Metabolic CNS disease Flashcards
Most lysosomal storage disorders are _____
Most affect the ______
How common are they
Auto Recessive (few X linked)
most effect CNS
seen in about 1:100,000 pts
When to suspect a Metabolic disorder
Prsentaiton doesn’t fit text book, not respond to tx, look for diagnostic clues
May only become recognizable in stress, illness, injury
Not reconginzing can lead to irreversible brain injury or organ injury or death
Do the right thing when you suspect Metabolic disorder
PE with medical hx, check glucose/ammonia/pH, call metabolic specialist, check electorlytes, CK, LFT, lactate and urine, store critical sample at hypoglycemic state, get metabolic panel workup, think of three I’s: infection, intox, idiopathic
General things to do when you suspect metabolic disorder
Lethargy/somnolence/metabolic alkalosis or acidosis, excess lactate or ketosis, recurrent hypoglycemia, progression w/ regression, weird imaging,
Intracell digestion, acid hydrolase to break down macro, get LDS if missing essential protein for fnx
Lysosomes
Neuronal storage disease from accum. Gangliosides (lots in brain!) w/in neurons.
Gangliosides
GM2 gangliodisodse: deficiency of lysosomal enZ::
Tay Sachs = ______
Sandhoff = _____
Hexoaminidase A
Hexoaminidase B
Accumulation of INERT substrates or metabolites
Storage disorders
Examples of Lysosomal Storage disorders
Lysosome assembly (Golgi apparatus)
Trafficking of lysosomal enzymes (glycosylation)
Enzyme deficiency (single gene defect)
Co-factor defect
Transporter defect
{miners disease (silicosis) and asbestosis are not considered defects in lysosomal function}
Tay-Sachs disease:
High incidence in Ashkenazi Jews
Gene on chromosome______
DX: enzyme assay of serum, WBC, or cultured fibroblasts
15, >100 mutations described
Clincal picture of infant with Tay Sachs
Normal at birth then 6 mos. – psychomotor, retardation evident
S/S progress –> Blindness,motor incoordination, eventual flaccidity, mental deterioration,
eventual decerebrate state
Cherry red spot in macula
Death by 2-3 years
Normal at birth then 6 mos. – psychomotor, retardation evident
S/S progress –> Blindness,motor incoordination, eventual flaccidity, mental deterioration,
eventual decerebrate state
Cherry red spot in macula
Death by 2-3 years
Tay Sachs
Pathophysiology of Tay-Sachs
Alpha subunit of Hex A affected; lots of alpha subs in brain thus lots of neurological issues
What do we see on this image of child that has huge head and cherry red macula
Tay Sachs, Hex A, Chrom 15
Abnormal accumulation of gangliosides, Enlarged ballooned neurons filled with PAS positive material (stored gangliosides)
What do we see in pt w/ Tay Sachs thats in EM
have membranous cytoplasmic bodies (flvor of garbage)
Tx working on for Tay Sachs
enZ replacement or “chaperone” proteins to make Hex A fold the right fucking way
Globoid Cell Leukodystrophy: LSD that is_______ on chrom ______
::: death by 2 yrs
Autosomal Recessive
Chromsome 14
What is wrong in Krabbe disease?
Where does shit accumulate?
Deficienct Galactocerebroside B-galactosidase: get accumulation of psychosine (toxic) fucks up oligodentrocytes. Galactocerbroside part of myelin sheathà accumulates in the globoid cells
Krabbe: Deficienct ________: get accumulation of psychosine (toxic) fucks up oligodentrocytes.
Galactocerbroside part of myelin sheath–> accumulates in the _____
Galactocerebroside B-galactosidase
globoid cells
Clincal pt of baby dx with Krabbe disease
Is there a tx available for Krabbe disease?
