patient had beenDiscussion born full term to a then 31-year- failure symptoms, prompting admission at
clinical phenotypes has been reported to occur in complex I PGH.
old Gravida
A defect 4ofPara 3 (G4P3),
oxidative the 4th of 9 siblings,
phosphorylation with an
can be suspected Upon patients,
deficient admission the can
which patient was in into
be classified mildseveral
respiratory
main
apparently unremarkable delivery
in patients with an unexplained combination of at home facilitated by distress, with stable vital signs and no note
clinical phenotypes: severe lactic acidosis, Leigh syndrome, of fever. Pertinent
aneuromuscular
traditional birthand/or attendant. He was noted to symptoms,
non-neuromuscular be normal physical
neonatal examcardiomyopathy
findings included short withstature, lactic thick lips, non-
acidosis,
at birth. The patient was allegedly at
progressive course, and involvement of seemingly unrelated par with age both pitting periorbital edema, dry skin, a displaced
leukodystrophy with macrocephaly, hepatopathy with renal apical impulse,
physically
organs. These and mentally until eight years
clinical symptoms, eitheroldisolated
when heorwas in crackles
tubulopathyon both and lunga fields,
group and of bilateral
miscellaneousnon-pitting bipedal
unspecified
said to have stopped growing in height.
combination, may occur at any stage. These characteristics
4 He was brought to edema. There
mitochondrial was also a 3 cm
encephalomyopathies. x 3 cm reducible
11,12,13 umbilical
Patient 1
awere
private
seendoctor,
in our whose diagnosisPatient
two patients. was undisclosed,
1 presentedand he
in the hernia.
presentedHowever,
with there was no pallor,
encephalopathy no neck vein distention,
characterized by severe
was givenperiod
neonatal medications to increase
with severe height, which
encephalopathy the patient
associated with no apparent
neonatal congenital
seizures malformations,
suspected to be ano possible cardiac murmursOtahara
took for only one
intractable seizures. month with no improvement.
Newborns with mitochondrial Through the and no clubbing. There was also no
syndrome. Her lactic acidosis was only determined note of an anterior onceneck
and
years, the patient
respiratory chainwas apparently
disorders whowell, althoughinitially
presented still of short
with mass.
it was only mildly elevated. Her MRI findings as well as
stature,
symptoms with thick lips,
pertaining to coarse facial features
the nervous system wereand dry
found skin.
to laboratory
clinical courseworkupwere not showed cardiomegaly
compatible with Leigh with pulmonary
syndrome
He was notably slow in ambulation. He
evolve into a multisystem disorder on long-term follow-up was said to have congestion, thoracic dextroscoliosis, and
because Leigh syndrome usually manifests with early atheromatous aorta by
onset,
bronchial asthma at age 15 years, and since
and a remarkably high mortality rate was reported in the then he had been chest radiograph, and left ventricular hypertrophy
progressive neurologic disorder characterized by motor and by 12-lead
taking
first 3 salbutamol
months of tablets life.5 occasionally
Although many for bouts
of ourof patient’s
dyspnea electrocardiogram
intellectual developmental(12-l ECG) (Figures
delay, signs 1 and 2), normocytic
of brainstem and
occurring one to two times annually.
associated features can be attributed to her severe disease normochromic
basal ganglia involvement and increased lactate levelsand
anemia (Hgb 90 mg/dl), dyslipidemia, in
The
state and patient’s
sepsis, symptoms started inhypothyroidism
her liver problems, 2001 when he was and pre-renal
blood and/orazotemia
CSF.14(serumThesecreatinine
features were 123 mmol).
not seen Electrolytes
in patient
reported to have sudden
ocular manifestations are loss of consciousness.
all likely to have been Duringpart of thisthe on admission
1. However, showed
a rare slight hyponatremia,
manifestation of complex I deficiencyhypokalemia, has
time, the patient did not have any symptoms
mitochondrial respiratory chain disorder. 3 The second of heart failure; and hypochloremia (serum Na 136,
recently been reported in a neonate who presented K 3.35, Cl 86). Blood gaseswith
no prior seizures,
patient presented cyanotic episodes,
with chest pain, headache,
hyperlactacidemia on the or revealed partially compensated
Otahara syndrome that was very metabolic
similar to alkalosis
that seenwith inmild
our
blurring of
background of vision. He regained consciousness
developmental delay and muscular shortly after and hypoxemia.
patient.14 Since mitochondrial diseases are known based
The patient was noted to be hypothyroid to be
was brought Likewise,
hypotonia. to a privatethe physician, whose assessment
latter neurologic and muscularwas a on elevated
clinically veryserum thyroid-stimulating
heterogenous, hormone although
Otahara syndrome (TSH) and a
“heart problem”. He was prescribed
symptoms are among the commonest manifestations of a unrecalled medications markedly
rare complex I phenotype should be considered as The
decreased serum free thyroxine (FT4). one of exact
the
taken for a few
mitochondrial months4 and eventually discontinued when
disorder. values are shown
rare forms in Tables 1 and
of presentation of 2.a mitochondrial disease. 15
the syncopal episode did not recur. Upon admission to the wards, the patient was managed
Plasma lactate, although not specific, is a helpful marker Patient 2 had the m.8993T>G mutation associated with Leigh
In the next four years, the patient would develop as having congestive heart failure from cardiomyopathy
for a possible mitochondrial respiratory chain disorder. syndrome and neurogenic muscle weakness, ataxia, retinitis
intermittent, progressive exertional dyspnea and bipedal secondary to acquired hypothyroidism. oral loop diuretics,
However, it is important that correct sample collection and pigmentosa (NARP) phenotypes. The clinical presentation in
edema. later on this would be accompanied by generalized angiotensin-converting enzyme (ACE) inhibitors, beta-
handling are done to avoid secondary causes of elevated individuals carrying this mitochondrial DNA mutation
body weakness, anorexia, and constipation, severe enough to blockers, statins, and levothyroxine were started. Electrolyte
lactate. Persistently elevated lactate is very suggestive of varies with the degree of m.8993T>G heteroplasmy in
correction was 16instituted. The sections of Endocrinology
respiratory chain deficiency. This is brought about by the affected tissues. Heteroplasmy is a unique characteristic of
and Cardiovascular Diseases were co-managing the patient
functional impairment
Corresponding author: Ma.ofCzarlota
tricarboxylic acid (TCA) M.D.
Acelajado-Valdenor, cycle due mitochondrial genetics wherein coexistence of wild type and
Department of Medicine together with the General Medicine service.
to the excess of NADH and the lack of NAD+ leading to an mutant mtDNA varies in proportion in different tissues.2
Philippine General Hospital He soon developed respiratory failure, upon which the
increase in ketone body (-hydroxybutyrate/aceto-acetate) For this specific mutation, a phenotypic gradient exists in
Taft Avenue, Manila, 1000 Philippines considerations were acute pulmonary congestion, nosocomial
and lactate/pyruvate
Telephone: +632 554-8488molar ratios with secondary elevation which mutation heteroplasmy <60% typically does not result
pneumonia, to rule out an acute coronary event. He was later
Email: czarlota@yahoo.com

