small infarction in the frontal white

matter, the hypothalamic lesion may also have been lacunar.

References 1. Giles CL, Henderson JW. Horner's syndrome: an analysis of 216 cases. Am J Opthalmol.

1958;46:289-296. 2. Grimson BS, Thompson HS. Drug testing in Horner's syndrome. In: Glaser JS, Smith JL, eds. Neuro-Ophthalmology. St Louis, Mo: CV Mosby Co; 1975;8. 3. Keane JR. Oculosympathetic paresis: analysis of 100 hospitalized patients. Arch Neurol.

1979;36:13-15.

D, Schisano G, Liljequist B. Primary region of the thalamus. J Neurosurg. 1961;18:730-740. 5. Crill WE. Horner's syndrome secondary to deep cerebral lesions. Neurology. 1966;16:325. 6. Schiffter R, Reinhart K. The telodiencephalic ischemic syndrome. J Neurol. 1980;222:265-274. 7. Stone WM, deToledo J, Romanul FCA. 4. Tori

tumors of the

Horner's syndrome due to hypothalamic infarction. Arch Neurol. 1986;43:199-200. 8. Carpenter MB, Sutin J. Human Neuroanatomy. Baltimore, Md: Wililams & Wilkins; 1983; 721-724. 9. Fisher CM. The circle of Willis: anatomical

variations. Vase Dis. 1965;2:99-105. 10. Bogousslavsky J, Regli F. H\l=e'\miparesieavec atteinte linguale: h\l=e'\matom\l=e'\du genou de la cap-

sule interne. Rev Neurol (Paris). 1984;140:587-590. 11. Rascol A, Clanet M, Manelfe C, Guiraud B, Bonafe A. Pure motor hemiplegia: CT study of 30 cases. Stroke. 1982;13:11-17. 12. Fisher CM. Capsular infarcts: the underlying vascular lesions. Arch Neurol. 1979;36:65-73. 13. Graff-Radford NR, Damasio H, Yamada T, Eslinger PJ, Damasio, AR. Nonhemorrhagic thalamic infarction: clinical, neuropsychological and electrophysiological findings in four anatomical groups defined by computerized tomography. Brain. 1985;108:485-516. 14. Helgason C, Caplan LR, Goodwin J, Hedges T. Anterior choroidal artery territory infarction: report of cases and review. Arch Neurol. 1986; 43:681-686.

Successful Treatment of Pure Myopathy, Associated With Complex I Deficiency, With Riboflavin and Carnitine Pieter L. J. A. Bernsen, MD; Fons J. M. Gabre\l=e"\ls,MD, PhD; Wim Ad M. Stadhouders, MD, PhD; Willie O. Renier, MD, PhD

\s=b\ We describe a

6-year-old boy who with progressive muscle weakness. Additional investigations revealed the existence of a myopathy and a pure motor neuropathy. Biochemical studies in muscle tissue showed a defect of NADH dehydrogenase (complex I). The patient dramatically improved on treatment with riboflavin and l-carnitine. Seven months after the start of the treatment, complex I activity was determined again and appeared to be normalized. Normalization of the enzymatic defect at this level has not been reported before. We provide a survey of nine patients with pure myopathy, associated with complex I deficiency and onset of symptoms in childhood. (Arch Neurol. 1991;48:334-338)

presented

rPhe primary mitochondrial myopathies form a clinically, morpholog¬

ically, and biochemically heteroge¬ neous

group of inborn

errors

of

me¬

tabolism

affecting the energy-gener¬ ating pathway.1·2 The underlying bio¬ chemical defects

can

be classified into

Accepted for publication June 29, 1990. From the Institute of Neurology, Department of Child Neurology (Drs Bernsen, Gabre\l=e"\ls,and Renier), the Institute of Pediatrics (Drs Ruitenbeek and Sengers), and the Institute of Cell Biology (Dr Stadhouders), St Radboud University Hospital, Nijmegen, the Netherlands. Presented in part at the 14th World Congress of Neurology, New Delhi, India, October 24, 1989. Reprints not available.

