Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
    • Education
  • Online Sections
    • COVID-19
    • Inclusion, Diversity, Equity, Anti-racism, & Social Justice (IDEAS)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • Topics A-Z
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
    • Education
  • Online Sections
    • COVID-19
    • Inclusion, Diversity, Equity, Anti-racism, & Social Justice (IDEAS)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • Topics A-Z
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center
  • Home
  • Articles
  • Issues

User menu

  • My Alerts
  • Log in

Search

  • Advanced search
Neurology Genetics
Home
A peer-reviewed clinical and translational neurology open access journal
  • My Alerts
  • Log in
Site Logo
  • Home
  • Articles
  • Issues

Share

October 2018; 4 (5) Clinical/Scientific NotesOpen Access

AP4S1 splice-site mutation in a case of spastic paraplegia type 52 with polymicrogyria

Susana Carmona, Clara Marecos, Marta Amorim, Ana C. Ferreira, Carla Conceição, José Brás, Sofia T. Duarte, Rita Guerreiro
First published September 19, 2018, DOI: https://doi.org/10.1212/NXG.0000000000000273
Susana Carmona
From the Department of Molecular Neuroscience (S.C., J.B., R.G.), UCL Institute of Neurology, University College London, United Kingdom; Paediatric Neurology Department (C.M., S.T.D.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Genetics Department (M.A.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Reference Center of Inherited Metabolic Diseases (A.C.F.), Centro Hospitalar de Lisboa Central; Neuroradiology Department (C.C.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; UK Dementia Research Institute (J.B., R.G.), University College London, United Kingdom; and Department of Medical Sciences (J.B., R.G.), Institute of Biomedicine, iBiMED, University of Aveiro, Portugal.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Clara Marecos
From the Department of Molecular Neuroscience (S.C., J.B., R.G.), UCL Institute of Neurology, University College London, United Kingdom; Paediatric Neurology Department (C.M., S.T.D.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Genetics Department (M.A.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Reference Center of Inherited Metabolic Diseases (A.C.F.), Centro Hospitalar de Lisboa Central; Neuroradiology Department (C.C.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; UK Dementia Research Institute (J.B., R.G.), University College London, United Kingdom; and Department of Medical Sciences (J.B., R.G.), Institute of Biomedicine, iBiMED, University of Aveiro, Portugal.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marta Amorim
From the Department of Molecular Neuroscience (S.C., J.B., R.G.), UCL Institute of Neurology, University College London, United Kingdom; Paediatric Neurology Department (C.M., S.T.D.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Genetics Department (M.A.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Reference Center of Inherited Metabolic Diseases (A.C.F.), Centro Hospitalar de Lisboa Central; Neuroradiology Department (C.C.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; UK Dementia Research Institute (J.B., R.G.), University College London, United Kingdom; and Department of Medical Sciences (J.B., R.G.), Institute of Biomedicine, iBiMED, University of Aveiro, Portugal.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ana C. Ferreira
