Differential Diagnosis in Neurology

12.9. Mitochondrial Myopathies

• Cytochrome and oxidase deficiency
• Multiple cytochrome deficiency
• Pyruvate carboxylase deficiency
• Pyruvate decarboxylase deficiency

Carnitine Octanol Transferase Deficiency

• Clinical Characteristics
  • Recurrent encephalopathy
  • Cardiomyopathy
  • Dicarboxylic aciduria
  • Hypotonia
  • Decreased muscle carnitine

Methylene Tetrahydrofolate Reductase Deficiency

• Defect causes decrease of S-adenosylmethionine for carnitine synthesis
• Clinical features:
  • Progressive leukoencephalopathy
  • Flaccid paralysis
  • Homocystinuria and homocystinemia
  • Decreased muscle carnitine
  • Lipid storage in muscle

Idiopathic Reye Syndrome

• Clinical characteristics:
  • Associated with ketoacidosis
  • LC-ACD and M-ACD deficiencies are noted
  • Intermittent encephalopathy
  • Carnitine levels are normal between attacks

Valproate Therapy

• Decrease free serum carnitine: occurs primarily in children
• Increase serum ammonia: dose dependent
• Four to six day gradual increase of lethargy, vomiting, anorexia, jaundice and edema
• Hypo carnitinemia

Renal Fanconi Syndrome

• Increased fractional excretion of free carnitine and acylcarnitine
• Clinical characteristics:
  • Nephropathic calcinosis
  • Oculocerebrorenal syndrome
  • Hypoglycemia and hyperammonia
  • Decreased serum carnitine
  • A few patients have had muscle weakness and lipid storage myopathy

Chronic Renal Failure Treated by Hemodialysis

• Fall of serum carnitine during dialysis
• Increase of free fatty acids in serum

Diagnosis of Carnitine Deficiency

• Carnitine deficiency syndrome should be considered in a patient with a lipid storage myopathy
• Recurrent encephalopathy resembling Reye's syndrome is characteristic
• Recurrent hypoglycemia with or without ketoacidosis precipitated by:
  • Caloric deprivation
  • Exercise
  • Infection
  • Pregnancy
• Myalgia, increased fatigue
• Lactic academia induced by exercise
• Cardiomyopathy:
  • High precordial T waves
  • Left axis deviation
• Unexplained hepatomegaly
• Hypertrophic cardiomyopathy with or without family history of sudden death
• Established organic aciduria

Differential Diagnosis of Carnitine Deficiency

• Chanarin disease
• Lipid storage myopathy
• Polymyositis
• Debrancher enzyme deficiency
• Infantile acid maltase
• Urea cycle defects (intermittent encephalopathy)
• Fructose-1, 6-diphosphate deficiency (intermittent encephalopathy)
• Phosphoenolpyruvate carboxykinase deficiency

Seminal points of the Differential Diagnosis for Carnitine Deficiency

• Sporadic myopathic carnitine deficiency vs polymyositis:
  • Proximal weakness
  • Increased CK
  • Absence of fibrillation potentials in carnitine myopathy and muscle biopsy findings excludes an inflammatory myopathy
• Carnitine deficiency vs debrancher enzyme deficiency:
  • Intermittent episodes of hypoglycemia
  • Abnormal liver function tests
  • Liver and heart enlargement
  • Lactic academia
  • Hyperuricemia
  • Above occur in both entities:
  • Glycogen stored rather than lipid in debrancher enzyme deficiency
  • EMG has more irritability in debrancher deficiency
  • Distal weakness in debrancher deficiency
• Infantile acid maltase deficiency vs carnitine deficiency in maltase deficiency:
  • Enlarged tongue with fibrillation potentials
  • Progressive weakness not associated with episodic metabolic crisis
  • Cardiomyopathy (often congestive heart failure)
  • Irritative EMG with pseudomyotonic discharges and abnormal electrical irritability
  • Glycogen rather than lipid excess in muscle
• Systemic carnitine deficiency with intermittent encephalopathy vs urea cycle defects:
  • Metabolic acidosis does not occur in urea cycle defects
  • Patients with MUL-ACD and branched chain aminoacidurias may also suffer protein intolerance
  • Secondary carnitine deficiencies:
    • No oroticaciduria
    • Plasma levels of ureidosuccinic acid; arginine and citrulline are normal (elevated in urea cycle defects)
• Fructose 1–6 diphosphatase deficiency and phosphoenolpyruvate carboxykinase deficiency:
  • Impair gluconeogenesis
  • Episodes of hypoglycemia
  • Fatty liver
  • Ketoacidosis
  • Hypotonia

Chanarin Disease

• Genetics: AR
• Inability of cells to degrade endogenously synthesized triglycerides; cells can utilize exogenous phospholipids and triglycerides
• Clinical features:
  • Congenital ichthyosis
  • Age of onset: second decade in most patients
  • Ichthyosis:
    • Lamellar ichthyosis
    • Accentuated over the flexor creases
    • Mild erythema in affected area
    • Ectropion (eyelid)
  • Steatorrhea
  • Muscle weakness (when demonstrated):
    • Proximal greater than distal
    • Cranial muscles spared
    • Moderate severity
  • Ataxia, nystagmus, neurosensory, hearing loss are associated
• Laboratory evaluation:
  • Increased liver enzymes
  • EMG: myopathic
  • Increased CK
  • Stored lipid is triglyceride
  • No ketone bodies formed during a fast
  • Sudanophilic droplets in granulocytes
  • Pathologic features: triglyceride storage in all tissues

Differential Diagnosis of Lipid Storage Myopathy

Lipid Storage Myopathy Presenting at Birth

• Clinically heterogeneous group:
  • Onset in infancy
  • Non-progressive proximal myopathy
  • Benign course
  • Easily fatigued
• Fatal congenital variants:
  • Weakness at birth
  • Death from respiratory failure
  • Possible mitochondrial respiratory chain defects

Heterogenous Adult Onset Lipid Storage Myopathy

• Clinical features of a 21 year old patient:
  • Attacks of muscle weakness
  • Duration of weeks to years
  • Proximal > distal muscles; cervical muscle affected
• Lipid accumulation in muscle
• Mitochondrial defect
• Similar clinical pattern in an adult patient: responded to prednisone
• Identical twin sisters:
  • Lipid excess in muscle without weakness
  • Cramping pain after exercise, fasting, ingestion of high fat diet
  • Attacks of Myoglobinuria
  • Formed no ketone bodies during fasting or after ingestion of long chain fatty acids
  • Ketone bodies after ingestion of medium chain fatty acids

