Journal of Neuro-Ophthalmology, March 1995, Volume 15, Issue 1

Supranuclear Eye Movement Dysfunction in Mitochondrial Myopathy with tRNA Mutation

A patient with multiple neurological deficits and biopsy-proven mitochondrial myopathy with mutation of tRNA(LEU) at nucleotide 3243 was referred for eye movement evaluation. He had restricted range of voluntary motions in all directions and full range of eye movements on passive rotation of head while fixating a visual target. Eye movement recordings revealed decreased horizontal and vertical saccadic velocities and markedly decreased smooth pursuit gain in both directions. The vestibulo-ocular reflex showed gain abnormalities with many saccadic intrusions on the smooth reflex response. His brother, with similar mutation, was clinically asymptomatic. However, his eye movement recordings revealed slow horizontal saccadic velocities leftward and normal saccadic velocities rightward in both eyes as well as in upward and downward direction. Smooth pursuit and vestibulo-ocular reflexes were within normal limits. Although eye movement abnormalities are seen commonly in mitochondrial myopathies, the exact mechanism is not known. Our cases suggest supranuclear dysfunction as one of the mechanisms for ophthalmoparesis.

Journal of Neuro- Ophthalmology 15( 1): 20- 25, 1995. 1995 Raven Press, Ltd., New York Supranuclear Eye Movement Dysfunction in Mitochondrial Myopathy with tRNALEU Mutation Sudha R. Gupta, M. D., Mitchell Brigell, Ph. D., Meena Gujrati, M. D., and John M. Lee, M. D., Ph. D. A patient with multiple neurological deficits and biopsy-proven mitochondrial myopathy with mutation of tRNALEU at nucleotide 3243 was referred for eye move­ment evaluation. He had restricted range of voluntary motions in all directions and full range of eye move­ments on passive rotation of head while fixating a visual target. Eye movement recordings revealed decreased horizontal and vertical saccadic velocities and markedly decreased smooth pursuit gain in both directions. The vestibulo- ocular reflex showed gain abnormalities with many saccadic intrusions on the smooth reflex response. His brother, with similar mutation, was clinically asymptomatic. However, his eye movement recordings revealed slow horizontal saccadic velocities leftward and normal saccadic velocities rightward in both eyes as well as in upward and downward direction. Smooth pursuit and vestibulo- ocular reflexes were within normal limits. Although eye movement abnormalities are seen com­monly in mitochondrial myopathies, the exact mecha­nism is not known. Our cases suggest supranuclear dys­function as one of the mechanisms for ophthalmopare-sis. Key Words: Mitochondrial myopathy- Ophthalmople­gia- Supranuclear palsy. From the Department of Neurology ( S. R. G., M. B.) and Pa­thology ( Section of Neuropathology) ( M. G., J. M. L.), VA Hines Hospital, Hines; and Loyola University Medical Center, May-wood, Illinois, U. S. A. Address correspondence and reprint requests to Dr. Sudha R. Gupta, Neurology Service ( 127), VA Hospital, Hines, IL 60141, U. S. A. Mitochondrial encephalomyopathies are a group of disorders due to defects in the mitochondrial metabolism. These disorders usually involve mul­tiple organ systems, often dominated by muscle and brain dysfunction because of a greater depen­dence of these tissues on oxidative metabolism ( 1,2). Although extraocular muscle dysfunction is very common, the exact mechanism of ophthalmo-paresis in these disorders is not known. Both neu­ropathic and myopathic processes have been hy­pothesized ( 3- 11). We report a case of documented mitochondrial myopathy with tRNALEU mutation and his brother with similar mutation. Both had ophthalmoparesis due to supranuclear eye move­ment dysfunction. CASE REPORTS Casel Case 1 is a 49- year- old right- handed man devel­oped new onset of generalized seizures in Febru­ary 1992. Recurrent seizures continued in spite of various anticonvulsant therapy. In September 1992, progressive gait difficulty was noted. In Jan­uary 1993, h e was admitted with urinary retention and fecal impaction. The past history was signifi­cant for presence of diabetes mellitus since 1984 and bilateral hearing loss since childhood. There was no family history of seizures, hearing loss, gait disorder, or other significant