ACER3-related leukoencephalopathy: expanding the clinical and imaging findings spectrum due to novel variants

Ali Zare Dehnavi,Fatemeh Sadeghzadeh,Noushin Rostampour,Masoud Garshasbi,Erfan Heidari,Amir Bahraini,Morteza Heidari,Maryam Rasulinezhad,Mahmoud Reza Ashrafi,Mohammad Mahdi Hosseini,Mohammad-Sadegh Fallah,Ali Reza Tavasoli

doi:10.1186/s40246-021-00345-0

Abstract

BackgroundLeukodystrophies are the main subgroup of inherited CNS white matter disorders which cause significant mortality and morbidity in early years of life. Diagnosis is mostly based on clinical context and neuroimaging findings; however, genetic tools, particularly whole-exome sequencing (WES), have led to comprehending the causative gene and molecular events contributing to these disorders. Mutation in Alkaline Ceramidase 3 (ACER3) gene which encodes alkaline ceramidase enzyme that plays a crucial role in cellular growth and viability has been stated as an uncommon reason for inherited leukoencephalopathies. Merely only two ACER3 mutations in cases of progressive leukodystrophies have been reported thus far.ResultsIn the current study, we have identified three novel variants in ACER3 gene in cases with new neurological manifestations including developmental regression, dystonia, and spasticity. The detected variants were segregated into family members.ConclusionOur study expands the clinical, neuroimaging, electroencephalographic, and genetic spectrum of ACER3 mutations. Furthermore, we reviewed and compared the findings of all the previously reported cases and the cases identified here in order to facilitate their diagnosis and management.

Highlights

Leukodystrophies are the main subgroup of inherited central nervous system (CNS) white matter disorders which cause significant mortality and morbidity in early years of life
Leukodystrophies are a heterogeneous group of neurogenetic disorders which affect either myelin production or maintenance of the myelin mainly in the central nervous system (CNS)
We present three additional variants as a cause for Alkaline Ceramidase 3 (ACER3)-related leukoencephalopathy in 3 cases and discuss their clinical course and serial imaging findings in detail which has resulted in expanding the spectrum of this disorder

Summary

Introduction

Leukodystrophies are the main subgroup of inherited CNS white matter disorders which cause significant mortality and morbidity in early years of life. Leukodystrophies are a heterogeneous group of neurogenetic disorders which affect either myelin production or maintenance of the myelin mainly in the central nervous system (CNS). They are associated with substantial morbidity and mortality in children [1, 2]. Molecular studies especially whole-exome sequencing analysis are essential diagnostic tools to identify the causative genes [6]. Such studies in some cases may result in the expanding of the clinical and imaging findings in patients and a wider perception of cellular aspects of the known genes.

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Discussion

Conclusion