Journal ofNeurology, Neurosurgery, and Psychiatry
1989;52:122-125
Short report
Endocrine involvement in mitochondrialencephalomyopathy with
partial cytochrome c oxidasedeficiencyC DORIGUZZI, L PALMUCCI, T
MONGINI, N BRESOLIN,* L BET,* G COMI,*R LALAtFrom the Clinica
Neurologica II, Universita di Torino; Clinica Neurologica, Centro
Dino Ferrari, Universitai diMilano;* Servizio di Endocrinologia
Pediatrica, Ospedale Infantile Regina Margherita,t Torino,
Italy
SUMMARY A 19-year-old man born with thyroprivic hypothyroidism,
due to congenital develop-ment defect, manifested hypogonadism,
stunted growth, chronic progressive external ophthalmo-plegia
(CPEO), diffuse muscle weakness and wasting, right bundle branch
block, cerebral atrophy.Muscle biopsy showed mitochondrial
abnormalities. Biochemical investigations on muscle
disclosedpartial (50%) cytochrome c oxidase deficiency, 58%
decrease ofcytochrome aa3 and 41% decrease ofcytochrome b.
Enzyme-linked immunosorbent assay showed decrease ofthe
immunologically activeenzyme protein.
Cytochrome c oxidase deficiency has been reported inseveral
mitochondrial encephalomyopathies and hasvery heterogeneous
clinical manifestations.'!" Amongthem chronic progressive external
ophthalmoplegia(CPEO) is the most frequent. Endocrine
involvementhas not been reported in partial cytochrome c
oxidasedeficiency, but has been described in some cases ofCPEO with
mitochondrial alterations not bio-chemically investigated (see
refs: 2, 12).We describe a 19 year old patient with endocrine
involvement as the first sign of mitochondrial
en-cephalomyopathy. Biochemical investigations andELISA on muscle
homogenate disclosed partial cyto-chrome c oxidase deficiency.
Case report
The patient was born of non consanguineous parents withnegative
family history for neuromuscular diseases. At age 2months
thyroprivic hypothyroidism due to congenitaldevelopment defect was
found and the patient was treatedwith replacement therapy. In spite
of normalised thyroid
Address for reprint requests: Dr C Doriguzzi, Clinica
Neurologica II,Via Cherasco 15, 10126, Torino, Italy.
Received 17 May and in revised form 27 July 1988.Accepted 4
August 1988
hormone values, he had delayed developmental milestones,began to
walk at 30 months and was never able to cope withplaymates. At age
12 years primary hypogonadism wasfound with decreased testosterone
incretion (0-8 ng/ml withnormal values 3-9 ng/ml) both before and
after administra-tion ofhuman chorionic gonadotropin (HCG). Bone
age was7 years, height was 131 cm (
124
Material and methods
Triceps brachii muscle biopsy was performed under
localanaesthesia and the specimen was processed for light
andelectron microscopy. Specimens were immediately frozen,stored in
liquid nitrogen and described spectrophotometricassays9 were used
to measure succinate cytochrome creductase, DPNH cytochrome c
reductase, succinatedehydrogenase, NADH dehydrogenase, citrate
synthase andcytochrome oxidase activities.