Lipid Storage Myopathy in Association with Other Diseases

• Type I glycogenosis (Von Gierke disease)
  • Mild muscle weakness and atrophy
• Pyruvate decarboxylase deficiency
  • No muscle weakness
  • No exercise intolerance
  • Intermittent ataxic attacks
• Familial B-hyperlipoproteinemia
  • Moderate myopathy
• Arthrogryposis multiplex congenita
  • Lipid storage in muscle (this from is rare)
• Scapuloperoneal muscular atrophy
• Patient with autonomic dysfunction:
  • Hepatitis B surface antigen positive hepatitis
  • Myalgia
  • Tachycardia
  • EKG abnormalities
  • Steroid responsiveness

Genetic Defects of Long Chain Fatty Acid Oxidation

• Autosomal recessive lipid storage myopathy:
  • AR
  • Onset in infancy
  • Clinical features:
    • Slowly progressive weakness
    • Muscle aching and cramping during and after exercise
    • Lipid droplets in leucocytes (Jordan's anomaly)
    • EMG: electrical but not clinical myotonia
    • Delay of ketogenesis on fasting
    • Treatment with carnitine and medium chain triglyceride:
      • Improved the myopathy
      • One patient abolished the myotonia
    • Defect in utilization of long chain fatty acids
    • Muscle biopsy: lipid storage myopathy Type I fiber predominance
• Autosomal dominant lipid storage myopathy with systemic abnormality of fat metabolism
  • AD
  • Clinical features:
    • Muscle weakness
    • Intolerance to fatty foods
  • Muscle biopsy:
    • Type I fiber predominance
    • Lipid and lipofuscin excess
    • Abnormal mitochondria
    • Medium chain triglyceride treatment
      • Clinical improvement

Carnitine Palmitoyltransferase Deficiency (CPT)

• General clinical features and differential points:
  • AR possible X-linked recessive
  • Myoglobinuria is major clinical feature of CPT
  • Frequency of myoglobinuria greater than that of glycogenoses
  • No painful cramps on exercise
  • Precipitating factors for myoglobinuria in CPT
    • Exercise (several hours)
    • Prolonged fasting
    • Viral illness
    • Cold
    • Sleep deprivation
  • No "second wind" phenomenon in CPT; noted in both phosphorylase and phosphofructokinase deficiency
  • Patients describe tightness and pain prior to pigmenturia
    • Aching of jaw muscles after chewing
    • Aching of facial muscles after speech
  • Myalgia and weakness:
    • After exercise
    • Limb or trunk muscles most commonly affected
  • Respiratory muscles affected
  • Myoglobinuria earlier than in phosphorylase or phosphofructokinase deficiency; first attacks in adolescence
  • Renal failure less than 25% of patients
  • Permanent weakness in CPT is rare
  • Women less myoglobinuria than men
• Laboratory evaluation:
  • CK normal at rest or between attacks
  • Some patients have elevated triglycerides and cholesterol
  • EMG: normal in general; occasionally abnormal between attacks
  • Prolonged fasting (30–72 hours):
    • Delayed or decreased rise of blood ketone bodies (50%)
    • Increased CK (50%)
• Pathology:
  • Muscle biopsy interictally is normal in 80% of patients
  • Lipid storage when present is less severe than in carnitine deficiency
  • CPT I and II decreased in muscle

Myoadenylate Deaminase Deficiency (AMPD)

• Genetics: AR (unique to skeletal muscle)/AMPD-1 gene (Q12X)
• Most common of known enzyme defects of skeletal muscle
• Clinical features:
  • Onset: early adulthood or middle age; some patients are asymptomatic
  • Post exertional fatigue or weakness
  • Soreness and muscle cramps
  • Fatigue and soreness increase during exertion and throughout the day
  • Extremity muscles most commonly involved greater than chest and back muscles; face and extraocular eye muscles spared
  • Some patients:
    • Fixed weakness
    • Periodic paralysis
    • Repeated childhood infections
  • No second wind phenomenon
  • No post exertional myoglobinuria
  • 50% of patients:
    • Mild to moderate muscle weakness
    • Atrophy and muscle tenderness
    • Early muscle fatigue with exercise
  • Higher incidence of malignant hyperthermia
  • AMPD-1 gene Q12X may be expressed in common with McArdle disease V and Tarui's VII glycogenoses
• Laboratory evaluation:
  • CK mildly elevated; may become markedly elevated with exercise
  • EMG: myopathic
  • Normal AMP deaminase in RBC's, lymphocytes and neutrophiles
  • Lactate ammonia exercise test (LAER) is positive
  • Some patients elevated uric acid levels
  • Normal patient in LAER test:
    • Increase ammonia of 1.5% of lactate generated
    • 1 + test < 0.4%
  • Muscle biopsy:
    • Adenylate deaminase deficient
    • 50% of AMP deaminase deficiencies in association with collagen vascular disease, muscular dystrophy, trichinosis and diabetes
• Differential Diagnosis:
  • Polymyositis
  • Benign congenital hypotonia (children)

The Mitochondrial Myopathies

General Features of Mitochondrial Disorders

• Mitochondrial oxidation of substrates: most of the energy of most cell types
• Disorders of oxidative metabolism due to defects of:
  • Substrate transport or utilization:
    • TCA cycle
    • Beta-oxidation of fatty acids
    • Defects in the respiratory chain
  • Tissues most reliant on oxidative metabolism:
    • Brain
    • Skeletal muscle
    • Cardiac muscle
  • Most patients with these disorders present with symptoms and signs of:
    • Myopathy
    • Encephalopathy
• The respiratory chain:
  • Final pathway for all substrates of oxidative metabolism
  • Consists of 5 complexes (I–V)
    • Subunits coded from both mitochondrial and nuclear DNA
    • Succinic dehydrogenase (complex II) is completely nuclearly encoded

Features of Mitochondrial DNA

• A double stranded circular molecule of 16,569 nucleotides
• 2–10 DNA copies in each mitochondrion:
  • Multiple mitochondria in each cell
  • Normal and mutant mt DNA can coexist in different proportions within each cell or tissue
• Mitochondrial DNA:
  • Contains 37 genes
  • Encodes 13 protein subunits of complexes I, III, IV and V of the respiratory chain
  • 2 ribosomal RNAs and 22 transfer RNAs are required for intramitochondrial translation
  • No introns; therefore all mutations change coding sequences
  • No repair enzymes
  • No protective histones
  • Exposed to oxygen free radicals derived from oxidative phosphorylation
  • Maternal inheritance
  • No recombination
  • High replication and mutation rate
• Mitochondrial heteroplasia:
  • mt DNA is randomly distributed to daughter cells
  • Replicative segregation
  • Mixed mutant and normal genomes in tissues that explains the differential clinical expression of mitochondrial dysfunction in different tissues
  • Variable prototypes of identical mitochondrial genetic defects
  • A shift in proportion of mutant to normal mt DNA can occur in daughter cells
  • Threshold effect:
    • The proportion of mutant mt DNA to express symptoms:
      • Varies among persons, organ systems and tissues
      • Depends on the balance between energy supply and demand
      • Results in intermittent symptoms
      • Brain retina, heart and muscle have the lowest threshold

