Brain Involvement—The Ultimate Challenge

Abstract

Lysosomal storage disorders (LSDs) typically present with a spectrum of phenotypes. More severe disease in terms of progression and complications is usually seen in patients with early neuronopathic manifestations. The primary central nervous system (CNS) pathology has traditionally been thought to be caused mainly by intracerebral storage of undegraded substrates of the deficient lysosomal enzymes. Visceral organs such as the liver, spleen, and kidney are easily reached by IV administration of enzyme replacement therapy. These therapies can overcome and prevent local substrate accumulation, whereas avascular tissues, such as cartilage and cornea, are not within reach for circulating enzymes. The brain presents a particular challenge, as the blood‐brain barrier (in health) prevents therapeutic enzymes from entering brain parenchyma. Despite this, some clinical indications of (partial) CNS progression/prevention effects of various “systemic-intended” enzyme replacement therapies in neuronopathic patients, especially with Gaucher disease, mucopolysaccharidosis (MPS) I, and MPS II, have been observed. As a result, additional adapted ideas regarding the possible etiopathology of CNS manifestations in LSDs have emerged. Among these are questioning whether the blood‐brain barrier is “leaky” in some LSDs, whether secondary damage to the brain can be a consequence of systemic disease (eg, hypoxia in MPS with sleep apneas), and whether aggregation of mutated proteins could cause disruption of neuronal cell function. New management approaches have also emerged. Among them is earlier and higher doses of IV enzyme replacement therapy. One concern with this treatment is that antigenicity may play a more important role in neuronopathic patients since they often have more nonsense mutations. The impact of antigenicity and immune response, especially in the CNS, to repeated delivery of exogenous proteins must be studied in more detail in animal models (MPS IIIA, MPS I). Another approach is the development of strategies to bypass the blood‐brain barrier, specifically targeting therapeutic enzymes to the CNS and peripheral nervous system. Lonser et al 1 recently published an approach with “direct convective delivery” of glucocerebrosidase in the CNS of 1 patient with chronic neuronopathic Gaucher disease. Other pharmacologic delivery techniques have been investigated, but they are limited in how they can be used clinically. Yet other therapeutic strategies—such as substrate reduction therapy, enzyme enhancement with chaperones, or gene therapy—have the theoretical potential to be effective in the brain but may have to be combined with enzyme replacement therapy. It is clear that specific advanced pathophysiologic changes (eg, neuronal cell loss, ectopic dendritogenesis) are not reversible; hence, early diagnosis, referral, intervention, and prevention are essential. The success of old and new therapeutic strategies depends on a small and early time window critical for intervention. In addition, timely and adequate use of supportive therapies and interventions is needed (eg, positive pressure ventilation in MPS, antiepileptic agents in Gaucher disease). Systematic and collaborative research in this field is warranted. Therefore, natural history studies, with a focus on manifestation and progression of neurologic signs and symptoms, as well as new techniques to examine and measure “neuronopathic disease,” are needed.