Brain Proton Magnetic Resonance Spectroscopy and Neuromuscular Pathology in a Patient With GM1 Gangliosidosis

Abstract

The authors report the clinical, neuroradiologic, and neuromuscular pathological findings in a patient with GM1 gangliosidosis. The proton magnetic resonance spectroscopy, previously reported in a single patient with GM1 gangliosidosis, detected a mild reduction of N-acetylaspartate, consistent with relative paucity of axons and neurons and increased levels of myoinositol suggestive of gliotic white matter changes along with the accumulation of an additional compound that could represent either guanidinoacetate or Gal beta 1-6Gal beta 1-4)GlcNAc, an oligosaccharide previously isolated from the urine of GM1 gangliosidosis patients. Although these findings will have to be further confirmed in more patients with GM1 gangliosidosis, they suggest that proton magnetic resonance spectroscopy may provide useful end points to assess the efficacy of novel treatments that could soon become clinically available. Histologically, no significant alterations were found in axons, but there was evidence of redundant and inappropriately folded myelin, which is a feature attributed to disturbed axon-glial interactions.

Novel Biomarkers of Human GM1 Gangliosidosis Reflect the Clinical Efficacy of Gene Therapy in a Feline Model

“…MRS has been used to evaluate human GM1 gangliosidosis at lower field strengths 41,42 and most recently at 3 T. 39 Because our clinical rating scale for GM1 cats was based largely on symptoms that involve the cerebellum, correlation between clinical scoring and cerebellar MRS was encouraging. Also noteworthy was the reduction of NAA in untreated GM1 cats early in the disease process (4 months of age) and in an asymptomatic GM1 cat years after gene therapy .…”

Myelin Abnormalities in the Optic and Sciatic Nerves in Mice With GM1-Gangliosidosis

“…Retinal and visual defects have been found in mice and other animals with GM1-gangliosidosis ( Read et al., 1976 ; Murray et al., 1977 ; Sheahan et al., 1978 ; Suzuki et al., 2001 ; Denny et al., 2007 ; Baek et al., 2010 ; NINDS, 2011 ). These abnormalities are characterized by ganglioside accumulation in the retinal ganglion cells and altered myelination of the optic nerve ( Sheahan et al., 1978 ; Kaye et al., 1992 ; Shen et al., 1998 ; Folkerth et al., 2000 ; Muller et al., 2001 ; Di Rocco et al., 2005 ; Gururaj et al., 2005 ; Brunetti-Pierri et al., 2008 ). GM1 ganglioside accumulates in retinal ganglion cells in humans and mice with GM1-gangliosidosis ( Emery et al., 1971 ; Weiss et al., 1973 ; Cogan et al., 1984 ; Bieber et al., 1986 ; Denny et al., 2007 ).…”

GM1 Gangliosidosis: Mechanisms and Management

“…With this spectroscopic method, which is coupled to magnetic resonance imaging (MRI), suppression of brain water and lipid signals allows for the quantification of metabolites in specific brain regions, localizing dysfunctional processes biochemically and providing a picture of disease severity (Table 1). 3,25,60,152,154 Erol et al ( 2006) first described the use of MRS in an infantile GM1 patient noting an increase in choline (Cho), which includes glycerophosphocholine (GPC) and phosphocholine (PCh), and a decrease in N-acetylaspartate (NAA) when normalized to creatine (Cr) in the thalamus relative to normal controls. 25 (When normalizing NAA to Cr, it is important to verify that Cr itself does not to change with disease progression, as in the feline GM1 model discussed in the following paragraph.)…”

“…A study of a different infantile GM1 patient similarly identified a decrease in NAA, while also noting an increase in myoinositol (Ins) in the basal ganglia. 154 Regier et al (2016) performed a more comprehensive MRS analysis of fifteen patients having late infantile/juvenile GM1 by quantifying metabolites at four brain regions: superior cerebellar vermis, left thalamus, left centrum semiovale, and midline parietal gray matter. In all four regions, a significant decrease in NAA was measured, which continued to decrease over time in concordance with disease progression.…”

“…3,25 Other metabolic alterations, including elevation of Ins, are indicative of gliosis, which is supported by histopathological findings. 154 Excess membrane turnover, or the inability to assemble choline-containing molecules in myelin, may explain the elevation in brain Cho and the overall isointensity of white and gray matter in advanced GM1. 25 One challenge noted in the acquisition and comparison of data from affected individuals is the absence of values from age-matched controls.…”