Quantitative neuroimaging in mucolipidosis type IV

Abstract

Mucolipidosis type IV (MLIV) is an autosomal recessive disorder resulting from mutations in the MCOLN1 gene. This gene encodes the endosomal/lysosomal transient receptor potential channel protein mucolipin-1 (TRPML1). Affected patients suffer from neurodevelopmental abnormalities and progressive retinal dystrophy. In a prospective natural history study we hypothesized the presence of an additional slow cerebral neurodegenerative process. We have recruited 5 patients, tested their neurodevelopmental status, and measured cerebral regional volumes and white matter integrity using MRI yearly. Over a period of up to 3 years, MLIV patients remained neurologically stable. There was a trend for increased cortical and subcortical gray matter volumes and increased ventricular size, while white matter and cerebellar volumes decreased. Mean diffusivity (MD) was increased and fractional anisotropy (FA) values were below normal in all analyzed brain regions. There was a positive correlation between motor scores of the Vineland Scale and the FA values in the corticospinal tract (corr coef 0.39), and a negative correlation with the MD values (corr coef -0.50) in the same brain region. We conclude from these initial findings that deficiency in mucolipin-1 affects the entire brain but that there might be a selective regional cerebral neurodegenerative process in MLIV. In addition, these data suggest that diffusion-weighted imaging might be a good biomarker for following patients with MLIV. Therefore, our findings may be helpful for designing future clinical trials.

Keywords: Lysosomal disorder; Mucolipidosis; Natural history; Volumetry.

Figure 1

Brain MRI of patient 2. A. T2-weighted (T2W) and B. Fluid Attenuated Inversion Recovery (FLAIR) images show increased signal in white matter suggesting dysmyelination (hypomyelination). C. Sagittal T1-weighted image (T1W) showing marked thinning of the corpus callosum and midline cerebellar hypoplasia or atrophy. D. Coronal T1-weighted image (T1W) showing normal white matter signal as well as hypoplastic or atrophic cerebellar hemispheres.

Figure 2

The sagittal T1-weighted image, and sagittal, coronal, and axial FA maps (from left to right) of two MLIV patients. Line arrow points towards left corticospinal tract, dashed arrow towards corpus callosum. Color codes to give directions: Red is left (L) to right (R). Green is anterior (A) to posterior (P). Blue is superior (S) to inferior (I). FA value is coded by brightness, i.e. higher FA values are portrayed with brighter colors. a: Patient 1 (visit 3), b: Patient 5 (visit 1). Note lower FA values on FA map images, and thinner corpus callosum, presence of cerebellar atrophy, enlarged third ventricle on T1W images in patient 5 compared to patient 1