Medical Problem Solving
Case study
A young Mennonite Patient JE was 20 months of age when first referred by her pediatrician to a
university health center child neurologyclinic. 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
Your Task:
Spend some time using OMIM database to see if you can diagnose this child’s condition. How
do I do that? Well this data base 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
Candidate Gene
Gene location (locus)
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?________________________
Fig. 2. Genome-wide SNP mapping study localizes unexplained DD phenotype in two Old Order
Mennonite children.
A: Concise pedigree showing the relationship between the two affected children.
Question: Is this homozygous dominant or recessive?__________________________
How could you tell?_________________________________________
B: 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. Fifty-five contiguous
SNPs delimited the linked region, which contained 55 genes including SLC17A5. This
analysis did not explicitly rely on genotype or haplotype data from theparents, except that
the untransmitted alleles from the parents were used to determine population-specific allele
frequencies
Question: 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?__________________________________
What do you think the first part of 6q12-14 is telling you?______________________
. C: 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.
Question: Using your best deductive reasoning-Is Salla disease a missense, nonsense or other
mutation?__________________________Why?