University of Chicago

Letter to Dr. Harry Chugani-

D was seen in the company of his parents in the Medical Genetics Clinic at the University of Chicago on 8/29/2006. He is a 12 month old boy with previous infantile spasms associated with bilateral perisylvian polymicrogyria (PMG). The PMG is relatively extensive, and he has associated seizure disorder, developmental delay and spasticity that more marked in his arms. However, his level of alertness and mobility are good considering the PMG. His parents had questions about cause and especially questions about the outcome. Given the extent of the PMG, mildly small head circumference and spasticity, I think that D will have continuing problems from the PMG including a reverse (arms greater than legs) spastic diplegia, mental handicap and ongoing risk for seizures. The severity of his mental handicap is unclear, but I expect at least a moderate mental retardation, although it is possible it could be more severe. As always, time will tell.

The appropriate genetic testing for D has not all been done. He should have chromosome analysis, telomere FISH, and FISH for deletion 22q11.2 (DiGeorge). None of these tests results were included in his records from the office and his parents are not sure they have been done. So I hope that you can order any not done at his next visit. We also obtained samples for PMG research.

His family history is negative for any similar developmental problems. He is his parents' first child but his mother has four older children, all girls. His mothers pregnancy was complicated by gestational diabetes treated with diet. She has never been on insulin. She had no problems with blood pressure or any other illnesses or trauma during pregnancy. She had 3 to 4 prenatal ultrasounds, all normal, and was age 38 at time of birth. He weighed 5 pounds 8 ounces and length 19 inches. His head size was described as small but his parents did not recall the specifics. His Apgar scores were good. He had slightly elevated bilirubin but fed well and went home at age 2 days.

D seemed to do well at first including apparently normal early development. He had good head control as well as active smiling and laughing early on and learned to roll stomach to back by about three and half months of age. He was having no feeding or other problems at that time. He had the onset of seizures at this time as I will describe below. The seizures were associated with striking regression of his developmental skills, particularly after treatment with the seizure medications Topamax and Klonopin. He did not regain his developmental skills until after successful treatment of his seizures with Vigabatrin. He, thus, began rolling again at about 7 months of age. At present, he had fairly good head control but is still unable to sit except for sitting very briefly when propped.

His parents first saw brief little episodes in which his eyes would open wide as if with a brief stare, followed by a quick return to normal. Within a week they were seeing his tongue out and his mouth help open for a few brief moments. Within another week after that, his arms were flying up and these spells were clearly occurring in clusters. Over the next several weeks, the clusters were obviously occurring more while he was waking until they got to be very frequent, at which time they were occurring at any time of day. His maximum frequency was about 8-15 clusters per day. He saw a nearby neurologist who ordered a routine EEG that was normal, and then a 24-hour EEG, which showed some abnormality leading to diagnosis of infantile spasms. I presume this was hypsarhythmia. He was started on treatment with Topamax and two days later with Klonopin. Very soon after, he began a striking developmental regression.

His parents sought second opinion in your clinic 6 to 8 weeks later, at which time he was sleeping most of the time and irritable. Seizures were continuing although they were hard to see because he was sleeping most of the time. I do not have results of his EEG's at this time. Treatment was changed to vigabatrin with fast tapers of the other two medicines, resulting in much improved alertness and no recurrence of seizures. He actually has had no seizures since that time. His parents do see an occasional stare now, but they are not sure that these are really seizures. An EEG in April 2006, continued to show the "potential for seizures" per his parents, which suggests to me that you saw continuing spike discharges.

Developmentally, he is making progress. He has good visual tracking and will play peek-a-boo. He has had no significant illnesses and had not been in the hospital except for video monitoring. His feeding has been good. When he was quite young, he was a poor feeder because of a lot of spitting up, but still gained weight well. This seemed to get better quite quickly at about 10 months of age. Since then, he has fed well with little if any coughing or gagging. He will occasionally choke on juice. He now takes a full 8 ounce bottle in about 20 minutes and a full meal in 30 to 40 minutes. His parents are adding a little bit of rice or oatmeal cereal to his baby foods to thicken them up. Review of systems was mostly negative except for the problems noted above. He has had no problems with HEENT. He does have consistent drooling and somewhat slow feeding. He has had no problems with his lungs, heart, abdominal organs or kidneys. He has had no problems with hormones or allergies. His developmental problems are noted in the HPI.

On examination, his weight was 9.81 kg., length was 78.5 cm and OFC 43.6 cm. His OFC was -2.5 standard deviations. His pulse was 109, blood pressure 92/54 in the right arm, respiration 24 and temperature 36.6 C. His head appeared slightly small but his facial appearance was normal. He did drool most of the time. I found no other external congenital anomalies. HEENT examination was unremarkable other than the drooling. He had good respiratory effort, clear lung sounds and normal heart. His skin was normal. His abdomen was soft without masses and he had normal male genitalia. His limbs were completely normal except for some mildly deep palmar creases. Neurologically, he was alert and did make good visual contact. I did not hear him produce any words or use any other communication skills. His eye movements were full with no nystagmus. His face was symmetric but he did drool. His motor examination showed normal muscle bulk, but abnormal tone. He had moderate spasticity in the legs and moderate to severe in the arms with brick 3+ tendon reflexes. I also saw some arching, which his parents say has gotten slowly better.

his brain MRI showed extensive PMG involving 80+% of the brain. This was clearly symmetric and most severe in the perisylvian regions. It spared the occipial and anterior frontal regions at lower or inferior levels of the scan. He had mildly enlarged ventricles, which is typical of PMG but normal structures otherwise.

In summary, D had typical moderately severe perisylvian PMG. This is associated with a mild microcephaly, moderate spasticity and infantile spasms, which have fortunately responded favorably to treatment. His overall prognosis is most likely for moderate mental retardation although this could be more severe. This may relate to in part to your continued success in controlling his seizures. I expect he will make some continued progress with his motor skills, but of course the spasticity will not completely resolve given the PMG. More than 90% of children with PMG go on to have recurrent seizures, so he needs to be monitored carefully. I would encourage relatively aggressive treatment of any future seizures.

The genetics of PMG is just getting worked out. Most PMG is sporadic, although X-linked forms are known. The empiric recurrence risk is probably in the 10% range for D's parents, a little higher for male probands than for female probands. PMG has only rarely been seen as an autosomal recessive syndrome and has been associated with ~10 chromosomal deletions or duplications. Chromosome analysis and FISH for telomeres and DiGeorge are the way to start looking for these. I may be able to look for other loci on a research basis. I counseled his parents for a 10% recurrence risk, although they plan no further children. Given the modest risk of X-linked inheritance, his maternal half sisters need to be counseled for a small risk of PMG prior to their childbearing years. They certainly could receive counseling in Detroit, but I would need to speak with the geneticist or genetic counselor ahead of time to provide them some unpublished data. Thank you for sending D for additional opinion and review of the PMG.

From William B. Dobyns