Eur J Pediatr (1996) 155 : 898-903
© Springer-Verlag 1996

P. S. Kishnani
J. L. K. Van Hove
J. S. Shoffner
A. Kaufman
E. H. Bossen
S. G. Kahler

Received: 16 October 1995
Accepted: 4 March 1996

P. S. Kishnani (N~) • J. L. K. Van Hove
S. G. Kahler
Box 3528, Division of Medical Genetics,
Department of Pediatrics,
Duke University Medical Center, Durham,
North Carolina 27710, USA
Tel. +919-684-2036; Fax: 919-684-8944
J. S. Shoffner • A. Kaufman
Department of Neurology,
Emory University, School of Medicine,
Atlanta, Georgia, USA
E. H. Bossen
Department of Pathology,
Duke University Medical Center, Durham,
North Carolina, USA

Acute pancreatitis in an infant
with lactic acidosis and
a mutation at nucleotide 3243
in the mitochondrial DNA tRNALe"luuej gene

Abstract The A to G point mutation
at position 3243 of the mitochondrial
DNA tRNA Leu(U~R)gene is commonly found in patients with the
syndrome of mitochondrial encephalomyopathy, lactic acidosis and
stroke-like episodes (MELAS). A
male patient was referred at 7
months with failure to thrive, developmental delay, microcephaly and
hypotonia since age 2 months. He
had developed lactic acidosis and increasingly frequent seizures since
age 5 months. The patient was admitted at 15 months with pleural and
pericardial effusions, which resolved.
Three weeks later he developed evidence of pancreatitis with hyperglycemia, sudden profound increase
in lactic acidosis and increased
serum lipase. He died unexpectedly
the next day of cardiorespiratory collapse following an acute gastro-intestinal hemorrhage. Analysis of mitochondrial DNA (mtDNA) in muscle showed heteroplasmy for the mutation M T T L l * M E L A S 3 2 4 3 G

Introduction
Respiratory chain disorders can present in a variety of
ways in childhood. Mutations in mitochondrial D N A
(mtDNA) have been associated with specific clinical presentations. The tRNA Leu(UUa)3243 mutation has been seen
in 80% of patients who present with the syndrome of
mitochondrial encephalomyopathy, lactic acidosis and
stroke-like episodes (MELAS). These patients typically

(> 95%). Infants with this mutation
commonly present with failure to
thrive, significant developmental delay, and hypotonia, while stroke-like
episodes occur later in survivors.
They usually have lactic acidosis and
a high percentage of mutant m t D N A
in muscle.

Key words M E L A S • Infantile
presentation • Lactic acidosis
Pancreatitis
Abbreviations M E L A S mitochondrial encephalomyopathy with lactic
acidosis and stroke-like episodes.
m t D N A mitochondrial D N A

have normal early development and later present with
stroke-like episodes with evidence of focal brain abnormalities on CT or MRI, lactic acidosis, focal or generalized seizures, progressive dementia, short stature, recurrent headache, vomiting, and "ragged red fibers" on muscle biopsy [3, 25]. Occasionally patients with this point
mutation have presented in early childhood. We describe a
patient with this mutation who presented in infancy with
lactic acidosis, hypotonia, failure to thrive, profound de-

899

velopmental delay and infantile spasms. Of particular interest was the development of fatal acute pancreatitis.