Clinical Features of Mitochondrial Disorders

Systemic Signs and Symptoms

• Short stature
• Diabetes mellitus
• Pigmentary retinopathy
• Cardiac conduction defects
• Cardiomyopathy (dilated)
• Cataracts
• Liver disease
• Psychiatric manifestations (depression)
• Hypoparathyroidism
• Exocrine pancreatic dysfunction
• Episodic nausea and vomiting
• Lactic acidosis
• Pancytopenia
• GI pseudo obstruction
• Glomerulopathy
• Fanconi syndrome

Neurologic Manifestations

• Myopathy (limb girdle)
• Exercise intolerance
• Ataxia
• Seizures
• Myoclonus
• Migraine headache
• Dystonia
• Ophthalmoplegia
• Optic atrophy
• VIII nerve deficits (sensorineural hearing loss)
• Stroke in the young
• Posterior leukoencephalopathy
• MRI basal ganglia defects
• Mental retardation
• Optic atrophy
• Peripheral neuropathy
• Dysarthria
• Somnolence
• Choreoathetotic movements
• Cortical blindness
• Salt craving
• Specific patterns of myopathy:
  • Limb girdle
  • Distal
  • FSH
  • Ophthalmoplegia

Laboratory Evaluation

• High resting lactate in serum and CSF
• EMG: myopathic; axonal and demyelinating peripheral nerve deficits
• EKG: conduction block
• MRI:
  • Basal ganglia calcification and signal change
  • Focal stroke like changes
  • Posterior leukoencephalopathy
• Muscle Biopsy:
  • Ragged red fibers (RRF); (Gomori tricome strain) are the muscle morphological marker of these diseases:
    • Large peripheral and intermyofibrillar collections of abnormal mitochondria
    • Intense staining for intramitochondrial enzyme succinic dehydrogenase (SDH)
    • Affected fibers contain increased lipid droplets
    • Some excess peripheral fiber glycogen
    • RRF may fail to stain with cytochrome C oxidase
      • May be associated with by Type I paracrystalline mitochondrial inclusions
  • Electron microscopic abnormalities in RRF negative patients:
    • Increased collections of subsarcolemma mitochondria
    • Abnormal mitochondrial structure; increased, distorted and abnormally arranged cristae
  • Abnormal mitochondria may be seen in:
    • Normal muscle
    • Denervated muscle
    • Acid maltase deficiency
    • Polymyositis
  • Brain neuropathology in mitochondrial disorders:
    • Spongiform degeneration
    • Cavitation
    • Neuronal loss
    • Demyelination

General Principles of Genetic Organization of Mitochondrial Encephalomyopathy

• All mitochondrial clinical syndromes:
  • May have several different underlying genetic defects
  • Severity varies among patients
  • A specific genetic defect may cause different phenotypes
• Clinical manifestations are influenced by:
  • Nuclear genes
  • Tissue threshold effects
  • Heteroplasmia
• Defects of mitochondrial DNA:
  • Point mutations (maternal inheritance):
    • mt DNA that code gene mutations:
      • Leber's hereditary optic neuropathy (LHON)
      • LHON with dystonia
      • Maternally inherited Leigh syndrome
      • Neuropathy, ataxia, retinitis polyneuropathy (NARP)
  • Mitochondrial (t) RNA gene mutations:
    • Mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS)
    • Mitochondrial encephalomyopathy with ragged red fibers (MERRF)
    • Chronic progressive ophthalmoplegia (CPEO)
    • Diabetes mellitus and deafness
    • Maternally inherited cardiomyopathy
    • Maternally inherited deafness
    • Isolated mitochondrial myopathy
    • Acute rhabdomyolysis
  • Mitochondrial ribosomal (rRNA) gene mutations:
    • Maternally inherited deafness with aminoglycoside sensitivity
  • Deletions and duplications (sporadic inheritance):
    • CPEO
    • Kearns–Sayre syndrome
    • Pearson syndrome
    • Diabetes mellitus and deafness
    • Mitochondrial myopathy
• Defects of nuclear DNA (Mendelian inheritance):
  • Defects in nuclear genes that encode mitochondrial proteins:
    • Structural proteins – Leigh's disease or Krebs cycle enzymes
    • tRNA gene mutations that affect multiple proteins
  • Defects of mitochondrial protein transport
  • Defects of nuclear encoded factors:
    • Multiple mt DNA deletions:
      • AD or AR CPEO
      • MNGIE (mitochondrial neurogastrointestinal encephalopathy)
      • SANDO (sensory ataxic neuropathy, dysarthria and ophthalmoplegia)
      • Acute rhabdomyolysis
      • ARCO
      • IBM
      • Peripheral neuropathy and lipomatosis
  • mt DNA depletion:
    • Hepatic dysfunction
    • Myopathy
    • Encephalopathy

Biochemical and Physiological Classification of Mitochondrial Defects

• Defects of mitochondrial substrate transport:
  • Mono carboxylate translocase deficiency
  • Defects of the carnitine acylcarnitine carrier:
    • Primary muscle carnitine deficiency
    • Primary systemic carnitine deficiency
    • Mixed forms of carnitine deficiency
    • Secondary carnitine deficiencies
    • Carnitine palmityl transferase deficiencies (CPT 1 and 2)
    • Combined deficiency of carnitine and CPT
• Defects of substrate utilization:
  • Pyruvate:
    • Pyruvate decarboxylase deficiency
    • Dihydrolipoyl transacetylase deficiency
    • Dihydrolipoyl dehydrogenase deficiency
    • Pyruvate dehydrogenase phosphatase deficiency
    • Pyruvate carboxylase deficiency
    • Carnitine acetyltransferase deficiency
  • Free fatty acids
    • Defects of Beta Oxidation
• Defects of the respiratory chain:
  • Defects of NADH-CoQ reductase complex:
    • With normal carnitine levels
    • With carnitine deficiency
  • Defects of the CoQ-cytochrome reductase complex:
    • CoQ10 deficiency
    • Deficiency of Fe-S proteins
    • Cytochrome b deficiency
    • Combined deficiency of cytochromes
  • Cytochrome aa3 deficiency
  • Deficiency of cytochromes a 3 and b
• Defects of energy conservation and transduction:
  • Loose coupling with hypermetabolism (Luft's disease)
  • Loose coupling without hypermetabolism
  • Mitochondrial ATPase deficiency
  • Deficiency of the adenine nucleotide translocase