Ruitenbeek, PhD; Rob C. A. Sengers, MD, PhD;

four groups3 as follows: (1) defects of substrate transport; (2) defects of sub¬ strate utilization; (3) defects of the respiratory chain; and (4) defects of energy conservation and transduction. There is no correlation between the clinical picture and the biochemical defect. Patients with a defect of the respiratory chain may present from early infancy to adulthood. A de¬ creased activity of NADHQ, oxidoreductase (NADH dehydrogenase or complex I) is frequently found. Only nine patients with a combination of symptoms and onset at an infantile age and a clinically pure myopathy, associated with a complex I deficiency, have been described to date.410 In these patients the diagnosis of complex I de¬ ficiency has been established by indi¬ rect estimation of NADH-dependent substrate oxidation rates. Effective treatment of mitochondrial myopa¬ thies remains extremely limited. We describe a 6-year-old boy who presented with a progressive myopa¬ thy and motor neuropathy in whom complex I activity was found to be de¬ ficient. The defect could be demon¬ strated by indirect estimation of the NADH oxidation rate and by direct measurement of NADH:Qi oxidoreductase activity. His condition

dramatically improved during treat¬ ment with riboflavin and L-carnitine.

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REPORT OF A CASE

The patient was the first child of healthy, unrelated parents. Pregnancy, delivery, and motor development were normal. His family history was unremarkable. He had been completely well until August 1987. At that time he started to complain about weakness in his legs, and it was noticed that he was subject to sudden falls. He became unable to run and play games at school. He had difficulty in climbing stairs. Two months later, he developed weakness in his hands to such an extent that he became un¬ able to hold a cup. His gait became waddling and he needed help with his daily activities. Three months after the start of his com¬ plaints he was referred to our hospital. On examination, the patient was an alert and cooperative 6-year-old boy. Results of general physical and ophthalmologic exam¬ ination revealed no abnormalities. On neu¬ rologic examination the cranial nerves were normal. There was a mild weakness of neck flexion, an increased lumbar lordosis, and winging of the scapulae. He had a waddling gait and was unable to sit up from the su¬ pine position without using his arms. Gow¬ ers' sign was positive. Muscles were gener¬ ally thin, with a moderate wasting of the proximal musculature. Muscle tone was impaired. There was a diffuse weakness (shoulder girdle, Medical Research Council [1] MRC grade 3; forearms, grade 4; intrin¬ sic hand muscles, grade 3%; pelvic girdle, quadriceps muscle, and hamstring muscle, grade 3; and ankle flexion and extension, grade 4) of all muscle groups that was more pronounced in the proximal musculature.

The deep tendon reflexes were absent and the plantar reflexes were flexor. Sensation and coordination were normal. Treatment and

Progress

Once the diagnosis of complex I defi¬ ciency was established, oral treatment with L-carnitine (2 g daily) and riboflavin (9 mg daily) was initiated. In the following months there was a dra¬ matic improvement of the patient's symp¬ toms. When he was reexamined, 7 months later, he was able to run, albeit with mild footdrop, and to ride a bicycle again. The strength in his hands was almost normal. On examination, he still had a slight diffuse weakness that was more pronounced in the peroneal muscles. Gowers' sign was nega¬ tive. Tendon reflexes could now be elicited although the ankle jerks were still dimin¬ ished. Eighteen months after discharge he was seen again. This time he only had a slight weakness of the peroneal muscles. Tendon reflexes were normal.

Radiological and Electrophysiological Studies

On admission the computed tomographic brain scan, electroencephalogram, electro¬ cardiogram, and echocardiogram were nor¬ mal. Nerve conduction velocity studies showed slowing of motor conduction velocities (per¬ oneal nerve, 26 m/s, distal latency, 6.1 mil¬ liseconds; posterior tibial nerve, 30 m/s, di¬ stal latency, 3.7 milliseconds; median nerve, 37 m/s, distal latency, 3.3 milliseconds). Sensory action potentials recorded from the median and sural nerves were within normal limits. The electromyogram showed polyphasic motor unit action potentials, predominantly of high amplitude and long duration (3 to 4 mV and 20 to 24 millisec¬ onds, respectively), but also of low ampli¬ tude and brief duration (until 0.5 mV and 6 to 7 milliseconds, respectively) in the tibia¬ lis anterior and extensor digitorum communis muscles. Seven months later, nerve conduction velocity studies and electromyo¬ gram were repeated. Motor conduction ve¬ locities were improved (peroneal nerve, 38 m/s, distal latency; 4.2 milliseconds) and the electromyogram of the tibialis anterior muscle was normal.

