ABSTRACT
Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.
Subject(s)
Genetic Variation , Kinesins/genetics , Mutation/genetics , Nerve Tissue Proteins/genetics , Oculomotor Muscles/pathology , Ophthalmoplegia/congenital , Amino Acid Sequence , Child , Female , Fibrosis , Genetic Linkage , Heterozygote , Humans , Male , Molecular Sequence Data , Ophthalmoplegia/pathology , Pedigree , Phenotype , Sequence Homology, Amino AcidABSTRACT
Oculomotor ophthalmoplegic migraine is a rare episodic childhood condition in which a unilateral oculomotor palsy is preceded by headache. I describe six new cases that had magnetic resonance imaging signal abnormalities during the acute phase, consisting of a thickened and enhancing ipsilateral oculomotor nerve at its exit from the midbrain. During the quiescent phase, when the headache had resolved, the signal abnormalities were still present but less dramatic. Seventeen similar cases have been previously reported. The pathophysiology may be a trigeminovascular migraine epiphenomenon that is dependent on the unique oculomotor nerve anatomy and porous blood-nerve barrier at the emergence of the oculomotor nerve from the brainstem and the sequelae of demyelination. Early high-dose corticosteroid treatment is recommended to rapidly resolve an acute episode and to potentially prevent permanent abnormal oculomotor nerve signs.
