Abstract
We report about a patient with infantile-onset neurodegenerative disease associated with isolated mitochondrial respiratory chain complex III (cIII) deficiency. The boy, now 13 years old, presented with language regression and ataxia at 4 years of age and then showed a progressive course resulting in the loss of autonomous gait and speaking during the following 2 years. Brain MRI disclosed bilateral striatal necrosis. Sequencing of a panel containing nuclear genes associated with cIII deficiency revealed a previously undescribed homozygous rearrangement (c.782_786delinsGAAAAG) in TTC19 gene, which results in a frameshift with premature termination (p.Glu261Glyfs*8). TTC19 protein was absent in patient’s fibroblasts.
TTC19 encodes tetratricopeptide 19, a putative assembly factor for cIII. To date TTC19 mutations have been reported only in few cases, invariably associated with cIII deficiency, but presenting heterogeneous clinical phenotypes. We reviewed the genetic, biochemical, clinical and neuroradiological features of TTC19 mutant patients described to date.
Competing interests: None declared
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Acknowledgments
This work was supported by Fondazione Pierfranco e Luisa Mariani (CM23), Fondazione Telethon (grant GGP11011), Cell line and DNA Bank of Genetic Movement Disorders and Mitochondrial Disesases of Telethon Network of Genetics Biobanks (grant GTB12001), Italian Ministry of Health (GR 2010–2316392) and the Italian Association of Mitochondrial Disease Patients and Families (Mitocon ONLUS)
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Communicated by: Wolfgang Sperl, MD, PhD
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Synopsis
We describe a novel deleterious mutation in TTC19 associated with early onset severe and progressive neurological deterioration. The review of previous cases does not suggest a strict and univocal genotype/phenotype correlation, but demonstrates that some clinical hallmarks and common MRI pattern are available in spite of different age of onset. Biochemical (decreased cIII activity) and molecular data (all known TTC19 mutations were associated with or are predicted to result in the absence of the protein) are common in spite of different phenotypes.
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Conflict of Interest
Dr. Ardissone reports no conflict of interest.
Dr. Granata reports no conflict of interest.
Dr. Legati reports no conflict of interest.
Dr. Diodato reports no conflict of interest.
Dr. Melchionda reports no conflict of interest.
Dr. Lamantea reports no conflict of interest.
Dr. Garavaglia received funding and grants for research from Fondazione Mariani (CM23), Telethon Network of Genetics Biobank (GTB12001).
Dr. Ghezzi received funding and grants for research from the Italian Ministry of Health, Telethon Italy (GGP11011), and CARIPLO foundation.
Dr. Moroni received funding and grants for research from Telethon Italy (GUP11001; GUP13006).
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from patient’s parents for being included in the study.
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This article does not contain any studies with animal subjects performed by any of the authors.
Details of the Contributions of Individual Authors
AA, TG, and IM evaluated the patient and wrote the case report. LM and DD performed genetic analyses; AL analyzed targeted resequencing data. EL performed biochemical analyses under the supervision of BG. DG monitored genetic/protein analyses. AA and DG wrote the manuscript; IM critically revised the manuscript for important intellectual content. All authors read and approved the manuscript.
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Ardissone, A. et al. (2015). Mitochondrial Complex III Deficiency Caused by TTC19 Defects: Report of a Novel Mutation and Review of Literature. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 22. JIMD Reports, vol 22. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_419
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DOI: https://doi.org/10.1007/8904_2015_419
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