Reduced-minus-oxidised spectra of cytochromes wererecorded at
room temperature as previously reported.'3 Theimmunological
analysis was carried out by enzyme-linkedimmunosorbent assay
(ELISA) using an antiserum againstpurified cytochrome c
oxidase.'3
Results
Light microscopic examination showed the typicalpicture of a
mitochondrial myopathy (fig a, b): 10%muscle fibres were ragged
red. The same fibres stainedmore intensely with the reactions for
NADH-tetrazolium reductase, lactate dehydrogenase, succin-ate
dehydrogenase, and several of them showedincreased staining with
periodic acid Schiff and OilRed 0 stains. In 20% fibres
histochemical stainingshowed absence of cytochrome c oxidase
activity.Electron microscopy demonstrated abnormal mito-chondria
with paracrystalline inclusions both underthe sarcolemma and within
muscle fibres (fig c). Therewas also a slight increase of free
glycogen and lipids.Biochemical studies showed 50% decrease of
cyto-chrome c oxidase activity in muscle homogenate(27.95
nmol/min/mg protein; controls = 55 9, SD10-2), and normal values of
other mitochondrialenzymes. A parallel decrease of
immunologicallyreactive enzyme protein was demonstrated by ELISAof
muscle homogenates (50 mg/ml protein) from con-trol and patient
muscle, with progressive dilutions ofpurified antihuman cytochrome
c oxidase immun-oglobulin G. The spectra of
reduced-minus-oxidisedcytochromes of isolated muscle mitochondria
showed58% decrease of cytochrome aa3 (273.8 pmol/mgmitochondrial
protein; controls = 652-83, SD 104)and 41% decrease of cytochrome b
(385.3 pmol/mgmitochondrial protein; controls = 653, SD 42).
Discussion
In the reported case, the association ofCPEO, diffusemuscle
weakness and wasting, ECG alterations, CTbrain abnormalities,
stunted growth and endocrinedisturbances could suggest the
diagnosis of Kearns-Sayre syndrome, but the absence of retinitis
pigment-osa does not agree with this.' The mitochondrialdysfunction
proved by lactic acidosis and by theresults of morphological,
histochemical and bio-
Doriguzzi, Palmucci, Mongini, Bresolin, Bet, Comi, Lala
chemical investigations ofmuscle biopsy indicates thatour
patient may be included in the group of so called"mitochondrial
encephalomyopathies". In these syn-dromes endocrinopathies have
already been reportedas additional features, more frequently in the
form ofdiabetes3""-' and hypoparathyroidism'72
whereashypothyroidism32' and hypogonadism7 22-24 are lesscommon.
Thyroprivic hypothyroidism, as in ourpatient, is quite unusual and
probably representsanother sign of the multisystem involvement in
mito-chondrial encephalomyopathies.
In our patient histochemical, biochemical andimmunological
investigations showed partial cyto-chrome c oxidase deficiency.
Cytochrome c oxidasedeficiency has been reported in infancy,
morefrequently with fatal outcome,'92 less commonly witha benign
course.2627 In all these forms the enzymeactivity is almost
completely absent in the newbornperiod when severe generalised
weakness is present.Cases of partial deficiency of cytochrome c
oxidasehave also been reported, usually with juvenile or adultonset
and slow progression of the disease.78011 Thesignificance of these
partial defects is debatable: in factsingle muscle fibres devoid of
histochemical activity ofcytochrome c oxidase are relatively common
in mito-chondrial myopathies (personal observation)56 andhave also
been reported in patients with defects of therespiratory chain
other than complex IV.22829 Thesefindings suggest that partial
defect of activity of theenzyme may be secondary, as stressed by
the progres-sive decline ofthe enzyme activity in a case'3 and by
thelow levels of the enzyme found in patients withcomplex I
defects.9 As we did not perform polaro-graphic studies we cannot
exclude complex Ideficiency, but biochemical determinations of
mito-chondrial enzymes activity did not suggest this defect.On the
other hand the parallel deficiency of theimmunologically active
protein, observed in our caseand already reported," is difficult to
interpret assecondary.The partial decrease of cytochrome aa3 and
b,
demonstrated in isolated muscle mitochondria, doesnot establish
a more accurate correspondence betweenthe biochemical defect and
the clinical picture. In factthe other reported cases with partial
deficiency ofcytochrome aa3 and b23 " presented clinical
featuresdifferent from our case and very heterogeneous.Our report
confirms the multisystemic involvement
in mitochondrial encephalomyopathies and stressesthat
endocrinopathy may be an unusual onset of thesediseases.
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