Metallothioneins as dynamic markers for brain disease in lysosomal disorders

Lysosomal storage disorders (LSDs) comprise a class of inherited diseases characterized by disruption of normal lysosomal function. Incompletely degraded substrates accumulate, accompanied by cellular dysfunction and death. Neuroinflammation occurs as a reaction to substrate accumulation within microglia and astrocytes or as a response to primary neuronal or oligodendroglial damage.1 Neuroinflammation is of particular relevance in mediating the neuropathology associated with LSDs. Metachromatic leukodystrophy (MLD; Online Mendelian Inheritance in Man database #250100), a demyelinating LSD caused by mutations in the arylsulfatase A (ARSA) gene,2 is a prototypical example of LSD with progressive accumulation of undegraded sulfatides in the nervous system as well as neuroinflammation and neurodegeneration. MLD is an autosomal recessive disease with an estimated incidence of 1:40,000 to 1:100,000.3 The disease is classified into late infantile, juvenile, and adult forms according to the age at onset of symptoms. Clinical manifestations, which consist of unrelenting motor and cognitive impairment, progress rapidly and are more severe in the early onset variants, frequently leading to death within the first decade of life. A correlation between MLD phenotype and ARSA mutations has recently been suggested.4,5 Considerable research activity is currently focused on developing strategies to target brain disease in MLD and other LSDs with central nervous system (CNS) involvement. Gene therapy,6–8 enzyme replacement therapy,9 and small molecular weight compounds are advancing from preclinical to early clinical studies and may enable disease-modifying treatments for these thus far incurable, devastating diseases. Clinical phenotypes and disease progression are highly variable, thus complicating the study of new therapies. Tracking aspects of the complex CNS pathology and their response to novel treatments is particularly challenging. To facilitate therapeutics development, biomarkers of brain disease that can be monitored in support of clinical endpoints would be helpful. Molecular changes have been increasingly appreciated in various neurological diseases in cells outside the nervous system, including in circulating blood cells.10–13 We hypothesized that deciphering the molecular networks progressively perturbed in patients with MLD, and possibly in other LSDs, could highlight novel markers potentially useful for accelerating therapeutics development.