Sporadic hemiplegic migraine and delayed cerebral oedema after minor head trauma: a novel de novo CACNA1A gene mutation

Abstract

SIR–Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura in which attacks are associated with some degree of motor weakness or hemiparesis during the aura phase. Sporadic hemiplegic migraine (SHM) differs from FHM by the absence of affected family members.1, 2 Mutations have been reported in three genes: CACNA1A (19p13 – FHM1) coding for the α1 sub-unit of a calcium channel, ATP1A2 (1q23 – FHM2) coding for the Na+/K+ATP1A2α1 sub-unit, and SCN1A (FHM3 – 2q24) coding for the α1 sub-unit of a sodium channel. Patients with SHM only rarely have mutations in the FHM gene CACNA1A.3 The female patient was born at term by normal vaginal delivery after an uneventful pregnancy. Motor delay became apparent, with hypotonia, ataxia, and dysarthria. She sat at 3 years, and was unable to walk. She normally used a chair for mobility and had limited communication. Neurological signs were consistent with ataxic cerebral palsy, but with no causative diagnosis apparent. Comprehensive investigations, including magnetic resonance imaging (MRI) of the brain and muscle biopsy, were normal. At age 5 the patient sustained a head injury after her wheelchair was accidentally tipped over, causing her to strike the left side of her head. Over the course of a few hours she developed a reduced level of consciousness and was admitted to hospital. There was no focal neurological sign and a brain computed tomography was normal. Her level of consciousness returned to normal. However after 24 hours she developed a fever of 39°C. No infective focus was apparent and routine investigations, including cerebrospinal fluid examination, were unremarkable. Over the subsequent 48 hours she developed increasing right-sided weakness, with decreased tone, increased deep tendon reflexes, an extensor plantar response on the right, and unilateral upper motor neuron facial nerve palsy. She had a right-sided focal seizure on day 8, and on day 10 following the injury MRI demonstrated marked enlargement of the left cerebral hemisphere with generalized sulcal effacement and significant mass effect (Fig. 1). T2 weighted image D10 after injury showing left-sided cerebral oedema. Subsequently she developed a mild right hemiparesis, but otherwise she returned to her previous clinical state. Repeat MRI 7 months after the episode showed residual abnormal signal in the left caudate and lenticular nucleus (Fig. 2). There was no family history of migraine or disability. She continued to have migrainous attacks, some associated with brief episodes of hemiplegia. T2 weighted image 8 months after trauma with abnormal signal in the left caudate and lenticular nucleus (arrow). DNA of the patient was extracted from peripheral blood using standard procedures. The exons of CACNA1A coding for the segments S4, S5, S6, and the P-loop of the four domains of the protein were screened by a combination of single strand conformation polymorphism and direct sequencing. This screening identified a nucleotide substitution in exon 25 (c.4046G>A) leading to the missense mutation p.Arg1349Gln. This mutation affects a highly conserved residue within the domain III-S4 and was not present in a panel of 280 control chromosomes. This mutation was absent in her parents. We describe a novel de novo mutation in CACNA1A (p. Arg1349Gln) in a child with severe hemiplegic migraine induced by minor head trauma. There was no clinically affected first-degree relative, and neither parent carried the Arg1349Gln mutation confirming the de novo occurrence and leading to a diagnosis of genetic SHM. CACNA1A mutations have been reported only in a very small number of SHM patients prior to our case.4-11 SHM after minor head injury has been previously described. Curtain et al.10 described a previously well child with no relevant family history who developed delayed cerebral oedema following a fall of less than 3 feet, leading to coma and permanent disability. Kors et al. reported three patients who developed cerebral oedema following minor head trauma. Two patients were from the same family with severe FHM, but in the other patient there was no family history. All three were found to have the same C-to-T substitution of serine for lysine at codon 218 in the CACNA1A gene (S218L).11 The broad clinical spectrum of SHM may cause diagnostic difficulties. Clinical features in the patient described (severe motor delay, hypotonia and ataxia, and the absence of any paroxysmal neurological episodes) were non-specific. Her first recognized hemiplegic migraine attack occurred at age 5 after relatively minor head trauma, and only then was the diagnosis suspected. We would suggest that CACNA1A gene screening be considered when a child presents similarly in the absence of another causative diagnosis.