From the Department of Molecular Neuroscience (S.C., J.B., R.G.), UCL Institute of Neurology, University College London, United Kingdom; Paediatric Neurology Department (C.M., S.T.D.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Genetics Department (M.A.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Reference Center of Inherited Metabolic Diseases (A.C.F.), Centro Hospitalar de Lisboa Central; Neuroradiology Department (C.C.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; UK Dementia Research Institute (J.B., R.G.), University College London, United Kingdom; and Department of Medical Sciences (J.B., R.G.), Institute of Biomedicine, iBiMED, University of Aveiro, Portugal.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carla Conceição
From the Department of Molecular Neuroscience (S.C., J.B., R.G.), UCL Institute of Neurology, University College London, United Kingdom; Paediatric Neurology Department (C.M., S.T.D.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Genetics Department (M.A.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Reference Center of Inherited Metabolic Diseases (A.C.F.), Centro Hospitalar de Lisboa Central; Neuroradiology Department (C.C.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; UK Dementia Research Institute (J.B., R.G.), University College London, United Kingdom; and Department of Medical Sciences (J.B., R.G.), Institute of Biomedicine, iBiMED, University of Aveiro, Portugal.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
José Brás
From the Department of Molecular Neuroscience (S.C., J.B., R.G.), UCL Institute of Neurology, University College London, United Kingdom; Paediatric Neurology Department (C.M., S.T.D.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Genetics Department (M.A.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Reference Center of Inherited Metabolic Diseases (A.C.F.), Centro Hospitalar de Lisboa Central; Neuroradiology Department (C.C.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; UK Dementia Research Institute (J.B., R.G.), University College London, United Kingdom; and Department of Medical Sciences (J.B., R.G.), Institute of Biomedicine, iBiMED, University of Aveiro, Portugal.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sofia T. Duarte
From the Department of Molecular Neuroscience (S.C., J.B., R.G.), UCL Institute of Neurology, University College London, United Kingdom; Paediatric Neurology Department (C.M., S.T.D.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Genetics Department (M.A.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Reference Center of Inherited Metabolic Diseases (A.C.F.), Centro Hospitalar de Lisboa Central; Neuroradiology Department (C.C.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; UK Dementia Research Institute (J.B., R.G.), University College London, United Kingdom; and Department of Medical Sciences (J.B., R.G.), Institute of Biomedicine, iBiMED, University of Aveiro, Portugal.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rita Guerreiro
From the Department of Molecular Neuroscience (S.C., J.B., R.G.), UCL Institute of Neurology, University College London, United Kingdom; Paediatric Neurology Department (C.M., S.T.D.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Genetics Department (M.A.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Reference Center of Inherited Metabolic Diseases (A.C.F.), Centro Hospitalar de Lisboa Central; Neuroradiology Department (C.C.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; UK Dementia Research Institute (J.B., R.G.), University College London, United Kingdom; and Department of Medical Sciences (J.B., R.G.), Institute of Biomedicine, iBiMED, University of Aveiro, Portugal.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Full PDF
Citation
AP4S1 splice-site mutation in a case of spastic paraplegia type 52 with polymicrogyria
Susana Carmona, Clara Marecos, Marta Amorim, Ana C. Ferreira, Carla Conceição, José Brás, Sofia T. Duarte, Rita Guerreiro
Neurol Genet Oct 2018, 4 (5) e273; DOI: 10.1212/NXG.0000000000000273

