The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 1 125-129
Copyright © 1998 by The Endocrine Society
Mitochondrial Encephalomyopathy and Hypoparathyrodism Associated with a Duplication and a Deletion of Mitochondrial Deoxyribonucleic Acid1
C. H. Tengan2,
B. H. Kiyomoto,
M. S. Rocha,
V. L. S. Tavares,
A. A. Gabbai and
C. T. Moraes3
Departments of Neurology (C.H.T., C.T.M.) and Cell Biology
and Anatomy (C.T.M.), University of Miami School of Medicine, Miami,
Florida 33136; and Disciplina de Neurologia Clínica,
Universidade Federal de São Paulo (C.H.T., B.H.K., A.A.G.), and
C. S. Santa Marcelina (M.S.R., V.L.S.T.), Sao Paulo, Brazil
Address all correspondence and requests for reprints to: Carlos T. Moraes, Ph.D., Department of Neurology, University of Miami, 1501 NW 9th Avenue, Miami, Florida 33136. E-mail:
cmoraes{at}mednet.med.miami.edu
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Abstract
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Diabetes mellitus is the most frequent endocrinopathy associated with
mitochondrial disorders, particularly in patients with duplications of
mitochondrial DNA (mtDNA). Although hypoparathyroidism has also been
described in mitochondrial diseases, there have been few molecular
studies in these cases, most of which identified the presence of single
mtDNA deletions in the patients’ tissues. We studied muscle DNA of a
12-yr-old patient with incomplete Kearns-Sayre syndrome and
hypoparathyroidism. Southern analysis showed that muscle DNA contained
three populations of mtDNA: wild type (26%), deleted (65%), and
duplicated (9%). To determine the sequence of the breakpoint region
from deleted and duplicated mtDNA independently, we isolated the
deleted and duplicated mtDNA by gel fractionation of a
PstI-digested total DNA. The breakpoint was located at
mtDNA positions 5788 and 15448 for both duplicated and deleted
molecules. Our study reinforces the concept that endocrinopathies other
than diabetes can be associated with a duplication of mtDNA and gives
additional support to the hypothesis that the duplication and deletion
of mtDNA are generated from the same recombination event.
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Introduction
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AMONG ALL mitochondrial DNA (mtDNA)
mutations described to date, single deletions are among the most
frequent (1). Patients with mtDNA deletions are most commonly
associated with three types of syndromes: Kearns-Sayre syndrome (KSS),
chronic progressive external ophthalmoplegia, and Pearson syndrome (2).
KSS is a multisystemic disorder manifesting with ophthalmoplegia and
retinitis pigmentosa with onset before 20 yr of age. Other
manifestations include ataxia, heart block, high cerebrospinal fluid
(CSF) protein level, and, in many patients, endocrinopathy, most
commonly diabetes mellitus.
Although it is well established that mtDNA is transmitted exclusively
through the maternal lineage (3), in the vast majority of patients with
mtDNA deletions, the disease has a sporadic nature (1). The mechanisms
involved in the generation of deletions are not completely understood.
It was suggested that most deletions are generated by a homologous
recombination event involving direct nucleotide repeats (4). Since the
first description of a duplication in human mtDNA (5), the explanations
for the mechanisms associated with rearrangements (deletions and
duplications) became more complex, especially when two types of
rearrangements were found in the same patient (6, 7, 8, 9, 10). Poulton proposed
that the duplicated mtDNA could be transmitted from the mother and
later evolved to deleted mtDNA (8). Two findings support this idea:
maternal transmission of the duplicated mtDNA in some patients (11, 12)
and decrease in the proportion of duplicated molecules concomitant with
an increase in the deleted mtDNA during life (13).
Because several patients with a duplication of mtDNA manifested with
diabetes mellitus, it was suggested that a duplication of mtDNA would
be associated with this endocrinopathy (8, 9, 10, 11, 12, 13). This association was
supported by the finding of a patient with a partial duplication of
mtDNA manifesting only with diabetes. The duplicated mtDNA was found in
blood and muscle, but muscle contained only 15% of the mutant mtDNA,
whereas blood contained 80% (13).
Several endocrinopathies have been described in mitochondrial disorders
(14). However, there are few descriptions of molecular studies on
patients with a mitochondrial disorder with hypoparathyroidism; most of
them show the presence of a single deletion of mtDNA (15, 16, 17, 18, 19).
Recently, Wilichowski et al. (20) reported four patients
with KSS and hypoparathyroidism presenting deletion/duplication of
mtDNA in white blood cells (WBC).
In the present study, we characterized the mtDNA rearrangements in
muscle of a patient with a mitochondrial encephalomyopathy and
hypoparathyroidism and compared our findings with previously reported
cases of mitochondrial disorders with hypoparathyroidism.
