Patient 22: Miopatia Mitocondriale Isolata Associata a Deficit di CoQ

Author: elena rindone
Date: 09/02/2009


Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency

Coenzyme Q deficiency triggers mitochondria degradation by mitophagy

1) Definizione del paziente e della storia

sesso: male
Anno di nascita : 1993
Peso: ** Statura: ** BMI: **

Anamnesi patologica prossima

Insidious onset of exercise intollerance and proximal muscle weakness began 4 months prior to evalutation, manifested by difficulty ascending stairs and lifting heavy objects. This was preceded by constitutional fatigue for several months.
He lost weight over this interval and complained of lower extremity muscle cramps.
There was no history of unexplained fever, rash, ataxia, hearing loss, or seizures.
On physical examination he was noted to have significatly reduced proximal muscle strength at the shoulders and the hips, with mild wasting of the shoulder muscle. The Gower maneuver was noted when arising from a seated position. There was no evidence of ofthalmoplagia or ataxia.
His creatine kinase level was elevated at 359 U/L (reference range, 55-215 U/L).
His lactate level was 33.33 mg/dL (3.7 mmol/L)(reference range, 1.80-18.01 mg/dL or 0.2-2.0 mmol/L).
Urinalysis did not reveal myoglobinuria, and urine organic acid analysis detected abnormal metabolites including ethylmalonic acid, methylsuccinic acid, hexanoylglycine and lactid acid.
The plasma acylcarnitine profile exhibited elevations of butyrylcarnitine, pentanoylcarnitine, hexanoylcarnitine, octanoylcarnitine and decanpylcarnitine, with no evidence of plasma total carnitine depletion.
Nerve conduction velocity measurements were normal.
The electromyogram showed low-amplitude polyphasic units consistent with myophaty.
A skeletal muscle histochemical revealed rare pale-staining myofibers with the Cytochrome-c oxidase satin and scattered ragged red fibers with the Gomori trichrome stain.
On electron microscopy, there was an increase in the number of mitochondria, although no abnormally shaped or enlarged mitochondria were found. A prominent increase in lipid droplets and subsarcolemmal and intermyofibrillar accumulation of free glycogen were found.
The RC enzyme analyses showed partial reduction in complex I, I+III, III activities with greater than 200% of normal citrate synthase activity, suggestive of increased mitochondrial content and corroborating histochemical findings.

Respiratory Chain Analysis of Patient’s Skletal Muscle Tissue

Enzyme (μmol/min-1 x gg-1)
NADH-dehydrogenase (complex I): 5.1 (14.74±4.48)
Succinate-dehydrogenase (complex II): 0.53 (0.87±0.21)
NADH-cytochromo-c-reductase (I-III): 0.35 (0.81±0.20)
cytochromo-c-oxidase (complex IV): 1.53 (2.43±0.70)|
Succinate-cytochromo-c-reductase ( II-III): 0.46 (1.03±0.31)
Succinate-citocromo-c-reductase + CoQ: 3.74 (2.56±0.72)
Citrate synthetase: 36.54 (15.74±4.44)
CoQ10: 9.11 (19.81±2.61)

Results of magnetic resonance imaging an magnetic resonance spectroscopy of the brain were normal.

Anamnesi patologica remota
He was a previously healty, developmetally normal child, born at 34 weeks' gestation to healty, non consaguineous parents.

Anamnesi familiare

2) Le basi molecolari degli eventi descritti, tenendo conto di tutti i sintomi ed utilizzando i link alle informazioni pertinenti

This case study suggest that CoQ deficiency and the concomitant significant reductions in complex I, I+III, and II+III enzymatic activities in respiratory chain (RC) were responsable for the mitochondrial disorders observed in this patient. The observed muscle carnitine deficiency is most likely related to an increased reduced nicotinamide adenine dinucleotide-nicotinamide adenine dinucleotide ratio associated with respiratory chain defects. The increased ratio could impair beta-oxidation at the level of 3-hydroxyacyl- coenzyme A dehydrogenases, with a subsequent accumulation of acyl-coenzyme A beta-oxidation intermediates. These intermediates, released as carnitine esters, are transported into plasma and eliminated in urine, leading to secondary carnitine deficiency.
CoQ plays an important role in the Mitochondrial RC by acting as a redox carrier, transferring reducing equivalents from complex I and complex II to complex III. CoQ10 allows the extrusion of protons from the matrix to the intermembran space along with the electron flow through the RC. Deficiency of CoQ10 impairs the proton transfer across the inner mitochondrial membrane, thus affecting generation of adenosine triphosfate and all adenosine triphosfate-dependent metabolic processes. Although the antioxidant treatement for RC defects has no proven efficacy, treatement of ubiquinone deficiency might represent an exception.

3) Eventuali proposte di terapia, volta al ripristino delle condizioni ottimali

Treatement with Coenzyme Q (150 mg/day) and Carnitine for 3 month (100 mg/kg/day).

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