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168 MITOCHONDRIAL MYOPATHY

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J Oral Maxillofac Surg

45:1a-172,1997

Mitochondrial Myopathy Presenting as Temporomandibular Dysfunction

JOSEPH E. VAN SICKELS, DDS,* ALLEN B. GRUBER, MD,t KATHLEEN S. KAGAN-HALLET, MD,* AND DONNA C. DOWD, MD5

The diagnostic signs and symptoms for temporomandibular dysfunction are impaired mobility of the mandible, deviation upon opening or closing, and pain on palpation of the masticatory muscles. Additional symptoms may include temporomandibular joint (TMJ) sounds, fatigue or stiffness of the jaws, pain in the face and jaws, and pain when opening of the mouth wide.1-5 In epidemiologic studies, masticatory muscle tenderness has ranged from 13 to 66%.’ Despite this emphasis on muscular involvement in TMJ disorders, little attention has been directed at systemic muscular pathology. Ob-

* Associate Professor, Department of Oral and Maxillofacial Surgery, University of Texas Health Science Center at San An- tonio, Texas.

t Assistant Professor, Department of Medicine, Division of Neurology, University of Texas Health Science Center at San Antonio, Texas.

$ Assistant Professor, Department of Pathology, University of Texas Health Science Center at San Antonio, Texas.

Address correspondence and reprint requests to Dr. Van Sickels: Department of Oral and Maxillofacial Surgery, Univer- sity of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284.

0278-2397187 $0.00 + .25

viously, a variety of diseases that affect other muscles of the body may also affect the masticatory apparatus and present as a primary orofacial problem. This paper documents three family members with a generalized myopathy who presented with facial pain and were treated for TMJ dysfunction with a wide range of dental and med- ical procedures. Ultimately, al1 three cases were diagnosed as having mitochondrial myopathy.

Mitochondrial Myopathy

Mitochondrial myopathies encompass well-defined clinical entities such as the Kearns-Sayre Syndrome,6,7 others with well-defined biochemical defects such as cytochrome C oxidase deficiency, and many other ill-defined conditions.8

Both structural and functional abnormalities of mitochondria occur in this category of myopathies.*-I* Typical morphological alterations consist of unusually large mitochondria with various inclu- sions, such as characteristic paracrystalline inclu- sions, and distortions of mitochondrial cristae.*-lo Mitochondrial proliferations occur in type I and

VAN SICKELS ET AL. 169

sometimes in type II muscle fibers, in which they form subsarcolemmal and intermyofibrillar aggre- gates.9,1i

Biochemically, mitochondrial myopathies can be divided into defects of substrate utilization, oxidation and phosphorylation coupling, and defects within the respiratory chain.8*9 Some authors distin- guish between mitochondrial myopathies in which there is an underlying biochemical defect and those where there are morphologically abnormal mitochondria.‘* However, in some of these cases a biochemical defect is suspected but not demonstrated. As the site of oxidative phosphorylation of ADP to ATP, any dysfunction in the mitochondria can be assumed to impair the function of muscle fibers.

The muscle from a patient with a mitochondrial disorder may appear normal in routine histopatho- logical preparations. i”,i2 A modified Gomori trichrome stain shows accumulations of mitochondria as purplish blotches (“ragged red” appear- ance), usually with excessive lipid droplets.6*8J0 In- creased blood concentration of lactic acid, not seen in all cases, varies considerably in severity among different patients.8*9 Lactic acidosis is explained by impaired utilization of pyruvate in the Krebs cycle and by increased glycogen utilization and glycolytic activity in muscle with defective aerobic metabolism. If the lactate concentration is normal or only slightly increased, moderate exercise has been shown to induce a disproportionately large rise in venous lactate.*

Luft et al.i3 have described a patient with a nonthyroidal hypermetabolism due to a defective coupling of oxidation and phosphorylation in muscle mitochondria. Since then, many subsets of mitochondrial myopathies have been identified. Clinical presentation is varied as the disease may encompass several disorders.‘O It may include con- genital to late onset disorders, progressive or re- versible weakness, progressive external ophthal- moplegia, and exercise intolerance.8J0 Muscle and brain disease have also been reported with different mitochondrial encephalomyopathies. The cerebral involvement may include seizures, strokes, de- mentia, and hearing loss. Cerebral symptoms are sometimes more important than those from the muscles.*JO The vulnerability of muscle and brain to mitochondrial dysfunction may be due to the high energy demand of these tissues.8 Heart, kidney, liver, and other organs may also be in- volved.*

In a given family with mitochondrial myopath- ology, patients may demonstrate a clinical spectrum ranging from a total lack of symptoms to severe impairment. ii