Tx: Cord/BM transplant in pre-symptomatic phase;
Pathology characterized by
loss of myelin and oligodendrocytes (and Schwann cells in the PNS) reactive astrogliosis
multinucleated macrophages called globoid cells accumulate around blood vessels
Krabbe’s Disease (Globoid Cell Leukodystrophy
Gross specimen shows loss of white matter adn preservation of U fibers from 2 year old. Disease caused by EnZ deficency causing accumulaiton of pyschosine that damaged oligodentrocytes
Krabbes: globoid cell leukodystrophy; deficeint galactocerebroside-B-galactosidase
*deterioration of white matter, preserve U fibers
Histology shows Globoid macrophagtes adn clusters around vessels, tehre is SEVERE astrocytosis with decreaed number of oligodendrocytes.
KRabbes
EM you see globoid cells with crstalloid strait or tubular profiles
Pattern of inhreitance for Metachormasia leukodystrophy
Gene
LSD that is Auto.Recessive
Gene 22
What is defieincy in metachromatic leukodystrophy and what is the result
Deficiency of ARYL SULFATASE A
Metachromatic lipids (sulfatides) accumulate in brain, peripheral nerves, and kidney
How do we screen for metachromatic leukodystrophy
How do we diagnose it?
Screen of urinary sediment for metachromatic deposits
aDX: demonstrate enzyme deficiency in urine, WBC, or fibroblasts
IN metachormatic leukodystrophy_____ accumulation leads to breakdown of_____, but how this happens is not known
Sulfatide
myelin
Young child has gait disorder and motor syptoms
see sulfatidile accumulation in urine
Metachromatic leukodystrophy; lives 5-10 more years
How do adults present with metachromatic Leuko?
is there a tx?
Adult – usually present with psychosis & cognitive impairment, eventual motor symptoms
Treatment: bone marrow stem cell transplantation (before
symptoms appear)
Brain is normal exterior but white matter is firm.
Has marked loss of myelin with preservation of U fibers
Metachromatic leukodstrophy
Describe findings in histology this pt, what is the missing enZ
metachromatic leukodystrophy
missing aryl sulfatase A
see metachrmosia of white matter deposits
Peroxisomal disorder
Peroxisomes - cytoplasmic spherical “microbodies”
Contain catalase
Involved in fatty acid ß-oxidation (and more)
Adrenoleukodystrophy
Decreased activity of very long chain fatty acyl-CoA synthetase (in peroxisomes) : results in excess of very long chain fatty acid esters in plasma, cultured fibroblasts, and affected organs (CNS, PNS, adrenal glands)
Adrenoleukodystrophy
Genetics in adrenoleukodystrophy
X linked
Onset 5-9 years or 11-21 years
Dementia, visual/hearing loss, seizures
Adrenal insufficiency follows Neuro S/S
Classic form of adrenoleukodystrophy
Occurs in adult (20-30 years)
Slowly progressive leg clumsiness/stiffness; eventual spastic paraplegia
Adrenal insufficiency may precede Neuro S/S
Adrenomyeloneuropathy
Describe adrenoleukodystrophy grossly
gray discoloration of white matter with marked firmness : see laked of white staining
preservation of U fibers and sever demyelination
What do we see on histlogy in adrenoleukodystrophy
perivascular inflammation and PAS positive macrophages
Can occur as a complication of severe liver disease or chronic portocaval shunting
Pathogenesis is incompletely understood, but is partially related to hyperammonemia
Hepatic Encephalopathy
Early vs late manifestations in Hepatic Encephalopathy
Early manifestations include inattentiveness and short term memory impairment
Later features include confusion, asterixis (flapping tremor of outstretched hands), drowsiness, stupor, and coma
***Patients may also have foul breath (fetor hepaticus), hyperventilation, gait disturbances, and choreoathetosis
MRI abnormalities include increased T1 signal in the globus pallidus, subthalamus, and midbrain, and cortical edem
hepatic encephalopathy
Concerns with Acute hepatic encephalopathy, what about chronic?
is there tx?
Acute hepatic encephalopathy can be rapidly fatal.
Chronic or repeated episodes can lead to permanent and progressive neuropsychiatric disturbances
Liver transplant!
You see cleared out cytoplasm in cells that are scattered thorughout the cortex, there are type 2 Alzeheimer astrocytes present
Hepatic encephalopathy