Defects of Mitochondrial Substrate Transport

• Mitochondrial outer membrane:
  • Permeable to small molecules and ions
• Mitochondrial inner membrane
  • Acts as barrier to most hydrophilic and ionized metabolites
  • Specific transmembrane translocaters move these molecules into the mitochondrial matrix
  • Translocaters are within the mitochondrial inner membrane
  • Pyruvate, fatty acyl-CoA, ketone bodies:
    • Major mitochondrial substrates for ATP production
    • Require carrier mediated entry

Defects of Pyruvate Transport

• Possible primary pyruvate translocase deficiency in 2 patients:
  • Clinical features:
    • Progressive external ophthalmoplegia
    • Paracrystalline mitochondrial inclusions on muscle biopsy
• Mitochondrial pyruvate and ketone body transport are defective in:
  • Phenylketonuria
  • Maple syrup urine disease

General Features of Fatty Acid Transport

• L-carnitine:
  • Obligate carrier molecule for medium and long chain free fatty acids (FFA)
  • Synthesized in the liver
  • Transported to tissues in the blood
  • Active uptake mechanism into cardiac and skeletal muscle

Defects of the Carnitine Acylcarnitine Carrier System

• Primary defect in muscle:
  • Deficient transport of fatty acyl-CoA derivatives through the inner membrane into the mitochondrial matrix
  • Neutral lipid accumulates within muscle fibers

Mixed Carnitine Deficiency

• Clinical features of primary or systemic carnitine deficiency:
  • Associated with the biochemical parameter of the other
  • Some patients: recurrent hepatic encephalopathy with normal plasma carnitine
  • Other patterns: low plasma carnitine with systemic clinical disease
  • One family cardiomyopathy secondary to endocardial fibroelastosis
• CPT-1 deficiency:
  • Genetics: gene on 11q
  • Starts in infancy
  • Clinical presentation:
    • Encephalopathy
    • Hypotonia
    • Non-ketotic hypoglycemic coma
    • Hyperammonia
    • Hepatic dysfunction
    • Renal tubular acidosis
    • Cardiomyopathy
    • Seizures
    • Induced by fasting
• CPT-II deficiency:
  • Infantile forms:
    • Lethal neonatal from
    • Hypoketotic hypoglycemia
    • Generalized steatosis
    • Multiple malformations
  • Infantile hepatomuscle forms:
    • Hypoketotic hypoglycemia
    • Lethargy seizures
    • Cardiomegaly and hepatomegaly
    • Cardiac arrhythmia
• Carnitine transporter defect:
  • not a mitochondrial disease
  • AR
  • Onset in infancy
  • Clinical presentation:
    • Encephalopathy
    • Lipid storage proximal myopathy
    • Cardiomyopathy
  • Laboratory evaluation: decreased uptake of labeled carnitine into fibroblasts

Defects of Substrate Transport

• Carnitine palmitoyltransferase deficiency (CPT II):
  • AR; onset in late adolescents and young adults; male > female
  • The enzyme that facilitates the entry of long chain fatty acid into the mitochondrial matrix
  • CPT I is attached to the outside of the inner mitochondrial membrane; loads carnitine; palmityl CoA methylated to polymethyl carnitine
    • encoded by gene on 11 q
  • CPT II is attached to the inner surface of the inner mitochondrial membrane; releases carnitine from palmityl carnitine; on 1p32
  • Carnitine acylcarnitine translocase:
    • Exchanges acylcarnitine and carnitine across the inner mitochondrial membrane
  • Clinical manifestations of CPT II:
    • Severity of the disease depends on residual enzyme activity
    • Pain and muscle tenderness with cramps initiated by:
      • Sustained exercise; not necessarily strenuous
      • Excessive ingestion of fat
      • Starvation
      • Cold exposure
      • Lack of sleep
      • Infection
    • Muscle damage with recurrent myoglobinuria
    • Generalized muscle weakness
    • Severe episode may cause respiratory failure
    • Between episodes:
      • No weakness
      • Normal CK between attacks
      • Some children develop a fixed myopathy
      • Myoglobinuria not accomplanied by painful cramps
  • Laboratory evaluation:
    • Delayed production of ketone bodies in blood and urine after a fast
    • Increased CK with myoglobinuria after sustained aerobic exercise
  • Muscle biopsy:
    • Lipid droplets
    • May be normal
    • Enzyme measurement in muscle, fibroblasts or platelets for definitive diagnosis

Defects of Mitochondrial Substrate Utilization and Gluconeogenesis

• Pyruvate carboxylase deficiency:
  • AR
  • Onset in infancy:
    • Metabolic acidosis
    • Lactic academia
    • Developmental delay
    • Hypotonia
    • Death in childhood
  • French phenotype:
    • Greater severity than North American phenotype
    • Hepatomegaly
    • Hyperammonemia, lysinemia, citrullinemia
    • Clinical manifestations otherwise similar to North America phenotype
• Pyruvate dehydrogenase (PDH) complex deficiency
  • Pyruvate:
    • Metabolized in the matrix of the mitochondrion
    • Decarboxylated to acetyl-CoA
    • Carbonized by intramitochondrial enzymes: collectively known as the pyruvate dehydrogenase complex (PDHC)
• Components of the complex:
  • Pyruvate decarboxylase (E1)
  • Dihydrolipoyl transacetylase (E2)
  • Dihydrolipoyl dehydrogenase (E3)
  • Two regulatory enzymes of the complex
    • Pyruvate dehydrogenase kinase
    • Pyruvate dehydrogenase phosphatase
• General clinical manifestations of PDHC deficiency:
  • Fatal congenital lactic acidosis
  • Intermittent ataxias
  • Intermittent movement disorders
  • Clinical manifestations depend on the severity of the deficit and not the particular enzyme that is deficient
• Clinical Features of PDHC:
  • Presentation at birth
  • Males > Females; may be X-linked
  • Progressive encephalopathy:
    • Psychomotor retardation
    • Seizures
    • Generalized hypotonia
    • Metabolic and lactic acidosis
    • Rapid respiration
    • Infantile or neonatal onset
    • Facial dysmorphism
    • Ataxia
  • Increased serum lactate, pyruvate and alanine; spill over into the urine
  • If decreased dihydrolipoyl dehydrogenases (E3)
    • Increased blood levels of branched chain amino acids and a-ketoglutarate

