P-Tau and Subunit c Mitochondrial ATP Synthase Accumulation in the Central Nervous System of a Woman with Hurler–Scheie Syndrome Treated with Enzyme Replacement Therapy for 12 Years

Abstract

We report an autopsy case of a woman with mucopolysaccharidosis type I (MPS I) Hurler-Scheie syndrome who was treated with enzyme replacement therapy (ERT) for 12 years. This was the first case of MPS I treated with ERT in Japan. Pathological analysis showed no glycosaminoglycan accumulation in the liver and spleen as a result of long-term ERT, although severe aortic stenosis, diffuse intimal hyperplasia of the coronary artery, and fibrous hypertrophy of the endocardium were observed. Additionally, we detected subunit c mitochondrial ATP synthase (SCMAS) accumulation and mild tauopathy (hyperphosphorylated tau or p-tau, both 3-repeat and 4-repeat tau accumulation) in the same area of the cerebral limbic system and central gray matter of the mid brain and pons. Tauopathy is an important pathological finding in Alzheimer's disease and other neurodegenerative disorders; however, in MPS I, it is unclear whether tauopathy is a primary or secondary phenomenon. Thus, in this report, we describe pathological accumulation of p-tau and SCMAS in the context of MPS I and discuss the mechanisms and importance of these findings in the pathogenesis of MPS I.

Pathogenesis of Mucopolysaccharidoses, an Update

“…This finding was already evident at 1 month of age and was shown to increase with time [65]. Similar findings were observed post-mortem in the cerebral limbic system and central gray matter of the mid brain and pons in a patient with Hurler-Scheie MPS I [66].…”

Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses

“…Unlike other neurodegenerative disorders in which lesion localization is specific to each disease (e.g., the nigrostriatal dopaminergic system in Parkinson's disease [28] and caudate nucleus and putamen in Huntington's disease [29]), neuropathic MPS is considered to affect the brain in a more global fashion. This is shown in a postmortem report on a patient with MPS-I, which revealed wide substance accumulation throughout both the central and peripheral nervous system and no clear correlation between the neuropathological findings and the clinical picture [30]. This implies that the distribution patterns of GAG accumulation and the resultant neuropathological changes and/or neurotransmission defects may not be disease specific enough to give them pathognomonic or diagnostic value.…”

The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy

“…Mitochondrial dysfunction caused by impaired autophagy has been recognized in several LSDs, such as sphingolipidoses (Gaucher disease, Niemann-Pick disease type C, Krabbe disease), gangliosidoses, multiple sulfatase deficiency and neuronal ceroid lipofuscinoses (Parenti et al, 2021) and proposed as one of the mechanisms underlying MPS neurodegeneration (Saffari et al, 2017;Annunziata et al, 2018). Findings were observed post-mortem in a MPS I patients brain, in particular in the cerebral limbic system, central gray matter and pons (Kobayashi et al, 2018). Another link between autophagy and MPS has been reported recently.…”