Abstract
Complex I (CI) is the largest component of the mitochondrial respiratory chain (MRC) and it is made up of 7 mitochondrial DNA (mtDNA)-encoded and at least 38 nuclear DNA-encoded subunits. Isolated CI deficiency is the most common single enzyme deficiency in the heterogeneous group of MRC disorders and it is a relatively common etiology of Leigh-like syndrome (LS). With a few exceptions, descriptions of the clinical spectrum of specific mutations in CI are scarce. We here present three unrelated Italian children who harbored the homoplasmic m.10197G>A mutation in MT-ND3 associated with reduced enzyme activity of CI in muscle. Compared with the spectrum of phenotypes seen in 13 previously described families with the same mutation, these children showed some novel clinical features. Two of the boys presented with subacute onset of dystonia, which showed a remitting-relapsing clinical course in one of them. The third boy presented acute symptoms consisting of speech impairment, progressive left-sided hemiparesis, and also vertebral and arterial malformations. In all the children, molecular studies identified a similar mutation load in tissues, and neuroimaging findings were consistent with the features seen in LS. Functional investigations in cultured skin fibroblasts suggested low ATP production in homoplasmic cells. Our results confirm that the m.10197G>A mutation is relevant to these patients' clinical and biochemical phenotypes, which thus expand the array of phenotypes associated with this variant.
| Original language | English |
|---|---|
| Pages (from-to) | 69-75 |
| Number of pages | 7 |
| Journal | Journal of the Neurological Sciences |
| Volume | 399 |
| DOIs | |
| Publication status | Published - Apr 15 2019 |
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Keywords
- Complex I deficiency
- Leigh syndrome
- mtDNA
- ND3 gene
ASJC Scopus subject areas
- Neurology
- Clinical Neurology
Cite this
Clinical and neuroimaging features of the m.10197G>A mtDNA mutation : New case reports and expansion of the phenotype variability. / Tolomeo, D.; Rubegni, A.; Severino, M.; Pochiero, F.; Bruno, C.; Cassandrini, D.; Madeo, A.; Doccini, S.; Pedemonte, M.; Rossi, A.; D'Amore, F.; Donati, M. A.; Di Rocco, M.; Santorelli, F. M.; Nesti, C.
In: Journal of the Neurological Sciences, Vol. 399, 15.04.2019, p. 69-75.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Clinical and neuroimaging features of the m.10197G>A mtDNA mutation
T2 - New case reports and expansion of the phenotype variability
AU - Tolomeo, D.
AU - Rubegni, A.
AU - Severino, M.
AU - Pochiero, F.
AU - Bruno, C.
AU - Cassandrini, D.
AU - Madeo, A.
AU - Doccini, S.
AU - Pedemonte, M.
AU - Rossi, A.
AU - D'Amore, F.
AU - Donati, M. A.
AU - Di Rocco, M.
AU - Santorelli, F. M.
AU - Nesti, C.
PY - 2019/4/15
Y1 - 2019/4/15
N2 - Complex I (CI) is the largest component of the mitochondrial respiratory chain (MRC) and it is made up of 7 mitochondrial DNA (mtDNA)-encoded and at least 38 nuclear DNA-encoded subunits. Isolated CI deficiency is the most common single enzyme deficiency in the heterogeneous group of MRC disorders and it is a relatively common etiology of Leigh-like syndrome (LS). With a few exceptions, descriptions of the clinical spectrum of specific mutations in CI are scarce. We here present three unrelated Italian children who harbored the homoplasmic m.10197G>A mutation in MT-ND3 associated with reduced enzyme activity of CI in muscle. Compared with the spectrum of phenotypes seen in 13 previously described families with the same mutation, these children showed some novel clinical features. Two of the boys presented with subacute onset of dystonia, which showed a remitting-relapsing clinical course in one of them. The third boy presented acute symptoms consisting of speech impairment, progressive left-sided hemiparesis, and also vertebral and arterial malformations. In all the children, molecular studies identified a similar mutation load in tissues, and neuroimaging findings were consistent with the features seen in LS. Functional investigations in cultured skin fibroblasts suggested low ATP production in homoplasmic cells. Our results confirm that the m.10197G>A mutation is relevant to these patients' clinical and biochemical phenotypes, which thus expand the array of phenotypes associated with this variant.
AB - Complex I (CI) is the largest component of the mitochondrial respiratory chain (MRC) and it is made up of 7 mitochondrial DNA (mtDNA)-encoded and at least 38 nuclear DNA-encoded subunits. Isolated CI deficiency is the most common single enzyme deficiency in the heterogeneous group of MRC disorders and it is a relatively common etiology of Leigh-like syndrome (LS). With a few exceptions, descriptions of the clinical spectrum of specific mutations in CI are scarce. We here present three unrelated Italian children who harbored the homoplasmic m.10197G>A mutation in MT-ND3 associated with reduced enzyme activity of CI in muscle. Compared with the spectrum of phenotypes seen in 13 previously described families with the same mutation, these children showed some novel clinical features. Two of the boys presented with subacute onset of dystonia, which showed a remitting-relapsing clinical course in one of them. The third boy presented acute symptoms consisting of speech impairment, progressive left-sided hemiparesis, and also vertebral and arterial malformations. In all the children, molecular studies identified a similar mutation load in tissues, and neuroimaging findings were consistent with the features seen in LS. Functional investigations in cultured skin fibroblasts suggested low ATP production in homoplasmic cells. Our results confirm that the m.10197G>A mutation is relevant to these patients' clinical and biochemical phenotypes, which thus expand the array of phenotypes associated with this variant.
KW - Complex I deficiency
KW - Leigh syndrome
KW - mtDNA
KW - ND3 gene
UR - http://www.scopus.com/inward/record.url?scp=85061540535&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061540535&partnerID=8YFLogxK
U2 - 10.1016/j.jns.2019.02.010
DO - 10.1016/j.jns.2019.02.010
M3 - Article
VL - 399
SP - 69
EP - 75
JO - Journal of the Neurological Sciences
JF - Journal of the Neurological Sciences
SN - 0022-510X
ER -