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68 Cards in this Set
- Front
- Back
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What are the 2 major classes of metabolic diseases?
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-Poliodystrophies
-Leukodystrophies |
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What type of tissue do the Poliodystrophies affect?
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Gray matter - neuronal cell bodies
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What type of tissue do the Leukodystrophies affect?
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White matter - axons and myelin sheaths
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What clinical manifestations result from neuronal cell body involvement in poliodystrophies?
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-Mental retardation
-Seizures |
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What clinical manifestations result from axon and myelin sheath involvement in leukodystrophies?
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-Motor dysfunction (spasticity and ataxia)
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What happens to the symptomatic findings in either polio or leukodystrophies over time?
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They eventually combine as neuronal changes lead to degeneration of white matter and vice versa
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So when can clinical manifestations really be used as a clue to the type of metabolic disease a patient has?
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Only in early stages of the disease
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How are most metabolic diseases of the nervous system caused? When do they often present?
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Most: by genetic defects, and present in childhood
Some: nongenetic, present in adulthood |
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What type of genetic inheritence is exhibited by most of the metabolic diseases of the nervous system?
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Autosomal recessive
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What is the typical onset and severity of symptoms for autosomal recessive and sex linked metabolic diseases?
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Variable
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What is the typical onset and severity of symptoms for Autosomal dominant metabolic diseases of the CNS?
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-Late onset
-Mild symptoms |
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What are most of the poliodystrophic diseases that affect gray matter a result of?
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Lysosomal enzyme deficiencies
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What is the result of deficiency of a lysosomal enzyme?
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Incomplete catabolism of the substrate of that enzyme, and accumulation of the substrate within lysosomes.
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What are the 4 major groups of lysosomal enzyme deficiencies that affect gray matter?
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-Sphingolipidoses
-Mucopolysaccharidoses -Glycogenoses -Mucolipidoses |
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How do these abnormal lysosome accumulations affect the neurons in which the lysosomes reside?
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-Initially the cell body elarges
-Later it degenerates or bursts |
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What is the accompanying change in the brain when neurons enlarge and then burst?
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Initially: megalencephaly
Later: atrophy |
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What are the most common diseases in the Sphingolipidosis group?
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Gangliosidoses
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Where do the Gangliosides accumulated in gangliosidosis?
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In the cytoplasm of neurons
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What are 4 subclases of gangliosidoses?
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GM1
GM2 Tay-Sach's Sandhoff's |
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What tissue is mainly affected by GM1 gangliosidosis?
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General - liver/spleen
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What tissue is mainly affected by GM2 gangliosidosis?
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Brain
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Which type of gangliosidosis is seen in infants and children?
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GM1
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What are the 2 GM2 gangliosides?
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GM2 gangliosidosis
-Tay-Sach's -Sandhoff |
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In what population is Tay-Sach's prevalent?
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Jews of Eastern european origin
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What is a diagnostic feature of Tay-Sach's disease?
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A cherry-red spot on the macula
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What is the cherry-red spot on the macula in Tay-Sach's due to?
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Accentuation of the normal macula by opacity of the surrounding retina due to ganglionic cell involvement
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What electron microscopy morphology is characteristic of Tay-Sach's?
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Swollen lysosomes that appear like membranous bodies within neurons.
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What are the 2 sulfatidoses?
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-Niemann-Pick disease
-Gaucher disease |
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What is the enzyme deficiency and accumulated metabolite in Niemann-Pick disease?
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Sphingomyelinase - so Sphingomyelin accumulates
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What is the enzyme deficiency and accumulated metabolite in Gaucher disease?
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Glucocerebrosidase - so Glucocerebroside accumulates
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What cells are mainly affected in the sulfatidoses? What is the clinical manifestation of this?
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-Macrophages
-Hepatosplenomegaly results |
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What are 2 mucopolysaccharidoses?
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-Hurler's disease
-Hunter's disease |
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What enzyme is deficient in Hurler's disease and what metabolites accumulate as a result?
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-alpha-L-Iduronidase is deficient
-Heparan sulfate/Dermatan sulfate accumulate |
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When do symptoms of Hurler's disease first appear?
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In the 1st year of life
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What are 7 major clinical manifestations of Hurler's disease?