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
348

Share

  • Article
  • Figures & Data
  • Info & Disclosures
Loading

Hereditary spastic paraplegias (HSPs) are a group of rare inherited neurodegenerative disorders that result from primary retrograde dysfunction of the long descending fibers of the corticospinal tract, causing lower limb spasticity and muscular weakness. This group of diseases has a heterogeneous clinical presentation. An extensive list of associated genes, different inheritance patterns, and ages at onset have been reported in HSPs.1 Spastic paraplegia type 52 (SPG52) is an autosomal recessive disease caused by AP4S1 mutations. The disease is characterized by neonatal hypotonia that progresses to hypertonia and spasticity in early childhood, developmental delay, mental retardation, and poor or absent speech. Febrile or afebrile seizures may also occur.2,–,4

Clinical case presentation

We report the case of a Portuguese 2-year-old boy born to healthy nonconsanguineous parents after a full-term gestation with intrauterine growth restriction after week 37. During the first months of life, the patient presented poor weight gain, hyperammonemia with elevation of glutamine and ornithine, low citrulline, and negative orotic acid. Weight recovery and normalization of amino acid profile were observed after protein restriction and remained normal after reintroduction of normal diet. Genetic study of urea cycle disorders (NAGS, CPS, and OTC) was negative. Around 9 months of age, global developmental delay, hypotonia, and strabismus were evident. Brain MRI with spectroscopy (performed at 10 months) showed delayed myelination/hypomyelination associated with a posterior perisylvian polymicrogyria, thinning of the corpus callosum, dilation and dysmorphia of the ventricles, and enlargement of the subarachnoid frontotemporal space (figure A). Spectroscopy suggested a possible discrete reduction of N-acetylaspartate. EEG showed a slight intermittent lentification in the left temporal region. At 15 months of age, the patient had 1 afebrile episode of status epilepticus. Two previous shorter episodes with fever had also occurred. Levetiracetam was started. No regression of psychomotor development after seizure was observed, and the patient has been evolving gradually with improvement of axial hypotonia. He says a few simple words, responds to his name, and has some nonverbal communication. The most recent neurologic evaluation revealed an alteration of the muscle tone (hypertonia) in the left lower limb and pyramidal signs in both legs.

Figure
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure Patient's brain imaging, pedigree, and consequences of AP4S1 c.294+1G>T variant

(A) Left image: sagittal T1 weighted image showing thin corpus callosum. Central and right images: axial T2 weighted images showing delayed myelination, bilateral posterior perisylvian polymicrogyria, dysmorphic and enlarged ventricles, and enlargement of subarachnoid space. (B) Family pedigree. The proband presents the splice-site variant chr14:g.31542180G>T NM_001128126.2:c.294+1G>T in the homozygous state, and both parents are heterozygous for the variant. +: c.294+1G>T allele; −: wild-type allele. (C) AP4S1 transcript size of the homozygous patient, both heterozygous parents, and the wild-type individual. A shorter transcript is produced in the presence of the variant. Each band of the marker ladder represents 100 bp (band size from gel bottom to top: 100, 200, 300, 400, 500, 600, 700, 800, 900, and 1000 bp). (D) Alignment of the wild-type protein sequence (NP_001121598) to the mutated protein. The alignment was performed with Clustal Omega. The variant leads to the loss of amino acids 76–98. C− = negative control; F = father; M = marker ladder; Mo = mother; mut = mutated protein; P = patient; WT = wild-type.

Exome sequencing of the proband and parents was performed as described in Supplementary Material (links.lww.com/NXG/A86) and revealed the homozygous AP4S1 splice site NM_001128126.2:c.294+1G>T r.619_687del variant in the proband, present in the heterozygous state in the parents (figure B). The variant was located in a 2.4-Mb homozygous region of chromosome 14. This variant is extremely rare in the population, with only 1 heterozygous individual present in the Genome Aggregation Database. In silico analysis predicted the loss of the donor splice site of exon 4. A transcript size analysis and Sanger sequencing of cDNA confirmed the presence of a shorter transcript skipping exon 4 associated with the variant (figure C). As a consequence, the polypeptide of 23 amino acids (76 a.a.–98 a.a.) encoded by exon 4 is lost (figure D).

Discussion

AP4S1 encodes the small subunit of the adaptor protein complex-4 (AP4 complex). This complex is recruited to the trans-Golgi network, where it mediates vesicle trafficking to endosomes or basolateral plasma membrane in a clathrin-independent manner.5 Mutations in the 4 subunits of the complex have been associated with similar autosomal recessive phenotypes mainly characterized by spastic tetraplegia.6 The mutation found in our patient leads to the loss of exon 4, with predicted important consequences to the protein structure and the AP4 complex function. Anatomical changes similar to those observed in patients have been reported in an AP-4 complex knockout mouse model: enlargement of the lateral ventricles and thinning of the corpus callosum.7 Similar changes have also been seen in the patient described here, together with febrile and afebrile seizures. When exome sequencing was performed and analyzed, the patient did not show hypertonia in the lower limbs. However, as reported in other patients, this clinical entity may progress from hypotonic to hypertonic status. The most recent neurologic evaluation revealed the presence of hypertonia in the left leg, associated with pyramidal signs, suggesting the possibility of future development of a spastic paraparesis, typical of this disease.