Laboratory Investigations Results of the following laboratory tests normal: complete blood cell count; se¬ rum electrolyte levels; renal and hepatic function tests; serum protein content, and its electrophoretic pattern; serum lipids; amino acids in plasma and urine; organic acids in urine; lysosomal enzyme activities (including acid maltase) in leukocytes; and urinalysis. Appropriate studies ruled out endocrinologie, immunologie, and chronic infectious diseases, deficiencies (including riboflavin), and disorders caused by toxic agents. Creatine kinase activity, serum myoglobin, and serum carnitine concentra¬ tion were normal. Antibodies against ace¬ tylcholine receptors could not be found. Resting venous blood lactate concentra¬ tion, measured on separate occasions, was were

Table 1.—Oxidation Rates of Mitochondrial Substrates and ATP Production Rates in Supernatants of Muscle From the Patient and Control Subjects* Substrate Plus Inhibitors

Control Range

Patient

(1-I4C) pyruvate + malate (1-,4C) pyruvate + carnitine (U-14C) malate + pyruvate + malonate (U-14C) malate -I- acetylcarn. + malonate (U-,4C) malate + acetylcarn. + arsenite ATP + creatine-P production from pyruvate ATP + creatine-P production from succinate * Measurements given are in nanomoles hr '

51

273-705

266-941 320-996

19

198-517

1053 493 mg

'

of

1833-8075

25

protein.

·

Table 2.—Mitochondrial Enzyme Activities and Carnitine Content in Muscle From the Patient Before and After 7 Months of Therapy, and From Control

Specimens Subjects*

Patient Before Therapy After Therapy 237 73 Cytochrome c oxidase NADH:Q, oxidoreductase _LO _17.1 Succinate:cytochrome c oxidoreductase Not 4.5 Pyruvate dehydrogenase complex

Control Range 73-284

2.9-7.0

39

13

determined Citrate synthase Carnitine, total Carnitine, nonesterified

46 0.79

48-146

2.5

2.7-4.6

21

0.61

Enzyme activity levels are measured in milliunits g"1 wet weight.

micromoles

122

mg"1

of

protein;

carnitine content is measured in

·

·

normal. Twenty-four-hour lactate excre¬ tion in urine was normal. The cerebrospinal fluid showed a normal white blood cell count. The total protein content was ele¬ vated (0.88 g/L). Protein electrophoresis of the cerebrospinal fluid showed a transudative protein spectrum. Isoelectric focusing was normal. Cerebrospinal fluid lactate was 2.06 mmol/L (normal, 1.38 to 1.90 mmol/L). The results of routine laboratory blood tests and cerebrospinal fluid studies, re¬ peated 7 months later, were normal.

Specific Laboratory Studies Measurement of the substrate oxidation rates was performed in 600 g supernatant of

a freshly obtained biopsy specimen from the quadriceps muscle of the patient, as de¬ scribed by Bookelman et al." In parallel experiments the production rate of ATP plus creatine phosphate was determined.12 Carnitine and protein con¬ tents, and activities of cytochrome c oxi¬

dase, NADH:Q,, succinate:cytochrome c ox¬ idoreductase, and citrate synthase were de¬ termined in frozen samples, as described previously.13 Pyruvate dehydrogenase com¬ plex activity was measured according to Van Laack et al.14 Enzyme activities were

measured in a second muscle specimen ob¬ tained from the patient after a 7-month supplementation period with L-carnitine and riboflavin. Skeletal muscle specimens from patients without known neuromuscu¬ lar disease were used as control specimens. The patient's muscle specimens were han¬ dled identically to control specimens.