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Experimental Subject
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A 12-yr-old girl presented with generalized seizures and ptosis
at 5 yr of age. The seizures were controlled with anticonvulsant
therapy (phenobarbital) for 2 yr. The patient sought medical attention
because the treatment was interrupted, and she started to have seizures
again. There was no family history of endocrine or neuromuscular
disease and no consanguinity. On physical examination, the nails and
teeth were normal, Trousseau’s and Chvostek’s signs were negative,
and short stature (on the 2.5 percentile) was observed. Neurological
examination demonstrated ophthalmoplegia, mild weakness, deep tendon
areflexia in upper and lower extremities, and cerebellar ataxia.
Funduscopy showed no retinal changes. Laboratory tests revealed mild
increase in creatine phosphate (CK) (247 IU/L; normal, 24–170 IU/L)
and lactate (20 mg/100 mL; normal, 9–16 mg/100 mL) in blood, elevated
CSF protein concentration (123 mg/100 mL; normal, 10–43 mg/100 mL),
computed tomography scan with basal ganglia calcifications, serum
calcium of 7.7 mg/dL (normal, 9–11 mg/dL), serum phosphate of 8.8
mg/dL (normal, 4–6 mg/dL), serum magnesium of 1.0 mg/dL (normal, 2–3
mg/dL), PTH of 4 ng/dL (normal, 10–65 ng/dL), and normal levels of
alkaline phosphatase, glucose, Na, K, urea, creatinine, aspartate
aminotransferase, alanine aminotransferase, albumin, total protein, and
-glutamyl transferase. Thyroid function was normal, and LH and FSH
levels demonstrated a prepuberal pattern. Bone age was compatible for
10 yr. No skeletal abnormalities were found. Electroencephalogram,
electrocardiogram, electromyogram, and nerve conduction velocities were
normal. The seizures disappeared with the introduction of
carbamazepine, but after the initial investigations the patient did not
return for follow-up. Muscle biopsy showed mitochondrial proliferation
(ragged red fibers) and focal cytochrome c oxidase
deficiency. No treatment was given for the hypocalcemia because the
patient did not return for follow-up, and carbamazepine, introduced
just after the initial evaluation, successfully controlled the
seizures.
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Materials and Methods
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DNA analysis
DNA studies were conducted on a muscle biopsy specimen as part
of diagnostic procedures and were approved by the Universidade Federal
de Sao Paulo Institutional Review Board. Muscle DNA was obtained by
organic extraction as previously described (1) and digested with two
restriction enzymes, separately, PvuII and PstI,
at 37 C for 2 h. Digested DNA was electrophoresed through a 0.6%
agarose gel and stained with ethidium bromide. The DNA was then
transferred to a nylon membrane, hybridized independently to two
32P-labeled probes: probe B (specific to mtDNA segment from
positions 11,680–12,406) and probe A (specific to mtDNA segment from
positions 526–1,768). The autoradiography exposures were scanned and
quantitated by digital densitometric analysis using the NIH freeware
package (Image version 1.57).
Determination of deletion/duplication breakpoint region
A whole genome PCR was performed from total DNA according to the
method of Tengan and Moraes (21) using the Expand long template system
(Boehringer Mannheim, Indianapolis, IN) and primers located 16,425 bp
apart (forward primer corresponding to mtDNA positions 10–40 and
reverse primer corresponding to mtDNA positions 16,496–16,465). The
deletion/duplication breakpoint region was mapped by restriction
fragment length polymorphism of the fragment obtained by this method
using the following endonucleases: PvuII, BspEI,
NdeI, AspI, SnaBI, and
BamHI. The rearrangement/breakpoint region was determined by
direct sequencing of a PCR fragment encompassing the breakpoint. This
fragment was obtained by PCR-amplifying total muscle DNA from the
patient or DNA extracted from gel slices with primers encompassing
mtDNA nucleotides 5,472–5,491 and 16,060–16,033, using standard
conditions (30 cycles consisting of 94 C for 1 min, 65 C for 1 min, and
72 C for 1 min) with Taq DNA polymerase (Boehringer
Mannheim).
Fractionation of deleted and duplicated mtDNA
Total muscle DNA was digested with PstI and
electrophoresed through a preparative low melting agarose gel (0.6%)
at 4 C. The lane was sectioned transversally every 2–3 mm from the
origin of the running. DNA was obtained from each slice of gel by
organic extraction, and two thirds of the extracted DNA was
electrophoresed through a 0.6% agarose gel, transferred to a nylon
membrane, and hybridized with probe A to identify the fractions
containing the DNA from wild-type, deleted, and duplicated mtDNA. The
bands were identified by comparison to a PstI digestion from
total DNA. A PCR amplification was obtained from deleted and duplicated
mtDNA fractions, and the PCR fragments, harboring the deletion or
duplication breakpoint, from each fraction were direct sequenced in an
ABI automatic sequencer (Applied Biosystems, Foster City, CA).
