DEFICIENCY OF METABOLITE SELECTIVE VULNERABILITY (HYPOXIA AND HYPOGLYCEMIA)

-SPECIFIC CELL TYPE -HYPOXIA AND HYPOGLYCEMIA NEURONS>OLIGODENDROCYTES>ASTROCYTES -HYPOVITAMINOSIS -SPECIFIC BRAIN REGION PYRAMIDAL NEURONS OF SOMMER’S SECTOR (HIPPOCAMPUS CA1) PURKINJE CELLS OF CEREBELLUM NEURONS OF GLOBUS PALLIDUS NEURONS OF CORTICAL LAYERS 3 AND 5

HYPOVITAMINOSIS

THIAMINE ( B1) COBALAMIN ()

Chronic alcoholics Gastrointestinal disease Long-term TPN Degeneration of CA1 post ischemia

Acute Wernicke’s WERNICKE’S DISEASE ( deficiency)

CLINICAL FEATURES OCULAR DISTURBANCES (Gaze Palsies) RETROGRADE and , = KORSAKOFF’S PSYCHOSIS, WITH CHRONIC DISEASE, IRREVERSIBLE

NEUROANATOMIC LOCALIZATION MAMMILLARY BODIES MEDIAL DORSAL THALAMIC NUCLEUS NUCLEI AROUND IIIrd and IVth VENTRICLES

1 Chronic Wernicke’s Encephalopathy SUBACUTE COMBINED DEGENERATION ()

• Obtain in meat, dairy products, yeast

• Untreated pernicious anemia, gastrectomy/tumors, malabsorption, tapeworms, HIV infection, vegetarians,

• Early symptoms = paresthesias in lower limbs, then loss of fine touch, vibration, position sense

• Progression to spastic paraparesis, ataxia, anesthesia of lower limbs and trunk

• Defective methylation of basic protein and other CNS proteins Associated with Korsakoff’s

INBORN ERRORS OF METABOLISM

MITOCHONDRIAL DISORDERS SUBACUTE NECROTIZING ENCEPHALOPATHY (LEIGH’S) PEROXISOMAL DISORDERS CEREBRAL HEPATORENAL (ZELLWEGER) LYSOSOMAL DISORDERS GANGLIOSIDOSES

Subacute combined degeneration MUCOPOLYSACCHARIDOSES in spinal cord white matter tracts. CEROID LIPOFUSCINOSIS

SUBACUTE NECROTIZING ENCEPHALOPATHY (LEIGH’S DISEASE) CLINICAL: Onset in early childhood (juvenile and adult forms also) Arrest and regression of psychomotor development Hypotonia, ataxia, dystonias, tremors , bizarre eye movements Deafness Seizures (blood and CSF)

DEFECT: Disorders in pyruvate dehydrogenase complex or cytochrome C oxidase - autosomal recessive or X-linked

OVERLAPS with MELAS and MERRF mitochondrial syndromes

2 GM2 GANGLIOSIDOSIS (TAY-SACHS AND OTHER VARIANTS) AUTOSOMAL RECESSIVE; Hexosaminidase mutations lead to accumulation of GM2 ganglioside CARRIERS 1:30 of Ashkenazii Jewish descent 1:300 in others CLINICAL: INFANTILE - Severe retardation Myoclonic seizures “Cherry red” spot in retina LATE INFANTILE JUVENILE ADULT

GM2 GANGLIOSIDOSIS - PATHOLOGY

MACROCEPHALY MICROSCOPIC - Abnormal central and peripheral neurons Ballooned cytoplasm (“storage”) “Meganeurites” - enlarged dendrites and proximal axons Membranous cytoplasmic bodies

3 Membranous cytoplasmic bodies seen in mucopolysaccharidoses and other neuronal “storage” disorders Retinal pigmentary degeneration in NCL

Neuronal cytoplasmic ballooning due to storage disorder EXCESS OF TOXIC METABOLITES

ETHANOL ABUSE UREMIC ENCEPHALOPATHY WILSON’S DISEASE KERNICTERUS

Alzheimer Type 2 are associated with hepatic disease Cerebellar vermal degeneration

Chronic

4 Basal ganglionic degeneration in Wilson’s disease • Autosomal recessive, defect in copper transporting-ATPase, export of copper from cells • Usually present end of second decade, or severe mutations in early childhood • Dysarthria, , dystonia and painful muscle spasms, coarse tremor, dementia; Kayser-Fleisher rings in eye • Low serum ceruloplasmin, copper in urine • Treat with copper chelating agents • Severely affects caudate and putamen, to cavitation; less severe in globus pallidus and • Neuronal loss, gliosis, macrophages, Alzheimer type II astrocytes

Kernicterus Now seen in small, preterm infants with asphyxia, acidosis, hypoglycemia or septicemia. Are very sensitive to even low levels (10 mg/dl) of unconjugated bilirubin.

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