Medical Problem Solving Case study
Name:
A young Mennonite patient, JE, was 20 months of age when first referred by her pediatrician to
a university health center child neurology clinic. Her mother’s pregnancy period was normal. There
were no concerns about her physical or neurological health until age 8 months, when she began to fall
over from a crawling position. She sat at 12 months, cruised at 16 months, and was not walking when
first evaluated at age 20 months.
Neurological examination was notable for truncal ataxia only when standing (not when sitting),
‘‘clumsy’’ upper extremity movements (without true target-seeking tremor), and symmetrically brisk
patellar tendon reflexes. Muscle power and tone were normal and she was adept at crawling. During
the initial evaluation, she was speaking in short sentences. Intellectual function and social interactions
were appropriate for age.
Linear growth delay was recognized at age 2.5 years and she had a poor endogenous growth
hormone (GH) response to arginine loading. She continued to have gross and fine motor delays, and
did not ambulate independently until after age 3 years. Gait subsequently
deteriorated, necessitating the use of canes and ankle supports. She walked with a wide base, continued
to have truncal titubation, and developed a target-seeking tremor. Tendon reflexes, initially brisk, were
hypoactive by age 4 years.
Language and cognitive delays became more evident with advancing age, and significant
learning disabilities were apparent once she entered school. Over a 4.5 year period, JE was evaluated
by specialists in pediatric neurology and biochemical genetics, had two sedated MRIs, a
fluorodeoxyglucose PET scan, karyotype testing, and a variety of biochemical test.
MRI findings were similar at ages 2 and 4 years, showing supratentorial hypomyelination and a thin
corpus callosum.
In 2003, JE’s parents informed the doctor about a second cousin of the proband exhibiting a
similar clinical course. With IRB approval and appropriate signed consents, doctors initiated a
genome-wide mapping study using the two affected patients, their parents, and Affymetrix GeneChip
Mapping 10K Arrays.
Medical Problem Solving Student Worksheet
Name:_________________
Your Task:
Spend some time using OMIM database to see if you can diagnose this child’s condition. How do you
do that? Well this database is useful if you can pick out key words pertaining to this illness. Go back
and write down some important facts about this patient. Need a clue? Mennonite would be a good
one. (Hint )If you are listing multiple symptoms, capitalize the A in “And” in your search.
Website for Online Mendelian Inheritance and Man=
http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim What did you use to search at first?
_____________________________________________________________________________
.________________________________________________________________________________
Fill in the chart with your top three genes from the website
Gene location (locus)
Candidate Gene
Example 10q17-q20
Physical location (click on
Map viewer located to the
right) Your gene will be
highlighted. The # will be on
the ruler
Having some trouble? ? Try gross motor delay Mennonite And truncal ataxia And slow linear growth.
This will give you one disorder. What is it?_____________________________________________
What does this gene do?
What is the actual name of this disorder in the Mennonite population?________________________
Use the following figure to answer the questions below.
Fig. 2. Genome-wide SNP mapping study localizes unexplained DD phenotype in two Old Order
Mennonite children.
1. Find A in the figure above. Area A is a concise pedigree showing the relationship between the
two affected children.
a. Question: Is this homozygous dominant or recessive?__________________________
b. How could you tell?_________________________________________
2. Find B in the figure above. Two mapping parameters, homozygous haplotype length (i.e.,
number of contiguous homozygous SNPs) and location score (as previously described in
Puffenberger et al., 2004), were maximized on chromosome 6q12-14 in the two patients. Fiftyfive contiguous SNPs delimited the linked region, which contained 55 genes including
SLC17A5. This analysis did not explicitly rely on genotype or haplotype data from the parents,
except that the untransmitted alleles from the parents were used to determine populationspecific allele frequencies
a. If the X axis is the actual 23 chromosome pairs, for these two patients with the disorder,
which chromosome do they share the greatest homozygous haplotype
length?__________________________________
b. What do you think the first part of 6q12-14 is telling you?______________________
3. Find C in the figure above. Sequence analysis of the SLC17A5 exon 2 revealed a homozygous
pathogenic sequence variant, 115C!T (R39C), in both patients. This is the common variant
found in Salla disease patients from Finland.
a. Using your best deductive reasoning, is Salla disease a missense, nonsense or other
mutation? __________________________ Why?