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Persistent basal ganglia involvement in aminoacylase-1 deficiency: expanding imaging findings and review of literature

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Abstract

Background

Aminoacylase-1 deficiency (ACY1D) is an autosomal recessive rare inborn error of metabolism, which is caused by disease-causing variants in the ACY1. This disorder is characterized by increased urinary excretion of specific N-acetyl amino acids. Affected individuals demonstrate heterogeneous clinical manifestations which are primarily neurologic problems. In neuroimaging, corpus callosum hypoplasia, cerebellar vermis atrophy, and delayed myelination of cerebral white matter have been reported.

Aims

Finding disease-causing variant and expanding imaging findings in a patient with persistent basal ganglia involvement.

Methods

Whole-exome sequencing was performed in order to identify disease-causing variants in an affected 5-year-old male patient who presented with neurologic regression superimposed on neurodevelopmental delay following a febrile illness. He had inability to walk, cognitive impairment, speech delay, febrile-induced seizures, truncal hypotonia, moderate to severe generalized dystonia, and recurrent metabolic decompensation.

Results

All metabolic tests were normal except for a moderate metabolic acidosis following febrile illnesses. The results of serial brain magnetic resonance imaging (MRI) at ages 1 and 4.5 years revealed persistent bilateral and symmetric abnormal signals in basal ganglia mainly caudate and globus pallidus nuclei with progression over time in addition to a mild supratentorial atrophy. A homozygous missense variant [NM_000666.3: c.1057C>T; p.(Arg353Cys)] was identified in the ACY1, consistent with aminoacylase-1 deficiency. Variant confirmation in patient and segregation analysis in his family were performed using Sanger sequencing.

Conclusions

Our findings expanded the phenotype spectrum of ACY1-related neurodegeneration by demonstrating persistent basal ganglia involvement and moderate to severe generalized dystonia.

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Availability of data and materials

Human variant and pertinent phenotypes have been reported to ClinVar (Submission ID: SUB9358917; Accession ID: SCV001547499).

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Acknowledgements

We thank the families’ patients to participate in this study. The authors are especially thankful to the personnel of the DeNA laboratory (https://dna-lab.ir/) and Pardis Gene Technology company (http://www.pardisgene.com) for supporting the study. The authors appreciate the contribution of the staffs of Medical Genetics Department of Medical Sciences Faculty, Tarbiat Modares University, Tehran, Iran.

Funding

The results of this publication were supported and funded by Tehran University of Medical Sciences (grant number: 96-02-30-35551). In addition, the National Institute for Medical Research Development (Proposal No. 983886) provided financial and logistic support for this study but had no role in study design, data collection and analysis, data interpretation, and writing of the report, or in making decision to submit the article for publication.

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Authors and Affiliations

  1. Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran

    Mohammad Farid Mohammadi

  2. PardisGene Co., Tehran, Iran

    Mohammad Farid Mohammadi, Seyyed Mohammad Kahani & Pouria Mohammadi

  3. Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Ali Dehghani, Kiana Zarabadi, Seyyed Mohammad Kahani, Setareh Sayyad, Pouria Mohammadi & Masoud Garshasbi

  4. Myelin Disorders Clinic, Pediatric Neurology Division, Children’s Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran

    Mahmoud Reza Ashrafi, Morteza Heidari, Pouria Mohammadi & Ali Reza Tavasoli

  5. Pediatric Headache Program, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, USA

    Ali Reza Tavasoli

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  1. Mohammad Farid Mohammadi
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Contributions

MG, ART, and PM conceived and designed the experiments. MFM, AD, KZ, SMK, SS, MRA, MH, and AHB conducted the experiments. MG, MFM, AD, ART, and SMK analyzed and interpreted the data. ART, MG, and MFM contributed reagents/materials/analysis tools. AHB, AD, KZ, SMK, SS, and MFM wrote the paper. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Masoud Garshasbi or Ali Reza Tavasoli.

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Ethics approval

Ethics approval for the study protocol was confirmed by The Human Ethics Committee of Tarbiat Modares University.  

Inform consent

Written consent was obtained from parents as legal guardians of the proband.

Consent for publication

The study was performed following the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Competing interests

The authors declare no competing interests.

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Mohammad Farid Mohammadi and Ali Dehghani contributed equally to this work.

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Mohammadi, M.F., Dehghani, A., Zarabadi, K. et al. Persistent basal ganglia involvement in aminoacylase-1 deficiency: expanding imaging findings and review of literature. Ir J Med Sci 193, 449–456 (2024). https://doi.org/10.1007/s11845-023-03452-0

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