Clinical and biochemical characteristics in patients with a high mutant load of the mitochondrial T8993G/C mutations

Abstract

We retrospectively analyzed the clinical, histological, and biochemical data of 11 children, five of which carried the maternally-inherited mitochondrial T8993C and six carrying the T8993G point mutations in the ATP synthase 6 gene. The percentage of heteroplasmy was 95% or higher in muscle and in blood. All patients had an early clinical presentation with muscle hypotonia, severe extrapyramidal dysfunction and Leigh disease demonstrated by the cranial MRI. A slower clinical progression and more frequent sensory-neuronal involvement were noted in the patients carrying the T8993C mutation in a high mutation load in muscle and blood. No histological abnormality was found. In 9 out of 11 patients a decreased ATP production was detected, and complex V activity was deficient in all children. The activities of the respiratory enzyme complexes II and IV were normal, whereas an associated combined complex I and III deficiency were present in two patients. No obvious difference was found between the biochemical parameters of the two patient groups harboring different mutations in the same gene. No correlation was found between the degree of complex V enzyme deficiency and the severity of the phenotype. We confirmed an impaired assembly/stability of complex V in our patients. This is the first report of decreased activity and impaired assembly/stability of complex V in patients with T8993C mutations measured in muscle tissue.

Mitochondrial Complex V Expression and Activity in Cystinotic Fibroblasts

“…In the present study, the ATP generating enzyme complex V of the oxidative phosphorylation system was investigated. We used an enzymatic method to measure hydrolase activity of complex V, which is used in diagnosing complex V deficient patients (7). Here, we found normal expression, intact assembly, and activity of complex V in cystinotic fibroblasts with elevated cystine levels compared with fibroblasts derived from healthy controls.…”

“…Mitochondrial fractions of control and cystinotic fibroblasts were prepared as described before (6). Complex V activity was determined in presence and absence of specific inhibitor oligomycin (8 mg/mL) in mitochondrial fractions incubated with ATP (5 mM) as substrate (7). Briefly, the ADP generated by complex V reacts with phosphoenolpyruvic acid (1 mM) to pyruvate in the presence of pyruvate kinase (1.5 U /mL).…”

Long‐term outcome of Leigh syndrome caused by the NARP‐T8993C mtDNA mutation

“…Moreover, the clinical phenotype found in patients with nucleotide 8993 mtDNA mutations was not always typical NARP or LS and included presentations mimicking cerebral palsy or nonspecific developmental delay [Fryer et al, 1994]. The 8993C mutation was associated with a less severe phenotype, often resulting in later onset disease and slower progression [Santorelli et al, 1996;Morava et al, 2006]. Moreover, the threshold of mutant load triggering neurological disease was higher for 8993C mutation [White et al, 1999a].…”

“…To asses phenotypic variability, we examined available clinical data on all reported cases with T8993C mutation and LS using medline database searches [van Erven et al, 1987;de Vries et al, 1993;Santorelli et al, 1994Santorelli et al, , 1996Chakrapani et al, 1998;Fujii et al, 1998Fujii et al, , 2002Suzuki et al, 1998;Vilarinho et al, 2001;Hurvitz et al, 2002;Sciacco et al, 2003;Morava et al, 2006]. Developmental milestones, age at first signs, neurological and ophthalmological status at the last examination, clinical outcome, MRI, and molecular data were reviewed.…”

Leigh Syndrome: A Rare Mitrochondrial Disorder

“…Mutation studies have shown T8993C mutation was found to be associated with a slower clinical progression and more frequent sensory neuronal involvement. 7 Also Preliminary studies have proven the utility of mutation analysis in prenatal diagnosis and of Leigh Syndrome. 8,9 Affected children presents in early life with psychomotor regression, abnormal muscle tone, weakness, brainstem and cerebellar ataxia, nystagmus, external ophthalmoplegia, ptosis, optic atrophy and decreased visual acuity, even visual loss, tachypnea, and seizures [10].…”