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Results
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The presence of ophthalmoplegia, ataxia, weakness, elevated CSF
protein concentration, and mitochondrial abnormalities on muscle biopsy
from the patient, suggested the presence of mtDNA rearrangements in
affected tissues. Southern blot analysis of muscle DNA digested with
PvuII showed the presence of two bands, the wild-type band
[16.5 kilobases (kb)] and a smaller one of approximately 7 kb. A 7-kb
band could also be obtained after a whole genome PCR (see
Materials and Methods). Restriction fragment length
polymorphism analysis of this PCR-amplified fragment demonstrated that
the breakpoint region was located between mtDNA positions 5,472 and
15,574. We then performed a PCR amplification from total DNA using
oligonucleotide primers flanking mtDNA positions 5,685–16,060. This
amplification gave rise to a 715-bp fragment, which could only be
possible if this segment contained the rearrangement breakpoint,
because the expected wild-type fragment (10,374 bp) was too long to be
effectively amplified under the conditions employed. The abnormal band
observed in the Southern blot and PCR experiments could represent a
mtDNA deletion of 9.5 kb or a duplication of 7 kb. To distinguish
between these rearrangements, we digested total DNA with
PstI, which has two sites in the normal mtDNA, giving rise
to two fragments (14.5 and 2 kb). Probes A and B (see Fig. 1
for location of probes) could hybridize
to the 14.5-kb band. Upon digestion with PstI, a putative
duplicated mtDNA would give rise to a larger fragment (21.5 kb), and
the deleted mtDNA would display an abnormal migration pattern because
it would not have any sites for PstI. Probe B was able to
hybridize to fragments originating from the wild-type and duplicated
mtDNA, whereas probe A was able to hybridize to the D loop region of
all types of mtDNA. Digestion with PstI demonstrated the
wild-type band (14.5 kb) and a larger band, which corresponded to the
duplicated mtDNA. Probe A identified an additional band after
PstI digestion, corresponding to the deleted mtDNA (Fig. 1).
Densitometric analysis of the bands revealed that deleted mtDNA
corresponded to 65% of the total mtDNA, duplicated mtDNA to 9%, and
wild-type mtDNA to 26%.
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Figure 1. Muscle mtDNA analysis in a patient with a
mitochondrial encephalomyopathy and hypoparathyroidism. The two panels
on the left show the Southern blots obtained after the
digestion of patient’s muscle DNA with PvuII,
PstI, and undigested DNA hybridized to probes A
(specific to the mtDNA segment from positions 526–1,768) and B
(specific to the mtDNA segment from positions 11,680–12,406). Note
that probe B can detect only one (duplicated mtDNA) of the two abnormal
bands observed in the PstI digest probed with probe A
(duplicated and deleted mtDNA). The cartoon shows representations of
the deleted mtDNA and duplicated mtDNA. Deleted mtDNA does not have any
sites for PstI (mtDNA positions 6,910 and 9,020), and in
the duplicated mtDNA, the PvuII site (mtDNA position
2,650) is also duplicated. The star indicates the
localization of probes A and B.
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Southern blot of the DNA obtained by gel fractionation of the
PstI digest (Fig. 2) showed
the isolated bands from the deleted and duplicated mtDNA. The wild-type
band could not be completely isolated because of the proximity of a
subspecies of deleted mtDNA (probably relaxed circles). The PCR
amplification, using the same pair of primers described above, from the
isolated deleted (fraction 18, Fig. 2) and duplicated (fraction 24,
Fig. 2) mtDNA gave rise to identical bands (715 bp), suggesting that
the breakpoint was the same for both rearrangements. To better define
the breakpoint region, PCR products obtained from total DNA, duplicated
mtDNA, and deleted mtDNA were sequenced. All three fragments had
exactly the same nucleotide sequence in the breakpoint region. The
breakpoint region for the deletion/duplication corresponded to mtDNA
positions 5,784–5,788 and 15,444–15,448 involving a five-nucleotide
direct repeat (CTTCT) present in the wild-type mtDNA (Fig. 3).
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Figure 2. Characterization of mtDNA fractions obtained
by gel fractionation of a PstI digestion of muscle DNA.
Total DNA from the patient’s muscle was digested with
PstI and electrophoresed through a 0.6% low melting
agarose gel. After electrophoresis, the lane was sliced every 2–3 mm,
and an aliquot of the DNA obtained from each slice was electrophoresed
through a 0.6% agarose gel, transferred to a nylon membrane, and
hybridized to probe B (see Fig. 1 ). The autoradiography obtained showed
the separation of deleted, duplicated, and wild-type mtDNA. T,
PstI digest from total DNA. Fractions 18 (deleted mtDNA)
and 24 (duplicated mtDNA) were used in the sequence analyses.
