Severe Episodic Neurological Deficits and Permanent Mental Retardation in a Child with a Novel FHM2 ATP1A2 Mutation K. R. J. Vanmolkot, MSc, 1 H. Stroink, MD, 2 J. B. Koenderink, PhD, 3 E. E. Kors, MD, PhD, 4 J. J. M. W. van den Heuvel, 3 E. H. van den Boogerd, BSc, 1 A. H. Stam, MD, 4 J. Haan, MD, PhD, 4,5 B. B. A. de Vries, MD, PhD, 6 G. M. Terwindt, MD, PhD, 4 R. R. Frants, PhD, 1 M. D. Ferrari, MD, PhD, 4 and A. M. J. M. van den Maagdenberg, PhD 1,4 Objective: Attacks of familial hemiplegic migraine (FHM) are usually associated with transient, completely reversible symptoms. Here, we studied the ATP1A2 FHM2 gene in a young girl with episodes of both very severe and transient neurological symptoms that were triggered by mild head trauma as well as permanent mental retardation. Her family members suffered from hemiplegic and confusional migraine attacks. Methods: Mutation analysis of the ATP1A2 gene was performed by direct sequencing of all exons and flanking intronic regions, using genomic DNA of the proband. Functional consequences of the mutation were analyzed by cellular survival assays. Results: We identified a novel G615R ATP1A2 mutation in the proband and several of her family members. Functional analysis of mutant Na,K-ATPase in cellular survival assays showed a complete loss-of-function effect. Interpretation: Permanent mental retardation in chil- dren may be caused by ATP1A2 mutations. Ann Neurol 2006;59:310 –314 Familial hemiplegic migraine (FHM) is a rare autoso- mal dominant subtype of migraine, in which attacks are associated by hemiparesis in addition to other neu- rological aura symptoms. 1,2 Typically, these symptoms are fully reversible. The majority of patients have mu- tations in the neuronal calcium channel gene CACNA1A (FHM1). 3,4 Approximately 20% of FHM in families is linked to chromosome 1q23 (FHM2), 5 with mutations in the ATP1A2 gene, 6 encoding the 2-subunit of a Na,K-ATPase. Recently a mutation in the sodium channel gene SCN1A has been associated with FHM (FHM3). 7 The clinical spectrum associated with ATP1A2 mu- tations is expanding as childhood epilepsy, alternating hemiplegia of childhood, coma, sensory deficits, as well as transient and permanent cerebellar signs have been reported. 8,9 –13 Apart from cerebellar ataxia, permanent neurological symptoms have rarely been described in FHM. Here, we describe a novel ATP1A2 loss-of- function mutation in a young girl with permanent mental retardation after a few episodes of severe neu- rological deficits that were triggered by mild trauma. Several family members with the mutation suffered from hemiplegic and confusional migraine attacks, which were initially misdiagnosed as epilepsy. Patients and Methods Patient and Family Description The proband, III-10, was a 9-year-old girl who initially showed a normal psychomotor development. For ped- igree, see Figure 1. At age 2 years, she had two episodes of transient blindness, restlessness, and fever that were triggered by mild head trauma. The first episode lasted a few hours, the second several days. Cerebral magnetic resonance imaging (MRI) was unremarkable; the elec- troencephalogram (EEG) showed diffuse  and  activ- ity. After the second episode, there was a severe regres- sion in development and she showed autistic behavior that recovered slowly and incompletely over the next 2 years. She remained mildly retarded (IQ [Wechsler In- telligence Scale for Children–Revised] of 70 at age 8 From the 1 Department of Human Genetics, Leiden University Medical Centre, Leiden; 2 Department Neurology, St. Elisabeth and Tweesteden Hospital, Tilburg; 3 Department Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen; 4 Department Neurology, Leiden University Medical Centre Leiden, Leiden; 5 De- partment Neurology, Rijnland Hospital, Leiderdorp; and 6 Depart- ment Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Received Jul 14, 2005, and in revised form Oct 18. Accepted for publication Oct 25, 2005. Published online Jan 23, 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.20760 Address correspondence to Dr Ferrari, Department of Neurology, K5Q Leiden University Medical Centre, P.O. Box 9600, 2300 RC Leiden, the Netherlands. E-mail: m.d.ferrari@lumc.nl 310 © 2006 American Neurological Association Published by Wiley-Liss, Inc., through Wiley Subscription Services