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RESULTS

From the data summarized in Table rate of substrates for the mitochondrial en¬ ergy metabolism is diminished under all conditions tested, while the produc¬ tion rate of ATP is disturbed as well. This can be ascribed to a decreased ac¬ tivity of NADH:Q, oxidoreductase (Ta¬ ble 2). The muscular carnitine content was impaired. Fatty acid oxidation ca¬ pacity in muscle was normal. In the needle biopsy specimen taken after a 7-month supplementation period, the mitochondrial enzymes tested ap¬ peared to have normal activities, NADH:Q, oxidoreductase showing the most impressive increase in activity. The muscular carnitine content was almost within normal limits at that time.

1, it is clear that the oxidation

HISTOPATHOLOGICAL STUDIES Muscle Biopsies

During the first admission, histopathological studies were done on bi¬ opsy specimens of the quadriceps and soleus muscles. In the quadriceps mus¬

cle there was an increased fiber size distribution. The type I fibers (65%; normal, 35% to 50%) were often en¬ larged. The checkerboard pattern was normal, Modified Gomori-trichrome staining did not reveal ragged red

fibers. The Sudan black staining showed large lipid droplets in some of the muscle fibers (Fig 1). There was no increased endomysial connective tis¬ sue. Type grouping or other signs of denervation were not seen. In the soleus muscle biopsy speci¬ men there also was a distinct increase in fiber size distribution with clearly atrophie muscle fibers. The checker¬ board pattern was slightly disturbed. Modified Gomori-trichrome staining did not reveal ragged red fibers and Sudan black staining was normal. There was an increased variability of the mean diameter of the muscle fibers between the fascicles. There were small angular and targetoîd fibers scattered in the biopsy specimen. There was no type grouping. The axons present showed a normal myelination, but the density of the myelinated nerve fibers was diminished. There was no increased endomysial connec¬ tive tissue. At the electron microscopic level many muscle fibers, particularly in the soleus muscle biopsy specimen, showed degeneration of myofibrils, and streaming and disintegration of disks. Lipid droplets were observed in some of the muscle fibers of the quad¬ riceps muscle biopsy specimen (Fig 2). The number of mitochondria was nor¬ mal. The ultrastructure of the mito¬ chondria showed no abnormalities. Particularly in the soleus biopsy specimen there were nerve fibers that contained both normally myelinated axons as well as axons that were clearly demyelinated. There was an accumulation of myelin debris in many Schwann cells. In the quadriceps muscle needle bi¬ opsy material, taken 7 months after discharge, histochemical findings were essentially as found before. Somewhat varying between the fascicles, there were irregularities in fiber size distri¬ bution, with clearly atrophie fibers present. Storage of lipid droplets, how¬ ever, was not observed.

Fig 1. Sudan black stain of first quadriceps muscle biopsy specimen with increased number of lipid droplets (bar equals 25 Mm). —

Sural Nerve Biopsy

Light-microscopic and electron-mi¬ croscopic studies, including teased nerve fiber studies, were normal. The histogram was normal. COMMENT

The mitochondrial myopathies form a clinically and biochemically hetero¬ geneous group of disorders. The clini¬ cal picture may be dominated by symp¬ toms and signs limited to the muscle system, as in our patient, or with syn¬ dromes predominantly involving the central nervous system. The histo-

Fig 2.—Electron micrograph of quadriceps muscle specimen with regular myofibrillar arrangement, increased number of lipid droplets (arrows) (magnification, X4200; bar equals 2 pm).

pathological hallmark of the mito¬ chondrial myopathies is the ragged red fiber. Our patient was suffering from a biochemically demonstrated

myopa-

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thy with a complex I defect. Only a limited number of patients with pure myopathy, associated with complex I deficiency, and symptoms

Table 3.—Clinical and Laboratory Features of 10 Patients With Pure First Patient No.