Leigh's Syndrome (Subacute Necrotizing Encephalopathy; SNE)

• Composed of different genetic and biochemical defects
• Genetics: AR; X-linked
• Some phenotype results from different genetic defects
• Pathology:
  • Hemorrhagic lesions of the brainstem, thalamus, basal ganglia and cerebellum
  • Spares the mammillary bodies

Specific Causes of Leigh's Syndrome

• PDH-complex deficiency:
  • E1 Subunit
    • Genetics:
      • Gene point mutation
      • X-chromosome
      • AR
    • Variant:
      • Mutation impairing the affinity of binding of E1 to thiamine pyrophosphate (TPP)
      • Thiamine responsive PDH-complex deficiency
  • E3 deficiency:
    • AR
    • Decreased lipoamide dehydrogenase
    • Causes combination of both PDH and alpha-ketoglutarate dehydrogenase dysfunction (both contain E3 subunit)
• Complex IV deficiency:
  • AR
  • Nuclear encoded subunits
• ATP synthase (complex 5) subunit 6 gene:
  • NARP (mt DNA 8993 or 9176 point mutations)
  • Early onset; rapid progression
• Complex I deficiency

Clinical Features of Leigh's Syndrome

• Earlier the onset the more rapid and severe the illness with death in infancy
• Onset one year (60%) and 2 years (20%); rare after infancy (20%)
• COX deficiency patients develop symptoms after the first year:
  • Diarrhea, vomiting
  • Failure to thrive
  • Slower progression
  • Exacerbation with infections
• Adult onset rare:
  • Ataxia
  • Seizures
  • Polyneuropathy
  • Central hypoventilation
• Usual symptom complex:
  • Hypotonia
  • Seizures
  • Cheyne-Stokes breathing
  • Central hypoventilation
  • Ophthalmoplegia
  • Nystagmus
• Laboratory evaluation:
  • Both lactate and pyruvate elevated at rest
  • MRI:
    • BG lesions
    • Adjacent to III ventricle
    • Necrosis of GP
  • Enzyme and mt DNA analysis are definitive

Differential Diagnosis of Leigh's Syndrome

Alpers Disease (Progressive Infantile Poliodystrophy)

• Sporadic cases putative causes:
  • Anoxia
  • Prion or slow virus disease
• Clinical manifestations:
  • Some familial cases now thought to be mitochondrial myopathy:
    • Pyruvate carboxylase deficiency
    • Complex I and IV deficiency
  • Onset in early childhood
  • Seizures (may present with status epilepticus)
  • Psychomotor regression
  • Blindness
  • Progressive degeneration of cerebral gray matter
  • Carbohydrate load increases clinical symptomatology and lactate levels

Menkes Syndrome (Trichopoliodystrophy)

• Defect in intestinal copper transport
• Secondary deficiency of copper-dependent enzymes; particularly COX
• Clinical features:
  • Onset by three months
  • Lethargy
  • Myoclonic seizures
  • Developmental regression
  • Vegetative state by 18 months
  • Sparse poorly pigmental wiry hair
  • X-ray evidence of osteogenesis imperfecta
  • Low copper plasma levels

Multiple Carboxylase and Biotinidase Deficiencies

• Genetics: AR
• Clinical features:
  • Present in infancy
  • Immunodeficient state
  • Dermatopathy
  • Alopecia
  • Breathing irregularities
  • Lactic and metabolic acidosis
• Laboratory evaluation: definite diagnosis made by enzyme analysis in fibroblasts

Beta-Oxidation Defects

• Genetics: AR
• Clinical features:
  • Onset from neonatal life to early childhood
  • Symptoms and signs depend on size of fatty acid involved

Acyl CoA Dehydrogenases Deficiencies

• Medium chain fatty acid:
  • Sudden infant death syndrome
  • Reye's type encephalopathy
  • Hypoglycemia
  • Hyperuricemia
• Short chain fatty acid:
  • Recurrent vomiting
  • Failure to thrive
• Long chain fatty acid:
  • encephalopathy
  • cardiomyopathy
  • hypoglycemia
• Multiple defects:
  • Metabolic acidosis
  • Hypoglycemia
  • Hyperammonia
  • Encephalopathy
  • Facial dysmorphism
  • Polycystic kidneys
• Late onset variant:
  • Metabolic acidosis
  • Hypoglycemia
  • Vomiting
  • Polyneuropathy

Defects of the Carnitine Acylcarnitine Carrier System

• Primary defect in muscle:
  • Deficient transport of fatty acyl-CoA derivatives through the inner membrane into the mitochondrial matrix
  • Neutral lipid accumulates within muscle fibers
• Krebs Cycle Defects:
  • Biochemical reactions take place in the semifluid state of the mitochondrial matrix
  • Reactions lead to oxidative decarboxylation of acetyl-CoA utilizing:
    • Pyruvate
    • Fatty acids
    • Amino acids
  • All TCA cycle enzymes are nuclearly encoded
• Deficiencies:
  • a-ketoglutarate dehydrogenase (a-KGDH): chromosome 7q and 14q
  • a-KGDH plus PDH complex:
    • AR; chromosome 7q
    • deficiency of E3 subunit of the PDH complex (respiratory chain)
    • recurrent myoglobinuria
  • Fumarase:
    • AR
    • chromosome 1q
  • SDH (succinic dehydrogenase):
    • Complex II of the respiratory chain
    • AR; chromosome 5q
  • SDH plus aconitase deficiency:
    • Mutation in common iron sulfur subunit
    • Chromosome 1q
• General clinical characteristics:
  • Encephalopathy
  • Myopathy
  • Cardiomyopathy (some patients)

