MR Spectroscopy in Patients with Hereditary Diffuse Leukoencephalopathy with Spheroids and Asymptomatic Carriers of Colony-stimulating Factor 1 Receptor Mutation.

PURPOSE: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare neurodegenerative disorder with various clinical presentations. Mutation of the colony-stimulating factor 1 receptor (CSF1R) gene is considered to be a cause of this autosomal dominant disorder. The purpose of this study was to report magnetic resonance spectroscopy (MRS) findings in patients with HDLS and asymptomatic carriers and to clarify the use of MRS in this disease. MATERIALS AND METHODS: In this retrospective, institutional review board-approved study, we included four consecutive patients, genetically diagnosed with HDLS, and two asymptomatic carriers after acquiring informed consent. We performed single-voxel MRS of the left centrum semiovale on a 3-T clinical scanner. We also included a sex-matched normal dataset. We quantified N-acetylaspartate (NAA), creatine, choline-containing compounds (Cho), glutamine, glutamate (Glu), myo-inositol (Ins), glutathione, lactate (Lac), and gamma-amino butyric acid using LCModel. We performed statistical analysis, and P value <0.05 was considered significant. RESULTS: In HDLS cases, MRS revealed decreased NAA and Glu concentrations, which probably reflected neuronal damage and/or loss, and a subsequent reduction of neurotransmitters. A patient with HDLS also had increased Cho and Ins concentrations, indicating gliosis, and increased Cho concentration was also observed in an asymptomatic carrier. This suggests that metabolic changes had already occurred in an asymptomatic state. CONCLUSION: We demonstrated changes in metabolite concentrations not only in patients with HDLS but also in asymptomatic CSF1R mutation carriers. Our study indicates that MRS is a potentially useful tool for the analysis of metabolic and pathophysiological findings of HDLS, even during the early stages of disease.

Late-onset spastic paraplegia: Aberrant SPG11 transcripts generated by a novel splice site donor mutation.

We identified a novel homozygous mutation in the splice site donor (SSD) of intron 30 (c.5866+1G>A) in consanguineous Japanese SPG11 siblings showing late-onset spastic paraplegia using the whole-exome sequencing. Phenotypic variability was observed, including age-at-onset, dysarthria and pes cavus. Coding DNA sequencing revealed that the mutation affected the recognition of the constitutive SSD of intron 30, splicing upstream onto a nearby cryptic SSD in exon 30. The use of constitutive splice sites of intron 29 was confirmed by sequencing. The mutant transcripts are mostly subject to degradation by the nonsense-mediated mRNA decay system. SPG11 transcripts, escaping from the nonsense-mediated mRNA decay pathway, would generate a truncated protein (p.Tyr1900Phefs5X) containing the first 1899 amino acids and followed by 4 aberrant amino acids. This study showed a successful clinical application of whole-exome sequencing in spastic paraplegia and demonstrated a further evidence of allelic heterogeneity in SPG11. The confirmation of aberrant transcript by splice site mutation is a prerequisite for a more precise molecular diagnosis.