Sex F

14

Symptoms Appeared Early

Age at Admission, y 26

Exercise

Intolerance

Muscle Weakness Generalized

childhood Childhood

M

10 years

23

Generalized

Proximal

20

Myopathy Associated

With

Muscle

Electromyogram Myopathie changes

Biopsy Specimen Ragged red

Complex I Deficiency Carnitine Content in Plasma and Muscle Normal

fibers

Myopathie changes

Ragged red

Normal

Ragged

Normal

fibers

Family History Sister similarly affected (pa¬ tient 2) Sister similarly affected tient 1)

red

Normal

Negative

(pa¬

fibers

Childhood

Generalized

Normal

Negative

Proximal

Myopathie changes

Not reported Lipid storage myopathy

Normal

10 years

Deficient In plasma and

Mother with simi¬ lar defect

Generalized

Not

Ragged red

Normal

Sister with

muscle

F

11 years

21

fibers

reported

bly

possi¬

similar de¬

fect

8,o

F

Childhood

Generalized

Myopathie changes

Ragged red

F

3 years

Generalized

Not

Ragged red

Normal

Negative

Normal

Cousin of patient 9; mother with similar symp¬

Normal

Cousin of patient 8; mother with similar symp¬

Deficient in muscle

Negative

fibers fibers

reported

toms

M

Generalized

2 years

Not

Ragged

reported

red

fibers, lipid

droplets present Present

M

6 years

6

Generalized;

proximal

case

greater than

distal

dating back to childhood have been described (Table 3). Our patient is re¬

markable insofar that he differs from the other patients in clinical features as well as in data found in routine lab¬ oratory studies. He had no history of excessive fatigability or clear exercise intolerance, but presented with slowly progressive weakness. His serum lac¬ tate concentration was normal. The lactate level in the cerebrospinal fluid was only slightly elevated. Histochemical studies of the quadriceps muscle showed lipid-containing vacuoles in some of the muscle fibers, but no ragged red fibers. Special biochemical studies re¬ vealed, besides the impaired NADH dehydrogenase activity, a decreased muscle carnitine content. The latter finding has been reported in other cases with complex I deficiency.7'10131516 Low levels of carnitine in muscle have also been described in other disorders of muscle.1617 Increased numbers of lipid droplets are often seen in mitochondrial myop¬ athies, including complex I defi¬ ciency.7101518 In mitochondrial myopa¬ thy the proportion of muscle fibers giving evidence of ragged red fibers is known to be variable, but complete ab¬ sence of ragged red fibers in a case of

Myopathie changes; neurogenic changes

Myopathie

complex I deficiency has only occasion¬ ally been reported.71018 Peripheral neuropathy is known to

be associated with mitochondrial my¬

opathy. This has been studied more extensively by Yiannikas et al.19 In the study by Petty et al,20 three adult patients with a complex I deficiency had a neuropathy. These authors con¬ clude that peripheral neuropathy is not uncommon in patients with a mi¬ tochondrial myopathy. Most patients have a mild sensorimotor neuropathy with evidence of axonal degeneration, sometimes associated with mild demy¬ elination. In our patient, motor con¬ duction velocities were impaired while sensory action potentials and latencies

within normal limits. Histopathological and morphometric stud¬ ies of the sural nerve were normal. Motor nerve fibers, present in the so¬ leus muscle biopsy specimen, however, showed signs of axonal atrophy and some segmental degeneration ultrastructurally. Together with the clini¬ cal findings, these results indicate that the patient was suffering from a pure motor neuropathy with predominantly axonal degeneration. Effective treat¬ ment of mitochondrial myopathies re¬ mains limited. Our patient was treated with riboflavin and L-carnitine. A drawere

