Paciorkowski, Et Al. MEF2C Haploinsufficiency Syndrome1

Paciorkowski, et al. MEF2C haploinsufficiency syndrome1

Supplementary Data

Clinical Data

Subject IS09-024 presented at 6 months with infantile spasms (ISS), gastroesophageal reflux, and laryngomalacia. His epilepsy was resistant to valproic acid, but the spasms ceased after transition to tiagabine. He had a single further seizure at 5 years of age. Brain MRI at 6 months of age (unavailable for review) reportedly showed “mild calvarial asymmetry”. He sat at 3 years of age, began taking steps with a walker at 6 years, but by age 13 years either rolled on the floor to get across the room or used a wheelchair. He did not develop a pincer grasp. He made frequent vocalizations, but did not have any clear use of spoken language or signs and did not respond consistently to voice. He appeared to recognize his parents. He had frequent hyperkinetic stereotypies, particularly of his hands.

Subject LR11-305 developed myoclonic epilepsy at 11 months of age. She had previously been noted to have global developmental delay. An initial brain MRI (unavailable for review) reportedly showed “mild Dandy-Walker variant”, but this apparently improved on a second scan (also not available) and may have in fact been a mega cisterna magna. At 11 months she was in constant motion, with frequent episodes of dystonia and opisthotonus.

Subject LR11-306 presented at 6 months with global developmental delay. Epilepsy of unclear type began after 1 year of age. By the age of 5 years he was starting to pull to stand by himself, but was nonambulatory. He was able to drink from a cup and was learning to use a spoon. He was averbal. He had constant flapping and nonpurposeful movements of his hands.

Subject LR11-307 presented at 4 months with myoclonic seizures, and then developed ISS at 9 months. Brain MRI showed a dysmorphic corpus callosum and mild cerebellar vermis hypoplasia. She began walking with assistance at 5 years of age. She rocks constantly, holds her hands at midline, flaps them when excited, and has a history of biting her thumbs and fingers.

Subject LR11-308 presented at 4 months of age with developmental delay. At the age of 3 years, he was not sitting, talking, or able to feed himself. A diagnosis of cerebral palsy was made, and he had severe scoliosis. By the age of 46 years, he had never had a seizure. His movements were largely hypokinetic, with some midline hand wringing and dystonia.

Subject LR11-309 presented at 3 months with poor visual tracking. A brain MRI was normal. By 4 months of age she was hypertonic with constant “fidgety movements” of the extremities. She developed myoclonic and generalized seizures at 13 months of age. By 17 months she was globally delayed, unable to roll or hold her head up, made vocalizations, and started to make eye contact.

Subject LR11-310 presented at 11 months of age with developmental delay. She had repetitive rocking movements. At 12 months she had a febrile seizure and at 18 months developed myoclonic seizures and atonic seizures manifesting as head drops. A brain MRI showed mildly thin white matter. Her seizures were refractory to levetiracetam, but improved with zonisamide. At 22 months she had multiple stereotypic hand movements.

Subject LR11-312 was noted to have hypotonia and poor visual fixation in early infancy, and began having myoclonic seizures at 3 months of age. These evolved into ISS with hypsarrhythmia on EEG. She was treated with adrenocorticotropic hormone (ACTH). Brain MRI was normal. She had chronic thrombocytopenia. She had poor weight gain, slow gastric emptying, and constipation. She had frequent self-stimulatory behaviors, with rocking and side-to-side head movements.

Subject LR11-325 presented at 4 months of age with ISS and were refractory to levetiracetam, topiramate, and vitamin B6. Brain MRI was normal. At 1 year he was starting to hold his head up and hold his hands at midline, but was not yet sitting. He had frequent “squirming” movements during infancy.

Subject LR11-387 was born at 31 ½ weeks gestation and had bradycardia at birth that persisted until 8-9 months of age. He was on oxygen for the first year of life. A patent foramen ovale spontaneously resolved. At 18 months he had a febrile seizure, and subsequently had numerous febrile convulsions, and one afebrile convulsion. A brain MRI showed mildly dilated lateral ventricles. He had hypotonia during infancy, global developmental delay, and at the age of 6 years was able to use a stander and take steps with a gait trainer. He had frequent jerking movement of the legs, dystonic movements of the hands, and occasional myoclonic jerks. At 6 years he was averbal.

