1. Leigh Syndrome
Intern 莊育權
VS 俞芹英

2. Introduction Denis Leigh, in 1951,first described at autopsy
Also known as subacute necrotizing encephalomyelopathy
Definition: genetically heterogeneous mitochondrial disorder characterized by progressive neurodegeneration.

3. Pathophysiology
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

4. 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

5. Epidemiology Mitochondrial disorder: 1:8,500
Leigh syndrome in child< 6 y/o: 1:32,000
Most common mitochondrial disease in this age group
Incidence increased in some population isolates
Saguenay-Lac-Saint-Jean (Quebec): 1:2,063

6. Clinical Manifestation
No gender predilection
No ethnic predilection
Natural history: progressive neurodegeneration leading to respiratory failure and death in childhood

7. Clinical Manifestation
Hypotonia
Episodic
Vomiting
Ataxia
Hyperventilation
Encephalopathy: Loss verbal milestones
Motor: Spasticity; Abnormal breathing rhythm
Brainstem & Basal ganglia signs
Hearing loss
Cerebellar: Ataxia; Nystagmus
Dystonia

8. Clinical Manifestation
Ophthalmologic: Visual loss; Ophthalmoparesis
Peripheral neuropathy
Often subclinical: Prevalence by nerve conduction testing: 45%
Pathology: Reduced Myelinated & Unmyelinated axons; ? Demyelination
Clinical signs may become manifest with
Stress: Intercurrent infection
Carbohydrate intolerance
Course
Progression: Motor & Intellectual regression
Death often within 2 years of onset

9. Clinical Manifestation
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%
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%

10. Clinical Manifestation
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%)

11. Lab Finding Lactate: High in CSF > blood CNS pathology
Focal, bilaterally symmetric spongiform lesions
Location: Especially in thalamus and brain stem
MRI: Symmetrical hyperintense lesions on T2

12. Imaging Finding General features
Best diagnostic clue: bilateral, symmetric ↑T2/FLAIR putaminal and periaqueductal gray matter
Common location:
Basal ganglia
Brain stem: periaqueductal gray matter, substantia nigra, subthalamic nuclei, pons, medulla
Thalami, dentate nuclei

13. Imaging Finding CT findings:
Non-contrast: hypodense; occasionally normal
Contrast enhanced: enhancement uncommon

14. Imaging Finding MR findings T1WI: hypointense T2WI: hyperintense
FLAIR: hyperintense
DWI: restricted diffusion in acute disease
T1 C+: enhancement uncommon
MRS: ↑choline, ↓NAA, (+)lactate

15. Differential Diagnosis
Profound perinatal asphyxia
Hyperintense T1 & T2WI image in dorsolateral putamina, lateral thalami, dorsal brain stem
Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes
Glutaric aciduria type 1
Hyperintense T2/FLAIR corpora striata, globi pallidi
Wilson disease
Hyperintense T2/FLAIR putamina, globi pallidi, midbrain, thalami
Hyperintense T1 of globi pallidi secondary to hepatic failure

16. 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

17. Prognosis DISMAL!! 50% would die at 3 y/o
Less than 20% could live until teenage
Late onset had slower progression