Mitochondrial Myopathies

(Oxidative Phosphorylation Diseases)

General Overview
● Definition:
● Complex systemic conditions affecting multiple organ systems.
● Impair the ability of mitochondria to generate ATP.
● Genetics:
● Varied and complex.
● Causative mutations affect mitochondrial ATP production.
● Can involve nuclear mitochondrial genes (Mendelian inheritance) or mitochondrial genome
(maternally inherited).
Clinical Manifestations
● Skeletal Muscle Involvement:
● Manifestations: Weakness, ↑ CK, rhabdomyolysis.
● Variable anatomic pattern of muscle weakness.
● Extraocular eye muscle involvement is common, seen in chronic progressive external
ophthalmoplegia.
Genetics and Inheritance
● Mitochondrial Proteins and tRNAs:
● Encoded by nuclear genome or mitochondrial genome (mtDNA).
● Mutations in nuclear mitochondrial genes follow Mendelian inheritance.
● mtDNA mutations are maternally inherited.
● Disease manifestation linked to the threshold of mutated mtDNA copies in at-risk cells.
Morphological Changes
● Skeletal Muscle Pathology:
● Abnormal aggregates of mitochondria.
● Preferentially seen in the subsarcolemmal area.
● Result in "ragged red fibers" appearance.
● Electron microscopy reveals morphologically abnormal mitochondria.
● Enzymatic Assays and Genetic Analyses:
● Some mitochondrial diseases lack morphologic changes.
● Diagnosis through enzymatic assays or genetic analyses.
Clinical Features and Genotype/Phenotype Relationships
● Genotype/Phenotype Relationships:
● Not straightforward due to the complexity of mitochondrial genetics.
● Single point mutations or deletions in mtDNA may result in diverse phenotypes.
● Examples include chronic progressive external ophthalmoplegia CPEO, Kearns-Sayre
syndrome (Pigmentary retinopathy), myoclonic epilepsy with ragged red fibers, Leber
hereditary optic neuropathy (Sudden vision loss, typically affecting young males), and Leigh
syndrome (Progressive neurological deterioration, developmental delay, motor symptoms, and
other systemic manifestations).
● Heterogeneity:
● Many mitochondrial disorders are genetically heterogeneous.
● Mutations in various genes with essential roles in mitochondrial metabolism can cause
conditions like Leigh syndrome.
Diagnosis and Treatment
● Diagnosis:
● Based on history, physical exam, ↑ CK, genetic studies confirming mitochondrial mutations.
● Treatment:
● Challenging; primarily supportive care.
● Ongoing research focuses on restoring mitochondrial function.
Spinal Muscular Atrophy (SMA) and Infantile Hypotonia
Spinal Muscular Atrophy (SMA)
● Nature:
● Neuropathic disorder.
● Loss of motor neurons leading to muscle weakness and atrophy.
 ● Incidence:
● Autosomal recessive.
● Incidence: 1 in 6,000 births.
● Genetics:
● Caused by loss-of-function mutations in SMN1 (survival of motor neuron-1) gene.
● Function of the SMN1 gene is uncertain, potentially involved in RNA splicing.
● Pathological Features:
● Denervation of skeletal muscle.
● Characteristic morphologic changes:
● Large zones of severely atrophic myofibers.
● Scattered normal-sized or hypertrophied myofibers.
● Normal or hypertrophied fibers retain innervation from remaining motor neurons.
Differential Diagnosis for Infantile Hypotonia
​ Primary Diseases of Skeletal Muscle:
● Congenital myasthenic syndrome.
● Congenital myotonia.
● Congenital myopathies.
● Congenital muscular dystrophies.
​ Abnormalities of the Brain:
● Encephalopathy.
​ Neuronopathies:
● Spinal Muscular Atrophy (SMA) - Prototypic example in this category.
Characteristic Features of Infantile Hypotonia
● Presentation:
● Generalized hypotonia ("floppy infant").
● Diagnostic Challenges:
● Requires thorough evaluation of neurologic and neuromuscular symptoms.
● Morphologic Changes in SMA:
● Denervation-related muscle changes.
● Large zones of severely atrophic myofibers.
● Normal or hypertrophied fibers with retained innervation.
Clinical Implications and Management
● Clinical Presentation:
● Motor neuron loss leading to muscle weakness.
● Diagnosis:
● Autosomal recessive inheritance, genetic testing for SMN1 mutations.
● Management:
● Supportive care to address symptoms.
● Ongoing research for potential targeted therapies.
Ion Channel Myopathies (Channelopathies) Overview
Definition:
● Group of Diseases:
● Inherited diseases caused by mutations affecting ion channel protein function.
● Inheritance Pattern:
● Most channelopathies are autosomal dominant.
● Variable penetrance observed.
Clinical Manifestations:
● Varied Symptoms:
● Epilepsy.
● Migraine.
● Movement disorders with cerebellar dysfunction.
● Peripheral nerve disease.