Case report
A 7-month-old black male was referred to our hospital for failure
to thrive, developmental delay, hypotonia and a seizure disorder.
He was born to a 16-year-old mother after an uncomplicated fullterm pregnancy and was delivered by Cesarean section for failure
to progress. Apgar scores were 6 and 9 at 1 and 5 min respectively.
Birth weight was 3.1 kg (25th percentile), head circumference was
33.5 cm (10-25th percentile) and length was 50 cm (25th percentile). Developmental delay was first noticed at age 2 months
when the parents observed that he was floppy and unable to track
objects. At 5 months he developed infantile spasms increasing to
3 0 - 4 0 episodes daily over the next 2 months. He was referred to
our hospital at age 7 months. Physical examination revealed a hypotonic, malnourished child with severe developmental delay.
Head circumference (41 cm), height (62.5 cm), and weight (5.4 kg)
were all below the 2rid percentile for chronological age and at the
50th percentile for age 3 months. He had poor head control, could
not tm'n from side to side, and was unable to sit without support.
He did not show eye-to-eye contact. Light reflexes and fundoscopy
were normal. Deep tendon reflexes were accentuated in all four extremities. There was no organomegaly.
Initial laboratory data revealed normal blood counts, transaminases, aldolase, PT, PTT, free T4, TSH, glucose, urea nitrogen,
creatinine, calcium and phosphate. He had a metabolic acidosis
with a bicarbonate of 19 mEq/l and an anion gap of 22 mEq/1 (normal < 15). Simultaneous free flowing arterial blood lactate and
pyruvate were 12.9 m M and 0.39 m M respectively (normal
0.5-3.1; 0.03 0.08 respectively) with a lactate/pyruvate ratio of 33
(elevated). Plasma alanine was 937 g M (normal 143-439). Lactate
and pyruvate in cerebrospinal fluid were 7.7 (normal 0.5-3.1) and
0.24 m M (normal 0.06-0) with a lactate/pyruvate ratio of 31 (elevated). Total CPK was 406 U/I (normal 41-186), and LDH 866
IU/1 (normal 60-260). Plasma acylcarnitine profile was normal.
Urine organic acid analysis showed increased lactate, pyruvate, 3hydroxybutyrate, acetoacetate, and the Krebs cycle intermediates
succinate, fumarate, ~-ketoglutarate, cis-aconitate and citrate. The
EEG showed multifocal epileptiform activity and mild diffuse
slowing of background activity. MRI of the brain revealed normal
myelination for age with a mild prominence of cortical sulci and
ventricular system. M R spectroscopy showed increased lactate in
the basal ganglia. Activity of pyruvate dehydrogenase was 1.55 +
0.07 nmole/min per m g protein (normal 1.07 + 0.13) and pyruvate
carboxylase was 1.72 nmole/min per mg protein (normal 1.38) in
cultured skin fibroblasts, and the cellular lactate/pyruvate ratio was
20.3 + 3.9 (normal 15.4 + 0.87) (B. Robinson, Toronto, Canada).
There was no obvious improvement of acidosis with thiamine
(100 mg/day), biotin (10 mg/day), pyridoxine (50 rag/day) and
lipoate (50 mg/day). A 2-week trial of ACTH (40 IU on alternate
days for 1 week, with gradual tapering of the dose the next week)
did not improve the seizures. Failure to thrive, myoclonic seizures,
severe hypotonia, and developmental delay persisted. At 15
months he was readmitted with a respiratory tract infection. A
virus could not be identified. He was extremely hypotonic and had
not achieved any new developmental milestones since age 7
months. He subsequently developed a pleural and pericardial effusion which resolved over 1 week. Pleurocentesis gave transudative
fluid. Wolf-Parkinson-White syndrome and T-wave inversion
were initially noted on electrocardiogram. A week later he developed Pseudomonas sepsis which rapidly responded to intravenous
piperacillin and gentamicin. He was stable and afebrile. Two
weeks later he had sudden onset of glucosuria and hyperglycemia
(529 mg/dl 29.4 mM). The anion gap was increased to 32 mEq/l,
and lactate was 21.6 mM, far above his normal baseline. Serum

amylase was 83 U/l (30-110 U/l), but serum lipase was 358 (normal < 208 U/l); the previous day it had been 136 U/l and serum
amylase had been 37 U/l. A clinical diagnosis of acute pancreatic
dysfunction was made. A single dose of insulin was followed by
euglycemia and no clinical change from his usual state. Twentyfour hours later he suddenly deteriorated with shock and poor respiratory effort. A large amount of bright red blood was present in
his stomach. He could not be resuscitated. Permission for autopsy
was refused. The family history was negative for migraine, strokelike episodes, myopathy, retinopathy, hearing loss, cardiac conduction defects, diabetes or renal disease. Ptosis has recently occurred in the mother; however, she has not been available for more
detailed studies.

Methods
After obtaining informed consent, a muscle biopsy was taken from
the right quad~iceps under general anesthesia and quickly frozen in
isopentane cooled by liquid nitrogen. Hematoxylin and eosin,
modified Gomori trichrome, adenosine triphosphatase pH 9.4 and
4.35, and nicotinamide adenine dehydrogenase-tetrazolium reductase (NADH) stains were performed [8, 10, 21]. A glutaraldehyde
fixed specimen was stained in lead acetate for electron microscopy
by standard procedures. The remaining specimen was stored at 70°C for muscle enzyme studies [2] and mitochondrial D N A mutation analysis. Mutation designation is according to the Human

Fig. 1 Electron microscopy of muscle showing mitochondria
which are enlarged and contain focal crystalloids (arrow) Final
magnification: x 29,575

900

Genome Mapping convention [39]. Analysis for the MTTLl*MELAS3243G, MTT*MERRF8344G, MTATP6*NARP8993C,
mad MTATP6*NARP8993G mutations by polymerase chain reaction was performed as described elsewhere [30-33]. Southern blot
analysis using Apa I to detect the MTTLl*MELAS3243G mutation and laser densitometry to quantitate the percentages of mutant
and normal mtDNAs were performed as described [32].