Subject LR11-388 presented with poor visual tracking and hypotonia at 3-4 months of age. Myoclonic seizures began at 2 years, treated initially with valproic acid but due to allergic reaction was changed to levetiracetam. At 5 years 5 months of age she has been seizure-free for 3 years and is now off all anticonvulsants. She was not able to walk independently, no purposeful hand use, and makes some vocalizations but no words. She had frequent hand flapping, bruxism, and head shaking.

Subject LR12-013 had developmental delay and mixed tone (episodes of leg extension and back arching varying with hyptonia) as an infant. Had a febrile seizure at 17 months of age, followed by clusters of febrile seizures and was started on phenobarbital. Febrile seizures recurred at 2.5 years and although he has never had a nonfebrile convulsion he was transitioned from phenobarbital to carbamazepine. Had difficulties with gastroesophageal reflux when younger, but that improved over time. Was described as “constantly in motion” with rocking behaviors, arm flapping, and repetitive jaw movements. Brain MRI showed mildly enlarged lateral ventricles but was otherwise normal.

Subject LR12-021 had hypotonia combined with repetitive back arching in infancy, and only began sitting at 13 months. He has never had a seizure. At 30 months was vocalizing and babbling, but no clear words. Continued to have repetitive back arching, hand batting behaviors, head shaking, and bruxism. Brain MRI showed hypoplasia of the splenium of the corpus callosum.

Subject LR12-022 presented at 2 months with hypotonia, but with stiffening when held. Gastroesophageal reflux was significant during infancy, but improved. Sat unsupported at 14 months, and began walking at 4 years of age with a wide-based gait. Continued to have limb and trunk stiffening when excited, with repetitive midline hand movements and bruxism. Had a single generalized seizure at 3.5 years. At age 7 years had 10 consistent words and a lot of jargon and inappropriate laughter. Brain MRI at 2.5 years showed delayed myelination and a second study at 5 years showed a thin corpus callosum.

Subject LR12-031 was irritable as a newborn, with poor sleep and difficulty latching on. Two capillary malformations of the skin were visible at birth. At 12 weeks was noted to be hypotonic. Myoclonic seizures began at 6 months of age. Seizures became intractable and at age 6 years were daily despite lamotrigine and peracetam therapy. He began sitting on his own at 3 years, and at age 6 years required help to stand. Sleep was severely disrupted throughout early childhood. Feeding remained a difficulty and at age 6 years was on a pureed diet only. Had a very happy demeanor, with inappropriate nocturnal laughter, laughter during vaccinations and painful events, and no verbal language. Described as “always moving” with frequent waving of hands in front of eyes and looking through his fingers at lights. Brain MRI at 1 year of life showed increased extra-axial spaces, immature white matter with increased T2 FLAIR signal posteriorly, and a thickened, shortened corpus callosum.

Subject LR12-275 presented at 2 months with left gaze preference, hypotonia, and plagiocephaly. At 21 months was not yet able to sit and had continued difficulty with gagging on foods requiring a pureed diet. Had vocalizations and babbling, and was fascinated by light-up toys. Had never had a clear seizure but had frequent “head-drop” behaviors with two overnight electroencephalograms showing no epileptiform activity. Exam notable for constant movements, with leg kicking and scissoring, and back arching. Brain MRI at 8 months showed delayed myelination.

Supplementary Table 1: Relative expression values for Mef2c and Mecp2 probes present in array dataset GSE2161, from the Dlx1/2-knockout mouse ( after correction for multiple comparisons.These values demonstrate statistically significantlyreduced expression of Mef2c and Mecp2 in the absence of Dlx1/2.

Supplementary Table 2: Relative expression values for Mef2c and Mecp2 probes present in array dataset GSE8311, from the Dlx1/2-knockout mouse ( after correction for multiple comparisons.These values demonstrate statistically significantly reduced expression of Mef2c and Mecp2 in the absence of Dlx1/2.