medical or neurolog­ical illness. On examination in June 1993, he was alert with explosive dysarthric speech. The pupils were 4 mm and reacted normally to light and accommo­dation. Funduscopic examination did not show any abnormality. He had moderate to severe bilat­eral hearing loss. Diffuse muscle wasting was seen 20 MITOCHONDRIAL MYOPATHY 21 without any focal atrophy, fasciculation, or weak­ness. The muscle stretch reflexes were hyperactive with bilateral extensor plantar response. Position sense was impaired in toes. He had mild limb ataxia with a wide- based gait. Neuropsychological testing revealed mild mental retardation with su­perimposed mild dementia. Magnetic resonance imaging of the brain showed diffuse cerebral and cerebellar atrophy, enlarged cisterna magna, and bilateral basal ganglia calcification. An electroen­cephalogram showed diffuse slowing. Electromy­ography and nerve conduction studies showed de-myelinating neuropathy. Blood tests revealed hy­ponatremia, hyperkalemia, decreased aldosterone level, and normal levels of Cortisol, lactate, pyru­vate, and very long chain fatty acids. Workup for a systemic malignancy was negative. Sural nerve and quadriceps muscle biopsy was performed. The hematoxylin and eosin stained sections of the mus­cle revealed marked variation of fiber size, many angulated atrophic fibers, numerous nuclear bags, and a number of the fibers having basophilic stip­pling in subsarcolemmal areas. Modified Gomori Trichrome stained sections showed numerous FIG. 1. Modified Gomori Trichrome- stained frozen section of a ragged red fiber and angulated muscle fibers ( x200). FIG. 2. Electron micrograph of abnormal paracrystal-line inclusions in muscle mitochondria ( x60,000). ragged red fibers with eosinophilic subsarcolem­mal accumulations in approximately 2% of the muscle fibers examined ( Fig. 1). DPNH and cy­tochrome oxidase stains revealed increased subsar­colemmal staining in scattered fibers. ATPase stains at pH 9.4 and 4.6 revealed atrophic fibers of both types, but no evidence of type grouping or group atrophy was noted. The ultrastructural ex­amination of the muscle revealed numerous sub­sarcolemmal intramitochondrial paracrystalline in­clusions ( Fig. 2). Many of the inclusions showed a " parking lot" configuration. In addition, there were a number of mitochondria with abnormal cristae and concentric inclusions. The sural nerve biopsy revealed mild to focal moderate loss of large myelinated fibers ( Fig. 3). There was some loss of small myelinated and unmyelinated fibers, as well. There was no evidence of inflammation, meta­chromatic granules, or amyloid deposition. A sam­ple of muscle was sent to Dr. S. DiMauro's labo­ratory ( Columbia University College of Physicians and Surgeons, New York). Southern blot analysis revealed a point mutation in the tRNA ( LEU [ UUR]) at position 3243, which is associated with / Neuro- Ophthalmol, Vol. 15, No. 1, 1995 22 S. R. GUPTA ET AL. FIG. 3. Epon- embedded osmium stained cross sec­tion of sural nerve. Note loss of large and small my­elinated fibers ( x400). MELAS ( mitochondrial encephalopathy, lactic aci­dosis, and strokelike episodes). Clinical examination of eye movements revealed a restricted range of voluntary motion in all direc­tions. Upward gaze was restricted to 20% of full range and downward gaze was restricted to ap­proximately 50% of full range. Horizontal gaze was less affected with both directions of lateral gaze restricted to 70% of full range. Despite the restric­tion of voluntary gaze, a full range of eye motion was demonstrated when the patient was in­structed to fixate at a visual target while his head was passively rotated. All eye movements were conjugate, and alternate cover testing showed the eyes to be orthophoric in all fields of gaze. No pathologic nystagmus was observed and conver­gence was present. Eye movements were recorded using direct- current electro- oculography ( ICS Medical, Schaumburg IL). Saccadic eye move­ments were obtained to red light- emitting diode targets that appeared at random time intervals at a random location between 5 and 35 degrees in the left or right visual field. A sample of the patient's horizontal eye movements is shown in Fig. 4. Sac-cades were generally accurate without evidence of dysmetria. However, saccadic velocities