Medical Problem Solving Case Study: What is the cause of the seizures?

 

1) Case summary

 

                An Amish baby was born healthy at 39 weeks gestational age. For the first year of life she grew well and made good developmental progress. At age 12 months, her head was large (90th percentile for age) relative to her height (25th percentile for age), and she seemed slightly "clumsy" compared to her siblings.  She did not walk independently until 18 months of age. She first said single words at age 14 months, and by 22 months of age was using 2- and 3-word combinations. 

At 23 months of age she had an unprovoked complex partial seizure. While sitting at the kitchen table, she suddenly became frozen in her chair, looked straight ahead, and then turned her eyes to the left as her face became flushed, her back muscles stiffened, and her right arm went into a flexed posture. After one minute, she suddenly relaxed and slumped in her chair. She slept soundly for the next hour.

                Her parents recounted the story to a neurologist, who told them she probably had a left temporal lobe seizure.  The only abnormality he noted was complete absence of deep tendon reflexes in response to knee and ankle taps. He ordered brain magnetic resonance imaging (MRI) and an electroencephalogram (EEG).  The MRI was normal, but the EEG showed abnormalities: frequent spike and slow wave discharges over the left temporal lobe.  Over ensuing weeks, seizures increased in frequency.  By 30 months of age they were occurring 10 times daily despite treatment with anticonvulsant medication. Over this same time period, her language skills regressed. She lost all use of words and became increasingly hyperactive, inattentive, and aggressive. By 36 months of age, she was mute and autistic. Her parents could not leave her alone, for fear she would run away or try to hurt their other children.

                In an attempt to control her seizures, a part of her temporal lobe was surgically removed (temporal lobe resection). The surgical specimen showed neurons out of place and in abnormal formations (focal neuronal dysplasia).  Additionally, there were extensive areas of the hippocampus with abnormally high amounts of astrocytes, the non-neuron, “helper” cells in the brain (granule cell hyperplasia, gliosis and reactive astrocytosis).  Her seizures initially stopped, but 6 months later recurred from the right temporal lobe. At her present age of 6 years, she is autistic, mute, and severely retarded. She continues to have 2-3 focal seizures per week despite treatment with two anticonvulsant medications.

 

Spend five minutes using the OMIM database (Online Mendelian Inheritance and Man: http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim) to see if you can diagnose this child’s condition.

 

1.       Fill in the chart below with some of the possible genes that could be related to the condition described above.

                             

 

Candidate Gene

Genetic Location

Physical Location

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2) Genetic investigations

 

During a routine follow-up visit, the mother volunteers that she has two nephews with symptoms similar to her daughter. These two boys are examined and found to be strikingly similar to the first patient. The boys’ parents relate that a fourth child in the extended family also appears to have the same disorder. This child is a first cousin to the mother of the affected boys. Eventually, all four children (starred in Figure 1) are examined and it is determined on clinical grounds that they all have the same disorder. A pedigree for these families is constructed (Figure 1).

 

2.       Is the gene likely dominant or recessive? Why?

3.       What is your strategy to find a mutated gene potentially causing these symptoms?

 

 

Recognizing the high probability of a recessive genetic disorder in these closely-related Amish children, you decide to genotype them. You use a microarray containing about 10,000 single nucleotide polymorphisms (SNPs) randomly distributed across the genome. You scan each child’s SNP results for blocks of homozygous markers.  You look for areas of homozygosity common to all four children by combining their SNP data (shown as peaks in Figure 2).

 

 

4.       Using Figure 2, identify which chromosomes have the largest areas of homozygosity.

 

Figure 3 provides the genotype data for the homozygous block on chromosome 7. All four patients are identically homozygous for 18 SNPs in a row in this region.