Results
A p p r o x i m a t e l y 5% o f the fibers were slightly larger and
m o r e coarse than usual on h e m a t o x y l i n and eosin stain,
and stained m o r e intense on the N A D H tetrazolium blue
stain; they were identified as " r a g g e d red fibers" b y their
increased s u b s a r c o l e m m a l staining on trichrome stain.
M o s t o f these fibers were T y p e [ or intermediate b e t w e e n
Type I and Type II fibers. Electron m i c r o s c o p y s h o w e d
accumulations o f large d y s m o r p h i c m i t o c h o n d r i a beneath
the s a r c o l e m m a . L a r g e m i t o c h o n d r i a with bizarre concentric cristae and irregularly l a m e l l a t e d cristae with n o r m a l
m i t o c h o n d r i a b e t w e e n the m u s c l e fibers were seen (Figs.
1, 2). B l o o d vessels were normal. Skin b i o p s y was n o r m a l

Fig.3 Southern blot analysis
of skeletal muscle mtDNA for
the MTTLI*MELAS3243G
mutation. Lane 1: Apa[ digestion of normal mtDNA produces the following fragment
sizes: 7190 base pairs (bp),
4837 bp, 3822 bp, 2695 bp,
1576 bp, and 1016 bp.
Lane 2: when the MTTL 1*
MELAS3243G mutation is
present, the 2965 bp fragment
is digested, producing 1780
and 1185 bp fragments. Laser
densitometry revealed that the
MTT1 l*MELAS3243G mutation accounted for > 95% of
the total mtDNAs

1
7190

2

m

4837
382~ )

296S

1780
1576

1185
1016

on light m i c r o s c o p y and s h o w e d n o r m a l m i t o c h o n d r i a on
electron microscopy.
M u s c l e e n z y m e studies s h o w e d deficiencies o f C o m p l e x I to IV activities. C y t o c h r o m e c o x i d a s e was 1.28
g m o l substrate o x i d i z e d / m i n p e r g tissue; (normal values
m e a n and SD: 1.8 + 0.52) succinate c y t o c h r o m e C reductase 0.331 + .228), N A D H c y t o c h r o m e C reductase 0.141
(1.020 + 0.38) N A D H - d e h y d r o g e n a s e 7.53 (35.48 + 7.07),
citrate synthase 13.21 (9.88 _+ 2.55) and succinate d e h y d r o g e n a s e 0.241 (1.00 + 0.526).
M u s c l e m t D N A from the patient was tested for the
M T T L l * M E L A S 3 2 4 3 G m u t a t i o n b y Southern blot using
A p a I for m u t a t i o n detection and b y p o l y m e r a s e chain reaction a m p l i f i c a t i o n o f an m t D N A fragment containing the
t R N A Leucine(UUR)gene using HaeIII for mutation detection.
The M T T L l * M E L A S 3 2 4 3 G mutation was present in >
95% o f the total m t D N A in skeletal m u s c l e (Fig. 3; L a n e
2). T h e M T T K * M E R R F 8 3 4 4 G , M T A T P 6 * N A R P 8 9 3 C ,
and M T A T P 6 * N A R P 8 9 9 3 G mutations were not identified
in the p a t i e n t ' s skeletal m u s c l e m t D N A .
Fig.2 Illustrated is a skeletal muscle fiber with enlarged subsarcolemmal mitochondria with concentric cristae (arrow); compare
with normal mitochondria (arrowhead). Final magnification:
x 24,500

