Background: About 20%of patients with familial hemiplegic migraine (FHM) deve lop progressive cerebellar signs. Genetic studies have established an associatio n with mutations in the CACNA1A gene. However, the mechanisms underlying cerebel lar involvement are largely unknown. Objective: To use proton MR spectroscopy (1 H-MRS) to investigate metabolic alterations in the cerebellum as well as cortic al regions known to be involved in the propagation of migraine aura. Methods:Fif teen CACNA1A mutation carriers from three FHM families and 17 healthy control su bjects were studied. Eleven patients had clinical signs of cerebellar involvemen t. LCModel fits were used to estimate absolute concentrations of N-acetylaspart ate (NAA), myo-inositol (ml), glutamate (Glu), choline containing compounds, to tal creatine, and lactate in the superior cerebellar vermis (SCV), parietal cort ex, and occipital cortex.To control for atrophy effects, automated image segment ation was performed using SPM99. The brain parenchyma fraction(BPF) was determin ed for all three regions. Results: Compared with controls, the brain parenchyma fraction (BPF), NAA,and Glu were significantly reduced and mI was significantly elevated in the SCV of patients with FHM. In contrast, no metabolite alterations were found in supratentorial regions. BPF and NAA in the SCV significantly corr elated with cerebellar scores, in particular, gait ataxia. Conclusions: The find ings suggest that there is a regionally distinct neuronal impairment in the superio r cerebellar vermis that exceeds macroscopic tissue loss. Correlations with clin ical scores emphasize the functional relevance of localized atrophy (brain paren chyma fraction) and N-acetyl aspartate levels. These measures may be useful to monitor disease progression. The observed reductionin glutamate may in part refl ect impaired glutamatergic neurotransmission. Genetic studies have established an associatio n with mutations in the CACNA1A gene. However, the mechanisms underlying cerebel lar disease are large unknown. Objective: To use Proton MR spectroscopy (1 H-MRS) to investigate metabolic alterations in the cerebellum as well as cortic al regions known to be involved in the propagation of migraine aura. Methods: Fifteen teen CACNA1A mutation carriers from three FHM families and 17 healthy control su bjects were studied. Eleven patients had clinical signs of cerebellar involvemen t. LCModel fits were used to estimate absolute intensities of N-acetylaspart ate (NAA), myo-inositol (ml), glutamate and lactate in the superior cerebellar vermis (SCV), parietal cort ex, and occipital cortex. To control for atrophy effects, automated image segment antion was performed using SPM 99. T Results: Compared with controls, the brain parenchyma fraction (BPF), NAA, and Glu were significantly reduced in mI was significantly elevated in the SCV of patients with FHM. In contrast, no metabolite alterations were found in supratentorial regions. BPF and NAA in the SCV significantly corrlated with cerebellar scores, in particular, gait ataxia. Conclusions: The find ings suggest that there is a regionally distinct neuronal impairment in the superio cerebellar vermis correlations with clinical lesions emphasize the functional relevance of localized atrophy (brain parenchyma fraction) and N-acetyl aspartate levels. These measures may be useful to monitor disease progression. The observed reduction in glutamate may in part reflct impaired glutamatergic neurotransmission.