Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene

Abstract

Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) is a rare mitochondrial disorder that has previously been associated with mutations in PUS1 and YARS2. In the present report, we describe a 6-year old male with an MLASA plus phenotype. This patient had features of MLASA in the setting of developmental delay, sensorineural hearing loss, epilepsy, agenesis of the corpus callosum, failure to thrive, and stroke-like episodes. Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N). Whole exome sequencing did not identify mutations or variants in PUS1 or YARS2 or any known nuclear genes that could affect mitochondrial function and explain this phenotype. Studies of fibroblasts derived from the patient revealed a decrease in oligomycin-sensitive respiration, a finding which is consistent with a complex V defect. Thus, this mutation in MT-ATP6 may represent the first mtDNA point mutation associated with the MLASA phenotype.

Keywords: ATP6; Lactic acidosis; MLASA; Mitochondria; Mitochondrial myopathy.

Figure 1

Brain MR imaging performed during first stroke-like episode. A. A midline sagittal T1-weighted image demonstrates agenesis of the corpus callosum. B. An axial image demonstrates T1 hypointensity in a non-vascular pattern of distribution in the right posterior parietal region. C. The ADC (apparent diffusion coefficient) image of the same demonstrates a mixed pattern of restricted (black) and unrestricted (white) diffusion most consistent with metabolic failure

Figure 2

Conservation of serine residue at position 148 in ATP6. The serine at position 148 in mtATP6 is conserved from yeast to human.

Figure 3

Heteroplasmic m.8969G>A (p.S148N, ATP6) detected in the proband.

Figure 4

Cellular respiration measured in fibroblast cell line derived from patient #1 and controls in the presence of 5 mM glucose (A) or 5 mM galactose (B). Data is representative of two replicate analyses. The control cells are shown in blue and the patient cells are shown in red. OCR = oxygen consumption rate. A&R = antimycin A and rotenone. BR = basal respiration. OSR = oligomycin-sensitive respiration. RC = respiratory capacity. SRC = spare respiratory capacity. An unpaired Student’s t-test was used to compare the patient fibroblast cell line with the control fibroblast cell lines.

Figure 4

Cellular respiration measured in fibroblast cell line derived from patient #1 and controls in the presence of 5 mM glucose (A) or 5 mM galactose (B). Data is representative of two replicate analyses. The control cells are shown in blue and the patient cells are shown in red. OCR = oxygen consumption rate. A&R = antimycin A and rotenone. BR = basal respiration. OSR = oligomycin-sensitive respiration. RC = respiratory capacity. SRC = spare respiratory capacity. An unpaired Student’s t-test was used to compare the patient fibroblast cell line with the control fibroblast cell lines.