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Cytochrome C oxidase deficiency and Long-Chain acyl coenzyme A dehydrogenase deficiency with Leigh's subacute necrotizing encephalomyelopathy.

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Cytochrome c Oxidase
Deficiency and Long-Chain
Acyl Coenzyme A
Dehydrogenase Deficiency
with Leigh’s Subacute
Necro tizing
Heinz Reichmann,* Helmut Scheel,? Bert Bier,$
Uwe-Peter Ketelsen,§ and Siegfried Zabranskyt
A female infant was seen at the age of 2 months because
of hypotonia, delayed motor development, and lactic acidosis, and she died at age 13 months due to respiratory
failure. In a muscle specimen taken at 11 months and in a
liver specimen obtained 1.5 hours postmortem, we found
decreased activities of cytochrome c oxidase and longchain acyl coenzyme A dehydrogenase. Neuropathological changes were typical for Leigh’s subacute necrotizing
encephalomyelopathy. To our knowledge, this is the first
report of a combined defect of complex IV of the respiratory chain and of the long-chain specific acyl coenzyme A dehydrogenase of @-oxidation in muscle and
Reichmann H , Scheel H, Bier B, Ketelsen U-P,
Zabransky S. Cytochrome c oxidase deficiency
and long-chain acyl coenzyme A dehydrogenase deficiency with Leigh’s subacute
necrotizing encephalomyelopathy.
Ann Neurol 1992;31:107-109
Since the first description of mitochondrial myopathy
{l], a body of literature has emerged concerning defects of mitochondrial energy metabolism (for review,
see [2-4]), mainly due to defects of the respiratory
chain. Because the brain is often also affected by the
metabolic defect, the term mitochondrial encephalomyopathy was introduced by Shapira and colleagues
[ S ] (for review, see [6,7)).Leigh’s disease, an encephalomyelopathy is often associated with cytochrome c oxidase (COX) deficiency {S-1 11. Although COX activity is decreased in various tissues, there are reports of
From the *Department of Neurology, University of Wiirzburg,
Wurzburg; Departments of ?Pediatrics and $Pathology, University
of Homburg/Saar, Homburg; and SDeparrment of Pediatrics, University of Freiburg, Freiburg, Germany.
Received Mar 29, 1991, and in revised form Jun 24 and Jul 26.
Accepted for publication Jul 27, 1991.
Address correspondence ro Dr Reichmann, Professor of Neurology,
Department of Neurology, University of Wiirzburg, Josef-Schneider-Strasse 11, D-8700 Wurzburg, Germany.
patients with normal COX activity in liver [27, contrasting with decreased activity in muscle and other
tissues. In the present report, we describe a patient
with a biochemical defect of the respiratory chain and
of (3-oxidation presenting as Leigh’s disease.
Patient Report
Our patient was the first child of healthy nonconsanguineous parents. Pregnancy and delivery were uneventful; birth
weight was 3,080 gm. At the age of 7 months, she was admitted because of petechial hemorrhages on her face and trunk.
She had rhinitis and a mild chronic bronchitis. She was lethargic and showed motor retardation (she had no head control
and could not roll over from back to front or sit without
support); she had atrophy in the lumbar and gluteal region.
Deep tendon reflexes were increased in the lower extremities, where brief rnyoclonus could also be induced. Metabolic
acidosis (pH 7.25) with respiratory compensation was found.
Lactate was up to 5.22 mmol/L, pyruvate to 240 nmoliL, and
alanine to 60 fmol/L. After an oral glucose tolerance test,
there was excessive rise in lactate, pyruvate, and alanine.
Blood triglycerides were increased to 480 m g q with a rise
of very low density lipoproteins. Screening for amino acids,
ketone bodies, reducing substances, and mucopolysaccharides was negative. A slightly elevated excretion of ethylrnaIonic, oxalic, adipic, and glutaric acids was found. Total serum
carnitine levels were normal; however, acylcarnitines were
increased and free carnitine was decreased. Ammonium,
ascorbic acid, transaminases, thyroid hormones, cross-reacting protein; rheumatoid factor, coagulation status, thrombocyte function, urinary steroid excretion, and immunoglobulins were normal. Urinalyses revealed erythrocyturia. Cranial
computed tomography showed moderate enlargement of
the ventricles and cisterns. Electroencephalogram (EEG)
and electromyogram were normal. Liver and kidneys were
slightly enlarged. The renal scintigram was normal. Slight
hypertrophy of the septum and left ventricular wall was observed. A skin biopsy indicated vasculitis without evidence
of connective tissue disorder.
