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April 2022; 8 (2) Research ArticleOpen Access

Cross-sectional Observations on the Natural History of Mucolipidosis Type IV

View ORCID ProfileAlbert L. Misko, Levi B. Wood, Madeline DeBono, Rebecca Oberman, Annick Raas-Rothschild, Yulia Grishchuk, Florian Eichler
First published March 10, 2022, DOI: https://doi.org/10.1212/NXG.0000000000000662
Albert L. Misko
From the Department of Neurology and Center for Genomic Medicine (A.L.M., M.D., R.O., Y.G., F.E.), Massachusetts General Hospital and Harvard Medical School, Boston, MA; George W. Woodruff School of Mechanical Engineering (L.B.W.), Wallace H. Coulter Department of Biomedical Engineering, and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA; The Institute for Rare Diseases (A.R.-R.), The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel HaShomer, Israel; Sackler Faculty of Medicine (A.R.-R.), Tel Aviv University, Tel Aviv, Israel.
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  • ORCID record for Albert L. Misko
Levi B. Wood
From the Department of Neurology and Center for Genomic Medicine (A.L.M., M.D., R.O., Y.G., F.E.), Massachusetts General Hospital and Harvard Medical School, Boston, MA; George W. Woodruff School of Mechanical Engineering (L.B.W.), Wallace H. Coulter Department of Biomedical Engineering, and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA; The Institute for Rare Diseases (A.R.-R.), The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel HaShomer, Israel; Sackler Faculty of Medicine (A.R.-R.), Tel Aviv University, Tel Aviv, Israel.
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  • For correspondence: levi.wood@me.gatech.edu
Madeline DeBono
From the Department of Neurology and Center for Genomic Medicine (A.L.M., M.D., R.O., Y.G., F.E.), Massachusetts General Hospital and Harvard Medical School, Boston, MA; George W. Woodruff School of Mechanical Engineering (L.B.W.), Wallace H. Coulter Department of Biomedical Engineering, and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA; The Institute for Rare Diseases (A.R.-R.), The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel HaShomer, Israel; Sackler Faculty of Medicine (A.R.-R.), Tel Aviv University, Tel Aviv, Israel.
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  • For correspondence: mdebon19@g.holycross.edu
Rebecca Oberman
From the Department of Neurology and Center for Genomic Medicine (A.L.M., M.D., R.O., Y.G., F.E.), Massachusetts General Hospital and Harvard Medical School, Boston, MA; George W. Woodruff School of Mechanical Engineering (L.B.W.), Wallace H. Coulter Department of Biomedical Engineering, and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA; The Institute for Rare Diseases (A.R.-R.), The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel HaShomer, Israel; Sackler Faculty of Medicine (A.R.-R.), Tel Aviv University, Tel Aviv, Israel.
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  • For correspondence: roberman@mgh.harvard.edu
Annick Raas-Rothschild
From the Department of Neurology and Center for Genomic Medicine (A.L.M., M.D., R.O., Y.G., F.E.), Massachusetts General Hospital and Harvard Medical School, Boston, MA; George W. Woodruff School of Mechanical Engineering (L.B.W.), Wallace H. Coulter Department of Biomedical Engineering, and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA; The Institute for Rare Diseases (A.R.-R.), The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel HaShomer, Israel; Sackler Faculty of Medicine (A.R.-R.), Tel Aviv University, Tel Aviv, Israel.
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  • For correspondence: arclin2020@gmail.com
Yulia Grishchuk
From the Department of Neurology and Center for Genomic Medicine (A.L.M., M.D., R.O., Y.G., F.E.), Massachusetts General Hospital and Harvard Medical School, Boston, MA; George W. Woodruff School of Mechanical Engineering (L.B.W.), Wallace H. Coulter Department of Biomedical Engineering, and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA; The Institute for Rare Diseases (A.R.-R.), The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel HaShomer, Israel; Sackler Faculty of Medicine (A.R.-R.), Tel Aviv University, Tel Aviv, Israel.
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  • For correspondence: ygrishchuk@partners.org
Florian Eichler
From the Department of Neurology and Center for Genomic Medicine (A.L.M., M.D., R.O., Y.G., F.E.), Massachusetts General Hospital and Harvard Medical School, Boston, MA; George W. Woodruff School of Mechanical Engineering (L.B.W.), Wallace H. Coulter Department of Biomedical Engineering, and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA; The Institute for Rare Diseases (A.R.-R.), The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel HaShomer, Israel; Sackler Faculty of Medicine (A.R.-R.), Tel Aviv University, Tel Aviv, Israel.
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  • For correspondence: feichler@mgh.harvard.edu
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Cross-sectional Observations on the Natural History of Mucolipidosis Type IV
Albert L. Misko, Levi B. Wood, Madeline DeBono, Rebecca Oberman, Annick Raas-Rothschild, Yulia Grishchuk, Florian Eichler
Neurol Genet Apr 2022, 8 (2) e662; DOI: 10.1212/NXG.0000000000000662

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Abstract

Background and Objectives Mucolipidosis type IV (MLIV) is an ultra-rare lysosomal disorder initially described as a static neurodevelopmental condition. However, patient caregivers frequently report progressive muscular hypertonicity and functional decline. We evaluated a cohort of patients with MLIV to determine whether neurologic disability correlates with age.

Methods We performed a cross-sectional, observational study of 26 patients with MLIV in the United States and Israel ranging in age from 2 to 40 years. Medical history was obtained from caregivers, and patients underwent a full neurologic examination. The Brief Assessment of Motor Function (BAMF), Gross Motor Function Classification System, and modified Ashworth scales were applied. Caregivers identified developmental skills on the Oregon Project for Visually Impaired and Blind Children checklist that their child had lost the ability to perform.

Results Three patients were clinically classified as mildly affected and the remaining 23 patients as typical, severely affected cases. Timing of first symptom onset ranged from 1.5 months to 8 years of age (median 7.25 months). Across typical patients, modified Ashworth scores demonstrated a positive age dependence illustrating worsening spasticity across the lifespan. Signs of extrapyramidal motor dysfunction were also qualitatively observed. In parallel, gross and fine motor function assessed with the BAMF and Gross Motor Function Classification System scales declined across age. All typical patients had restricted tongue mobility and lacked rotary jaw movement when chewing, but BAMF scores for deglutition declined only in the oldest patients. In contrast, scores for articulation were low in all patients and did not correlate with age. Finally, loss of developmental skills frequently occurred in early adolescence.

Discussion This cross-sectional natural history study of MLIV demonstrates worse motor function in older patients. These data support a neurodegenerative component of MLIV that manifests as developmental regression in the second decade of life. Whether the emergence of functional decline results from the cumulative, nonlinear interactions of steadily progressive neurodegenerative processes or reflects an inflection from impaired CNS development to degeneration is uncertain. However, understanding the relationship between CNS pathology and clinical course of disease will be imperative to guiding future interventional trials and optimizing patient care.

Glossary

BAMF=
Brief Assessment of Motor Function;
Cr=
creatine-phosphocreatine;
GMFCS=
Gross Motor Function Classification System;
MLIV=
mucolipidosis type IV;
NAA=
N-acetylaspartate

Footnotes

  • Go to Neurology.org/NG for full disclosures. Full information is provided at the end of the article.

  • The Article Processing Charge was funded by the NIH.

  • Received September 10, 2021.
  • Accepted in final form January 4, 2022.
  • Copyright © 2022 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.

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