Mitochondrial Energy Metabolism Disorders

Patricia L. Musolino

Katherine B. Sims

INTRODUCTION

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.

CLINCAL PRESENTATION

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

Neurologic	Cerebral stroke-like lesions in a nonvascular pattern
	Basal ganglia dysfunction or mineralization
	Encephalopathy: recurrent or w/ low/moderate dosing of valproate
	Neurodegeneration
	Epilepsia partialis continua, generalized or myoclonic seizures
	Myoclonus
	Ataxia
	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)
Cardiovascular	Hypertrophic cardiomyopathy w/ rhythm disturbance
	Unexplained heart block in a child
	Cardiomyopathy w/ lactic acidosis
	Dilated cardiomyopathy w/ muscle weakness
	Wolff-Parkinson-White arrhythmia
Ophthalmologic	Retinal degeneration w/ signs of night blindness, colorvision deficits, decreased visual acuity, or pigmentary retinopathy
	Ophthalmoplegia/paresis
	Fluctuating, dysconjugate eye movements
	Ptosis
	Sudden- or insidious-onset optic neuropathy/atrophy
Gastroenterologic	Unexplained or valproate-induced liver failure
	Severe dysmotility
	Pseudo-obstructive episodes
Other	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

DIAGNOSTIC APPROACH

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

Disorder	Primary Features	Additional Features
NUCLEAR DNA MUTATIONS
Alpers-Huttenlocher syndrome	Hypotonia Seizures 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
MITOCHONDRIAL DNA MUTATIONS
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 Myopathy Dysphagia Diabetes mellitus Hypoparathyroidism Dementia
Neurogenic weakness with ataxia and retinitis pigmentosa (NARP)	Late-childhood or adultonset peripheral neuropathy Ataxia Pigmentary retinopathy	Basal ganglia lucencies Abnormal electroretinogram Sensorimotor neuropathy
Myoclonic epilepsy with ragged-red fibers (MERRF)	Myoclonus Seizures Cerebellar ataxia Myopathy	Dementia Optic atrophy Bilateral deafness Peripheral neuropathy Spasticity Generalized lipomatosis
Leber hereditary optic neuropathy (LHON)	Subacute painless b/l visual failure M:F, 4:1 Median age of onset 24 y	Dystonia 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 Pancytopenia Exocrine pancreatic failure	Renal tubular defects
Myoclonic epilepsy myopathy sensory ataxia (MEMSA or MIRAS)	Myopathy Seizures Cerebellar ataxia	Dementia Peripheral neuropathy Spasticity
Coenzyme Q₁₀ deficiency	Encephalopathy, myopathy Seizures, cerebellar ataxia Cardiomyopathy Renal failure	Growth retardation Early infancy LS (severe form) Late onset: myopathy, ataxia, seizures, mild encephalopathy
Modified from genereviews.org. Chinnery PF. Mitochondrial Disorders Overview. 2000 Jun 8 [Updated 2010 Sep 16]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews^TM [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1224/

GENETIC COUNSELING

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)
Ophthalmoplegia¹ Facies myopathica Exercise intolerance Muscle weakness Rhabdomyolysis Abnormal EMG	Dev delay Loss of skills Stroke-like Migraine Seizures Myoclonus Cortical blindness Pyramidal signs Extrapyramidal signs Brainstem involvement	Hematology GI tract Endocrine/growth Heart Kidney Vision Hearing Neuropathy Recurrent/familial	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
	Blood
		Basic chemistries
		CBC, CPK
		LFTs, ammonia
		Blood lactate, pyruvate (lactate/pyruvate ratio), coenzyme Q₁₀ (WBC, tissue)
		Quantitative plasma amino acids
		Plasma carnitines (free, total, esterified) and acylcarnitines
	Urine
		Quantitative urine organic acids
	Echocardiogram & EKG
	Ophthalmologic examination
	Audiology testing
If Neurological Symptoms: All of above plus:	Brain MRI/MRS Only gold members can continue reading. Log In or Register to continue Share this: Click to share on Twitter (Opens in new window) Click to share on Facebook (Opens in new window) Related Related posts: Neurodevelopment and Neurologic Examination Neuromuscular Disorders Metabolic Disorders Headache and Pain Syndromes Sleep Disorders in Child Neurology Neuro-ophthalmology Stay updated, free articles. Join our Telegram channel Tags: Handbook of Pediatric Neurology Jun 20, 2016 \| Posted by drzezo in NEUROLOGY \| Comments Off on Mitochondrial Energy Metabolism Disorders Full access? Get Clinical Tree Get Clinical Tree app for offline access Get Clinical Tree app for offline access