Myopathy, Lactic Acidosis, And Sideroblastic Anemia 2

A number sign (#) is used with this entry because of evidence that myopathy, lactic acidosis, and sideroblastic anemia-2 (MLASA2) is caused by homozygous mutation in the YARS2 gene (610957) on chromosome 12p11.

Description

Myopathy, lactic acidosis, and sideroblastic anemia-2 is an autosomal recessive disorder of the mitochondrial respiratory chain. The disorder shows marked phenotypic variability: some patients have a severe multisystem disorder from infancy, including cardiomyopathy and respiratory insufficiency resulting in early death, whereas others present in the second or third decade of life with sideroblastic anemia and mild muscle weakness (summary by Riley et al., 2013).

For a discussion of genetic heterogeneity of MLASA, see MLASA1 (600462).

Clinical Features

Sasarman et al. (2002) reported a 34-year-old man of Lebanese descent (patient E) with a lifelong history of muscle weakness, exercise intolerance, occasional muscle cramping and stiffness after running, and small muscles. Around age 31 years, he was found to have sideroblastic anemia. Physical examination showed asymmetric ptosis, limited lateral gaze, muscle atrophy, muscle weakness of the proximal upper extremities and distal lower extremities, and areflexia. Serum lactate was increased. Muscle biopsy showed ragged-red fibers and a generalized severe defect in mitochondrial respiratory chain activity, with a decrease in mtDNA-encoded COX subunits as assessed by immunoblot analysis. Electron microscopy of muscle biopsy showed subsarcolemmal accumulation of abnormal mitochondria, many with paracrystalline inclusions. Studies of cybrid cells with patient nuclei and control mitochondria indicated that the defect was nuclear in origin; in addition, mutations in mitochondrial genes were ruled out. Patient-derived myotubes showed a defect in mitochondrial translation, whereas mitochondrial translation in myoblasts was similar to that in controls. Sasarman et al. (2002) concluded that this patient had a defect in a nuclear-encoded and developmentally-regulated gene important for mitochondrial translation in skeletal muscle. There was no family history of a similar disorder.

Riley et al. (2010) reported 2 sibs, born of consanguineous Lebanese parents, with MLASA2. Both developed transfusion-dependent sideroblastic anemia in infancy, followed by progressive lethargy, muscle weakness, and exercise intolerance in childhood associated with persistent lactic acidemia. By age 17 years the proband was wheelchair-dependent and had developed respiratory insufficiency necessitating ventilation. Both also had dysphagia requiring enteral nutrition in their teens. The proband had hypertrophic cardiomyopathy, which was not noted in his affected sister. Cognitive function remained normal in both patients. Skeletal muscle biopsy of the proband showed subsarcolemmal mitochondrial aggregates, some ragged-red fibers, and decreased cytochrome oxidase staining. Another Lebanese patient from an unrelated consanguineous family had a similar disorder, with the addition of delayed motor milestones and later onset of anemia at age 7 years. Despite the lack of blood transfusions, she was able to walk and showed only a mild skeletal myopathy and mild muscle weakness at age 24 years. Riley et al. (2013) reported follow-up of the sibs reported by Riley et al. (2010). The brother died of respiratory failure at age 18 years, whereas his sister showed some improvement in clinical features.

Shahni et al. (2013) reported a male child, born to unrelated Lebanese parents, with MLASA2. Anemia was diagnosed at 1 year of age; subsequent bone marrow analysis at age 5 years revealed ringed sideroblasts. He developed transfusion-dependent anemia at age 11 years. Other features included lactic acidosis, failure to thrive, hypertrophic cardiomyopathy, and severe myopathy, leading to respiratory failure. Shahni et al. (2013) reviewed the 5 reported patients with MLASA2 and YARS2 mutations and noted the characteristic features of gastrointestinal and feeding difficulties, respiratory failure requiring mechanical ventilation, and cardiomyopathy.

Riley et al. (2013) reported 3 additional patients with MLASA2 confirmed by genetic analysis. Two unrelated patients of Lebanese origin who were both homozygous for the P52L mutation (610957.0001) had markedly different phenotypes. One girl presented at age 8 weeks in hypotensive shock after an infectious illness and was found to have left ventricular hypertrophy, hepatomegaly with raised transaminases and coagulopathy, lactic acidosis, and sideroblastic anemia. She died of cardiorespiratory failure at age 3 months. The second patient was found to have sideroblastic anemia at age 23 years. She also had scoliosis and a mild restrictive pulmonary defect, but no other abnormalities. A sister of the second patient had died of cirrhosis induced from iron overload by transfusion for sideroblastic anemia.