● excitability⚡⚡
● Muscle disease.

● ↓ or ↑ .
Changes:

● Result in hypotonia or hypertonia.

Sub-Classification of Hypotonia Disorders:
● Hyperkalemic Periodic Paralysis:
● Elevated serum K+ levels.
● Hypokalemic Periodic Paralysis:
● Depressed serum K+ levels.
● Normokalemic Periodic Paralysis:
● Normal serum K+ levels.

Types and Mutated Gene Products

Gene/Product Associated Disorder Clinical Features

K+ channel affected, Andersen-Tawil Periodic paralysis, heart arrhythmias,

KCNJ2
syndrome skeletal abnormalities

Mutations affecting this Na+ channel,

SCN4A (myotonia to periodic paralysis)
Autosomal disorders

muscle Ca++ channel defect, Hypokalemic Most common cause of hypokalemic

CACNA1S
paralysis paralysis

CLC1 Cl- channel defect, Myotonia congenita CLC1 expression ↓ in myotonic dystrophy

ryanodine receptor defect, which regulates Hypermetabolic state triggered by

Ca++ release from the sarcoplasmic anesthetics
RYR1
reticulum.Congenital myopathy (central core tachycardia, tachypnea, muscle spasms,
disease), Malignant hyperthermia and later hyperpyrexia

Pathophysiology
●

●
⚡
Effect on Muscle Function: Mutations impact ion channels (K+, Na+, Ca++, Cl-), altering muscle
excitability and contractility.
RYR1 Mutations: Disrupt ryanodine receptor function, regulating Ca++ release from the
sarcoplasmic reticulum.

Clinical Implications and Management

● Diagnosis: Genetic testing to identify specific mutations.
● Treatment: Symptomatic management based on specific manifestations.
● Anesthetic Considerations (RYR1 Mutations): ↑ efflux of Ca++, leading to tetany and excessive heat
production; triggered by halogenated inhalational agents and succinylcholine.

Mitochondrial Spinal Muscular

Aspect Myopathies Atrophy (SMA) Ion Channel Myopathies

Complex systemic
Neuropathic disorder.
conditions affecting Group of inherited
Loss of motor
multiple organ systems. diseases caused by
Definition neurons leading to
Impair the ability of mutations affecting ion
muscle weakness
mitochondria to generate channel protein function.
and atrophy.
ATP.

Varied and complex. Autosomal recessive

Causative mutations disorder. Incidence: 1 Most are autosomal
Genetics affect mitochondrial ATP in 6,000 births. dominant disorders with
production. Involves Caused by variable penetrance.
nuclear mitochondrial loss-of-function
 genes or mitochondrial mutations in SMN1
genome (maternally gene.
inherited).

Varied symptoms,
Denervation of
including epilepsy,
Skeletal muscle skeletal muscle.
migraine, movement
involvement with Characteristic
disorders, peripheral nerve
Clinical weakness, ↑ CK, and morphologic
disease, and muscle
Manifestations rhabdomyolysis. changes, including
Extraocular eye muscle
involvement is common.
large zones of
severely atrophic
⚡
disease. Can cause either
↓ or ↑ excitability ,
resulting in hypotonia or
myofibers.
hypertonia.

Abnormal aggregates of
Morphological
mitochondria. "Ragged - -
Changes
red fibers" appearance.

Diagnosis involves genetic

Diagnosis through testing. Treatment focuses
Diagnosis through history,
genetic testing. on symptomatic
physical exam, ↑ CK, and
Diagnosis and Supportive care for management based on
genetic studies.
Treatment management. specific manifestations.
Challenging treatment,
Ongoing research for Close monitoring during
primarily supportive care.
potential therapies. anesthesia for individuals
with RYR1 mutations.