Myopathy, Lactic Acidosis, And Sideroblastic Anemia 1

A number sign (#) is used with this entry because of evidence that myopathy, lactic acidosis, and sideroblastic anemia-1 (MLASA1) is caused by homozygous mutation in the PUS1 gene (608109) on chromosome 12q24.

Description

Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) is a rare autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow (Bykhovskaya et al., 2004).

Genetic Heterogeneity of Myopathy, Lactic Acidosis, and Sideroblastic Anemia

MLASA2 (613561) is caused by mutation in the YARS2 gene (610957) on chromosome 12p11. MLASA3 (500011) is caused by heteroplasmic mutation in the mitochondrially-encoded MTATP6 gene (516060).

Clinical Features

Rawles and Weller (1974) reported 2 brothers with myopathy, lactic acidosis, and sideroblastic anemia with ringed sideroblasts. Both brothers reported exercise intolerance beginning in childhood. The first was studied at age 19 because of breathlessness on exertion and ankle edema. A high cardiac output was the only finding; cardiac catheterization ruled out a cardiac disorder. Electron microscopy of muscle from one of the brothers showed paracrystalline inclusion bodies in mitochondria. The asymptomatic father of the boys had chronic lactic acidosis.

Among 6 offspring of first-cousin parents, Inbal et al. (1995) identified a brother and sister with a seemingly 'new' syndrome characterized by myopathy, sideroblastic anemia, lactic acidosis, mental retardation, microcephaly, high palate, high philtrum, distichiasis, and micrognathia. The patients' muscle mitochondria contained very low levels of cytochromes a, b, and c. Deposition of iron within the mitochondria of bone marrow erythroblasts was observed on electron microscopy. Irregular and enlarged mitochondria with paracrystalline inclusions were also seen on electron microscopy of muscle. However, examination of DNA from the affected sibs showed no deletions in the mitochondrial DNA and no mutations of the type identified in the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS; 540000) or the syndrome of myoclonus and epilepsy associated with ragged-red fibers (MERRF; 545000).

Casas and Fischel-Ghodsian (2004) described this disorder in a Jewish Iranian family with 4 affected individuals living in the United States. Hallmark features included progressive exercise intolerance during childhood, onset of sideroblastic anemia around adolescence, basal lactic acidemia, and mitochondrial myopathy. The presence of 2 affected sib pairs, unaffected parents, an unaffected sib, and parental consanguinity suggested autosomal recessive inheritance.

Metodiev et al. (2015) reported a 26-year-old Turkish woman with a protracted form of MLASA1. She was diagnosed with transfusion-dependent congenital sideroblastic anemia at age 1 year, and bone marrow aspirate showed dyserythropoiesis. She had failure to thrive and reduced muscle bulk without major muscle weakness or ptosis. She needed special schooling, but was an otherwise friendly and outgoing adolescent and young adult. As a young adult, she had microcephaly (-3 SD), mild intellectual disability, and moderate muscle weakness with impaired long distance walking. Plasma lactate consistently remained normal, and she had no cardiac involvement. Skeletal muscle biopsy showed a few ragged-red fibers and a profound deficiency of mitochondrial respiratory chain complexes I and IV. Studies of cultured skin fibroblasts showed qualitative anomalies in the assembly of mitochondrial complex I. Metodiev et al. (2015) emphasized the unusually long survival of this patient.

Inheritance

The transmission pattern of MLASA in the families reported by Inbal et al. (1995) was consistent with autosomal recessive inheritance.

Mapping

Casas et al. (2004) applied linkage analysis and homozygosity testing in the families of Casas and Fischel-Ghodsian (2004) and in the family reported in Israel by Inbal et al. (1995), both of which originated from the same Iranian town, and localized a candidate region of 1.2 Mb within 12q24.33.

Molecular Genetics

By sequence analysis of each of the 6 known genes in the 12q24.33 MLASA candidate region defined by Casas et al. (2004), as well as of 4 putative genes with expression in bone marrow or muscle, Bykhovskaya et al. (2004) identified a homozygous missense mutation in the PUS1 gene, encoding pseudouridine synthase-1 (608109.0001), in all patients with MLASA from the families described by Inbal et al. (1995) and Casas and Fischel-Ghodsian (2004). The amino acid change affects a highly conserved residue and appears to be in the catalytic center of the protein.

In 2 Italian brothers with MLASA, born of sixth-cousin parents, Fernandez-Vizarra et al. (2007) identified homozygosity for a nonsense mutation in the PUS1 gene (E220X; 608109.0002). The hematologic and neurologic presentation was markedly different in the 2 brothers: the older brother had a very severe mitochondrial myopathy with muscle wasting, severe sideroblastic anemia requiring multiple blood transfusions, and severe growth retardation due to complete deficiency of growth hormone, but had normal psychomotor development and above-normal intelligence. He died of respiratory failure at 12 years of age. The younger brother, who was still alive at 13 years of age, had a much milder neuromuscular syndrome with no muscle wasting, and did not require transfusions for his sideroblastic anemia; however, he had cognitive and behavioral abnormalities with moderate mental retardation, hyperactivity, and panic attacks.

In a 26-year-old woman, born of consanguineous Turkish parents, with a protracted form of MLASA1, Metodiev et al. (2015) identified a homozygous missense mutation in the PUS1 gene (R295W; 608109.0003). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed.

Pathogenesis

Patton et al. (2005) isolated total RNA from lymphoblastoid cell lines from MLASA patients with the R116W mutation, their parents, unaffected sibs, and controls. They found that mitochondrial and cytoplasmic tRNAs from MLASA patients lacked modification at sites normally modified by PUS1, whereas tRNAs from controls, unaffected sibs, or parents all had pseudouridine at those positions. Immunohistochemical staining showed nuclear, cytoplasmic, and mitochondrial distribution of the PUS1 protein, and there was no difference between patients and unaffected family members. Patton et al. (2005) concluded that MLASA is associated with absent or greatly reduced tRNA pseudouridylation at specific sites.