Electroclinical Features of Epilepsy in Mucopolysaccharidosis III: Outcome Description in a Cohort of 15 Italian Patients

Rita Barone,Renata Rizzo,Agata Fiumara,Lara Cirnigliaro,Claudia Guida,Fabio Pettinato,Maria Donatella Cocuzza,Mariangela Gulisano,Maurizio Elia,Filippo Greco

doi:10.3389/fneur.2021.705423

Abstract

Mucopolysaccharidosis III (Sanfilippo syndromes) types A–D are rare lysosomal storage disorders characterized by heparan sulfate accumulation and neurodegeneration. Patients with MPS III present with developmental stagnation and/or regression, sleep disturbance, and behavioral abnormalities usually in the first years of life. Epilepsy may occur in a proportion of patients during the disease course. However, the progression of epilepsy and EEG changes in MPS III have not been systematically investigated. We report electroclinical features in a cohort of patients with MPS III over a follow-up period ranging from 6.5 to 22 years. Participants include 15 patients (11 females; aged 7–31 years) with MPS III A (n = 7, 47%), MPS III B (n = 5, 34%), MPS III C (n = 2, 13%), and MPS III D (n = 1, 6%). At the time of this study, 8 out of 15 patients (53%) had epilepsy. Epilepsy occurred in patients with advanced disease even in the first decade of life (mean age at onset: 12.1 ± 6.7 years). However, seizure onset may also be associated with abrupt worsening of the neurobehavioral phenotype. The main epilepsy types observed were generalized (four out of eight, 50%), followed by focal (three out of eight, 37%) and combined (two out of eight, 25%) epilepsy and status epilepticus (one out of eight, 12.5%). Seizures were generally controlled by one antiepileptic drug (AED) and most patients (seven out of eight, 87%) were still on therapy after a median follow-up period of 5 years (range: 1–9 years). A total of 66 EEGs were analyzed with a median EEG follow-up duration of 7 years (range: 6 months−14 years). Slowing of the background activity occurred in 7 (46%) patients aged 4–19 years. Epileptiform EEG abnormalities were observed in 10 patients at a mean age of 9.6 ± 2.9 years. EEG epileptiform discharges were not unavoidably linked to epilepsy. Early recognition and careful monitoring of electroclinical features in MPS III is necessary for appropriate care and for the detection of disease progression.

Highlights

Lysosomal storage disorders (LSD) are inborn errors of metabolism caused by a deficiency of lysosomal function
Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) includes four autosomal recessive lysosomal storage disorders (MPS III A–D), caused by a deficiency in one of the four enzymes involved in the degradation of the glycosaminoglycan heparan sulfate
We examined the course of epilepsy and EEG findings in a series of patients with MPS III diagnosed over a 24-year period

Summary

Introduction

Lysosomal storage disorders (LSD) are inborn errors of metabolism caused by a deficiency of lysosomal function. Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) includes four autosomal recessive lysosomal storage disorders (MPS III A–D), caused by a deficiency in one of the four enzymes involved in the degradation of the glycosaminoglycan heparan sulfate. The progressive storage of heparan sulfate in the MPS III brain is associated with neuroinflammation and oxidative stress, protein misfolding, cellular signaling defects, and impairment of autophagy causing loss of neurons as well as cognitive and motor decline [4]. MPS III is characterized by developmental delay, impaired cognition, behavioral problems, and sleep disturbances [5, 6] and by the possible onset of epileptic seizures [7]. One individual with MPS III A (ID# 2) on treatment with valproate since 8 years of age was seizure-free and without epileptiform discharges in the last EEG recording at age 12 years

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Discussion

Conclusion