901

Discussion
The clinical syndrome of MELAS was first described by
Pavlakis et al. [25] as a progressive neurodegenerative
disease characterized by stroke-like episodes and a mitochondrial myopathy. Approximately 80% of patients with
clinical features of MELAS are heteroplasmic for an A to
G point mutation in the dihydrouridine loop of the tRNA Le~(UvR)gene at 3243 (MTTLI * MELAS3243G) [11].
Patients with this mutation may present with varying
combinations of myopathy, retinopathy, cardiac conduction defects, lactic acidosis, proximal renal tubular disease
and easy fatiguability. They often present between 5 and
15 years of age with a history of migrainous headache followed by a stroke-like episode [3, 17, 25, 30]. A small
group of patients with the 3243 point mutation have an
early onset, in infancy. These patients present with more
generalized symptoms of failure to thrive, vomiting, lactic
acidosis and early onset cognitive regression before developing stroke-like symptoms [3, 9, 17]. Brain imaging
studies at initial presentation are frequently normal [17].
On follow-up, the children eventually develop the more
typical symptoms of stroke-like episodes. Younger age of
onset is associated with an increased percentage of mutant
mtDNA in muscle, infants having > 90% [3, 20], as did
our patient. It is possible that our patient would have subsequently developed the stroke-like episodes had he not
succumbed to the acute fulminant pancreatitis.
Pancreatitis is relatively rare in childhood, and its etiology less well understood. Recognized causes of pancreatitis in children include systemic disorders (e.g., infection, peritonitis, sepsis, inflammatory disorders, Reye
syndrome, trauma, cystic fibrosis, hypercalcemia), gallstones, drugs (e.g., valproic acid, steroid hormones, L-asparaginase), and malnutrition [ 19, 22, 36, 40]. Pancreatitis
has been reported in several metabolic diseases including several organic acidurias [13], some fatty acid oxidation disorders [34, 41], and disorders with elevated triglycerides [16]. Exocrine pancreatic insufficiency is uncommonly recognized in patients with oxidative phosphorylation diseases but is usually observed in individuals
with Pearson syndrome [5, 27]. Diabetes mellitus was observed in patients with MELAS syndrome [20] and the
M T T L l * M E L A S 3 2 4 3 G mutation is an important singlegene cause of diabetes mellitus. In three large screening
studies performed on Japanese patients with non-insulin
dependent diabetes mellitus and insulin dependent diabetes mellitus and two studies of Caucasians with non-insulin dependent diabetes mellitus, 1.6% (17/1095) of the
Japanese individuals [12, 14, 24] and 1.1% (3/283) of
the Caucasian individuals [1, 35] harbored the M T T L I *
MELAS3243G mutation. The endocrine pancreas is also
involved in the Wolfram syndrome, which is characterized by diabetes insipidus, diabetes mellitus, optic atrophy
and nerve deafness (DIDMOAD) in which a heteroplasmic mitochondrial DNA deletion has been identified [28].

Pancreatitis has been reported rarely in patients with respiratory chain disorders [6, 15]. Chronic pancreatitis has
been reported in a single case of cytochrome c oxidase deficiency. This Japanese boy presented at 6 years of age
with generalized muscular atrophy, weakness and growth
retardation [15]. At 10 years of age, during an admission
for recurrent epigastric pain of 3 years duration, diffuse
pancreatic calcification and pseudocyst of the pancreas
was diagnosed on abdominal CT, while serum and urinary
amylase levels were normal. Dougherty et al. [6] reported
an extended pedigree with a mtDNA 3243 point mutation
with MELAS in the proband and atypical symptoms in affected relatives. The proband, a 14-year-old boy with a
stroke-like episode, weakness, ventricular hypertrophy,
progressive dementia and hearing loss, developed pancreatitis during valproate therapy. The maternal grandmother,
who carried the 3243 mtDNA mutation and had strokelike episodes, also had a history of pancreatitis.
Our patient suddenly died of cardiorespiratory failure
during an episode of acute pancreatitis. The diagnosis of
pancreatitis was supported by the hyperglycemia, metabolic acidosis, elevated lipases, and the acute gastrointestinal hemorrhage, despite the normal amylasemia [4,
13, 18, 23, 37, 38]. The long interval since the initial respiratory illness of possible viral origin makes it unlikely
to be the cause. There are several possible ways the 3243
mtDNA mutation could cause pancreatitis. The severe
malnutrition induced by the systemic symptoms of the mitochondrial dysfunction could have contributed to the
pancreatitis [7]. More specifically, vascular damage typical of MELAS disorders, could involve the pancreatic
blood vessels and potentially cause pancreatitis [26] . Increased production of oxygen free-radicals, seen in patients with respiratory chain disorders, could inhibit the
release of endothelium-derived relaxing factors which are
generated by vascular endothelium leading to vasoconstriction [29]. Direct cellular energy deficit due to oxidative phosphorylation dysfunction could sufficiently impair pancreatic cell integrity, possibly resulting in infarcts,
and leading to direct damage to the pancreatic parenchyma.
In summary, the infantile presentation of M T T L I *
MELAS3243G mutation at mitochondrial DNA tRNA Leu(utna)
gene, as in our patient, is characterized by systemic signs
including failure to thrive, significant developmental delay and hypotonia. Most infants have had lactic acidosis
and a high percentage of mutant mtDNA in muscle.
Stroke-like episodes occur later in surviving infants. Pancreatic dysfunction and pancreatitis, both acute and
chronic, needs to be added to the list of symptoms of disorders of the respiratory chain. It can be overwhelming
and rapidly fatal, or may not be obvious by recognizable
clinically, and must be sought for.
Aeknowledgements We would like to thank Quinn Sadler for her
secretarial assistance with the preparation of the manuscript.

902

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