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(proximal) and

toms

neuro¬

genic (distal) changes

matic improvement of muscle strength observed. Clinical réévaluation, 7 months later, revealed improvement of motor conduction velocities, an al¬ most normal carnitine content in mus¬ cle, and normalization of complex I ac¬ tivity in the quadriceps muscle. To our knowledge, he is the first pa¬ tient reported in literature in whom the activity of complex I was restored to normal following supplementation with riboflavin and L-carnitine. The normalization of complex I ac¬ tivity is intriguing. It raises the ques¬ tion whether the impaired activity has been due to a primary genetic defect or to a secondary factor (eg, toxic, nutri¬ was

tional, infectious) influencing complex I functioning. Extensive investiga¬ tions made an exogenic origin unlikely. The clinical improvement might be explained by activation of the enzyme system, by stimulation of the biosyn¬ thesis, or by reduction in the break¬ down of complex I by riboflavin and/or

carnitine. Another possibility is that riboflavin has stabilized the mitochon¬ dria. Riboflavin is the precursor of the prosthetic group of flavoproteins, NADH dehydrogenase being one of them. Riboflavin-deficient rats showed abnormal morphological and biochem¬ ical aspects of the mitochondria,21 sug-

gesting an important role for this vi¬ tamin in stabilization or biosynthesis of this organelle. Therapeutic results in the treatment of complex I deficiency are variable and hardly interpretable. Arts et al6 successfully treated a 13-year-old girl with 100 mg of riboflavin daily. Clark et al7 treated a 24-year-old woman with DL-carnitine (6 g daily), and no¬ ticed considerable improvement.

Roodhooft et al18 administered a com¬ bination of carnitine, riboflavin, nicotinamide, L-valine, L-isoleucine, and ubiquinone to a 4-month-old infant with a combined complex I and com¬ plex IV deficiency, and reported con¬ tinuing improvement after cessation of the treatment. These patients all

suffered from the myopathie form of complex I deficiency. On the contrary, Ichiki et al22 mentioned disappointing

results in the treatment of four pa¬ tients with a MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) syn¬ drome due to complex I deficiency, who were subsequently treated with thia¬

mine, riboflavin, biotin, carnitine, ubiquinone, and ketogenic diet. The patient we describe emphasizes the clinical, biochemical, and morphologi¬ cal heterogeneity in complex I defi¬ ciency. Because of normal lactate lev¬ els in blood and urine, and aspecific findings in histochemical studies of the muscle biopsy specimen, he might have escaped a correct diagnosis if biochem-

ical studies of the mitochondrial me¬ tabolism in the muscle had been omit¬ ted. Therefore, it is advisable to per¬ form these studies in patients with progressive weakness and exercise in¬ tolerance in whom no precise diagnosis can be established otherwise. The clin¬ ical and biochemical improvement ob¬ served in our patient, together with those reported by a few other authors, indicates that a number of patients with complex I deficiency may improve on treatment with riboflavin and Lcarnitine. Unfortunately the results cannot be predicted. investigation is part of the research pro¬ System" of the University of Nijmegen (the Netherlands). This

gram "Disorders of the Neuromuscular

References 1. Morgan-Hughes JA. Mitochondrial disease. Trends Neurosci. 1986;9:15-19. 2. DiMauro S, Bonilla E, Zeviani M, Nakagawa M, DeVivo DC. Mitochondrial myopathies. Ann Neurol. 1985;17:521-538.

3. Morgan-Hughes JA, Hayes DJ, Clark JB, et al. Mitochondrial encephalomyopathies: biochemical studies in two cases revealing defects in the respiratory chain. Brain. 1982;105:553-582. 4. Morgan-Hughes JA, Darveniza P, Landon DN, Land JM, Clark JB. A mitochondrial myopathy with a deficiency of respiratory chain NADH\x=req-\ CoQ reductase activity. J Neurol Sci. 1979;43:27\x=req-\ 46. 5. Land JM, Morgan-Hughes JA, Clark JB. Mitochondrial myopathy: biochemical studies revealing a deficiency of NADH-cytochrome b reductase activity. J Neurol Sci. 1981;50:1-13. 6. Arts WFM, Scholte HR, Bogaard JM, Kerrebijn KF, Luyt-Houwen IEM. NADH-CoQ reductase deficient myopathy: successful treatment with riboflavin. Lancet. 1983;2:581-582. 7. Clark JB, Hayes DJ, Morgan-Hughes JA, Byrne E. Mitochondrial myopathies: disorders of the respiratory chain and oxidative phosphorylation. J Inher Metab Dis. 1984;7(suppl 1):62-68. 8. Morgan-Hughes JA. The mitochondrial myopathies. In: Engel AG, Banker BQ, eds. Myology. New York, NY: McGraw-Hill International Book

Co; 1986;2:1709-1743. 9. Shapira AHV, Cooper JM, Morgan-Hughes JA, et al. Molecular basis of mitochondrial myopathies: polypeptide analysis in complex I defi-

ciency. Lancet. 1988;1:500-503. 10. Koga Y, Nonaka I, Kobayashi M, Tojyo M, Nihei K. Findings in muscle in complex I (NADH coenzyme Q reductase) deficiency. Ann Neurol. 1988;24:749-756.