12 ACTA MEDICA
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 HeartMitochondrial
Failure and Short Stature in aChain
Respiratory 43 year-old male
Disorder

Table 1. Initial
in clinical laboratory
symptoms; Resultsheteroplasmy between 60-
mutation having a severely affected child and probability of a severe
75% is frequently associated with Retinitis Pigmentosa (RP), outcome in an individual based on the measured mutant
CBC Blood chem. Urinalysis ABG
75-90% with Neuropathy, Ataxia, and Retinitis Pigmentosa load.21 For the family of patient 2, the mother has yet to be
Reference Result
(NARP) andReference high level mutationResult heteroplasmy usually tested for the Color straw
level of heteroplasmy pH
in her blood 7.408
for
Value Value
greater
WBC than5-10
90% is commonly 4.5
associated
RBS with Leigh
3.9-6.1 recurrence
6.3 risk predictions.
Transp Some
Clear guidancepCo2 however, 49.1 be
can
syndrome.
RBC
16
4-6 Based on the results HGBA1C of patient 2, 4.27-6.07
it is obtained
6.4 from Sp theGravity
recurrence 1.010 risks predicted po2 by White 70 et al,
HGB
encouraging that her level of heteroplasmy
120-150 90 BUNin the skin is2.6-6.4
low i.e.,5.0the corresponding pH 8.0
proportion of HCo3
healthy oocytes 31.3 at
HCT
but 0.38-0.48to know what
it is impossible CREAare in the 53-115
0.27 her levels brain 123
maternal Sugar loads of
blood mutant NEG 60%, 70%o2and sat 80% would 93.6 be
MCV 80-100 Fl AlB 34-50 32 Protein NEG Fio2 21%
and other internal organs. Thus, it is difficult to classify at 32%, 23% and 16%, respectively.
MCH 27-31 PG TAG 0.34-1.7 0.82 RBC 0-1 Temp 36.9
this
MCHC point whether
320-360 G/lshe belongs to the HDlNARP or Leigh 0.91-1.56 There is currently
0.67 WBC no satisfactory 0-2 therapy for respiratory
spectrum
RDW of 11.5-15.5%
phenotypes. It is likewiselDl difficult to predict
1.1-3.8 chain
4.21 disorders. Cast Treatment remains largely PBS symptomatic
PlT this will200-400
how affect her in the ToTAl
Incfuture. This CHol
complexity 4.2-5.2
has and5.25 Epith cell
does not significantly alterRare
the course of the disease. It
Slight poikilocytosis,
RETIC
been shown in 0.005-0.015
a family described to have AST variable disease
15-37 95
includes avoidance Bacteria
of drugs and occ’lprocedures known
acanthocytes, to have
ovalocytes,
SEG 50-70% 48 AlT 30-65 91 Mucus th Rare slight toxic granulation,
severity
lYMPH
and tissue mitochondrial DNA T8993G mutant
Alk po4
detrimental
184
effects,
Crystals
slow infusion
Rare
of sodium bicarbonate
20-44% 50
loads.
MoNo
16,17 The
2-9%siblings who 2had high NA mutant loads in all
140-148 during
136.9 attacks of lactic acidosisslight
Am urates andanisocytosis
a dietary
tissues
Eo (>90%)0-4%had features of0 NARP and K LS while the3.6-5.2one recommendation
3.35 that include a high lipid, low carbohydrate
BASo
who had high 0-2%mutant load 0in tissues (93%) Cl derived 100-108
from diet86 specifically in patients with complex I deficiency.3
BlAST
endoderm 0% mesoderm but
and 0 had a lowerCA++ proportion 2.12-2.52
of 2.37 vitamins and co-factors such as thiamine, carnitine,
Various
P 2.27
mutant mtDNA in tissue derived from ectoderm MG++ (hair bulb)
0.74-1 riboflavin,
0.83 pantothenic acid have been used to help increase
presented only with speech delay and was attending normal the activity of the different complexes. Since defects of the
school. Given the shared embryonic origin of hair bulbs respiratory chain also result in the increased production of
and the brain, it was speculated that mutant load in hair free radicals, the use of antioxidants such as vitamin E, lipoic
bulbs could be aFunction
reflectionTests
of the brain mutant load. This fat
acidpad.andCardiac
coenzyme enzymes
Q also were
has a notsound consistent with an acute
basis. However, these
Table 2. Thyroid
type of investigation has not yet been done on patient 2, thus coronary
various therapies have proved helpful only in(IV)
event (Table 3), however, intravenous heparin
a very few
Reference Value Result (overlapping
it Free
is very
T4
difficult to (0.8-2.0)
predict at present how severe her
0.02 ng/dl
isolated caseswith andoral warfarin)
possibly was still
effective in given