were slower than age matched normal data, with only 11.6% of all horizontal saccades reaching normal peak velocities. The extent of the saccadic slowing increased as amplitude of the saccades increased. Vertical saccades showed decreased peak velocity that was similar to that obtained with horizontal movement. Horizontal smooth pursuit was elicited to sinusoidal oscillation of a visual target at fre­quencies between .2 Hz and .7 Hz over a range of 40 degrees. As can be seen in Fig. 5, pursuit gain was markedly decreased in both horizontal direc­tions for all frequencies of oscillation. Peak eye movement velocity was never greater than 30% of peak target velocity. The patient was not drowsy during the pursuit task and appeared to give max- Horizontal. Eue Posituon Pew. Velocity IJJ Hi- HCEftii, 2tt 4:: flSNQJWLx^ Sijhtwafd • ysHciiM Lef tware" CD i: 5 3 SACCADt flM? LJTUi? E 13 25 FIG. 4. Horizontal saccadic eye movement results. Top: Eye movement recordings. Upward deflections represent rightward movement. Signals are recorded across both eyes ( outer canthus to outer canthus) in the tracing. The solid line indicates target position and the dotted line represents eye position. Bottom: Sac­cadic peak velocity as a function of saccade ampli­tude. Each dot represents the velocity of a single sac-cade. The hatched area indicates abnormally slow saccadic velocity relative to an age- matched normal population. / Neuro- Ophtlulmol, Vol. 15, No. 1, 1995 MITOCHONDRIAL MYOPATHY 23 Horizontal Ew Position Frequency^ 8.30 Hz . r^ ekj, riu Gain R Gun- 1.24 L Sain- I. 35 398 A3 Phase Shift= - 15.** 1.25- 5 1. B9 if ft 73- f 19 .25 . '# isas& Rj. gfiT^ 3gT • • " • • • ' • * • . . . • • • • « . ' . " ; • ' ;. :::::::- Jt- KGP^ L. T EgjfSSra 9.7 8. S 8.5 8.+ 8.3 fl. 2 B.£ 3.3 8.4 9.5 TMGtT r£ EHJEKCY C. HZi .6 8.7 CvcLei: 36 FIG. 5. Results of smooth pursuit eye movements. Top: Target position { solid line) and eye position { dotted line) are shown for horizontal sinusoidal target oscillation at 0.3 Hz. Note the low gain of the pursuit eye velocity with many catch- up saccades interposed. Bottom: Mean pursuit gain as a function of leftward and rightward target frequency. The hatched area indicates abnormal gain relative to age- matched normal population. imum effort. Optokinetic nystagmus showed a de­creased velocity of both slow and fast phases. The vestibulo- ocular reflex obtained with active head shaking in the vertical and horizontal directions showed gain abnormalities with many saccadic in­trusions on the smooth reflex response. Case 2 Case 2 is a 47- year- old brother of Case 1 who has been diabetic since 1986 and has tRNALEU muta­tion similar to Case 1. Although clinically asymp­tomatic, his clinical examination revealed left pto­sis, which has been present since head trauma at the age of 3 years. Alternate cover testing showed evidence of large exophoria. The patient also held his head with a right head tilt. Pupils were equal in diameter and briskly reactive to light without rel­ative afferent defect. Eye movements were re­corded using direct- current electro- oculography. Recordings of horizontal saccadic eye movements showed conjugate slow saccades leftward and nor­mal saccadic velocities rightward OU ( Fig. 6). Re­cording of vertical eye movements suggested sac­cadic velocities within normal limits for both up­ward and downward direction. Smooth pursuit and vestibulo- ocular reflexes were also within nor­mal limits. DISCUSSION Disorders of mitochondrial metabolism can oc­cur due to defects in the transport system across the mitochondrial membrane, defects of substrate utilization, defects in the Kreb's cycle, or defects in the oxidation- phosphorylation system. Mitochon­drial encephalomyopathies can also result from specific deficiencies of complex I to IV of the respi­ratory chain ( 1). Because there are hundreds or thousands of copies of mitochondrial DNA in each cell, the phenotypic expression of a mitochondri-ally encoded gene depends on the relative propor­tion of the mutant and the wild- type mitochondrial DNA within any given cell. Clinically mitochon­drial encephalomyopathies are grouped into vari­ous subgroups with considerable overlap ( 12,13). These include MELAS ( 14,15); MERRF ( myoclonus epilepsy with ragged red fiber myopathy) ( 16,17), I Neuro- Ophthnlmol, Vol. 15, No. 1, 1995 24 S. R. GUPTA ET AL. Horiionrai fye Position m m t Lit- L2fl 3 •• 8 l u - r T = T 7 ^ 7 7 = : sea us • A Accuracy l 3 3 i , . : 3 , , - , \ ABNORMAL Llfl i-i HI •- 94 F L' MDSttAL m \ m HightwnT i " Tefti^ rT ; i Jeak Uelocity U u a a- NORMfiL W. 35 35* 25 15 5 " 5 15" SflCCflOE ftMPLITUDE ( DEO :::: n3HCR « lnl/ Leftward 35 Latere « 9- o G J • K itJH- 9 j X v M - X v ' • " • : ! •!