Reversible Leukoencephalopathy in a Man with Childhood-onset Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

Abstract

A 49-year-old Japanese man had shown developmental delay, learning difficulties, epilepsy, and slowly progressive gait disturbance in elementary school. At 46 years old, he experienced repeated drowsiness with or without generalized convulsions, and hyperammonemia was detected. Brain magnetic resonance imaging detected multiple cerebral white matter lesions. An electroencephalogram showed diffuse slow basic activities with 2- to 3-Hz δ waves. Genetic tests confirmed a diagnosis of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Leukoencephalopathy was resolved following the administration of L-arginine and lactulose with a decrease in plasma ammonia levels and glutamine-glutamate peak on magnetic resonance spectroscopy. Leukoencephalopathy in HHH syndrome may be reversible with the resolution of hyperammonemia-induced glutamine toxicity.

Keywords: HHH syndrome; MRS; glutamine toxicity; hyperammonemia; leukoencephalopathy; magnetic resonance spectroscopy.

Figure 1.

Brain MRI and MRS. (A) FLAIR sequence image showing multiple high-intensity lesions in the cerebral white matter. (B) Twenty-eight months after the initial MRI evaluation, FLAIR detected cerebral white matter lesions with progression of cerebral atrophy. (C) FLAIR showing improvement in leukoencephalopathy with mild progression of cerebral atrophy two months after L-arginine and lactulose therapy. (D) MRS demonstrates a high Glx peak with normal peaks for NAA and GPC-PCh before treatment. (E) The decreased Glx peak on MRS is apparent eight months after initiating L-arginine and lactulose therapy. All ¹H-MRS scans were obtained using a Prisma 3.0-T Siemens system (Siemens Medical Solutions, Erlangen, Germany). A single-voxel MRS scan was obtained with a point-resolved spectroscopy sequence with water suppression: TR/TE=2,000/30 ms, voxel size=8 mL (2×2×2 cm³). The voxel was placed in the right semioval center. A non-water-suppressed spectrum was also obtained for the eddy-current correction. All MRS metabolites were quantified by fitting the experimental data in the frequency domain using the LCModel method (22). Ratios of the metabolite concentrations were calculated with respect to the total Cr and PCr values. Cr: creatine, FLAIR: fluid-attenuated inversion recovery, Glx: glutamine plus glutamate, GPC: glycerophosphocholine, MRI: magnetic resonance imaging, MRS: magnetic resonance spectroscopy, NAA: N-acetyl aspartylglutamic acid, PCh: phosphocholine, PCr: phosphocreatine, TE: echo time, TR: repetition time

Figure 2.

EEG findings. (A) An EEG obtained while awake showed diffuse slow basic activity with 2- to 3-Hz δ waves before treatment. (B) The EEG findings improved and demonstrated an α wave of approximately 8 Hz in frequency 1 month after initiating L-arginine and lactulose therapy. EEG: electroencephalogram