A mitochondrial defect may occur randomly or

be inherited either in a mendelian fashion or by maternal transmission.8*9T’2 Because the mitochon- drion has its own genetic material, the transmission of mitochondrial disease can occur by nonmende- lian inheritance. Although nuclear DNA controls the synthesis of 90% of mitochondrial proteins, mitochondrial DNA (mt DNA) codes for RNA and polypeptides.*J4 In the formation of the zygote al- most all the mitochondria are contributed by the ovum; hence, the mitochondrial genome may be transmitted by maternal inheritance in a nonmen- delian fashion.*,‘* Since there are hundreds to thou- sands of copies of mt DNA in each cell, the pheno- typic expression of a mitochondrial coded gene de- pends on the relative proportions of mutant and wild type mt DNAs within a cell. A mutant pheno- type is expressed only when the proportions of mutant and wild type mt DNAs reach a threshold.8J’ Because mitochondria replicate more often than

nuclei, the relative proportion of mutant and wild

type mt DNAs may change within a cell cycle.

Report of Three Cases

Case 1

A 37-year-old white female presented with a IO-year history of jaw pain and a six-month history of leg and arm cramps. She had first presented to a dental practitioner 10 years before complaining of limited opening, pain, and swelling in her temporalis muscles after eating hard foods. Eventually, the swelling was precipitated by eating soft textured items. Early in her treatment occlusal splints were made and equilibration of her teeth occlu- sion was performed. During the first year of therapy she consulted a neurologist and an otorhinolaryngologist and received biofeedback therapy. After several years she was referred for surgical evaluation of her 4 mm mandibular deficiency, which was subsequently treated by mandibular advancement. She progressed poorly. Six months after her first surgery, she underwent coronoidectomies to improve opening. Additional splints and equilibrations proved equally unsuccessful. Wiring her jaws together on several occasions appeared to help her muscular spasms. Aggressive physical therapy did not seem to help and the patient was referred to a psychiatrist. Ten years later, after multiple manipulations, she was presented with a 20 mm vertical opening, which was unchanged from her initial consultation. She documented a long history of jaw spasms and a recent history of spasms in her arms. She continued to complain of swelling of the temporalis muscle after eating hard textured items. She was referred to one of the authors (AG) who found normal muscle strength and reflexes. He suspected a metabolic myopathy related to a specific enzyme deficiency.

An open biopsy of the biceps was performed. The specimen was prepared by freezing the fresh tissue in isopentane (Zmethylbutane) cooled to the temperature of liquid nitrogen (- 160°C). Sections were cut at 8 TV_ in a cryostat, and the following routine and special histo- chemical stains were used: hematoxylin and eosin (H & E), modified Gomori trichrome; nicotinamide adenine


FIGURE 1 (fefi). Photomicrograph showing staining at perimeter of muscle fibers (“ragged red fiber”). Gomori trichrome stain (UYTOMJS). (Original magnification, x 400.)

FIGURE 2 (right). Electron micrograph showing a large number of structurally normal mitochondria in the subsarco- lemma1 space. (Original magnification, X 7540.)

dinucleotide reductase (NADH); adenosine triphospha- tase (ATPase) preincubated at pH of 9.4 and 4.6; periodic acid-schif (PAS) with and without diastase; oil red 0; non- specific esterase, and myophosphorylase.15 Fresh tissue was also minced and fixed in 20% gluteraldehyde, post- fixed in 1% osmium tetraoxide, and embedded in epon for ultra-thin sectioning for electron microscopy.

Histologic examination of H & E stained sections showed rare opaque fibers indicative of a metabolic de- rangement. The NADH stain showed fibers with a coarsely reticulated pattern (“motheaten fibers”) and the Gomori trichrome stain revealed occasional fibers with irregular staining at their perimeter (“ragged red fibers”) (Fig. 1). Electron microscopy revealed increased numbers of mitochondria located in clusters in the subsarcolemmal space and within the interstitium (Fig. 2). The mitochondria were large, being an entire sarcomere in length, although the cristae were structurally normal.

A serum lactic acid level of 6.4 mmol/l was obtained, with a control of 0.5-2.2 mmol/l. A electromyographic examination using needle electrodes was normal. Fol- lowing an open arm biopsy the patient was placed on several medications including Dantrolene sodium, a calcium channel blocker, prednisone, various non-steroidal anti- inflammatory agents, and tocanamide. Currently her vertical opening is 20 mm, and she is limited to a soft diet.

