Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study

Abstract

Background GM1-gangliosidosis and GM2-gangliosidosis (Tay-Sachs disease and Sandhoff disease) are unrelenting heritable neurodegenerative conditions of lysosomal ganglioside accumulation. Although progressive brain atrophy is characteristic, longitudinal quantification of specific brain structures has not been systematically studied. Objectives The goal of this longitudinal study has been to quantify and track brain MRI volume changes, including specific structure volume changes, at different times in disease progression of childhood gangliosidoses, and to explore quantitative brain MRI volumetry (qMRI) as a non-invasive marker of disease progression for future treatment trials. Methods Brain qMRI studies were performed in 14 patients with gangliosidoses (9 infantile, 5 juvenile) yearly. Cerebellar cortex and white matter, caudate, putamen, corpus callosum, ventricles, total brain, and intracranial volumes were measured, as well as total brain volume. Age-matched controls were available for the patients with the juvenile phenotype. Results The infantile phenotype of all gangliosidoses showed a consistent pattern of macrocephaly and rapidly increasing intracranial MRI volume with both (a) brain tissue volume (cerebral cortex and other smaller structures) and (b) ventricular volume (P < 0.01 for all). In contrast to apparent enlargement of the total brain volume, and chiefly the enlarged cerebral cortex, a subset of smaller brain substructures generally decreased in size: the corpus callosum, caudate and putamen became smaller with time. The volume of cerebellar cortex also decreased in patients with infantile GM1-gangliosidosis and juvenile GM1- and GM2-gangliosidosis; however, infantile GM2-gangliosidosis cerebellar cortex was the exception, increasing in size. Elevated intracranial pressure (estimated by lumbar spinal pressure) was a common finding in infantile disease and showed continued increases as the disease progressed, yet lacked MRI signs of hydrocephalus except for increasing ventricular size. Notably, in patients with juvenile gangliosidosis, macrocephaly and elevated intracranial pressure were absent and total brain volume decreased with time compared to controls (P = 0.004). Conclusions The disease course of infantile versus juvenile gangliosidoses is clearly distinguished by the rate of brain disease progression as characterized by qMRI. Assessments by qMRI represent a robust non-invasive method for monitoring CNS changes in the clinical course of gangliosidoses and is ideally suited to monitor effects of novel CNS-directed therapies in future clinical trials.

The juvenile gangliosidoses: A timeline of clinical change

“…Magnetic resonance imaging exams were performed to evaluate brain changes and to measure changes in cerebral structure volumes. These results have been previously reported by Nestrasil, et al [ 15 ].…”

Intracerebroventricular enzyme replacement therapy with β-galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice

“…These patients rapidly lose all motor skills, with death occurring by 2–4.5 years of age ( 1 ). GM1 gangliosidosis patients with higher levels of residual mutant β-gal activity present with late-infantile, juvenile, and adult-onset forms of CNS-related disease progression, with a longer survival ( 5 , 6 ). GM1 gangliosidosis patients also manifest several additional symptoms due to substrate accumulation in various systemic tissues, which coincide with less life-threatening but severely debilitating symptoms of the skeletal system, including epiphyseal dysplasia, scoliosis, and hip dysplasia ( 5 ).…”

New Approaches to Tay-Sachs Disease Therapy

“…The infantile form, which is characterized by onset around 6 months of age and very low HexA activity levels (<0.5%), rapidly manifests with mental and motor developmental delay ( Sandhoff and Christomanou, 1979 ). In the most severe infantile forms symptoms may occur a few months after childbirth ( Nestrasil et al, 2018 ). Common neurodegenerative symptoms in infants are hypotension, inability to sit or hold their head unsupported, eye movement abnormalities, dysphagia, spasms, and hypomyelination ( Jarnes Utz et al, 2017 ).…”

“…Common symptoms are ataxia, dysarthria, dysphagia development, hypotension, and spasm progression. Most patients do not live past the age of 15 years ( Nestrasil et al, 2018 ). In adolescent patients the disease is less severe but has a wider range of symptoms ( Regier et al, 2016 ).…”