the shortto cover for
term. 22

neurologic involvement(0.4-6.0)
is, although there is more evidence the presence of a possible lV thrombus
Over the last decade, there has been little progress in the as demonstrated
TSH 24.75 Uiu/ml
that she falls within the spectrum of Leigh disease because of by rheologic stasis
development of novel on cardiac
treatments ultrasound. Medications
for nuclear-encoded
the diffuse basal ganglia changes and developmental delay were shifted to IV diuretics and inotropes;
disorders of the respiratory chain, but a number of strategies oral digoxin was
in nearly infancy. started. IV antibiotics were given for
are currently being explored for the treatment of primary possible pulmonary
Since the mitochondrial respiratory chain is controlled infection. The patient later
mtDNA abnormalities suchonas showed
delivery improvement,
of a normaland was
version
eventually weaned off from ventilatory support, extubated,
by both nuclear and mitochondrial genes, along with the of the affected gene into the mitochondria, altering the level
diversity of clinical manifestations, genetic counseling is a of heteroplasmy, alternative methods of manipulating the
considerable challenge. Mitochondrial diseases caused by Table
level of 3. Cardiac
mtDNAEnzymes and preferential expansion of wild type
nuclear gene mutations will be transmitted by Mendelian mtDNA through recruitment Reference Range of(mmoL)
satellite cells that contain
Result
inheritance. On the other hand, the inheritance of primary little or no
Qualitative mtDNA. 23
PoSITIVE
mtDNA mutations will be maternal, i.e. from the mother to In summary,
Troponin I we report two Filipino children who
all offspring, and subsequently transmitted by the daughters CK-MB
primarily presented with 0-6.0 neurologic and 1.14 muscular
alone. Finally, in some cases, particularly those individuals CK-ToTAl along with 21-232
symptoms lactic acidosis. They were 543 later on
who have large deletions of the mitochondrial genome, as confirmed to have a mitochondrial respiratory chain
seen in Kearns-Sayre syndrome, the deletion usually arises disorder based on enzymology and or mutation analysis The
as a de novo event and has a very low recurrence risk.18 first patient was a severe case of complex I deficiency
No mutation analysis was done on Patient 1, thus the leading to early death in the neonatal period. Patient 2 had
Figure
genetic1. Electrocardiogram
basis and recurrence upon admission
risk for the family are uncertain, the common m.8993T>G mtDNA mutation that is consistent
however empirical recurrence risks have been calculated in with either a Leigh or NARP phenotype, although clinically
complex 1 deficiency at 23-27%.18 Likewise, respiratory the former is more likely. Her disease has progressed and
transferred to the intensive care unit (ICU) for ventilatory
chain complex 1 deficiency has been found to be mostly she developed severe seizures in recent times. She had
support and closer monitoring. on bedside cardiac ultrasound,
inherited in an autosomal recessive manner, thus, a 25% regression in her previously learned skills and has become
there was a finding of eccentric left ventricular hypertrophy,
recurrence risk each pregnancy may be given as an more hypotonic. Her current management remains
global hypokinesia with depressed overall systolic function
estimate.19,20 supportive. Further investigations have to be done on the
with concomitant spontaneous echo contrast on left ventricular
The m.8993T>G mutation is one of the most common family members of both patients so that proper genetic
(lV) cavity suggestive of rheologic stasis, the ejection fraction
was 25%,mutations
mtDNA diagnosed
with moderate in children
mitral which moderate
regurgitation, shows a counseling can be addressed.
strong correlation between mutant load and
aortic regurgitation with aortic sclerosis, severe tricuspid symptoms.
These featureswith
regurgitation allowed the generation
mild pulmonary of logisticpulmonary
hypertension, regression
models relating to maternal blood mutant load
regurgitation, and minimal pericardial effusion or pericardial and risk of Figure 2. Chest radiograph on admission

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VOL. 43 NO.
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2011 ACTA MEDICA
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PHIlIPPINA 79
13
Mitochondrial Respiratory Chain Disorder CASE REPORT

___________ Heart Failure and Short Stature in a 43 year-old male

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He was notably slow in ambulation. He was
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said to have congestion, thoracic dextroscoliosis, and atheromatous aorta by
bronchial asthma at age
Ann Neurol. 1996; 39(3):343-51.15 years, and since then he had been chest radiograph, and left ventricular hypertrophy by 12-lead
taking salbutamol
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time,family
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with variable have
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no prior seizures, cyanotic episodes, chest pain, headache, or revealed partially compensated metabolic alkalosis with mild
17. Tatuch Y, Christodoulou J, Feigenbaum A, et al. Heteroplasmic mtDNA
blurring of vision. He regained consciousness shortly
mutation (T-G) at 8993 can cause Leigh disease when the percentage of after and hypoxemia. The patient was noted to be hypothyroid based
was abnormal
broughtmtDNA to a private physician,
is high. Am J Hum Genet. whose 1992;assessment
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“heart problem”.
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19. Kirby DM, Crawford M, Cleary MA, Dahl HH, Dennett X, Thorburn Upon admission to the wards, the patient was managed
InDR.the next chain
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the patient would develop
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generation disorder. 1999; 52(6):1255-64.
intermittent, progressive exertional dyspnea and bipedal secondary to acquired hypothyroidism. oral loop diuretics,
20. Triepels RH, van den Heuvel LP, Trijbels JM, Smeitink JA. Respiratory
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chain complex I deficiency. Am J Med Genet. 2001; 106(1):37-45. by generalized angiotensin-converting enzyme (ACE) inhibitors, beta-
bodyWhite
21. weakness, anorexia,
SL, Collins VR, Wolfe and constipation,
R, et severe and
al. Genetic counseling enough to
prenatal blockers, statins, and levothyroxine were started. Electrolyte
diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am correction was instituted. The sections of Endocrinology
J Hum Genet. 1999; 65(2):474-82.
and Cardiovascular Diseases were co-managing the patient
Corresponding
22. author:
Panetta J, Smith Ma. Czarlota
LJ, Boneh A. Effect Acelajado-Valdenor, M.D.
of high-dose vitamins, coenzyme Q
Department of Medicine
and high-fat diet in pediatric patients with mitochondrial diseases. J together with the General Medicine service.
Philippine General Hospital
Inherit Metab Dis. 2004; 27(4): 27:487-98 He soon developed respiratory failure, upon which the
Taft Avenue,
23. ChinneryManila, 1000 Philippines
PF, Turnbull DM. Epidemiology and treatment of considerations were acute pulmonary congestion, nosocomial
Telephone: +632 554-8488
mitochondrial disorders. Am J Med Genet. 2001; 106(1): 94-101.
pneumonia, to rule out an acute coronary event. He was later
Email: czarlota@yahoo.com

12 ACTA MEDICA
80 ACTA MEDICA PHILIPPINA
PHIlIPPINA Vol.45
VOL. 43NO.
N0. 44 2009
2011