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Year : 2022  |  Volume : 25  |  Issue : 6  |  Page : 1202-1204

MLASA-1: A rare cause of myopathy with sideroblastic anemia

Department of Pediatrics, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India

Date of Submission31-Jul-2022
Date of Decision20-Sep-2022
Date of Acceptance21-Sep-2022
Date of Web Publication17-Nov-2022

Correspondence Address:
Joshua R Xavier
Assistant Professor, Saveetha Institute of Medical and Technical Sciences, Chennai - 600 056, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aian.aian_661_22

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How to cite this article:
Sait B, Chidambaram AC, Dinesh Babu R M, Vidhyasagar K, Xavier JR, Sagayaraj B. MLASA-1: A rare cause of myopathy with sideroblastic anemia. Ann Indian Acad Neurol 2022;25:1202-4

How to cite this URL:
Sait B, Chidambaram AC, Dinesh Babu R M, Vidhyasagar K, Xavier JR, Sagayaraj B. MLASA-1: A rare cause of myopathy with sideroblastic anemia. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Feb 6];25:1202-4. Available from:

Dear Editor,

A 3-year-old girl, born to non-consanguineous parents, was brought with complaints of pallor, failure to thrive, and floppiness of all limbs since early infancy. Her perinatal history was uneventful, and there was no history of neonatal intensive care unit stay. There was a significant family history in the form of early sibling deaths. The first child was aborted in-utero due to holoprosencephaly and mid-line defects. The second child was a boy with a history of global developmental delay and hypotonia, who expired at 7 months. He was not evaluated anywhere and the underlying diagnosis was not proven. The index child had poor suck while breastfeeding, and floppiness of all limbs and neck was noticed by the mother since early infancy. Her developmental milestones were delayed in all domains. At 3 years of age, she could only sit with support, had an immature pincer grasp, had stranger anxiety, and could babble and tell a few monosyllables. She was admitted twice in the past at 1.5 years and 2.5 years, respectively, for breathlessness, where she was diagnosed with anemia and received blood transfusions at each visit. However, she was not completely evaluated during those admissions, and the cause of anemia was not ascertained. She was on iron supplements since her second admission. There was no history of seizures, loss of consciousness, altered sensorium, or difficulty in feeding. Her nutritional history revealed adequate consumption of calories and proteins for age. Her anthropometric parameters revealed severe undernutrition (weight-7.8 kg (< -3Z score); height-86 cm (< -3 Z score) and microcephaly (43 cm). General examination revealed severe pallor, mild facial dysmorphism in the form of frontal bossing, flat nasal bridge, and high arched palate. Her cardiovascular system examination revealed an apex beat at the sixth intercostal space, 2 cm lateral to the mid-clavicular line (pushed down and out). The first and second heart sounds were heard without any murmurs. Respiratory system and abdominal examination were non-contributory. Neurological examination revealed generalized wasting, hypotonia, muscle power of 4/5, exaggerated reflexes, and flexor plantar response. There were no cranial nerve deficits and the sensory, cerebellar, and autonomic system examinations were normal. The provisional diagnosis entertained was a metabolic disorder with central hypotonia like Pompe's disease. The initial investigations revealed microcytic hypochromic anemia with increased serum lactate levels [Table 1]. High-performance liquid chromatography was normal. Her serum iron and serum ferritin levels had improved on oral iron therapy, but there was no concomitant increase in hemoglobin, arousing the suspicion of sideroblastic anemia. Electrocardiogram revealed chamber enlargement and the echocardiogram showed gross dilatation of all four heart chambers with an ejection fraction of 38%, suggestive of cardiomyopathy. Magnetic resonance imaging of the brain revealed no abnormalities. Electromyography revealed short-duration small-amplitude motor unit potential, suggestive of myopathy, while the nerve conduction velocity studies were normal. She was treated with non-invasive ventilation, blood transfusions, and cardiac supportive medications in the form of furosemide and digoxin. Clinical exome sequencing revealed a novel homozygous missense variation in exon 5 of the PUS1 gene (chr12:g.131941897G>A; Depth: 145x) that resulted in the amino acid substitution of Lysine for Glutamic Acid at codon 384 (p.Glu384Lys; ENST00000376649.8), confirming a diagnosis of myopathy, lactic acidosis, and sideroblastic anemia-1 (MLASA-1). Our patient was discharged after 2 weeks of hospital stay on furosemide, digoxin, and pyridoxine. Appropriate genetic counseling was given to the parents regarding the disease.
Table 1: Investigations of the index case

