Diagnosis and treatment of mitochondrial myopathies

Figures & data

Figure 1. Clinical features of mitochondrial myopathies, by organ system.

Table I. Mitochondrial myopathy syndromes presenting with ocular myopathy.

Syndrome	Clinical symptoms/signs	Onset age	Genetics
Progressive external ophthalmoplegia (PEO)	Ptosis, ophthalmoplegia. Proximal myopathy often present. Various other clinical features variably present	Any age of onset. Typically more severe phenotype with younger onset	mtDNA single deletions; mtDNA point mutations (including m.3243A >G, m.8344A >G); nDNA mutations (POLG, ANT, PEO1, OPA1)
Kearns–Sayre syndrome (KSS)	PEO, ptosis, pigmentary retinopathy, cardiac conduction abnormality, ataxia, CSF elevated protein, diabetes mellitus, sensorineural hearing loss, myopathy	<20 years	mtDNA single deletions
Ataxia neuropathy syndromes (ANS): Including MIRAS, SCAE, SANDO, MEMSA	SANDO: PEO, dysarthria, sensory neuropathy, cerebellar ataxia. Other ANS: variable presence of PEO and/or myopathy	Teen or adult	nDNA mutations (POLG, PEO1)
Myopathy, neurogastrointestinal encephalopathy (MNGIE)	PEO, ptosis, GI dysmotility, proximal myopathy, axonal polyneuropathy, leukodystrophy.	Childhood to early adulthood	nDNA mutations in TYMP

MEMSA = myoclonic epilepsy myopathy sensory ataxia; MIRAS = mitochondrial recessive ataxia syndrome; SANDO = sensory ataxia neuropathy dysarthria ophthalmoplegia; SCAE = spinocerebellar ataxia with epilepsy.

Table II. Mitochondrial myopathy typically presenting without PEO.

Syndrome	Clinical symptoms/signs	Onset age	Genetics
Childhood or adult onset
Myopathy, encephalopathy, lactic acidosis, stroke like episodes (MELAS)	Stroke-like episodes with encephalopathy, migraine, seizures. Variable presence of myopathy, cardiomyopathy, deafness, endocrinopathy, ataxia. A minority of patients have PEO	Typically < 40 years of age but childhood more common	mtDNA point mutations (m.3243A>Gin 80%)
Myoclonus, epilepsy, and ragged red fibres (MERRF)	Stimulus-sensitive myoclonus, generalized seizures, ataxia, cardiomyopathy. A minority of patients have PEO	Childhood	mtDNA point mutations (m.8344A>Gmost common)
Ataxia neuropathy syndromes (ANS): Including MIRAS, SCAE, SANDO, MEMSA	Sensory axonal neuropathy with variable degrees of sensory and cerebellar ataxia. PEO in 50%. Epilepsy and dysarthria are present in some	Adult onset	nDNA mutations (POLG, TWINKLE, OPA1)
Mitochondrial myopathy (isolated) Congenital or infant-onset	Axial/proximal myopathy. May have other features of mitochondrial disease (ataxia, polyneuropathy)	Any age of onset	mtDNA point mutations (multiple, including A3243G); mtDNA single large-scale deletions
Congenital or infant-onset
Mitochondrial DNA depletion syndrome	Diffuse myopathy or hepatocerebral syndrome	Congenital or infantile presentation, with hypotonia, respiratory weakness, and death within few years of life. Infantile COX-deficiency myopathy occasionally reverses after first year of life	nDNA mutations (DGK, TK2, TWINKLE, POLG)
Infantile myopathy with COX-deficiency	Diffuse myopathy, lactic acidosis, encephalopathy	Congenital/infantile onset. Fatal in first year, or reversible after first year in some patients	mtDNA mutation (m.l4674T>C) in the reversible form

MEMSA = myoclonic epilepsy myopathy sensory ataxia; MIRAS = mitochondrial recessive ataxia syndrome; SANDO = sensory ataxia neuropathy dysarthria ophthalmoplegia; SCAE = spinocerebellar ataxia with epilepsy.

Table III. Confirmatory tests for organ dysfunction in mitochondrial myopathy.

