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 of future clinical trials.

Cognitive Development in a Young Child with Mucolipidosis Type IV: A Case Report

“…The child reported on in this study displayed significant developmental delays in these areas, but more mild delays relative to peers in receptive language and visual reception at 29 months. The age equivalence scores observed for this child were also somewhat more advanced than those reported in other studies of people with ML IV (Amir et al 1987;Schiffmann et al 2014). Possible explanations for this difference include the individual variation in disorder severity and course, the reporting style of the mother, the content of the direct Note: SICD scores represent estimated age equivalence in months, CDI scores represent total items endorsed by the parent from a total of 396 possible words assessment measures, or the effect of early intervention for the child.…”

“…The majority of people with ML IV are not able to walk independently (Mucolipidosis type IV 2015). Neuroanatomical studies reveal that people with ML IV exhibit decreased white matter volume, especially in the cerebellum (Schiffmann et al 2014).…”

“…Results of assessments of people with ML IV must be interpreted with great caution, however, due to the difficulty in making valid inferences about cognition from tasks that may be inaccessible to people with severe motor impairments (Martin et al 2008). There is also variability in reports of whether people with ML IV make developmental progress, regress, or remain static after infancy (Amir et al 1987;Schiffmann et al 2014).…”

White Matter Microstructure and Subcortical Gray Matter Structure Volumes in Aspartylglucosaminuria; a 5-Year Follow-up Brain MRI Study of an Adolescent with Aspartylglucosaminuria and His Healthy Twin Brother

“…Krabbe disease, Cystinosis, Niemann-Pick type C, Gaucher type I and II, Mucolipidosis type IV and Fabry disease), it has been suggested that GM volumetric analysis and/or quantitative DTI may be useful modalities for indexing illness stage and monitoring response to emerging treatment (Escolar et al 2009;Bava et al 2010;Walterfang et al 2010;Davies et al 2011;Schiffmann et al 2014;Paavilainen et al 2013). Based on our preliminary study, automated volumetric brain analysis and quantitative DTI may be suitable biomarkers for evaluating effects of possible AGU treatments, although further studies with a larger population size, including patients from different age groups, are necessary.…”

A novel homozygous MCOLN1 double mutant allele leading to TRP channel domain ablation underlies Mucolipidosis IV in an Italian Child

“…Schiffmann et al [Schiffmann et al 2014] recently demonstrated that a clear volumetric reduction of the cerebellum may occur in MLIV patients with a relatively stable neurological picture. White matter involvement was characterized by both incomplete myelination and additional focal areas of dysmyelination in the periventricular regions.…”