In spite of supplementation of thiamine and biotin, lactic
acidosis had not improved when the patient was seen at 11
months for a muscle biopsy (musculus quadriceps femoris).
Motor function was not improved. Myoclonic seizures were
observed. The EEG showed multifocal epileptic discharges.
When myoclonic seizures occurred daily, valproate was
started, whereupon the seizure activity in the EEG quickly
subsided, and the attacks occurred only infrequently. Transaminases remained within normal levels. Methylene blue was
administered intravenously and carnitine, ascorbic acid, and
vitamin K, were given orally without any noticeable biochemical or clinical improvement.
At 13 months, her general condition unexpectedly deteriorated. Respiratory insufficiency worsened, the acidosis became intractable, and she died within a few hours. One-half
hour post mortem, specimens of liver and of the abdominal
musculature were obtained. Postmortem examination of the
brain revealed macroscopically a slight degree of polymicrogyria, extensive gliosis and reduction in the number of ganglion cells, pronounced capillary proliferation in the paraventricular and brainstem regions, severe demyelination in the
Copyright 0 1992 by the American Neurological Association
anomalies or focal myofibrillar degeneration. The matrix of most mitochondria was condensed, but showed
no pathological inclusions. A few scattered mitochondria had marginal lipid droplets. The sarcoplasmic reticulum system was normal. The glycogen content was
slightly increased; there were no lysosomal glycogen
accumulations and no sarcoplasmic or nuclear inclusions.
In contrast, electron microscopic examinations performed on postmortem tissue showed ultrastructural
changes typical of mitochondriopathy. The liver cells
were enlarged and contained abnormal mitochondria
with lipid inclusions and irregular cristae. Muscle mitochondria displayed gross variation in size and shape
and also contained lipid inclusions.
capsula interna, capillary calcification in the brainstem ganglia, and severe gliosis in the nuclei of the pons and medulla
oblongata, wasting of the myelin sheaths, and capillary proliferation. There was hepatomegaly with centrolobular, finedroplet fatty infiltr,ition and a slight degree of muscle fiber
Materials and Methods
Routine histochemical methods were applied as outlined in
Dubowitz and Brooke [ 121. Muscle was homogenized as previously described [13]. Activity of enzymes of the respiratory
chain was analyzed as described [ 141; activity measurements
of all enzymes from 8-oxidation were performed as previously described [I?;, 15, 161. Control values were obtained
from biopsies that finally were shown to not represent a neurornuscular disorder. Liver biopsies were obrained from autopsies within the first 2 hours post mortem.
Enzymes of the Respiratory Chain
The results of the biochemical investigation are listed
in Tables 1 and 2. T h e activity of cytochrome c oxitlase
was markedly decreased both in the muscle biopsy
(19% of normal) and in the liver specimen obtained
postmortem (7% of normal). The activities of complex
I, 11, and 111 and of citrate synthase, a key enzyme of
the citric acid cycle, were normal, and histochemical
investigations revealed a normal stain for succinate Jehydrogenase and a normal adenosine triphosphatase
reaction. T h e carnitine content was low normal. In the
liver specimen, the activities of complex I, 11, and I11
Hzj.tologicul und El'ectron Mirro.tcopicul Findings
The histological and electron microscopical investigations of the muscle biopsy obtained at 11 months
showed no signs of fiber atrophy or of necrosis, no
inflammatory infiltration, and no changes in the blood
vessels. The distribution of type I and type I1 fibers
was normal. Oil red 0 staining showed a slight increase
of intracellular neutral fat droplets. Gomori trichrome
stain showed no ragged-red fibers. Electron microscopy showed no evidence of rnyofibrillar structure
Table 1 Biothemiral Analyses of Enzymes ofthe Respiratory Chain
Muscle Controls (n)
Cytochrome c oxidase
N A D H dehydrogenase
NADH-cytochrome c reductase
Succinate dehydrogenase
Succinate cytochrome c reductase
citrate synthetase
2.8 t 0.9 (113)
4 8 k 9.4 (121)
3.2 t 1.5 (98)
1.1 (160)
1.64 ? 0.6 (125)
5.3 t 2.1 (49)
Liver Controls ( n )
5 t 1.8 ( 4 )
101 t 32 (4)
1.3.1 t 1.7 ( 4 )
lr.7 ? 1.8 (4)
3.1 ? 1.0 (4)
Values of the enzyme activities are the mean f SD and arc expressed in units per gram of tissue ( I unir = 1 pmol ofsiibstr~tteturnowrimin).
Muscle was obtained at 11 months; liver was obtained 2.5 hours post mortem.
N A D H = reduced nicotinamide adenine dinucleotide.