Defects of Oxidative-Phosphorylation Coupling

Luft's Disease

• General features:
  • Sustained and high respiratory rate
  • Recycling of Ca⁺⁺ between the mitochondrial matrix and the cytosol
  • Energy production dissipated as heat rather than production of ATP
• Clinical presentation:
  • Onset in adolescence
  • Fever
  • Heat intolerance
  • Profuse sweating
  • Exercise intolerance
  • Hypermetabolic state
  • Polyphagia
  • Polydysphasia
  • Tachycardia
  • Death in middle age
  • Generalized weakness
• Laboratory evaluation:
  • Muscle biopsy:
    • Peripheral aggregations of abnormal mitochondria:
      • Over abundant tightly packed disorganized cristae of the mitochondrion
      • Small electron dense osmiophilic bodies in the mitochondrion
      • Occasional para crystalline inclusions
  • Basal metabolic rate: dramatically increased
• Loose oxidative phosphorylation coupling without hypermetabolism:
  • Loss of normal state 3/state 4 transition with a normal PO ratio
  • Possible AD or mitochondrial pattern of inheritance:
    • Mitochondrial myopathy
    • No features of a hypermetabolic state
    • Non-progressive or slowly progressive weakness in infancy, childhood or early adult life
    • Associated features in some families:
      • Diabetes mellitus
      • Cerebellar ataxia
      • Lactic acidemia

Defects of the Mitochondrial Respiratory Chain

• Complex I (NADH-CoQ reductase) deficiency:
  • Genetic: mutation in the gene that encodes subunit 4 of complex I
  • Fatal infantile multisystem disorder
  • Congenital lactic acidosis
  • Mental retardation
  • hypotonia
  • death in infancy from cardiorespiratory failure
• Myopathy: Carnitine deficient patient:
  • Onset in childhood or adult life
  • Clinical features:
    • Exercise intolerance
    • Muscle pain
    • Progressive weakness
    • Female affected relative
  • EMG:
    • Normal
  • Laboratory evaluation:
    • Low plasma and muscle carnitine
    • Muscle biopsy:
      • Lipid storage myopathy
      • Ragged red fibers (COX-positive)

Patients with Normal Carnitine Levels

• General features:
  • Age at onset: 16–46 years of age
  • Females have affected relatives
• Clinical characteristics:
  • Exercise intolerance
  • Muscle pain
  • Weakness and fatigue
  • Remittent paralysis (rare) associated with lactic acidosis
  • Heart failure (rare)
  • Dementia, dystonia, blindness (one patient)
• Laboratory Features:
  • Metabolic acidosis
  • Hypoglycemia
  • Lactic academia
  • Increased serum CK level
• EMG:
  • Normal

Complex II Succinic Reductase Deficiency

• Nuclear encoded enzyme possible involvement of the Fe-S subunit
• AR
• May present in adult life
• Clinical features:
  • May present in adulthood
  • Optic atrophy
  • Growth retardation
  • Spasticity
  • Pulmonary edema
  • KSS like presentation

Coenzyme Q10 (CoQ) Deficiency

• Onset may present in midlife:
  • Encoded by nuclear genome
  • Transfers electron from complex I and II to complex III
  • Final acceptor of electrons from B-oxidation
• Clinical features:
  • Mental retardation
  • Seizures
  • Ataxia
  • Progressive proximal weakness
  • Recurrent myoglobinuria (exercised induced)
  • Some bilateral ptosis in childhood
  • Exercise intolerance

Complex III Deficiency

• Three major presentations:
  • Genetics: mutations of the cytochrome b gene
  • Encephalopathy
  • Myopathy
  • Cardiomyopathy
• Encephalopathy:
  • Infant presentation (fatal)
  • Childhood or adult life:
    • Pigmentary retinopathy
    • Sensory neuropathy
• Myopathy:
  • Exercise intolerance
  • Fixed proximal weakness
  • May respond to vit K3 (menadione)
• Cardiomyopathy:
  • Histiocytoid cardiomyopathy of infancy

Complex IV (Cytochrome C Oxidase Deficiency)

• Myopathic phenotype:
  • Fatal infantile from:
    • Lactic acidosis
    • Respiratory distress
    • Renal failure
    • Death in first year
  • Benign form :
    • Patients improve and are normal by age three
    • Return of COX to muscle
    • Subunit VII, z, b and II involved
  • Adolescent:
    • Exercise induced myoglobinuria
    • Normal exam between attacks
    • Mild myopathy
    • No multisystem involvement
    • Premature fatigue and myalgia

Complex V (ATP Synthetase) Deficiency

Mutation in Subunit 6 (mt DNA-8993)

• Genetics: mt DNA mutation-8993
• Onset: childhood:
  • Mild progressive muscle weakness
  • Fatigue on exertion
  • Growth retardation
  • Sensorineural hearing loss
  • Recurrent vomiting
  • Pigmentary retinopathy
  • Dementia
  • Peripheral sensory neuropathy
  • Cerebellar ataxia
  • Multisystem disorder
• Laboratory Evaluation
  • Muscle biopsy:
    • Para crystalline deposits inner mitochondrial membrane
    • Lipid myopathy (secondary carnitine deficiency)
  • MRI:
    • BG calcification

Steps in Mitochondrial Importation

• Transport of nuclearly encoded proteins from the cytoplasm into mitochondria
  • Targeted to different intramitochondrial compartments
• Defects of translocation steps:
  • Address signals: amino terminal leader peptides
  • Cytoplasmic heat shock proteins: peptide transport protection
  • Leader peptide-receptor interaction at the mitochondrial membrane
  • Energy dependent translocation through the mitochondrial membrane
  • Intramitochondrial cleavage of leader peptides by peptidases
  • Intramitochondrial protein assembly

Defects of Mitochondrial Importation

• Heat shock protein 60:
  • Deficits of multiple mitochondrial enzymes
  • Infantile encephalopathy
  • Lactic acidosis
• Methylmalonic academia:
  • Mutation in the leader peptide of methylmalonic Co-A mutase
  • Inability to enter the mitochondria
• Frataxin (Friedreich's ataxia):
  • Trinucleotide expansion (CGG intron9) chromosome 6
  • Loss of regulation of iron transport into the mitochondria
  • Dysfunction of all enzymes that contain iron sulfur subunits:
    • Aconitase
    • Complex I, II, III
  • Paraplegia:
    • Chromosome 16q
    • AR hereditary spastic paraplegia
    • Regulator of metalloproteinase a chaperone of respiratory chain assembly
  • Putative defect of translocation
    • Reye's syndrome associated with multiple mitochondrial enzyme dysfunction

