alexa Intra- and inter-familial phenotypic heterogeneity of the m.7510T>C variant

ISSN: 2329-6895

Journal of Neurological Disorders

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Intra- and inter-familial phenotypic heterogeneity of the m.7510T>C variant

Josef Finsterer1* and Sinda Zarrouk-Mahjoub2
1Krankenanstalt Rudolfstiftung, Vienna, Austria
2University of Tunis El-Manar and Genomics Platform, Pasteur Institute of Tunis, Tunisia
*Corresponding Author: Josef Finsterer MD, PhD, Krankenanstalt Rudolfstiftung, Postfach 201180, Vienna, Austria, Tel: +43-1-71165, Fax: +43-1-4781711, Email: [email protected]

Received Date: Apr 02, 2018 / Accepted Date: Apr 23, 2018 / Published Date: Apr 28, 2018


In a recent article Kytövuori et al. reported a Finnish family with phenotypically variable multiorgan disease manifesting in the brain, ears, and endocrine organs, due to the variant m.7510T>C in the MT-TS1 (tRNA(Ser)) gene with high heteroplasmy. We have the following comments and concerns.

Keywords: Mitochondrial; mtDNA; Phenotype; Genotype; Epilepsy; Heterogeneity; Multisystem


Though the mutation m.7510T>C has been previously reported (Table 1) [1-5], the pathogenicity of this variant is not well supported. Currently it is recommended to assess the pathogenicity of tRNA variants according to the modified Yarham score [6]. According to this tool the variant m.7510T>C scores 9 (>1 independent report: 2, heteroplasmy: 2, segregation with variant: 2, biochemical defect in CI, CIII, or CIV: 0, variant segregation with biochemical defect on single fiber studies: 0, mutant mt-tRNA steady state level studies or evidence of pathogenicity in trans-mitochondrial cybrid studies: 0, evidence of normality in trans-mitochondrial cybrid studies: 0, evolutionary conservation of nucleotide: 2, histopathology: 1), indicating that the variant is only “possibly pathogenic” [6].

Variables Kytövuori(2017) Komlosi(2013) Labay(2008) Castillo (2002) Hutchin(2000)
Phenotype I/2 II/1 III/1 III/2 II/3 III/2 IV/1 n=11 n=26 III/9 IV/6 IV/7
Sex f f m f f f m f=5, m=6 f=16, m=10 f m f
Age 70y 46y 21y 17y nr nr 7y np 9-70y np np np
Onset np ES 20y 6y 20y 30y 4.5y 5-20y np np 15m 5y
Short stature np np np yes nr no nr nr no np np np
Hypoacusis yes yes yes yes yes yes yes yes yes yes yes yes
Epilepsy no no no yes no no no no no np np np
Ataxia yes yes no yes no no no no no np np np
Tremor yes no no no no no no no no np np np
Cognitive impairment no no no yes no no no no no np np np
RLS yes no no no no no no no no np np np
HP (blood), % 90 99 99 99 homoplasmic homoplasmic no >95 >95 >95
HP (muscle), % np np np 99 np np np np no np np np
HP (buccal mucosa), % np 99 np np np np np np no np np np
Haplotype H13a1a1d1   H variant H H1 np -- --
RLS: Restless Leg Syndrome, HP: Heteroplasmy, Np: Not Provided, ES: DuringElementary School

Table 1: Intra- and inter-familial phenotypic heterogeneity of the m.7510T>C variants.

The index patient had epilepsy with onset at age 9 years [1]. Why was valproate (VPA) initially chosen? It is well established that VPA, together with carbamazepine, phenytoin, and phenobarbital, is mitochondrion-toxic [7] and a pediatric patient with hearing impairment and epilepsy is highly suspicious of a mitochondrial disorder (MID). Were antiepileptic drugs other than valproic acid and levetiracetam prescribed? Were seizures well controlled with levetiracetam?


Which was the cause of the reduced tendon reflexes? Myopathy or neuropathy? Was there also wasting, hypotonia, or fasciculations? Which were the results of nerve conduction studies and the needle electromyography? Were biochemical or single fiber studies carried out with the muscle biopsy? Which were the results? Was creatinekinase elevated? mtDNA mutations usually cause multisystem disease either already at onset of the abnormalities or during the natural course of the disease. Thus, affection of organs can be mild or even subclinical at an early stage of the disease. However, since affection of multiple organs may strongly influence the outcome and prognosis of these patients, it is essential that they are prospectively investigated for multisystem involvement. Particularly important is the thorough investigation of the heart since patients with a mitochondrial disorder and cardiac involvement are prone to develop, cardiomyopathy, conduction defects, and arrhythmias, including sudden cardiac death (SCD). Which were the results of the routine ECG, long-term ECGs, and echocardiography? It is also important to screen MID patients for endocrine abnormalities, hypopituitarism, diabetes, hypo- /hyperthyroidism, hypoaldosteronism, Addison’s disease, and hypogonadism, for renal disease, for hematological abnormalities, and for gastrointestinal involvement.


Overall, this interesting report requires confirmation of the pathogenicity of the variant proposed to be causative, prospective clinical and instrumental investigations for mild or subclinical involvement of organs other than the brain, muscle, and ears, and discussion of possibly mechanisms for the extensive intra- and interfamilial phenotypic heterogeneity of the m.7510T>C variant.


Citation: Finsterer J, Zarrouk-Mahjoub S (2018) Intra- and inter-familial phenotypic heterogeneity of the m.7510T>C variant. J Neurol Disord 6:381. DOI: 10.4172/2329-6895.1000381

Copyright: © 2018 Finsterer J, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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