Abstract
BackgroundGM1-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.ObjectivesThe 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.MethodsBrain 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.ResultsThe 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).ConclusionsThe 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.
Highlights
Infantile and juvenile GM1-gangliosidosis and the GM2-gangliosidoses (Tay-Sachs disease and Sandhoff disease) are inherited metabolic diseases in which deficiency of a lysosomal enzyme results in accumulation of gangliosides in the central nervous system (CNS), leading to progressive neurodegeneration, and early death [1]
In contrast to apparent enlargement of the total brain volume, and 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 decreased in patients with infantile GM1-gangliosidosis and juvenile GM1- and GM2-gangliosidosis; infantile GM2-gangliosidosis cerebellar cortex was the exception, increasing in size
Summary
Infantile and juvenile GM1-gangliosidosis and the GM2-gangliosidoses (Tay-Sachs disease and Sandhoff disease) are inherited metabolic diseases in which deficiency of a lysosomal enzyme results in accumulation of gangliosides in the central nervous system (CNS), leading to progressive neurodegeneration, and early death [1]. In Tay-Sachs disease, mutations occurring on the HEXA gene result in a defective α-subunit [1,2]. In Sandhoff disease mutations occurring to the HEXB gene, prevent production of a normal β subunit [1,2,3]. In the B1 variant of Tay-Sachs disease, a heterodimer between the α-subunit and β-subunit of hexosaminidase is able to form, but defects in the catalytic site of the hexosaminidase A enzyme result in deficient catalytic activity of the dimer [1,2]. Progressive brain atrophy is characteristic, longitudinal quantification of specific brain structures has not been systematically studied
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