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.

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

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

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

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

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

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

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%

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%)

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

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

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

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

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

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

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