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-Short stature
-Coarse facial features -Thick lips/protruding tongue -Hepatosplenomegaly -Herniated umbilicus -Skeletal abnormalities |
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What neurologic defects can be seen in Hurler's disease?
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-Corneal clouding
-Mental retardation |
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What do patients with Hurler's disease usually die of?
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Cardiac ischemia due to arterial involvement
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How does Hunter's disease compare to Hurler's?
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-Different enzyme but same metabolites accumulate
-Symptoms slightly less severe |
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What will be seen microscopically in all of the poliodystrophies?
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Ballooned neurons containing the abnormal substrate for the deficient enzyme.
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What can be seen on EM of neurons in Hurler's and Hunter's disease?
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Zebra bodies
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What are Zebra bodies?
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Lysosomes containing accumulated heparan and dermatan sulfates
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How is Hunter's disease genetically transmitted?
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By sex-linked recessive inheritance
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What are the 3 leukodystrophies that are metabolic disorders?
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-Metachromatic leukodystrophy
-Globoid cell leukodystrophy (Krabbe's disease) -Adrenoleukodystrophy |
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What is the major effect of the leukodystrophies?
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Dysmyelination - so they're discussed in that lecture
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What are the 3 major diseases that affect both gray and white matter or cause other pathological changes?
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-Phenylketonuria PKU
-Galactosemia -Subacute necrotizing encephalomyelopathy |
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What is another name for Subacute necrotizing encephalomyelopathy?
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Leigh's syndrome
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What are 3 things that can cause PKU?
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-Phenylalanine hydroxylase deficiency
-BH4 cofactor deficiency -Dihydropteridine reductase deficiency |
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What do these enzyme deficiencies result in?
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High amounts of PHenylalanine in the blood/urine, and increased amts of metabolites.
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What does lack of DHPR lead to?
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Decreased hydroxylation of trypsin and tryptophan so less neurotransmitter synthesis.
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What are the changes in the brain in PKU like?
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Nonspecific and variable
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What are the 2 clinical manifestations of PKU?
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-Musty odor
-Retardation |
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How can PKU due to deficiency of phenylalanine hydroxylase be avoided?
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By reducing dietary intake of phenylalanine from birth on.
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What does care have to be given for if a female with PKU wants to have a child?
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She must not have hyperphenylalaninemia because even if the infant is only a heterozygote, they can still have PKU
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What is Galactosemia and what type of genetic inheritance pattern does it exhibit?
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-Disordered galactose metabolism
-Autosomal recessive |
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What accumulates in Galactosemia and in what tissues?
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Galactose-1-Phosphate
-In Brain/Eye/Liver |
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What are the clinical manifestations of Galactosemia?
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-Mental retardation
-Cataracts -Hepatomegaly |
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How is Subacute necrotizing encephalomyelopathy inherited?
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Autosomal recessive
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What is the resulting deficiency in most cases of Leigh's syndrome (SNE)?
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Decreased cytochrome C oxidase activity
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Where is Cyto C oxidase important?
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In oxidative phosphorylation in mitochondria
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What pathologic changes will be seen in Subacute necrotizing encephalopathy and where?
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-Brain necrosis
-Vascular proliferation -Gliosis Seen in the periventricular and periaqueductal gray matter |
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When is the usual onset of Leigh's syndrome?
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First year of life
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What are the clinical manifestations of Leigh's syndrome?
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-Psychomotor retardation
-Seizures -Ophthalmoplegia -Hypotonia -Feeding/respiratory problems |
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Why do we see such clinical manifestations in Leigh's syndrome?
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Because it affects the
-medulla -inferior cerebell peduncles -DMNX -hypoglossal nucleus |
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What is the usual outcome of Leigh's syndrome?
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Death within a few years
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What are the first steps to take in diagnosing metabolic diseases of the CNS?
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-Family history
-Look at clinical manifestations |
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When is the usual onset of Niemann-Pick's disease?
Gaucher's disease? |
NP = within 1st year
Gaucher's = later teens |
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What non-neurological features do patients with Hurler's disease often have?
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-Corneal opacity
-Hepatosplenomegaly |
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What non-neurological features do patients with adrenoleukodystrophy often have?
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Bronze skin due to adrenal deficiency
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