Case 2

After the biopsy on patient number one, inquiries were made as to her family history. Her 34-year-old sister also gave a history of jaw pains starting when she was 29 years old. She presented to a dental practitioner who prescribed a splint for her. The splint produced an excel- lent response. Some five years after her initial presentation, she noted spasms of her arms and legs. A neuromus-

cular examination was normal except for some limitation of elbow extension. Her lactic acid level was 0.6 megil. An open biopsy of her biceps was performed. Histologic examination showed variation in size and shape of muscle fibers, with scattered atrophic fibers and clumps of sarcolemmal nuclei. ATPase stains showed a predomi- nance of type II fibers. The Gomori trichrome stain revealed an increased deep red reticulated pattern within a number of fibers, as well as occasional “ragged red fibers.” Electron microscopic examination of these par- ticular fibers was unsuccessful due to their scarcity.

Case 3

The lPyear-old son of the second sister had noted jaw pains and headaches for approximately three years. A splint had been prescribed for him and he responded, as had his mother, with quick resolution of his headaches. When he stopped wearing the splint, however, his headaches returned. A neurologist diagnosed him as having migraine headaches. He had a long history of muscle cramps with exercise. However, his physical examination revealed a muscular individual, secondary to weight lifting. He had a mild chronic scoliosis, nonprogressive since age 13. His strength was normal, and his lactic acid level was 0.3 meg/l. An open biopsy of the left vastus lateralis was done. Histologic examination showed a pre- dominance of type II fibers; the oil red 0 stain showed increased lipid within approximately one-third of the fibers. The Gomori trichrome stain revealed a focal in- crease in red staining at the perimeter of some fibers, consistent with a mitochondrial abnormality. Electron microscopic examination of these fibers was unsuccessful because, as in case 2, the rarity of these fibers precluded their identification. Currently the opening of his jaw is 54 mm. Recent increases in headaches have

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been associated with stress. Treatment now includes splint therapy and administration of a nonsteroidal anti- inflammatory drug.

Discussion

Several authors have noted that temporomandibular joint (TMJ) dysfunction is not a single illness but rather a group of problems that have been clumped under one title. 3,5 Rugh and Solberg pre- dicted that little progress would be made in the treatment of TMJ dysfunction without dividing this group into smaller diagnostic subgroups. These three patients all had signs and symptoms which fit the diagnosis of TMJ dysfunction. Two responded relatively well to symptomatic care. The first patient, perhaps because her symptoms were so severe, received aggressive therapy from multiple practitioners with very little resolution of her problem. This range of symptoms in patients from the same family is compatible with the spectrum of symptoms described by Rosing et al.” in a family with mitochondrial myopathy. All of our patients had an abnormal Gomori trichrome stain: however, only the first one had an elevated lactic acid level. In the proband, the mitochondria were increased in number and, although structurally normal, they were elongated. A specific biochemical defect was not identified nor sought.

The presence of “ragged red” fibers on light microscopic examination of a muscle biopsy is a cru- cial part to the diagnosis of mitochondrial myopathy. However, these fibers can be seen in other myopathies such as myotonic dystrophy, polymyo- sitis, and in denervating diseases.6 “Ragged red” fibers represent the proliferation of mitochondria which stain red with Gomori Trichrome. Their proliferation in other neuromuscular diseases is felt to be secondary to interference with mitochondrial function by the underlying biochemical defect. The “ragged red” fibers are only a minor part of the pathology and are overshadowed by the changes characteristic of the primary muscle disorder. In mitochondrial myopathies, the “ragged red” fibers are the prominent pathologic change; they are sometimes associated with an elevated serum lactic acid. It seems unlikely that temporomandibular dysfunction causes the production of “ragged red” fibers. It is more likely that their presence is a man- ifestation of a primary muscle disease presenting in these cases with facial muscular symptoms.

Since our study group was very small, the exact mode of genetic inheritance could not be deter- mined. Two women and one of their sons being af- fected could represent a maternal pattern of inheritance, an autosomal dominant. or an x-linked domi-

nant. Two siblings from the first patient who are both symptomatic were unavailable for muscle biopsies. The grandparents, who are asymptomatic, were likewise unavailable for study. The second patient’s other offspring, a lo-year-old female, has no symptoms. The proband has an asymptomatic brother with two asymptomatic chil- dren.

Treatment for these patients is challenging. Two of the patients responded well to fiat splint therapy. Clark et al., l6 studying a group of patients with bruxism, showed a reduction in symptoms with splint therapy even though the level of bruxism re- mained high. They postulated that the reduction in symptoms was due to improve structure and distri- bution of forces provided by the splint. Perhaps structurally abnormal muscle responds to the same therapeutic modalities as normal muscle. The first patient, however, did not respond to a number of therapeutic procedures. Clinical experience sug- gests that 7040% of masticatory pain and dysfunction patients will improve regardless of the treatment employed.17~18 The remaining 20 to 30% of patients either have no improvement or suffer in- termittent recurrence of symptoms. This group of failures has been attributed to misdiagnosis, a pathophysiologic process yet to be discovered, in- correct dental therapy or psychological factors.19 Unfortunately, after repeated unsuccessful at- tempts are made to treat patients, those with chronic pain are often labeled as malingerers or psychologically unstable. Our first patient falls into this category, where multiple surgical and non-surgical procedures were used unsuccessfully to treat her. As she did not respond to therapy, and since she had unusual muscle spasms, she was sent for psychiatric help. The results of her eventual muscle biopsy illustrate that patients who do not respond as expected to conventional therapy may still be suffering from a recognizable pathologic entity rather than a psychiatric disorder.