Symptom/sign/disorder	Tests	Possible abnormalities	Examples of treatments
Seizures, encephalopathy	EEG	Epileptiform abnormality, diffuse slowing	Anticonvulsants
Stroke-like episodes	MRI brain	High-signal T2 abnormality not conforming to vascular territories, posterior-predominant	L-arginine a possible therapy
Sensory neuropathy	Nerve conduction studies	Axonal sensory or sensorimotor neuropathy	Symptomatic therapy
Myopathy	CK	Normal or slightly elevated. May be very high in CoQ10 deficiency
	EMG	Myopathic changes or normal
Respiratory failure	PFTs, sleep studies	Decreased FVC. Apnoeic episodes during sleep	CPAP or BiPAP
Cardiac	Electrocardiogram	Conduction abnormalities	Antiarrhythmics, pacemaker
	Echocardiogram	Cardiomyopathy	ACE inhibitors
Endocrinopathy	Fasting glucose, glucose tolerance test, HgBA1c, TSH, calcium, PTH, cortisol, synacthen test	Abnormalities consistent with type 2 diabetes mellitus, and/or hypothyroidism, and/or hypoparathyroidism, and/or adrenal failure	Oral antihyperglycaemic agents and/or insulin; L-thyroxine; hydrocortisone
Cognitive dysfunction	Mental status testing	May indicate cognitive impairment
Hearing loss	Audiography	Sensorineural-type hearing loss	Auditory aids, cochlear implantation
Ocular symptoms/signs	Ophthalmology referral	Oculomotor abnormalities, optic atrophy, pigmentary retinopathy	Corrective lenses, surgery for strabismus or ptosis
Dysphagia	Swallowing studies (video fluoroscopy or manometry)	Cricopharyngeal achalasia or oesophagealdysmotility	Dietary modification
Other general tests	Serum lactate	Normal, or elevated
	CSF lactate	Normal, or elevated
	CSF analysis	Normal, or elevated protein
	CT brain	Normal, or basal ganglia calcifications ± atrophy
	MRI brain	Basal ganglia signal abnormalities, non-specific white matter abnormalities, stroke-like lesions, cerebellar or brain-stem atrophy, or normal. MR spectroscopy may demonstrate elevated lactate

Figure 2. Abnormalities on skeletal muscle biopsy in mitochondrial myopathy. Serial sections through vastus lateralis in a patient with mitochondrial myopathy showing: (A) haematoxylin and eosin, (B) cytochrome c oxidase histochemistry (COX) (note the COX deficient fibres), (C) succinate dehydrogenase histochemistry (SDH) (note the sub-sarcolemmal accumulation of mitochondria analogous to a ragged red fibre), and (D) sequential COX-SDH histochemistry showing a mosaic COX defect as seen in patients with mtDNA disorders.

Table IV. Treatments with reported benefit in mitochondrial myopathy which may benefit from further study in blinded placebo-controlled trials.

Agent	Reported benefit	Evidence
Ascorbate and menadione	Improvement on ^31PNMR and symptomatic	Single case reports in complex III deficiency (92,93)
High-fat diet with vitamins and CoQ10	Short-term improvement in neurodevelopment, seizure control, level of consciousness	Open-label study of 15 paediatric patients(94)
Idebenone	Biochemical improvements; delayed disease progression; improvement of respiratory function	Single case reports(53–55)
L-arginine	Reduction in acute symptoms of stroke-like episodes, reduction of incidence of stroke-like episodes in MELAS; improvement of TCA metabolic rate on C11-PET in cardiomyopathy.	Non-blinded, placebo-controlled study of 24 MELAS patients(64); C11-PET study in 6 patients with MELAS(65)
Magnesium	Resolution of refractory status epilepticus in Alpers syndrome	Two patients(66)
Nicotinamide	Biochemical improvements. Reduced encephalopathy and stroke-like episodes in one case	Six-month open label trial of seven MELAS patients(95), and single case reports(96,97)
Succinate	Improvement of respiratory muscle weakness; decrease in stroke-like episodes.	Single case reports(98,99)

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