deficiency of metabolite - columbia university€¦ · inborn errors of metabolism mitochondrial...
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DEFICIENCY OF METABOLITE
-HYPOXIA AND HYPOGLYCEMIA-HYPOVITAMINOSIS
SELECTIVE VULNERABILITY(HYPOXIA AND HYPOGLYCEMIA)
-SPECIFIC CELL TYPENEURONS>OLIGODENDROCYTES>ASTROCYTES
-SPECIFIC BRAIN REGIONPYRAMIDAL NEURONS OF SOMMER’S SECTOR
(HIPPOCAMPUS CA1)PURKINJE CELLS OF CEREBELLUMNEURONS OF GLOBUS PALLIDUSNEURONS OF CORTICAL LAYERS 3 AND 5
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Degeneration of CA1 post ischemia
HYPOVITAMINOSIS
THIAMINE (VITAMIN B1)COBALAMIN (VITAMIN B12)
Chronic alcoholicsGastrointestinal diseaseLong-term TPN
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WERNICKE’S DISEASE(Thiamine deficiency)
CLINICAL FEATURESCONFUSIONOCULAR DISTURBANCES (Gaze Palsies)ATAXIARETROGRADE and ANTEROGRADE AMNESIA,
CONFABULATION = KORSAKOFF’S PSYCHOSIS, WITH CHRONIC DISEASE, IRREVERSIBLE
NEUROANATOMIC LOCALIZATIONMAMMILLARY BODIESMEDIAL DORSAL THALAMIC NUCLEUSNUCLEI AROUND IIIrd and IVth VENTRICLES
Acute Wernicke’s Encephalopathy
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Chronic Wernicke’s Encephalopathy
Associated with Korsakoff’s
SUBACUTE COMBINED DEGENERATION(Vitamin B12 Deficiency)
• Obtain in meat, dairy products, yeast
• Untreated pernicious anemia, gastrectomy/tumors, malabsorption, tapeworms, HIV infection, vegetarians,
• Early symptoms = paresthesias in lower limbs, thenloss of fine touch, vibration, position sense
• Progression to spastic paraparesis, ataxia, anesthesiaof lower limbs and trunk
• Defective methylation of myelin basic protein and other CNS proteins
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Subacute combined degeneration in spinal cord white matter tracts.
INBORN ERRORS OF METABOLISM
MITOCHONDRIAL DISORDERS
SUBACUTE NECROTIZING ENCEPHALOPATHY
(LEIGH’S)
PEROXISOMAL DISORDERS
CEREBRAL HEPATORENAL (ZELLWEGER)
LYSOSOMAL DISORDERS
GANGLIOSIDOSES
MUCOPOLYSACCHARIDOSES
CEROID LIPOFUSCINOSIS
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SUBACUTE NECROTIZING ENCEPHALOPATHY (LEIGH’S DISEASE)
CLINICAL:Onset in early childhood (juvenile and adult forms
also)Failure to thriveArrest and regression of psychomotor developmentHypotonia, ataxia, dystonias, tremorsNystagmus, bizarre eye movementsDeafnessSeizuresLactic acidosis (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
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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
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GM2 GANGLIOSIDOSIS - PATHOLOGY
MACROCEPHALY
MICROSCOPIC -
Abnormal central and peripheral neurons
Ballooned cytoplasm (“storage”)
“Meganeurites” - enlarged dendrites and proximal axons
Membranous cytoplasmic bodies
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Membranous cytoplasmic bodies seen in mucopolysaccharidoses and other neuronal “storage” disorders
Retinal pigmentary degeneration in NCL
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Neuronal cytoplasmic ballooning due to storage disorder
EXCESS OF TOXIC METABOLITES
ETHANOL ABUSE
HEPATIC ENCEPHALOPATHY
UREMIC ENCEPHALOPATHY
WILSON’S DISEASE
KERNICTERUS
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Alzheimer Type 2 Astrocytes are associatedwith hepatic disease
Cerebellar vermal degeneration
Chronic alcoholism
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Basal ganglionic degeneration in Wilson’s disease• Autosomal recessive, defect in copper
transporting-ATPase, export ofcopper from cells
• Usually present end of second decade,or severe mutations in early childhood
• Dysarthria, dysphagia, dystonia andpainful muscle spasms, coarse tremor,dementia; Kayser-Fleisher rings in eye
• Low serum ceruloplasmin, copper inurine
• Treat with copper chelating agents
• Severely affects caudate and putamen,atrophy to cavitation; less severe inglobus pallidus and thalamus
• Neuronal loss, gliosis, macrophages,Alzheimer type II astrocytes
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KernicterusNow seen in small, preterm infants with asphyxia, acidosis, hypoglycemiaor septicemia. Are very sensitiveto even low levels (10 mg/dl) of unconjugatedbilirubin.