Summary and Conclusion

Three patients, all of whom presented with orofacial pain, were initially diagnosed as having temporomandibular dysfunction. Subsequent muscle biopsies proved they had an underlying pathologic abnormality. It is not inconceivable that a number of patients who present with facial pain, whether or not they respond to traditional therapeutic modalities, have an underlying systemic myopathy. The myopathy may be hereditary and the mode of inheritance may be unusual. Practitioners who treat patients with facial pain are cautioned to be aware


of this possibility. Mitochondrial myopathy is prob- ably one of a series of pathologic abnormalities that may be present.

References

1. Solberg WK: Epidemiology, incidence and prevalence of temporomandibular disorders: a review. in Laskin D, Greenfield W, Gale E, et al (eds): The President’s Confer- ence on Examination Diagnosis and Management of Tem- poromandibular Disorders. Chicago, American Dental Association, 1982

2. Solberg WK: Neuromuscular problems in the orofacial re- gion: diagnosis-classification. signs and symptoms. Int Dent J 31:206, 1981

3. Moffett B: Classification and diagnosis of temporomandibular joint disturbances in temporomandibular joint problems, in Solberg WK, Clark GT, (eds). Chicago, Quintessence, 1980

4. Laskin DM: Etiology of the pain-dysfunction syndrome. J Am Dent Assoc 79: 147, 1969

5. Rugh JD, Solberg WK: Oral health status in the United States: temporomandibular disorders. J Dent Educ 49:398, 1985

6. Olson W, Engel WK, Walsh GO, Einaugler R: Oculocrani- osomatic neuromuscular disease with “ragged-red” fibers. Arch Neural 26:193, 1972

7. Berenberg RA, Pellock JM, Di Mauro S, et al: Lumping or splitting? “Opthalmoplegia-plus” or Kearyn-Sayre Syn- drome? Ann Neural 1:37, 1977

8. Dimauro S, Bonilla E, Zeviani M, et al: Mitochondrial my-

J (ed): Disorders of Voluntary Muscle. Edinburgh, Churchill Livingstone, 1981, pp 684-688

10. Kamieniecka Z, Schmalbruch H: Neuromuscular disorders with abnormal muscle mitochondria. Int Rev Cytol 65321, 1980

11. Rosing HS, Hopkins LC, Wallace DC. et al: Maternally inherited mitochondrial myopathy and myoclonic epilepsy. Ann Neural 17:521, 1985

12. Sengers RCA, Stadhouders AM, Trijbels JMF: Mitochon- dria myopathies, clinical, morphological and biochemical aspects. Eur J Pediatr 141: 192, 1984

13. Luft R, Ikkos D, Palmieri G, et al: A case of severe hypermetabolism of nonthyroid origin with a defect in the main- tenance of mitochondrial respiratory control: a correlated clinical, biochemical, and morphological study. J Clin In- vest 41:1776, 1962

14. Oliver N, Wallace DC: Assignment of two mitochondrial synthesized polypeptides to human mitochondrial DNA and their use in the study of intracellular mitochondrial interaction. Mol Cell Biol 2:30, 1982

15. Dubowitz V, Brooke MH: Muscle Biousv: a modem ap- proach. Philadelphia, WB Saunders, 1973

16. Clark GT, Beemsterboer PL, Solberg WK, et al: Nocturnal electromyographic evaluation of myofascial pain dysfunction in patients undergoing occlusal splint therapy. J Am Dent Assoc 99:607, 1979

17. Green CS, Laskin DM: Long-term evaluation of conserva- tive treatment for myofascial pain dysfunction syndrome. J Am Dent Assoc 89: 1365, 1974

18. Green CS, Markovic M: Response to nonsurgical treatment of patients with positive radiographic findings in the temporomandibular joint. J Oral Surg 34:692, 1972

19. Rugh JD: Psychological factory in the etiology of masticatory pain dysfunction, in Laskin D, Greenfield W, Gale E, et al (eds): The Presidents Conference on the Examina-

opathies. Ann Neural 17:521, 1985 tion, Diagnosis and Management of Temporomandibular 9. Engel AG: Metabolic and endocrine myopathies. in Walton Disorders. Chicago, American Dental Association, 1982

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