•'•!• ' ICvXyJJI- Iv'Xy! !' J* Xv.*! v. .•.'. .•."!" c^ BHGR^ ftL:^::^ >::'-:>•>:>:; \ m m 35 35 fright Ma nT" Leftward' 35 25 IS 5 5 15 25 SACCflDE AHPLITUOE ( DEO 25 15 5 5 15 25 35 SACCftDE AHPLITUDE (& EG> FIG. 6. Horizontal saccadic eye movement parameters for Case 2. Top Left: Slowing of leftward saccades. Top Right: Graphic quantification of this slowing. Bottom: Normal accuracy and latency parameters of horizontal saccades. CPEO ( chronic progressive external ophthalmo­plegia), including KSS ( Kearns- Sayer syndrome ( 7); NARP ( neuropathy, ataxia, and retinitis pig­mentosa) ( 18); LHON ( Leber's hereditary optic neuropathy) ( 19,20); and Leigh's syndrome ( 21). Recently, deletions, depletions, and mutations of mitochondrial DNA transfer RNA have been doc­umented in these disorders ( 2,22,23). While opthalmoparesis is one of the cardinal fea­tures of CPEO and KSS it can be seen in other subgroups, including MELAS ( 24). There has been controversy in the literature regarding whether the ophthalmoplegia observed in mitochondrial my­opathies is secondary to abnormality in the eye muscles or is neurogenic. The biopsy of extra­ocular muscles have shown evidence of myopathic changes or nonspecific degeneration ( 3,9). Atro­phy of abducens nerve and neuronal degeneration in oculomotor nucleus have also been reported ( 10,11). Based on these results the mechanism of ophthalmoparesis is considered to be of peripheral origin ( myopathic or neuropathic), even though spongiform changes have also been seen in cortex, white matter, optic radiation, and basal ganglia structures ( 6). Several of the eye movement findings in cases reported here suggest a supranuclear component to the ophthalmoplegia. In Case 1, the range of voluntary movement was restricted, although a full range of motion was obtained by vestibulo-ocular reflex. The dissociation of voluntary and re­flex ophthalmoplegia has been classically cited as evidence for a supranuclear component to the oph­thalmoplegia ( 25- 27). Another suggestion of a cen­tral component to this patient's ophthalmoplegia comes from the asymmetric involvement of verti­cal and horizontal movement. Jampel and col­leagues ( 28) have previously suggested that myo­pathic involvement of the superior rectus muscle should force the resting position of the eyes into downgaze. They furthermore suggest it is unlikely that a myopathic process would affect the superior rectus while sparing the levator palpebri. Finally, although this patient's saccadic velocity profile does not differentiate myopathic from neurogenic ophthalmoplegia, the relative sparing of saccadic velocity when compared to pursuit velocity is sug­gestive of a supranuclear disorder. The extra­ocular muscles were able to move the eyes with a peak velocity of over 300 deg/ s during saccadic eye / Neuro- Ophtlmlmol, Vol. 15, No. 1, 1995 MITOCHONDRIAL MYOPATHY 25 movements ( Fig. 4), yet the eyes could not follow a smooth pursuit target requiring a peak velocity of only 16 deg/ s and much less acceleration of the eye ( Fig. 5). It would be expected that pursuit would be spared relative to saccades in a purely myo­pathic process. In Case 2 slow leftward saccades in both eyes and normal rightward saccadic velocities indicate a partial left gaze palsy due to dysfunction in the left paramedian pontine reticular formation ( 29). In this patient the normal velocity of right-ward and vertical saccades suggests the absence of significant involvement of the extra- ocular mus­cles. Thus, supranuclear eye movement dysfunc­tion can precede peripheral involvement in pa­tients with mitochondrial myopathy. In summary, both of these cases have supranu­clear dysfunction of eye movements. Case 1 does have other clinical evidence of central nervous sys­tem dysfunction ( seizures and dementia). We con­clude that the eye movement disorder seen in mi­tochondrial myopathies may be attributable pri­marily to a supranuclear dysfunction in some cases. REFERENCES 1. Egger J, Lake BD, Wilson J. Mitochondrial cytopathy: a multisystem disorder with ragged red fibers on muscle bi­opsy. Arch Dis Child 1981; 56: 741- 52. 