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 (

Endocrine involvement in mitochondrial encephalomyopathy with partial cytochrome c oxidase deficiency 123

Wt.

4

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.

References

1 Di Mauro S, Bonilla E, Zeviani M, et al. Mitochondrial myo-pathies. Ann Neurol 1985;17:521-38.

Protected by copyright.

on July 8, 2021 by guest.http://jnnp.bm

j.com/

J Neurol N

eurosurg Psychiatry: first published as 10.1136/jnnp.52.1.122 on 1 January 1989. D

ownloaded from

http://jnnp.bmj.com/

Endocrine involvement in mitochondrial encephalomyopathy with partial cytochrome c oxidase deficiency2 Morgan-Hughes JA. The mitochondrial myopathies. In: Engel

AG, Banker BQ, eds. Myology. New York: McGraw-Hill, 1986:1709-42.

3 Petty RKH, Harding AE, Morgan-Hughes JA. The clinicalfeatures of mitochondrial myopathy. Brain 1986;109:915-39.

4 Bardosi A, Creutzfeldt W, Di Mauro S, et al. Myo-, Neuro-,gastrointestinal encephalopathy (MNGIE syndrome) due topartial deficiency of cytochrome-c-oxidase. A new mitochon-drial multisystem disorder. Acta Neuropathol 1987;74:248-58.

5 Johnson MA, Turnbull DM, Dick DJ, Sherratt HSA. A partialdeficiency of cytochrome c oxidase in chronic progressiveexternal ophthalmoplegia. JNeurol Sci 1983;60:31-53.

6 Mfiller-H&ker J, Pongratz D, Hiibner J. Focal deficiency ofcytochrome c oxidase in skeletal muscle of patients withprogressive external ophthalmoplegia. Virchows Arch (PatholAnat) 1983;402:61-71.

7 Byrne E, Dennett X, Trounce I, Henderson R. Partial cytochromeoxidase (aa3) deficiency in chronic progressive external ophthal-moplegia. Histochemical and biochemical studies. J Neurol Sci1985;71:257-71.

8 Turnbull DM, Johnson MA, Dick DJ, et al. Partial cytochromeoxidase deficiency without subsarcolemmal accumulation ofmitochondria in chronic progressive external ophthalmoplegia.J Neurol Sci 1985;70:93-100.

9 Bresolin N, Zeviani M, Bonilla E, et al. Fatal infantile cytochromec oxidase deficiency: decrease of immunologically detectableenzyme in muscle. Neurology 1985;35:802-12.

10 Pezenshkpour G, Krarup C, Buchtal F, et al. Peripheralneuropathy in mitochondrial disease. J Neurol Sci 1987;77:285-304.

11 Servidei S, Lazaro RP, Bonilla E, et al. Mitochondrial ence-phalomyopathy and partial cytochrome c oxidase deficiency.Neurology 1987;37:58-63.

12 Tome FMS, Fardeau M. Ocular myopathies. In: Engel AG,Banker BQ, eds. Myology. New York: McGraw-Hill, 1986:1327-47.

13 Bresolin N, Moggio M, Bet L, et al. Progressive cytochrome coxidase deficiency in a case of Kearns-Sayre syndrome: mor-phological, immunological, and biochemical studies in musclebiopsies and autopsy tissues. Ann Neurol 1987;21:564-72.

14 Bolthauser E, Jerusalem F, Niemeyer G, Huber C. Kearns-syndrom. Progressive externe Ophthalmoplegie, Pigmentdegen-eration der Retina und kardiale Reizleitungstorungen. SchweizMed Wschr 1977;107:1880-8.

15 Seigel AM, Shaywitz BA, Ciesieski T. Kearns-Sayre syndrome: the

importance of early recognition. Am J Dis Child 1977;131:711-12.

16 Robertson WC, Viseskul C, Lee YE, Lloyd RV. Basal gangliacalcification in Kearns-Sayre syndrome. Arch Neurol 1979;36:711-3.

17 Toppet M, Telerman-Toppet N, Szliwowski HB, et al. Oculocran-iosomatic neuromuscular disease with hypoparathyroidism.Am J Dis Child 1977;131:437-40.

18 Horwitz SJ, Roessmann U. Kearns-Sayre syndrome with hypo-parathyroidism Ann Neurol 1978;3:513-8.

19 Pellock JM, Behrens M, Lewis L, et al. Kearns-Sayre syndromeand hypoparathyroidism. Ann Neurol 1978;3:455-8.

20 Dewhurst AG, Hall D, Schwartz MS, McKeran RO. Kearns-Sayre syndrome, hypoparathyroidism, and basal ganglia cal-cification. J Neurol Neurosurg Psychiatry 1986;49-1323-4.

21 Fitzsimmons RB, Clifton-Bligh P, Wolfenden WH. Mitochondrialmyopathy and lactic acidaemia with myoclonic epilepsy, ataxiaand hypothalamic infertility: a variant of Ramsay-Hunt syn-drome? J Neurol Neurosurg Psychiatry 1981;44:79-82.

22 Danta G, Hilton RC, Lynch PG. Chronic progressive externalophthalmoplegia. Brain 1975;98:473-92.

23 Kearns TP, Sayre GP. Retinitis Pigmentosa, external ophthalmo-plegia, and complete heart block. Arch Ophthalmol 1958;60:280-98.

24 Julien J, Vital Cl, Vallat JM, et al. Myopathie oculaire avechypogonadisme primaire. Anomalies mitochondriales enultrastructure. Rev Neurol (Paris) 1973;128:365-77.

25 Sengers RCA, Stadhouders AM, Trijbels JMF. Mitochondrialmyopathies. Clinical, morphological and biochemical aspects.Eur J Pediatr 1984;141:192-207.

26 Di Mauro S, Nicholson JF, Hays AP, et al. Benign infantilemitochondrial myopathy due to reversible cytochrome coxidase defficiency. Ann Neurol 1983;14:226-34.

27 Zeviani M, Peterson P, Servidei S, et al. Benign reversible musclecytochrome c oxidase deficiency: a second case. Neurology 1987;37:64-7.

28 Bresolin N, Moggio M, Bet L, et al. Mitochondrial myopathy withcomplex I deficiency. Ital J Neurol Sci 1987;8:183.

29 Toscano A, Cooper JM, Morgan-Hughes JA, Clark JB. Correla-tions of histochemical and biochemical parameters in humancomplex I (NADH-CoQ reductase) deficiency. Neurology 1988;38(Suppl 1):187.

30 Di Mauro S, Mendel JR, Sahenk Z, et al. Fatal infantilemitochondrial myopathy and renal dysfunction due to cyto-chrome c oxidase deficiency. Neurology 1980;30:795-804.

125

Protected by copyright.

on July 8, 2021 by guest.http://jnnp.bm

j.com/

J Neurol N

eurosurg Psychiatry: first published as 10.1136/jnnp.52.1.122 on 1 January 1989. D

ownloaded from

http://jnnp.bmj.com/