Transcript Leigh Syndrome

Leigh Syndrome
Intern 莊育權
VS 俞芹英
Introduction
Denis Leigh, in 1951,first described at
autopsy
 Also known as subacute necrotizing
encephalomyelopathy
 Definition: genetically heterogeneous
mitochondrial disorder characterized by
progressive neurodegeneration.
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Pathophysiology
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Maternal inheritance, autosomal recessive, and
X-linked of mutated proteins involved in
mitochondrial energy production
Deficiency in oxidative phosphorylation
Brain & striated muscle highly dependent on
oxidative phosphorylation => most severely
affected
Induce demyelination, gliosis, necrosis,
spongiosis, capillary proliferation
Pathophysiology
Exact mechanistic relationship between
mitochondrial dysfunction and
neurodegeneration unknown
 Early onset, progressive neurodegenerous
disease which involve bilateral symmetric
area of brain stem, thalamus, basal
ganglia, cerebellum, spinal cord
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Epidemiology
Mitochondrial disorder: 1:8,500
 Leigh syndrome in child< 6 y/o: 1:32,000
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Most common mitochondrial disease in this
age group
Incidence increased in some population
isolates
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Saguenay-Lac-Saint-Jean (Quebec): 1:2,063
Clinical Manifestation
No gender predilection
 No ethnic predilection
 Natural history: progressive
neurodegeneration leading to respiratory
failure and death in childhood
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Clinical Manifestation
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Hypotonia
Episodic
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Vomiting
Ataxia
Hyperventilation
Encephalopathy: Loss verbal milestones
Motor: Spasticity; Abnormal breathing rhythm
Brainstem & Basal ganglia signs
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Hearing loss
Cerebellar: Ataxia; Nystagmus
Dystonia
Clinical Manifestation
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Ophthalmologic: Visual loss; Ophthalmoparesis
Peripheral neuropathy
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Clinical signs may become manifest with
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Often subclinical: Prevalence by nerve conduction
testing: 45%
Pathology: Reduced Myelinated & Unmyelinated
axons; ? Demyelination
Stress: Intercurrent infection
Carbohydrate intolerance
Course
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Progression: Motor & Intellectual regression
Death often within 2 years of onset
Clinical Manifestation
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Developmental Delay, 100%
Lactate raised, 91%
Hypotonia, 86%
CT/MRI typical for Leigh, 83%
Respiratory disturbance, 71%
Reflexes increased, 66%
Weakness, 57%
Spasticity, 54%
Bulbar problems, 49%
Failure to thrive, 49%
Nystagmus, 46%
Poor feeding, 46%
Seizures, 40%
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Ataxia, 37%
Ophthalmoplegia/squint, 34%
Optic atrophy, 34%
Unexplained vomiting, 34%
Involuntary movements, 29%
Dystonia, 20%
Reflexes decreased, 17%
Ptosis, 17%
CT/MRI normal, 12%
Cranial nerve palsies, 9%
Peripheral neuropathy, 6%
Cardiac problems, 6%
Lactate normal, 3%
Clinical Manifestation
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Different presentation if onset in different
age: (<12months vs. >18months)
Psychomotor retardation (64% vs. 25%)
 Vomiting (60% vs. 12%)
 Weight loss (48% vs. 0%)
 Weakness (48% vs. 12%)
 Movement disorders (2% vs. 38%)
 Coma (0% vs. 12%)
 Nystagmus and eye signs (0% vs. 12%)
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Lab Finding
Lactate: High in CSF > blood
 CNS pathology
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Focal, bilaterally symmetric spongiform
lesions
 Location: Especially in thalamus and brain
stem
 MRI: Symmetrical hyperintense lesions on T2
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Imaging Finding
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General features
Best diagnostic clue: bilateral, symmetric
↑T2/FLAIR putaminal and periaqueductal gray
matter
 Common location:
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 Basal
ganglia
 Brain stem: periaqueductal gray matter, substantia
nigra, subthalamic nuclei, pons, medulla
 Thalami, dentate nuclei
Imaging Finding
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CT findings:
Non-contrast: hypodense; occasionally
normal
 Contrast enhanced: enhancement uncommon
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Imaging Finding
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MR findings
T1WI: hypointense
 T2WI: hyperintense
 FLAIR: hyperintense
 DWI: restricted diffusion in acute disease
 T1 C+: enhancement uncommon
 MRS: ↑choline, ↓NAA, (+)lactate
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Differential Diagnosis
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Profound perinatal asphyxia
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Mitochondrial encephalopathy, lactic acidosis,
stroke-like episodes
Glutaric aciduria type 1
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Hyperintense T1 & T2WI image in dorsolateral
putamina, lateral thalami, dorsal brain stem
Hyperintense T2/FLAIR corpora striata, globi pallidi
Wilson disease
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Hyperintense T2/FLAIR putamina, globi pallidi,
midbrain, thalami
Hyperintense T1 of globi pallidi secondary to hepatic
failure
Treatment
No curative treatment
 Aimed at maximizing the oxidative or
bioenergetic ability of the patient's
mitochondria
 Variable improvement with quinone
derivatives, vitamins, dichloroacetate,
Coenzyme Q, Ketogenic diet
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Prognosis
DISMAL!!
 50% would die at 3 y/o
 Less than 20% could live until teenage
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Late onset had slower progression