Myopathy, Lactic Acidosis, And Sideroblastic Anemia 3

A number sign (#) is used with this entry because of evidence that myopathy, lactic acidosis, and sideroblastic anemia-3 (MLASA3) is caused by heteroplasmic mutation in the mitochondrial-encoded ATP6 gene (MTATP6; 516060). One such patient has been reported.

Description

MLASA3 is a severe mitochondrial disorder with early infantile presentation of transfusion-dependent sideroblastic anemia in the setting of failure to thrive, hearing loss, epilepsy, stroke-like episodes, and severe developmental delay (summary by Burrage et al., 2014).

For a general phenotypic description and a discussion of genetic heterogeneity of MLASA, see MLASA1 (600462).

Clinical Features

Burrage et al. (2014) reported a male patient born via repeat cesarean section at 32 weeks' gestation to nonconsanguineous parents. The pregnancy was complicated by oligohydramnios. There were no exposures to cigarettes, alcohol, or drugs. The infant was admitted to the neonatal intensive care unit (NICU) for oxygen and feeding difficulties for 5 weeks. Brain imaging, including ultrasound and MRI, revealed grade II intraventricular hemorrhage (IVH) and agenesis of the corpus callosum. Electroencephalogram (EEG) showed evidence of bicentral and bitemporal sharp spikes of low to moderate amplitude. The patient also had an abnormal brainstem auditory-evoked potential study and was eventually diagnosed with sensorineural hearing loss. At 2 months of age, he was diagnosed with sideroblastic anemia and required regular packed red blood cell transfusions to maintain his hemoglobin in the normal range. At 5 months of age, he developed epilepsy, and also had failure to thrive requiring gastrostomy feeds. Severe global developmental delay was noted. At 4 years of age, he showed evidence of a metabolic stroke, and at 6 years, he had a second episode. Electrocardiogram (EKG) confirmed Wolff-Parkinson-White syndrome (194200). At 6 years of age, the patient was nonambulatory and nonverbal; height and weight were below the 3rd percentile. Head circumference was at the 8th percentile. Physical examination revealed an inability to track, high-arched palate, contractures at knees and ankles, axial hypotonia, increased tone of lower extremities, muscle weakness, and atrophy. He also had bilateral postaxial toe duplication. Blood lactate was repeatedly elevated (2.4-6.1 mmol/L). In addition, large quantities of fumarate, malate, beta-hydroxybutyrate, and lactate were detected in urine organic acid analysis, and plasma amino acids showed elevated alanine. An acylcarnitine profile in plasma was normal. Pyruvate carboxylase and pyruvate dehydrogenase complex activities in cultured fibroblasts were also normal.

Molecular Genetics

Using Sanger sequencing of the mitochondrial genome in a patient with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia, Burrage et al. (2014) detected an apparently homoplasmic novel variant in the MTATP6 gene (m.8969G-A, S148N; 516060.0012). Next-generation sequencing confirmed the presence of this variant at 96% and 88% heteroplasmy in the proband's blood and muscle specimens, respectively, and did not detect the variant in his mother's blood sample. Two other apparently homoplasmic rare variants were also detected in the proband's muscle and blood specimens; these variants had been reported in the mtDB, occurred at evolutionarily nonconserved positions, and were present in the proband's asymptomatic mother, and so were considered unlikely to be causative. Functional studies using a patient-derived skin fibroblast line showed a profound reduction in oligomycin-sensitive respiration compared to control, consistent with a defect in mitochondrial complex V function. Whole-exome sequencing of relevant nuclear genes detected no pathogenic variants.