Defects of Ingenomic Interaction

• Mitochondrial genome dependent on:
  • Products of nuclear encoded genes that are important for:
    • mtDNA replication
    • Transcription
    • Translation
  • Transmitted by Mendelian inheritance
• Multiple mtDNA deletions noted in:
  • AD chronic progressive ophthalmoplegia (ADCPEO)
  • AR CPEO
  • MENGIE syndrome
  • ARCO:
    • AR
    • Cardiomyopathy
    • Ophthalmoplegia
  • Recurrent myoglobinuria
  • Peripheral neuropathy and lipomatosis
  • Inclusion body myositis
• Depletion of mtDNA:
  • AR inheritance
    • Severity relates to degree of depletion
    • Defect in nuclear genes required for mt DNA replication
  • Fatal infantile hepatopathy
    • Intractable hepatic failure during the first year of life
  • Congenital myopathy:
    • Similar to COX deficiency myopathy
    • Some patients have concomitant renal dysfunction
  • Infantile or childhood myopathy:
    • Onset after first year
    • Progressive proximal weakness
    • Muscle biopsy:
      • Ragged red fibers
      • Depleted mt DNA
      • No mt DNA encoded proteins
  • AZT treatment in AIDS treatment:
    • AZT incorporated into mt DNA by polymerase gamma
    • Inhibits mt DNA replication
    • Myopathy reversible after discontinuation of AZT therapy

Myopathic Syndromes with mtDNA Defects

• Kernes-Sayre Syndrome (KSS):
  • Sporadic large scale mitochondrial rearrangements
  • Single mtDNA deletions
  • Defects of several respiratory chain complexes: COX dysfunction most detrimental
  • Onset by age 20 years
  • Male and females affected equally
  • Clinical characteristics:
    • Chronic progressive external ophthalmoplegia
    • Ptosis; hearing loss
    • Retinitis pigmentosa
    • Cerebellar ataxia
    • Some patients with mental retardation
    • Rare seizure
    • Rare stroke
    • Cardiac conduction defects common
    • May present with syncope
    • Cerebral spinal fluid greater than 100 mg/dl
    • Frequent sensorineural hearing loss
    • Associated: DM, hypoparathyroidism, growth hormone deficit, irregular menses
    • Fanconi syndrome
    • Barter cilia syndrome
    • Lowe-like syndrome
    • Chorea
    • Anhydrosis
  • Parson's syndrome:
    • Same mtDNA defect
    • Clinical features:
      • Sideroblastic anemia
      • Pancreatic insufficiency
  • Imaging:
    • BG calcification
    • Pontine and cerebral atrophy
    • BG decencies

Chronic Progressive External Ophthalmoplegia (CPEO)

• AD-CPEO:
  • Sporadic multiple mtDNA deletions:
    • One deletion affects the heavy strand promoter – HSP region
    • Chromosome 3p
  • Clinical features:
    • Progressive external ophthalmoplegia
    • Severe ptosis (symmetrical)
    • No diplopia
    • Proximal myopathy
    • Cataracts
    • Tremor
    • Ataxia
    • Peripheral neuropathy
    • Onset from childhood to adult life
    • Weakness of the face, neck, trunk, respiratory muscles
• AR-CPEO:
  • AR; multiple mtDNA deletions; smaller proportion of DNA deleted 10% compared to AD-CPEO (30%) mtDNA deletions
  • Both sporadic and familial AD/AR patients multiple tRNA genes are affected
  • Regulator metalloproteinase (chaperone) at respiratory chain assembly are deficient
• Putative defect of translocation:
  • Reye's syndrome associated with multiple mitochondrial enzyme dysfunction

Differential Diagnosis of CPEO

• Oculopharyngeal muscular dystrophy (OPMD) with poly alanine repeats
• KSS (Kearne–Sayre Syndrome):
  • Heart block with syncope
  • Retinopathy
  • Ophthalmoplegia
• MNGIE (mitochondrial neurogastrointestinal encephalopathy)
  • GI dysmotility
• Myasthenia:
  • Fluctuation of cranial nerve signs
  • Asymmetrical muscle weakness
  • Diplopia
  • Bilateral ptosis
• Progressive supranuclear palsy:
  • Dramatic vertical gaze defects
  • Falls
  • Parkinsonian features
  • Cognitive decline
  • Head held in extension
• SCA ataxia (Type III):
  • AD
  • Cerebellar degeneration most prominent feature
  • Amyotrophy of the extremities

MELAS (Mitochondrial Encephalopathy, Lactic Acidosis and Stroke)

• Genetics:
  • 80–90% of patients have a mtDNA 3243 point mutation in:
    • tRNA Leu gene
  • Same mtDNA 3243 gene defect causes:
    • PEO
    • maternally inherited DM and deafness
  • Other mutations within tRNA Leu gene that cause MELAS are:
    • 3251; 3271; 3291; 5824; 1642 nucleotides
    • few patients have a 9957 mutation:
      • gene for subunit 3 of COX
  • Clinical features:
    • Normal early development
    • Onset prior to age 40
    • Stroke-like episodes; not in a vascular territory; maybe severe
    • Migraine headaches; preceded by nausea and vomiting
    • Encephalopathy:
      • Seizures
      • Progressive dementia
      • Hemiparesis
      • Hemianopia
    • Myopathy:
      • Proximal greater than distal
      • Exercise intolerance
    • Short stature
    • Less than 50% of patients:
      • Cardiomyopathy
      • Myoclonus
      • Ataxia
    • Oligosymptomatic maternal relatives are common
    • Lesions may affect the temporal lobe
    • Unusual to have full syndrome in more than one member of the pedigree
    • Optic atrophy
    • Congestive heart failure
    • Pigmentary retinopathy
    • Wolff–Parkinson–White Syndrome
    • PEO
    • DM
  • Pathology:
    • Spongiform encephalopathy:
      • Cortex primarily involved
      • Focal lesions: occipital lobes cerebellum, pons, inferior olives
      • Basal ganglia calcification
    • Muscle biopsy:
      • Ragged red fibers
    • Lactic acidosis

Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

• General features:
  • 80% of cases are familial:
    • Severity of presentation variable among family members
    • Oligosymptomatic maternal relatives
    • Many relatives within the pedigree have full syndrome
• Genetics:
  • 90% of patients have 8344 mtDNA mutation
  • 5–10% have the 8356 mt DNA mutation
  • tRNA Lys gene
  • 8363 mutation in Japanese patients
  • Mutation of tRNA genes:
    • Decreased protein synthesis
    • Multiple enzyme deficiencies
    • COX deficiency most profound
• Clinical features:
  • Onset in childhood; first manifestations may be in adults
  • Hearing loss
  • Optic atrophy
  • Sensory neuropathy
  • Short stature
  • Myoclonic epilepsy
  • Proximal myopathy
  • Encephalopathy
  • Ataxia
    • Degeneration of posterior columns and cerebellum
  • Exercise intolerance
  • Lactic acidosis
  • Large lipomas in patients and relatives
  • Pes Cavus
  • Impaired sensation
• Pathology:
  • Neuronal loss in the dentate, inferior olive
  • Diffuse gliosis in cerebellar white matter and brain