Nakajima et al. (2014) reported 2 sibs, born of consanguineous Turkish parents, with a severe fatal form of MLASA2. On the fourth day of life, the proband presented with poor feeding and tachypnea due to lactic metabolic acidosis. A few weeks later, he developed anemia and recurrent metabolic decompensation including lactic acidosis, ketosis, and hyperammonemia. At 2 months of age, he showed axial hypotonia, and brain MRI showed a thin corpus callosum. He also had cardiac hypertrophy and evidence of a proximal renal tubulopathy. He died at age 3 months from cardiopulmonary arrest. The patient's affected sib died at age 2 days following a similar clinical course.

Biochemical Features

In skeletal muscle cells isolated from patients with myopathy, lactic acidosis, and sideroblastic anemia, Riley et al. (2010) demonstrated low activities of mitochondrial respiratory complexes I, III, and IV, with normal or increased levels of nuclear-encoded complex II. These changes were not observed in fibroblasts. The skeletal muscle enzyme deficiencies were confirmed by immunoblotting, which also showed an increase in complex V.

Inheritance

MLASA2 is an autosomal recessive disorder (Riley et al., 2010).

Diagnosis

Shahni et al. (2013) suggested that the evaluation of patients with features of MLASA should include direct sequence analysis of the YARS2 gene as well as of the PUS1 gene (608109), which is mutated in MLASA1 (600462), to prevent the need for invasive muscle biopsy.

Molecular Genetics

By genomewide linkage analysis followed by candidate gene sequencing of 2 consanguineous Lebanese families with MLASA2, Riley et al. (2010) identified a homozygous mutation in the YARS2 gene (F52L; 610957.0001). In vitro functional expression assays showed that the mutant YARS2 protein had an overall 9-fold loss of catalytic efficiency. The findings indicated that the mutation resulted in reduced aminoacylation efficiency, causing a defect in mitochondrial protein synthesis with a subsequent impairment of mitochondrial respiratory activity.

By direct sequence analysis of the YARS2 gene in a Lebanese boy with MLASA2, Shahni et al. (2013) identified homozygosity for the previously identified F52L mutation. The boy's parents, who were not known to be related, were heterozygous for the mutation, consistent with the hypothesis that F52L is a Lebanese founder mutation.

In a Lebanese man with MLASA2, previously reported by Sasarman et al. (2002), Sasarman et al. (2012) identified a homozygous missense mutation in the YARS2 gene (G46D; 610957.0002). Immunoblot analysis showed undetectable levels of YARS2 protein in patient-derived myoblasts and myotubes. Expression of wildtype YARS2 rescued the mitochondrial translation defect in patient-derived myoblasts and myotubes. Levels of YARS2 present in control myotubes was about twice that of control myoblasts, suggesting increased requirement for YARS2 as muscle differentiation progresses.

Riley et al. (2013) identified homozygous or compound heterozygous YARS2 mutations (610957.0001; 610957.0003-610957.0004) in 3 (25%) of 12 unrelated patients with myopathy, lactic acidosis, and sideroblastic anemia who underwent direct Sanger sequencing of the YARS2 gene. There was marked phenotypic variability, even among patients with the same homozygous mutation (F52L; 610957.0001), which Riley et al. (2013) postulated may have resulted from different background mitochondrial haplogroups. The most severely affected individual died at age 3 months of cardiorespiratory failure, whereas the patient with the mildest phenotype had mild nontransfusion-dependent sideroblastic anemia that presented at age 23 years. Patient-derived muscle cells showed a more severe mitochondrial respiratory chain defect compared to fibroblasts, suggesting increased requirement for YARS2 function in muscle tissue.

In 2 sibs, born of consanguineous Turkish parents, with a severe from of MLASA2 resulting in death at ages 2 days and 3 months, Nakajima et al. (2014) identified a homozygous missense mutation (S435G; 610957.0005) in the highly conserved S4-like anticodon-binding domain of YARS2. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed.