Professional Documents
Culture Documents
4780-Article Text-49984-1-10-20211204
4780-Article Text-49984-1-10-20211204
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
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
12 ACTA MEDICA
78 ACTA MEDICA PHILIPPINA
PHIlIPPINA Vol.45
VOL. 43NO.
N0. 44 2009
2011
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
Vol. 45
VOL. 43 NO.
N0. 442009
2011 ACTA MEDICA
ACTA MEDICA PHILIPPINA
PHIlIPPINA 79
13
Mitochondrial Respiratory Chain Disorder CASE REPORT
12 ACTA MEDICA
80 ACTA MEDICA PHILIPPINA
PHIlIPPINA Vol.45
VOL. 43NO.
N0. 44 2009
2011