Differential Diagnosis of MERRF

• Unverricht-Lundborg disease (Baltic myoclonus):
  • AR-chromosome 21q
• Lafora Disease:
  • AR chromosome 6q
  • PAS +/- inclusion bodies
• Juvenile ceroid lipofuscinosis (Batten's disease)
• Sialidosis
• Gaucher Type III
  • Glucosylceramide lipidosis
• Ramsey Hunt syndrome

Neuropathy, Ataxia, Retinitis Pigmentosa (NARP)

• Genetics:
  • Maternal transmission
  • mtDNA point mutation 8993 in the ATP synthetase-subunit 6 gene
    • Same defect noted in some patients with Leigh's disease
• Clinical features:
  • Ataxia
  • Peripheral neuropath (sensory)
  • Retinitis pigmentosa
  • Dementia
  • Seizures
  • Spasticity
  • Myopathy (proximal)
  • Onset in young adults
  • Symptoms may be subtle in young adults

Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)

• Genetics:
  • Autosomal recessive
  • Chromosome 22q 13.32-qter
  • Thymidine phosphorylase gene
    • Loss of function mutation
• Clinical features:
  • PEO
  • Gastrointestinal dysmotility with pseudoobstruction
  • Peripheral neuropathy:
    • Pes cavus
    • axonal and demyelinating neuropathy
  • Cachexia:
    • Particularly during the later stage of the disease
    • Generally thin throughout the illness
  • Diffuse leukoencephalopathy
• Laboratory evaluation:
  • Lactic acidosis at rest
  • EMG:
    • Axonal and demyelinating features on EMG
• Muscle biopsy:
  • COX negative RRFs
  • Neurogenic atrophy
  • Abnormal mitochondria in Schwann cells
  • Multiple deletions of muscle mtDNA

Infantile Myopathy with Cytochrome C Oxidase Deficiency

Fatal Form

• General features:
  • Genetics:
    • Probably AR
    • Absent mitochondrial subunits of nDNA-encoded subunit VII ab:
      • Subunit II is present
    • COX deficiency is in skeletal muscle; but spares the heart, brain and liver
• Clinical presentation:
  • Generalized muscle weakness during infancy
  • Lactic acidosis
  • Death by respiratory insufficiency at one year of age
  • Some patients have de Toni-Fanconi Debre Syndrome

Reversible Infantile Myopathy

• General features:
  • Genetics:
    • AR absent
    • Subunit VI of nDNA encoded subunit VII ab
• Clinical presentation:
  • Severe myopathy with lactic acidosis after birth
    • May dramatically improve by age 2–3
  • Lactic acidosis and muscle histology resolves

Progressive External Ophthalmoplegia

• Genetics: AD
• Clinical features:
  • Age at onset is 24–30; death in middle age
  • PEO
  • Facial and limb weakness
  • Cataracts
  • Exercise intolerance
  • Dysphagic
  • Dysphonia
  • Febrile illness may cause respiratory failure
  • Depression and psychomotor retardation in some patients
• Laboratory evaluation:
  • Serum
    • Resting lactic acidosis
  • Muscle biopsy:
    • RRFs
    • Multiple mitochondrial deletions in skeletal muscle; not in lymphocytes or fibre blasts

Mitochondrial DNA Depletion Syndrome

• Heterogenous clinical features between different variants and within families
• Genetics:
  • Some AR
  • Mechanism not known for failure of mitochondrial replication
• Clinical variants:
  • Severe congenital myopathy
  • Intractable liver failure with death in the first year
  • Infantile myopathy:
    • Associated seizures (multifactorial)
    • Associated peripheral neuropathy (some patients)

Autosomal Recessive Cardiomyopathy and Ophthalmoplegia

• General features:
• Genetics:
  • mtDNA deletions
  • AR inheritance; male equals female in incidence
• Clinical presentation:
  • Childhood onset
  • Proximal myopathy
  • PEO
  • Hypertrophic cardiomyopathy

Azidothymidine (AZT)

• Nucleoside lacks 3-hydroxyl group:
  • Incorporated into replicating HIV virus DNA
    • Premature termination of the elongating DNA chain
    • Incorporating enzyme is a polymerase gamma
• Pathology (muscle biopsy):
  • RRF
  • Decreased amounts of mtDNA in muscle
• Clinical features:
  • Subacute onset
  • Proximal myopathy

Differential Diagnosis of Mitochondrial Myopathy

Any patient that presents with easy fatigability, bilateral symmetrical ptosis or ophthalmoplegia, diabetes, short stature and sensorineural, hearing loss and migraine should alert the clinician to the possibility that he is dealing with a mitochondrial myopathy.

There are few problems that demonstrate bilateral ptosis and ophthalmoplegia in concert with heart block. Syncope may be the presenting feature of Kearns–Sayre's syndrome. Congenital myasthenic syndromes and myasthenia gravis have no cardiac symptomatology. Interstitial myocarditis may be seen in adult patients with myasthenia and thymoma. Niemann Pick Type C has failure of upgaze and a supranuclear palsy, but AR inheritance, ptosis and heart conduction defects are not seen.

Oculopharyngeal muscular dystrophy may demonstrate the same pattern of weakness as KSS, but begins in the fourth to sixth decade, whereas, KSS starts prior to age 20. No cardiac conduction defects are noted with OPMD. AD-PEO with multiple mtDNA deletions has prominent ptosis and prominent face, neck flexor and proximal weakness, but no other manifestations of KSS. AR-PEO has ocular manifestations, but an associated hypertrophic cardiomyopathy cataracts, and early death. MNGIE's most dominant feature is gastrointestinal dysmotility and peripheral neuropathy, whereas, ARCO is dominated by a severe cardiomyopathy rather than conduction defects.

Mitochondrial point mutations such as the A3243G MELAS mutation is the most common cause of maternally inherited PEO.

The sentinel features of MERRF are the myoclonic seizures, dementia and lipomatosis. Hypoparathyroidism may be seen as well with KSS. Dementia is prominent in MELAS, MERFF, and KSS. Ptosis and PEO are most prominent in PEO, MNGIE, and ARCO. Occasionally, it is noted in MELAS. The stroke-like episodes and posterior leukoencephalopathy and migraine differentiate this entity. Pigmentary retinopathy is seen in KSS, MELAS and MERFF. Optic atrophy may be noted in MERFF. Peripheral neuropathy is seen in NARP and MNGIE, but the pseudoobstruction dominates the latter illness.