Transcript Case Study 8 - University of Pittsburgh

Case Study 8
Craig Horbinski, M.D., Ph.D.
Question 1
Clinical history: 45-year-old white female with type I
diabetes mellitus starting at age 13, complicated by
diabetic neuropathy, gastroparesis, and end stage renal
disease. She also had a history of retinal hemorrhages,
retinal detachment, pulmonary embolism,
schizophrenia, depression, hypertension, and
gastrointestinal bleeding. She was a non-smoker,
consumed no alcohol, and did not use illicit drugs. She
had a long history of repeated renal transplantations
and a pancreatic transplantation, all of which failed.
Ultimately she died from a combination of end stage
renal disease, atherosclerotic disease, and presumptive
cardiac arrhythmia. An autopsy was performed.
Answer
Ventriculomegaly and bilateral caudate nucleus atrophy
Question 2
Given the gross findings, what one thing was probably left
out of the clinical history on page 1 (i.e. what one other
disease did this woman likely have)?
Answer
History of movement disorder, Huntington disease on the
maternal side of her family (maternal grandmother,
mother, aunt, and older brother).
Question 3
Describe what you see.
Click here to view slide.
Answer
Atrophic caudate nucleus, old lacunar infarct at the
inferomedial caudate (note the macrophages the lacunar
infarct is likely related to the patient s type 1 diabetes).
Hard to do much else with this when it comes to
evaluating for neurodegenerative diseases, the absence
of neurons is harder to appreciate than the presence of
something that s not supposed to be there.
Question 4
Normally chronic neuronal loss is identified by reactive
astrocytosis, but in this case it s not readily apparent on
H&E. What immunostain might help?
Answer
GFAP
Question 5
Are there reactive astrocytes?
Click here to view slide.
Answer
Yes, but not a lot mostly around the medial (i.e.
subventricular zone) and near the old lacunar infarct.
Question 6
Despite the patient s extensive family history of
Huntington disease, she had refused testing while alive.
What s the diagnostic molecular test for HD?
Answer
PCR amplification of the CAG repeat region on
chromosome 4 where the huntingtin gene is located.
Normally it s done on fresh tissue (usually patient s
blood), but it can be done on formalin-fixed, paraffinembedded tissue.
Question 7
The PCR analysis showed alleles of ~20 and ~44 CAG
(polyglutamine) repeats.
Does this confirm HD?
Answer
Yes. Individuals who do not have HD usually have 28 or
fewer CAG repeats. Individuals with HD usually have 40
or more repeats. Some are within the borderline range of
repeats, and may or may not exhibit symptoms. Because
it is an autosomal dominant disease, only one allele need
have expanded repeats.
Question 8
What is the main type of neuron lost in Huntington
disease? What sort of movement disorder would you see
intention tremors or resting tremors?
Answer
Medium spiny GABAergic neurons in the caudate
nucleus. Due to the loss of inhibitory feedback
loops in the basal ganglia, the ability to fine-tune
movements is lost and severe tremors manifest
when the patient tries to move (intention tremors).
Resting tremors are the hallmark of Parkinson
disease, which involves the loss of substantia
nigra neurons in the midbrain and, thus, disrupts
an entirely different motor pathway
(dopaminergic).
Question 9
What is the best additional stain to order that would
further support these findings?
Answer
Ubiquitin immunostain. Huntington disease is
characterized microscopically by ubiquitin-positive
intranuclear inclusions within the caudate nucleus and,
later, in the putamen.
Question 10
Are there any ubiquitin-positive intranuclear inclusions?
Click here to view slide.
Answer
Yes many neurons in the caudate nucleus and putamen
have ubiquitin-positive intranuclear inclusions.
Nonspecific speckles in the white matter are also present.
Question 11
What phenomenon is commonly seen in multiple
generations affected by trinucleotide repeat diseases?
What causes this phenomenon?
Answer
Anticipation, where the onset of disease occurs earlier,
and the severity worsens, with each subsequent
generation. It is widely held that the expanded
trinucleotide repeats are physically slippery for the DNA
polymerase during meiotic cell division, and the
polymerase ends up adding a few more repeats during
each generation of germ cell proliferation.
Question 12
This patient is the third generation afflicted with HD, yet
she only has 40 polyglutamine repeats and survived 45
years (maybe longer if she hadn t had type 1 DM). How
do you reconcile this with the well-known anticipation
phenomenon?
Answer
The anticipation effect in HD is best seen when the
diseased gene is inherited through the paternal line. This
patient s HD was inherited through the maternal line.
Theories as to why this happens include some sort of
imprinting or X-linked comodifier, the former being favored
(Am J Hum Genet. 1995 Sep 57(3):593-602; Am J Hum
Genet. 1992 Mar 50(3):536-43).
Question 13
Go back to the original gross image. What is the grading
system used to describe the severity of HD? What is the
grade in this case?
Answer
Vonsattel grading system

Grade 0 no caudate atrophy seen grossly, no gliosis, 30-40% loss
of neurons microscopically

Grade 1 no caudate atrophy seen grossly, moderate gliosis, 50%
loss of neurons microscopically

Grade 2 grossly visible atrophy of head of caudate while retaining
convexity

Grade 3 caudate head is a flat line, with no
convexity at all

Grade 4 caudate is concave
This is a Vonsattel grade 2 of 4.