11. Bookelman H, Trijbels JMF, Sengers RCA, Janssen AJM, Veerkamp JH, Stadhouders AM. Pyruvate oxidation in rat and human skeletal muscle mitochondria. Biochem Med. 1978;20:395\x=req-\ 403. 12. Ruitenbeek W, Janssen AJM, Fischer JC, Sengers RCA, Trijbels JMF, Stadhouders AM. Investigation of the energy metabolism in diseased human muscular tissue. In: Scarlato G, Cerri C, eds. Mitochondrial Pathology in Muscle Diseases. Padua, Italy: Piccin Medical Books; 1983:197-201. 13. Fischer JC, Ruitenbeek W, Gabre\l=e"\lsFJM, et al. A mitochondrial encephalomyopathy: the first case with an established defect at the level of coenzyme Q. Eur J Pediatr. 1986;144:441-444. 14. Van Laack HLJM, Ruitenbeek W, Trijbels JMF, et al. Estimation of pyruvate dehydrogenase (E1) activity in human skeletal muscle: three cases with E1 deficiency. Clin Chim Acta. 1988;171:109\x=req-\ 118. 15. Morgan-Hughes JA, Landon DN. Mitochondrial respiratory chain deficiencies in man: some histochemical and fine-structural observations. In: Scarlato G, Cerri C, eds. Mitochondrial Pathology in Muscle Diseases. Padua, Italy: Piccin Medical Books; 1983:20-37. 16. Busch HFM, Scholte HR, Arts WF, Luyt\x=req-\

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Houwen IEM. A mitochondrial myopathy with a respiratory chain defect and carnitine deficiency. In: Busch HFM, Jennekens FGI, Scholte HR, eds. Mitochondria and Muscular Diseases. Beetsterzwaag, the Netherlands: Mefar; 1981:207-211. 17. Scholte HR, Busch HFM, Luyt-Houwen IEM. Functional disorders of mitochondria in muscular diseases\p=m-\respiratorychain phosphorylation\p=m-\thecarnitine system. In: Busch HFM, Jennekens FGI, Scholte HR, eds. Mitochondria and Muscular Diseases. Beetsterzwaag, the Netherlands: Mefar; 1981:133-145. 18. Roodhooft AM, Van Acker KJ, Martin JJ, Ceuterick C, Scholte HR, Luyt-Houwen IEM. Benign mitochondrial myopathy with deficiency of NADH-CoQ reductase and cytochrome c oxidase.

Neuropediatrics. 1986;17:221-226. 19. Yiannikas C, McLeod JG, Pollard JD, Baverstock J. Peripheral neuropathy associated with mitochondrial myopathy. Ann Neurol. 1986;20:249-257. 20. Petty RKH, Harding AE, Morgan-Hughes

JA. The clinical features of mitochondrial myopathy. Brain. 1986;109:915-938. 21. Addison R, McCormick DB. Biogenesis of flavoprotein and cytochrome components in hepatic mitochondria from riboflavin-deficient rats. Biochem Biophys Res Commun. 1978;81:133-138. 22. Ichiki T, Tanaka M, Nishikimi M, et al. Deficiency of subunits of complex I and mitochondrial encephalomyopathy. Ann Neurol. 1988; 23:287-294.

Successful treatment of pure myopathy, associated with complex I deficiency, with riboflavin and carnitine.

We describe a 6-year-old boy who presented with progressive muscle weakness. Additional investigations revealed the existence of a myopathy and a pure...
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