2. Schon EA. Mitochondrial disorders in muscle. Curr Opin Neurol Neurosurg 1993; 6: 19- 26. 3. Drachman DA. Ophthalmoplegia plus. Arch Neurol 1968; 18: 654- 74. 4. Stephens J, Hoover ML, Denst ]. On familial alaxia, neural amyotrophy, and their association with progressive eternal ophthalmoplegia. Brain 1958; 81: 566- 70. 5. Croft PB, Cutting JC, Jewesbury ECO, et al. Ocular myop­athy ( progressive external ophthalmoplegia) with neuro­pathic complications. Acta Neurol Scand 1977; 55: 169- 97. 6. Horowitz SJ, Roessmann U. Kearns- Sayre syndrome with hypoparathyroidism. Ann Neurol 1978; 3: 513- 18. 7. Berenberg RA, Pellouc JM, DiMauro S, et al. Lumping or splitting? " ophthalmoplegia- plus" or Kearns- Sayre syn­drome? Ann Neurol 1977; 1: 37- 54. 8. Sandifer PH. Chronic progressive ophthalmoplegia of my­opathic origin. / Neurol Neurosurg Psychiatry 1946; 9: 81- 3. 9. Kiloh LG, Nevin S. Progressive dystrophy of the external ocular muscles ( ocular myopathy). Brain 1951; 74: 115^ 3. 10. Groothius D, Schulman S, Vick N, et al. Radiculoneuropa-thy as a component of the Kearns- Sayre syndrome. Trans Am Neurol Assoc 1978; 103: 18- 22. 11. Sparaco M, Bovilla E, DiMauro S, Powers JM. Neuropathol­ogy of mitochondrial encephalopathies due to mitochon­drial DNA defects. / Neuropathol Exp Neurol 1993; 52: 1- 10. 12. DiMauro S, Bonilla E, Zeviani M, et al. Mitochondrial my­opathies. Ann Neurol 1985; 17: 521- 38. 13. Petty RK, Harding AE, Morgan- Hughes JA. The clinical features of mitochondrial myopathy. Brain 1986; 109: 915- 38. 14. Koo B, Becker LE, Chuang S, et al. Mitochondrial enceph-alomyopathy, lactic acidosis, stroke- like episodes ( MELAS): clinical, radiological, pathological, and genetic observations. Ann Neurol 1993; 34: 25- 32. 15. Ciafaloui E, Ricci E, Shauske S, et al. MELAS: clinical fea­tures, biochemistry, and molecular genetics. Ann Neurol 1992; 31: 391- 8. 16. Berkovic SF, Carpenter S, Evans A, et al. Myoclonus epi­lepsy and ragged- red fibers ( MERRF) 1. A clinical, patho­logical, magnetic resonance spectrographic and positron emission tomographic study. Brain 1989; 112: 1231- 60. 17. Nozmon SO, Berkovic S, Andermann F, et al. Myoclonus epilepsy and ragged- red fibers ( MERRF) 2. Electrophysio­logical studies and comparison with other progressive myoclonic epilepsies. Brain 1989; 112: 1261- 76. 18. Halt IJ, Harding AE, Petty RKH, Morgan- Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 1990; 46: 428- 33. 19. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neurop­athy. Science 1988; 242: 1427- 30. 20. Cortelli P, Montagna P, Avoni P, et al. Leber's hereditary optic neuropathy: genetic, biochemical, and phosphorus magnetic resonance spectroscopy study in an Italian fam­ily. Neurology 1991; 41: 1211- 15. 21. Tatuch Y, Christodoulou J, Feigenbaum A, et al. Fletero-plasmic mt. DNA mutation ( T -> 6) at 8993 can cause Leigh's disease when the percentage of abnormal mt. DNA is high. Am f Hum Genet 1992; 50: 852- 8. 22. Schapira AHV, Cooper JM, Morgan- Hughes JA, Landon DN, Clark JB. Mitochondrial myopathy with a defect of mitochondrial- protein transport. N Engl J Med 1990; 323: 37- 42. 23. Hammans SR, Sweeney MG, Brockington M, et al. Mito­chondrial encephalomyopathies: molecular genetic diagno­sis from blood samples. Lancet 1991; 337: 1311- 13. 24. Fang W, Huang CC, Lee CC, et al. Ophthalmologic mani­festations in MELAS syndrome. Arch Neurol 1993; 50: 977- 80. 25. Gowers WR. Note on a relax mechanism in the fixation of the eyeballs. Brain 1879: 2: 39- 41. 26. Brown JW, Coleman RF. Hereditary spastic paraplegia with ocular and extra- pyramidal signs. Bull Los Angeles Neurol Soc 1966; 31: 21- 34. 27. Rowland LP. Progressive external ophthalmoplegia, bland Clin Neurol 1975; 22: 177- 207. 28. Jampel RS, Okazaki H, Bernstein H. Ophthalmoplegia and retinal degeneration associated with spinocerebellar ataxia. Arch Ophthalmol 1961; 66: 247- 59. 29. Goebel HH, Komatsuzaki A, Bender MB, Cohen B. Lesions of the pontine tegmentum and conjugate gaze paralysis. Arch Neurol 1971; 24: 431^ i0. J Neuro- Ophtlmlmol, Vol. 15, No. 1, 1995