Infantile Convulsions and Paroxysmal Kinesigenic Dyskinesia with 16p11.2 Microdeletion
Paroxysmal kinesigenic dyskinesia (PKD) is a rare paroxysmal movement disorder characterized by involuntary movements triggered by sudden voluntary movements.1 PKD is a genetic disorder due to de novo mutations or autosomal dominant pedigree inheritance. Genetic linkage studies have generally localized the dominant gene to the pericentromic region of chromosome 16 (16p11-q21).2 Despite extensive searching, including mutation analysis of 157 genes in this region, the PKD gene remains unidentified.2
We present a child who had benign infantile convulsions and paroxysmal choreoathetosis (ICCA syndrome). Comparative genomic hybridization (CGH) microarray revealed a 0.60-Mb microdeletion in chromosome 16p11.2.
Case report.
The index male patient was born uneventfully to a family with no history of neurologic problems. His early development was slightly delayed, crawling at 15 months, walking at 18 months, with slightly slow language development compared to his peers. He always struggled slightly at school, but never enough to require additional school support or formal neuropsychological assessment. His social interaction and peer friendships were normal.
At 11 months of age, the patient had a short-lived cluster of tonic seizures over 3–4 days that were not associated with fever. His interictal EEG during this period was normal. He was treated with carbamazepine and the events never returned, although his compliance with carbamazepine was variable.
From the age of 7 years, he had events of PKD. His events were almost always triggered by a sudden movement such as sitting up. He described an aura of nonspecific discomfort. His events were characterized by involuntary movements of the upper limbs more than the lower limbs, with relative sparing of the face. An observed event demonstrated both chorea and dystonia. He retained awareness throughout events, and the events terminated within 10 seconds. He experienced a refractory period after events, during which time sudden movements usually did not precipitate an attack. The events occurred up to 5 times per day, but remitted completely when complying with carbamazepine 200 mg twice per day. Examination revealed intermittent distal limb posturing during gait examination, but no other abnormality.
His MRI brain showed an arachnoid cyst in the cerebellopontine angle of doubtful significance, and metabolic studies including calcium, magnesium, copper, and ceruloplasmin were normal.
A CGH 60K targeted microarray (agilent aCGH) with effective resolution of 0.25 Mb detected a 0.60-Mb microdeletion in chromosome 16p11.2 (chromosomal coordinates 29500284–30098069, ISCN 2009). This microdeletion included the genes between SL7A5P1 and CORO1A, and is not considered a benign variant. Testing of the parents with the same array had normal results.
Discussion.
We describe a case of benign infantile convulsions and childhood PKD that fulfills diagnostic criteria including responsiveness to carbamazepine.1 Linkage analysis of large PKD families have generally localized the PKD region to 16p11-q21 but have been unable to substantially narrow down this relatively large area. Kikuchi et al.2 screened 157 protein coding genes in the PKD critical region in up to 7 representative individuals, and were unable to detect consistent mutation abnormalities. Our case had a microdeletion involving a relatively small region (∼40 genes). Intriguingly, the microdeletion in our case was almost identical to a microdeletion recently reported in an atypical pediatric case of PKD who also had levodopa-responsive parkinsonism (chromosomal coordinates 29560500–30104842),3 and highlight potential candidate genes. KCTD13 is a potassium channel tetramerization domain, and interestingly autosomal recessive mutations in KCTD7 have recently been associated with a genetic form of myoclonic epilepsy with a degenerative course.4 DOC2A is also involved in this microdeletion and is involved in calcium-mediated neurotransmitter release. Likewise, SEZ6L2 is a seizure-related gene. PKD has autosomal dominant inheritance; therefore an alternate approach is to define deleted genes which are most likely to be haploinsufficient: MAPK3 ranks in the first centile for haploinsufficiency predictions using the Decipher UK Web site (https://decipher.sanger.ac.uk). MAPK genes are mitogen-activated protein kinase genes and are involved in cell signaling and response to cellular stress. MAPK genes have been shown to modulate neuronal voltage-gated sodium channels, so MAPK3 makes a further attractive candidate in PKD.5
Almost identical microdeletions in 16p11.2 have been described in ∼1% of cases of autism (de novo mutations), supporting the potential role in neurologic disease.6 The 16p11.2 microdeletions were not observed in 1,420 control individuals, and this microdeletion is not considered a benign variant.6 Why an almost identical microdeletion could result in differing phenotypes (autism or PKD) is unclear.
Methods to determine copy number variants such as CGH microarray may help to narrow the search for PKD genes, and may be a valuable tool in the search for novel genes in suspected genetic movement disorders.
Footnotes
-
Author contributions: Author contributions: R.C.D., P.G.S., V.S.C.F., and G.B.P. were involved in acquisition and interpretation of data. R.C.D., P.G.S., V.S.C.F., and G.B.P. were involved in writing of the report.
-
Disclosure: Dr. Dale has received grant funding from the National Health and Medical Research Council, University of Sydney, Star Scientific Foundation, and Tourette Syndrome Association; has received honoraria from Biogen-Idec; serves on a scientific advisory board for the Brisbane Children's Hospital; receives publishing royalties for Autoimmune and Inflammatory Disorders of the Nervous System in Children (Mac Keith Press, 2009); and has received research support from the American Tourette Syndrome Association and the Brain Foundation. Dr. Grattan-Smith reports no disclosures. Dr. Fung serves on scientific advisory boards for Abbott, Allergan, Inc., Boehringer Ingelheim, Hospira, Inc., Ipsen, Lundbeck Inc., Novartis, Solvay Pharmaceuticals, Inc., and UCB; has received funding for travel or speaker honoraria from Boehringer Ingelheim and Ipsen; serves on the editorial boards of Movement Disorders, ACTA Neuropsychiatrica, and Basal Ganglia; and receives research support from NH&MRC. Dr. Peters has received research support from Royal College of Pathologists, Australia, Human Genetics Society of Australasia, Genetics Society of Australasia, and Australasian Society of Cytogeneticists.
- Received April 11, 2011.
- Accepted June 14, 2011.
- Copyright © 2011 by AAN Enterprises, Inc.
Disputes & Debates: Rapid online correspondence
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.