Here, we report a case of SPG52 associated with posterior perisylvian polymicrogyria, unexplained transitory hyperammonemia, and absence of facial dysmorphisms, which suggest an expansion of the disease phenotype.

Author contributions

S. Carmona: study concept and design; acquisition, analysis and interpretation of data; and writing of the manuscript. C. Marecos, M. Amorim, A.C. Ferreira, and C. Conceição: acquisition of patient data and critical revision of the manuscript for intellectual content. J. Brás: study concept and design; analysis and interpretation of data; and critical revision of the manuscript for intellectual content. S.T. Duarte: acquisition of patient data; analysis and interpretation of data; and writing and critical revision of the manuscript for intellectual content. R. Guerreiro: study concept and design; analysis and interpretation of data; study supervision; and writing and critical revision of the manuscript for important intellectual content.

Study funding

This work was partially funded by the Alzheimer's Society.

Disclosure

S. Carmona, C. Marecos, M. Amorim, A.C. Ferreira, and C. Conceição report no disclosures. J. Brás serves on the editorial board of the Journal of Parkinson's Disease and has received research support from the Alzheimer's Society. S. Temudo Duarte has received travel funding from Nutricia. R. Guerreiro serves on the editorial boards of ScienceMatters, the American Journal of Neurodegenerative Disease, and the Journal of Parkinson's Disease and has received research support from the Alzheimer's Society. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.

Acknowledgment

The authors acknowledge the family who participated in this study.

Footnotes

  • ↵* These authors contributed equally to the manuscript.

  • Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.

  • The Article Processing charge was funded by the authors.

  • Received February 20, 2018.
  • Accepted in final form July 31, 2018.
  • Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

References

  1. 1.↵
    1. de Souza PVS,
    2. de Rezende Pinto WBV,
    3. de Rezende Batistella GN,
    4. Bortholin T,
    5. Oliveira ASB
    . Hereditary spastic paraplegia: clinical and genetic hallmarks. Cerebellum 2017;16:525–551.
    OpenUrlCrossRef
  2. 2.↵
    1. Abou Jamra R,
    2. Philippe O,
    3. Raas-Rothschild A, et al
    . Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet 2011;88:788–795.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Hardies K,
    2. May P,
    3. Djémié T, et al
    . Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly. Hum Mol Genet 2015;24:2218–2227.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Tessa A,
    2. Battini R,
    3. Rubegni A, et al
    . Identification of mutations in AP4S1/SPG52 through next generation sequencing in three families. Eur J Neurol 2016;23:1580–1587.
    OpenUrl
  5. 5.↵
    1. Park SY,
    2. Guo X
    . Adaptor protein complexes and intracellular transport. Biosci Rep 2014;34:e00123.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Tüysüz B,
    2. Bilguvar K,
    3. Koçer N, et al
    . Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features. Am J Med Genet A 2014;164A:1677–1685.
    OpenUrlCrossRef
  7. 7.↵
    1. Ivankovic D,
    2. López-Doménech G,
    3. Drew J,
    4. Tooze SA
    . AP-4 Mediated ATG9A Sorting Underlies Axonal and Autophagosome Biogenesis Defects in a Mouse Model of AP-4 Deficiency Syndrome. bioRxiv. Epub 2017. Available at: biorxiv.org/content/early/2017/12/16/235101.abstract. Accessed January 31, 2018.

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Clinical case presentation
    • Discussion
    • Author contributions
    • Study funding
    • Disclosure
    • Acknowledgment
    • Footnotes
    • References
  • Figures & Data
  • Info & Disclosures

Related Articles

  • No related articles found.

Topics Discussed

  • Developmental disorders

Alert Me

  • Alert me when eletters are published
Advertisement
Neurology Genetics: 8 (3)

Articles

  • Articles
  • Issues
  • Popular Articles

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • Neurology: Education
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology: Genetics | Online ISSN: 2376-7839

© 2022 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise