Dehnavi et al. Human Genomics (2021) 15:45 https://doi.org/10.1186/s40246-021-00345-0 PRIMARY RESEARCH Open Access ACER3-related leukoencephalopathy: expanding the clinical and imaging findings spectrum due to novel variants Ali Zare Dehnavi1†, Erfan Heidari2†, Maryam Rasulinezhad1, Morteza Heidari1, Mahmoud Reza Ashrafi1, Mohammad Mahdi Hosseini1, Fatemeh Sadeghzadeh1, Mohammad-Sadegh Fallah3, Noushin Rostampour4, Amir Bahraini5,6, Masoud Garshasbi2 and Ali Reza Tavasoli1* Abstract Background: Leukodystrophies 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. Results: In 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. Conclusion: Our 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. Keywords: Leukodystrophy, Alkaline Ceramidase 3, Whole-exome sequencing, Magnetic resonance imaging Background or 3.01/1000,000 in children under the age of 18 years de- Leukodystrophies are a heterogeneous group of neuroge- pending on the applied epidemiological methods [3, 4]. netic disorders which affect either myelin production or The diagnostic approach is usually based on the pre- maintenance of the myelin mainly in the central nervous cise review of neurologic and non-neurologic symptoms system (CNS). They are associated with substantial morbid- and recognition of white matter involvement patterns in ity and mortality in children [1, 2]. The incidence of leuko- brain magnetic resonance imaging (MRI) [5]. Molecular dystrophies has been estimated to be 1 in 7663 live births 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 * Correspondence: [email protected]; [email protected] expanding of the clinical and imaging findings in pa- † Ali Zare Dehnavi and Erfan Heidari contributed equally to this work. tients and a wider perception of cellular aspects of the 1Myelin Disorders Clinic, Pediatric Neurology Division, Children’s Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, known genes. Tehran, Iran Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Dehnavi et al. Human Genomics (2021) 15:45 Page 2 of 11 ACER3 is responsible for coding the alkaline cerami- spasticity in lower limbs. At the age of 1.5 years, she dase enzyme which is responsible for the conversion of needed to be supported significantly in order to sit. The ceramide to sphingosine. Ceramide is a critical building maximum speech ability was not exceeding 2–3 incom- block for sphingolipids that are required for both growth plete words’ expression, and she had several problems and viability of cells. On the other hand, Ceramide plays with feeding and swallowing as she was fed with mixed as a sensor of stress that controls several cellular reac- ground foods and clear drinks. She had undergone sev- tions such as growth arrest or cell death. For cellular eral occupational therapy sessions which were ordered well-being, cellular levels of sphingosine, which is the by her primary care physician. She faced remarkable and product of normal ceramidase activity, and sphingosine more rapid neurologic regression after routine vaccin- phosphate are important [7, 8]. Thus, human alkaline ation at the age of 18 months, which led to considerable ceramidase plays an important role in cell response to feeding difficulties, the inability of word expression, and stress by controlling the hydrolysis process of ceramides poor head and neck control. Then, she was referred to in cells [9]. our clinic. On examination, she had low set ears, high Mutated ACER3 which results in the accumulation of arch palate and beaked nose, flat nasal bridge, and thick multiple sphingolipids and long-chain ceramides in brain eyebrows in addition to significant four limb dystonia, and blood circulation has been reported to be associated truncal hypotonia, and a noticeable degree of spasticity with abnormal brain white matter signals. This in her distal parts of both upper and lower limbs. phenomenon potentially accounts for a rare form of Upon the follow-up visit at 27 months of age, her main ACER3-related genetic leukoencephalopathy [10, 11]. clinical findings were four limb spasticity, severe general- Faint abnormal white matter signals in deep and peri- ized dystonia, hyperreflexia with + 3 deep tendon re- ventricular areas, thinning of corpus callosum, mild flexes (DTRs), and upward plantar reflex. Her weight supratentorial and cerebellar atrophy, and ventriculome- was 8 kg (less than 3rd centile, Z-score −3SD) and HC galy are the imaging findings that have been reported in was 47 cm (Z-score 0SD). She was taking the following association with mutations in ACER3 coding alkaline medications: diazepam, tizanidine, baclofen, melatonin, ceramidase (Table 1). and trihexyphenidyl. So far, only two mutations in ACER3 have been re- Basic metabolic tests indicated a high plasma lactate ported. Herein, we present three additional variants as a level of 39.7 mmol/L (NL < 16 mmol/L), while the re- cause for ACER3-related leukoencephalopathy in 3 cases sults of serum ammonia, homocysteine, and metabolic and discuss their clinical course and serial imaging find- screen (MS/MS) were all normal. The first brain mag- ings in detail which has resulted in expanding the netic resonance imaging (MRI) which was done at the spectrum of this disorder. first visit showed abnormal deep white matter signal changes especially in the posterior periventricular area Results of T2-weighted and FLAIR sequences, deepening of the Clinical assessments Sylvain fissures, and mild supratentorial atrophy, in Case 1 addition to exvacue ventriculomegaly (Fig. 1 (1A, 1C The patient was a 3-year-old female who presented to white arrows)), near-normal appearance of T1-weighted Myelin Disorders Clinic due to progressive neurologic sequence (Fig. 1 (1B)), and thinning of the corpus callo- regression which was first noticed at the age of 18 sum (Fig. 1 (1D)). months. She was the only child of a consanguineous par- Imaging findings in the second brain MRI at the age of ent which was born at 39 weeks of gestational age 27 months were similar to the first MRI but the severity through a Cesarean section following an uneventful de- of atrophy had increased in both the supratentorial area livery with birth weight and head circumference of 3550 and cerebellar vermis (not shown). g(Z-score +1SD) and 35.5 cm (Z-score +1SD), respect- According to the progressive patient’s clinical scenario, ively. Her mother had received good prenatal care with- normal basic metabolic studies, and parents’ consan- out any significant problems. The patient achieved her guinity, whole-exome sequencing (WES) was considered developmental milestones normally until the age of 5–6 to diagnose a possible underlying neurodegenerative months. At this age, she had acceptable social interac- disease. In the follow-up visit, at the age of 29 months, tions and was able to hold her head up, could sit with her parents reported infrequent focal seizures; therefore, one hand support, could say mama and dada, and was levetiracetam was prescribed for her to control the able to recognize her parents. Since then, developmental seizures. The patient was admitted into the hospital with arrest and neurologic regression began firstly by feeding clinical manifestations of aspiration pneumonia at the ages and swallowing