Mitochondrial Energy Metabolism Disorders

Mitochondrial Energy Metabolism Disorders

Patricia L. Musolino

Katherine B. Sims


Mitochondrial oxidative-phosphorylation diseases are a clinically heterogeneous group of disorders that arise primarily as a result of dysfunction of the mitochondrial respiratory chain (electron transport chain [ETC]) and can present at any age. More than 70 different polypeptides interact on the inner mitochondrial membrane to form the respiratory chain. The vast majority of subunits are synthesized within the cytosol from nuclear DNA (nDNA) transcripts, but 13 essential subunits are encoded by the 16.5-kb mitochondrial DNA (mtDNA). See Figure 8.1.


Because of the presence of mitochondrial heteroplasmy (different amounts of mutant mitochondria) in different cells and tissues, some mitochondrial disorders may affect a single organ but more commonly involve multiple organ systems. Many disorders present with prominent neurologic (central, peripheral, and autonomic) as well as myopathic features. Moreover, variant mtDNA and nDNA mutations can present with the same clinical syndrome, or a single mutation can lead to different combinations of signs and symptoms. Common clinical features of mitochondrial disease include encephalopathy, seizures, dementia, migraine, stroke-like episodes,
ataxia, spasticity, ptosis, external ophthalmoplegia, myopathy (often with exercise intolerance), sensorineural hearing loss/deafness, optic atrophy/pigmentary retinopathy, and nonneurological symptoms (including cardiomyopathy, failure to thrive, hepatic failure, renal tubular acidosis, diabetes mellitus and other endocrinopathies, bone marrow failure, and immunologic alterations (Table 8.1). A high incidence of mid- and late pregnancy loss is a common occurrence that often goes unrecognized. Table 8.2 summarizes “red-flag” clinical S/S that should prompt the primary care team to trigger a mitochondrial disorder diagnostic work-up.

FIGURE 8.1 Simplified Energy Metabolic Pathways Affected in Mitochondrial Disorders.

TABLE 8.1 Signs and Symptoms Suggestive of Mitochondrial Disorder


Cerebral stroke-like lesions in a nonvascular pattern

Basal ganglia dysfunction or mineralization

Encephalopathy: recurrent or w/ low/moderate dosing of valproate


Epilepsia partialis continua, generalized or myoclonic seizures



MRI findings consistent w/ Leigh disease

Characteristic MRS peaks (lactate peak at 1.3 ppm, TE at 35 & 135; succinate peak at 2.4 ppm)


Hypertrophic cardiomyopathy w/ rhythm disturbance

Unexplained heart block in a child

Cardiomyopathy w/ lactic acidosis

Dilated cardiomyopathy w/ muscle weakness

Wolff-Parkinson-White arrhythmia


Retinal degeneration w/ signs of night blindness, colorvision deficits, decreased visual acuity, or pigmentary retinopathy


Fluctuating, dysconjugate eye movements


Sudden- or insidious-onset optic neuropathy/atrophy


Unexplained or valproate-induced liver failure

Severe dysmotility

Pseudo-obstructive episodes


A newborn, infant, or young child w/ unexplained hypotonia, weakness, failure to thrive, and metabolic acidosis (particularly lactic acidosis)

Exercise intolerance that is not in proportion to weakness

Hypersensitivity to general anesthesia

Episodes of acute rhabdomyolysis

Short stature

Autonomic dysfunction/postural orthostatic tachycardia syndrome (POTS)

Adapted from Haas RH, et al. Mitochondrial disease: a practical approach for primary care physicians. Pediatrics. 2007;120:1326-1333.10


In some individuals, the clinical picture is characteristic of a specific mitochondrial syndrome (e.g., LHON, NARP; see Table 8.2), and the diagnosis can be confirmed by molecular genetic testing of DNA extracted from a blood
sample. In many individuals, such is not the case, and a more structured approach is needed: family history, metabolic screening in blood, urine, and CSF, neuroimaging, cardiac evaluation, and muscle (or other tissue) biopsy for histologic, histochemical, or electron-microscopic evidence of mitochondrial disease, as well as ETC analysis or polography/ATP production (freshly frozen biopsy samples only). Molecular genetic testing for mtDNA and nDNA mutations is often best done in tissue. Diagnostic criteria have been developed1,2 (Table 8.3). Although ability to rule out diagnosis is limited, a proposed algorithm for initial diagnostic work-up is summarized in Table 8.4. In terms of genetic work-up, the strategy is based on clinical constellation, likelihood of mtDNA mutation (clinical syndrome, maternal inheritance), availability of tissue for depletion analysis (muscle, liver), and evidence from biochemical testing.

TABLE 8.2 Clinical Syndromes of Mitochondrial Diseases


Primary Features

Additional Features


Alpers-Huttenlocher syndrome



Liver failure

Renal tubulopathy

Leigh syndrome (LS)

Subacute relapsing encephalopathy

Cerebellar, brainstem signs

Infantile onset

Basal ganglia lucencies

Maternal lineage history of neurologic disease, Leigh syndrome, or increased spontaneous abortions

Infantile myopathy and lactic acidosis (fatal and nonfatal forms)

Hypotonia in 1st y of life

Feeding and respiratory difficulties

Fatal form may be associated with a cardiomyopathy and/or de Toni-Fanconi-Debre syndrome


Progressive external ophthalmoplegia (adPEO and arPEO)

External ophthalmoplegia

Bilateral ptosis

Mild proximal myopathy

Compatible with a normal life span

Kearns-sayre syndrome (KSS)

PEO onset at age <20 y

Pigmentary retinopathy

One of the following: CSF protein >1 g/L Cerebellar ataxia Heart block

Bilateral deafness



Diabetes mellitus



Neurogenic weakness with ataxia and retinitis pigmentosa (NARP)

Late-childhood or adultonset peripheral neuropathy


Pigmentary retinopathy

Basal ganglia lucencies

Abnormal electroretinogram

Sensorimotor neuropathy

Myoclonic epilepsy with ragged-red fibers (MERRF)



Cerebellar ataxia



Optic atrophy

Bilateral deafness

Peripheral neuropathy


Generalized lipomatosis

Leber hereditary optic neuropathy (LHON)

Subacute painless b/l visual failure

M:F, 4:1

Median age of onset 24 y


Cardiac preexcitation syndromes

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)

Stroke-like episodes at age <40 y

Seizures and/or dementia

Ragged-red fibers and/or lactic acidosis

Diabetes mellitus

Cardiomyopathy (initially hypertrophic, later dilated)

Bilateral deafness

Pigmentary retinopathy

Cerebellar ataxia

Pearson syndrome

Sideroblastic anemia of childhood


Exocrine pancreatic failure

Renal tubular defects

Myoclonic epilepsy myopathy sensory ataxia (MEMSA or MIRAS)



Cerebellar ataxia


Peripheral neuropathy


Coenzyme Q10 deficiency

Encephalopathy, myopathy

Seizures, cerebellar ataxia


Renal failure

Growth retardation

Early infancy LS (severe form)

Late onset: myopathy, ataxia, seizures, mild encephalopathy

Modified from Chinnery PF. Mitochondrial Disorders Overview. 2000 Jun 8 [Updated 2010 Sep 16]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviewsTM [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013. Available from:


Mitochondrial disorders caused by defects of nuclear DNA (nDNA) may be inherited in an autosomal recessive, autosomal dominant, or X-linked manner. mtDNA defects are transmitted by maternal inheritance. mtDNA deletions generally occur de novo and thus cause disease sporadically, with no significant risk to other family members. mtDNA point mutations and duplications may be transmitted down the maternal line. Thus both males and females can be affected by mtDNA pathologic lesions, but a male does not transmit the mtDNA mutation to his offspring. A female harboring a heteroplasmic mtDNA point mutation may transmit a variable amount of mutant mtDNA to her offspring (heteroplasmy), resulting in considerable
intrafamilial as well as interfamilial clinical variability. Prenatal genetic testing, and interpretation of test results for mtDNA disorders, are difficult because of this mtDNA heteroplasmy and should be deferred to the genetic counselor or mitochondrial expert. nDNA-encoded mitochondrial disorders are increasingly recognized. Up to 1,200 nuclear genes, presumably associated with broad mitochondrial dysfunction, are being currently screened in clinical cohorts. The majority of nDNA-associated disorders, identified to date, are those with infantile encephalopathy features. Increasingly, however, late-onset phenotypes are being recognized (myopathy, ataxia, PEO).

TABLE 8.3 Mitochondrial Disorders Diagnostic Criteria

Clinical Signs and Symptoms (max 4 Points)

Muscular Presentation (max 2 Points)

Cns Presentation (max 2 Points)

Multisystem Disease (max 3 Points)

Metabolic and Imaging Studies (max 4 Points)

Pathology (max 4 Points)


Facies myopathica

Exercise intolerance

Muscle weakness


Abnormal EMG

Dev delay

Loss of skills





Cortical blindness

Pyramidal signs

Extrapyramidal signs

Brainstem involvement


GI tract








Elevated lactate1

Elevated L/P ratio

Elevated alanine1

Elevated CSF lactate1

Urinary tricabon acid excretion1

Ethylmalonic aciduria

Stroke-like picture/MRI

Leigh syndrome/MRI1

Elevated lactate/MRS

Ragged-red/blue fibers2

COX-negative fibers2

Reduced COX staining2

Reduced SDH staining

SDH-positive blood vessels1

Abnormal mitochondria/EM1

Score 1: mitochondrial disorder unlikely; score 2-4: possible mitochondrial disorder; score 5-7: probable mitochondrial disorder; score 8-12: definite mitochondrial disorder.1 scores 2 points.2 If in a higher %, scores 4 points.

Modified from Morava E, et al. Mitochondrial disease criteria: diagnostic applications in children. Neurology. 2006;67:1823-1826, with permission.

TABLE 8.4 Screening Algorithm for Patients with Suspected Mitochondrial Disorder

For ALL Patients

Family History and Pedigree


Basic chemistries


LFTs, ammonia

Blood lactate, pyruvate (lactate/pyruvate ratio), coenzyme Q10 (WBC, tissue)

Quantitative plasma amino acids

Plasma carnitines (free, total, esterified) and acylcarnitines


Quantitative urine organic acids

Echocardiogram & EKG

Ophthalmologic examination

Audiology testing

If Neurological Symptoms:

All of above plus:


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Jun 20, 2016 | Posted by in NEUROLOGY | Comments Off on Mitochondrial Energy Metabolism Disorders
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