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Figure 3. Nucleotide sequence of the
deletion/duplication breakpoint region. Nucleotide sequence of
wild-type mtDNA between positions 5,774 and 5,798 (A) and positions
15,433 and 15,458 (B). The sequence shown in C describes the results
obtained from the gel-fractionated deleted and duplicated mtDNA with an
interruption between positions 5,784–5,788 and 15,444–15,448
(breakpoint). The underlined sequence represents the
5-bp direct repeat.
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Discussion
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Several studies suggest an association between diabetes mellitus
and a duplication of mtDNA (8, 9, 11, 13). Ballinger et al.
described a family that manifested only with diabetes mellitus, with a
duplication of mtDNA and maternal transmission (11). Dunbar et
al. described another patient with this type of rearrangement
manifesting with mitochondrial myopathy and diabetes (13). Poulton
et al. found 4 patients with KSS (among 10 patients) with
high levels of duplication and diabetes mellitus (8).
Different types of mutations of mtDNA were described in patients with
hypoparathyroidism: single deletions (15, 16, 17, 18, 19), multiple deletions (22),
and a point mutation in transfer ribonucleic acidLeu(UUR)
(23) (Table 1). The presence of a
duplication of the mtDNA was only detected in three studies (20, 24, 25), demonstrating higher proportions of duplicated mtDNA in WBC.
Interestingly, we detected a higher proportion of deleted mtDNA in our
patient’s muscle DNA. Unfortunately, WBC were unavailable for study
from the patient and her mother and siblings. Regardless of the mtDNA
defect, all patients reported had early onset of symptoms with a
multisystemic involvement, and in only three cases was
hypoparathyroidism the initial manifestation (Table 1). Abramowicz
et al. reported a patient with hypocalcemia and pernicious
anemia with 60% duplicated mtDNA molecules (24). Poulton et
al. found a partial duplication/deletion of mtDNA in 10 patients
with KSS and suggested that the duplication was characteristic of the
early onset of KSS, especially in those with diabetes mellitus (8).
Despite the early onset, the patient described here did not have
diabetes. Several cases with a duplication of mtDNA, with or without
deletion, manifested with diabetes mellitus (8, 9, 11, 13). The
presence of a duplication/deletion of mtDNA may be more frequently
associated with endocrinopathies, as suggested by Poulton et
al. (8). The frequency of the duplication in these cases could be
higher than previously suspected because most of the cases reported
earlier were not properly investigated for the presence of this
rearrangement. It is not known which rearrangement is pathogenic in
cases where a deletion and a duplication of mtDNA coexist. It is
reasonable to assume that the deletion would be the one causing the
disease because it is present in higher proportions in muscle, removes
important genes of mtDNA, and the proportion increases with age,
correlating with the worsening of symptoms (26). Supporting this
hypothesis, Manfredi et al. (27) demonstrated that deleted
mtDNA genomes cosegregated with cytochrome c
oxidase-deficient fibers in skeletal muscle of a patient with deleted
and duplicated mtDNA. However, the existence of patients with
duplicated mtDNA without deleted molecules (13) suggests that
duplications may also be pathogenic per se, possibly by the
synthesis of truncated fusion proteins.
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Table 1. Clinical and molecular features of patients with a
mitochondrial encephalopathy associated to hypoparathyroidism
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The occurrence of both rearrangements in the same patient is also
intriguing. Did the duplicated molecule gave rise to the deleted one,
or did they originate from the same recombination event? It appears
that homologous recombination is associated with the genesis of these
kind of rearrangements because of the presence of direct repeats
surrounding the duplication/deletion breakpoint. Restriction
endonuclease mapping suggested that both rearrangements had the same
breakpoint (11). This assumption, however, was not previously
documented at the nucleotide resolution from isolated deleted and
duplicated mtDNA. The fact that we found exactly the same breakpoint in
gel-fractionated deleted and duplicated mtDNA favors the hypothesis of
a common origin from the same recombination event.
Although the association between mtDNA duplications and endocrine
system dysfunction is difficult to explain, our study demonstrates that
endocrinopathies other than diabetes can be associated with the
presence of a duplication of mtDNA and gives additional support to the
hypothesis that the duplication and deletion of mtDNA are generated by
a coordinated mechanism.
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Footnotes
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1 This work was supported by grants from the Muscular Dystrophy
Association and the National Eye Institute (EY-10804). 
2 Supported by the Brazilian Research Council.
3 PEW Scholar in the Biomedical Sciences.
Received July 22, 1997.
Revised September 17, 1997.
Accepted September 22, 1997.
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Abstract
Introduction