Table 2. Enqme.r of ,&Oxidation
Muscle Controls ( n )
Liver Controls (n
Palmitoyl CoA DH
Octanoyl CoA DH
Butyryl CoA DH
Enoyl CoA hydratase
Hydroxyacyl CoA DH
Thiolase C 10
Ketone body metabolism
Thiolase C4
1.02 0.36 (65)
0.83 ? 0.31 (52)
0.84 ? 0.33 (63)
13.3 k 3.1 (41)
12.6 ? 3.43 (58)
2.12 t 1.47 (44)
4.66 2 2.38 (54)
? 0.43
0.9 2 0.23
1.4 ? 0.27
20.5 2 4.2
26.1 ? 1 . 7
12.3 2 5.5
* 7.2
Values o f enzyme activities are the mean
SD and are expressed in units per gram of muscle o r liver ( 1 unit = 1 pmol of substrate turnover/
min). Acyl CoA dehydrmogenase activity was measured according to Fong and Schulz 116).
CoA = coenzyme A; DH = dehydrogenase.
108 Annals of Neurology
Vol 31
No 1 January 1992
were normal, whereas cytochrome c oxidase activity
was reduced.
Enzymes of Poxidation
The activity of long-chain (palmitoyl) acyl coenzyme A
dehydrogenase was reduced in the muscle biopsy and
totally absent in the liver specimen obtained at autopsy
(see Table 2). In the muscle biopsy, the activity of
octanoyl CoA dehydrogenase, butyryl CoA dehydrogenase, thiolase C 10, and hydroxyacyl CoA dehydrogenase was normal, but the activities of enoyl CoA
hydratase and thiolase C4 were slightly decreased. Carnitine and pyruvate dehydrogenase were also normal
in muscle. In postmortem liver, the activities of octanoyl CoA dehydrogenase and butyryl CoA dehydrogenase and all other enzymes of P-oxidation were normal.
In our young patient, cytochrome c oxidase deficiency
was documented in muscle and liver at 11 months and
confirmed post mortem at 13 months. In both muscle
and liver, we also found a deficiency in palmitoyl CoA
dehydrogenase. Although the defect of palmitoyl CoA
dehydrogenase was expressed in the first muscle specimen, the decision to treat the patient with valproate
was made when the enzyme defect had not yet been
detected and the clinical situation made anticonvulsant
therapy unavoidable, despite the impairment in the
respiratory chain. Administration of valproate may well
have worsened the palmitoyl CoA dehydrogenase deficiency, but cannot have caused it because the deficiency already existed at 11 months.
How, then, can palmitoyl CoA dehydrogenase deficiency be explained? It is not likely that a general
breakdown of the respiratory chain would impair ETF
(electron transport flavoprotein) metabolism and affect
selectively the long-chain acyl CoA dehydrogenase as
we observed in our patient. Rather, we suggest an independent mitochondrial enzyme defect in the P-oxidation pathway, not secondary to the enzyme defect in
the respiratory chain. The concurrent clinical and
pathological signs of severe disturbance of fat metabolism (massive hypertriglyceridemia and fatty changes of
the liver), which have not been observed in other patients with cytochrome c oxidase deficiency, also support the concept of an independent defect of p-oxidation. Miyabayashi and colleagues “)I were able to
confirm cytochrome c oxidase deficiency in the brain
cells of a patient afflicted with Leigh‘s disease.
The therapeutic trials with thiamine, biotin, methylene blue, ascorbic acid, and vitamin K, were aimed at
supplying artificial electron transporters to “unload”
the defective respiratory chain. As in other reports,
our attempts did not succeed.
Many questions remain unanswered. We believe
that this was a rare occurrence of two independent
mitochondrial enzyme defects. Secondary carnitine de-
ficiency was described in patients with respiratory chain
defects, but measurements of P-oxidation have been
performed infrequently so far. Systematic studies of
P-oxidation enzymes would be of interest to clarify the
question raised by this patient’s condition of a possible
relationship between defects of the respiratory chain
and of P-oxidation. Only recently, Watmough and colleagues [17] reported on lipid accumulation in biopsies
from patients with a complex I defect of the respiratory
This study was supported by the Deutsche Forschungsgmeinschaft
(Re 265/5-3). H . Reichmann is grateful to S. Seufert for expert
technical assistance and B. Gobel for secretarial work.
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Brief Communication: Reichmann et al: Combined Enzymatic Defect in Leigh’s Disease
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cytochrome, subacuta, chains, encephalomyelopathy, deficiency, long, necrotizing, dehydrogenase, coenzyme, leigh, oxidase, acyl
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