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   Discussion Top

The list of differential diagnoses for a floppy infant is exhaustive, among which the major ones are summarized in [Table 2]. Considering a floppy infant with anemia, the differentials include infantile cobalamin deficiency, mitochondrial myopathy, Pearson syndrome, MLASA or rarely celiac disease, and lead poisoning. The syndrome of MLASA was first described by Inbal et al.[1] in 1995, which is now classified as MLASA-1, caused by pathogenic variants in the nuclear gene PUS1. This mitochondrial deficiency disorder essentially involves the bone marrow's skeletal muscle and erythrocytic cell line. This disorder is an ultra-rare genetic disease with only 34 pathogenic and 11 likely pathogenic variants described in ClinVar as of July 2022. MLASA2 is caused by a mutation in the YARS2 gene and MLASA3 is caused by the MTATP6 mutation.[2]
Table 2: Differential diagnoses of a floppy infant

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The literature on MLASA-1 is exceptionally sparse and is limited to a few case reports. The PUS1 gene codes for pseudouridylate synthase 1, present in both the nucleus and mitochondria, that plays a role in post-translational modification of cytoplasmic and mitochondrial tRNAs.[3] The combination of sideroblastic anemia and lactic acidosis strongly suggests a mitochondrial disorder. If the onset of sideroblastic anemia is during infancy, then Pearson-marrow-pancreas syndrome is the most common cause. MLASA is another condition that has been identified as a distinct cause of sideroblastic anemia, lactic acidosis accompanying myopathy. Unlike the pancreatic insufficiency of Pearson syndrome, MLASA may be accompanied by feeding difficulties and gastrointestinal disturbances.[2],[3],[4] Our patient had microcytic anemia as opposed to the macrocytic picture of Pearson syndrome, and there was no evidence of pancreatic insufficiency. MLASA is characterized by a broad spectrum of manifestations varying in severity ranging from asymptomatic patient till adolescence to severe anemia starting from early childhood. This heterogeneity is due to the PUS1 protein's dual spatial distribution in both cytoplasm and mitochondria.[4] The translation machinery may differ in cytoplasm and mitochondria, and the expression of the PUS1 isoform or its regulation may vary according to the nature of the mutation. The clinical phenotype is dominated by neurological and hematological involvement. Neurological involvement may be in the form of exercise intolerance, developmental delay, microcephaly, and mitochondrial myopathy. Hematological involvement comprises of sideroblastic anemia, which does not respond to vitamin supplements. Our patient had significant failure to thrive, accompanied by floppiness since birth and anemia manifesting from late infancy. She also had cardiomyopathy, an atypical feature of MLASA-1, characterized by the involvement of skeletal muscle.

Inbal et al.[1] described two siblings with MLASA during their evaluation of anemia and weakness.[1] Both had mild facial dysmorphism, myopathy, lactic acidosis, and mental retardation. Muscle biopsy revealed low cytochromes a, b, and c in mitochondria. Bone marrow also revealed ringed sideroblasts and iron deposits in erythroblasts, confirming sideroblastic anemia. Casas and Fischel-Ghodsian described four other patients who presented with exercise intolerance and found lactic acidosis and mitochondrial myopathy on evaluation.[5] Microcephaly and mental retardation were not found in all these four patients. Metodiev et al.[6] described another girl that presented with transfusion-dependent anemia since infancy, failure to thrive, and mental retardation but did not have lactic acidosis. This report emphasized the unusually long survival of the girl as she was 26 years at the time of reporting. Similar patients with hallmark findings were described in other case reports.[7],[8],[9] Cardiomyopathy has been described in patients with YARS2 mutation but has not been described in PUS1 mutation thus far.[10] To the best of our knowledge, this is the first pediatric case of MLASA to be reported.

   Conclusion Top

MLASA is an ultra-rare genetic disease that manifests with sideroblastic anemia and myopathy. Knowledge about this disease will help clinicians in early diagnosis of the condition, which would aid in providing appropriate genetic counseling to the parents.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Inbal A, Avissar N, Shaklai M, Kuritzky A, Schejter A, Ben-David E, et al. Myopathy, lactic acidosis, and sideroblastic anemia: A new syndrome. Am J Med Genet 1995;55:372-8.  Back to cited text no. 1
Burrage LC, Tang S, Wang J, Donti TR, Walkiewicz M, Luchak JM, et al. 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. Mol Genet Metab 2014;113:207-12.  Back to cited text no. 2
Shahni R, Wedatilake Y, Cleary MA, Lindley KJ, Sibson KR, Rahman S. A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations. Am J Med Genet A 2013;161A: 2334-8.  Back to cited text no. 3
Fernandez-Vizarra E, Berardinelli A, Valente L, Tiranti V, Zeviani M. Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA). J Med Genet 2007;44:173-80.  Back to cited text no. 4
Casas KA, Fischel-Ghodsian N. Mitochondrial myopathy and sideroblastic anemia. Am J Med Genet A 2004;12:5201-4.  Back to cited text no. 5
Metodiev MD, Assouline Z, Landrieu P, Chretien D, Bader-Meunier B, Guitton C, et al. Unusual clinical expression and long survival of a pseudouridylate synthase (PUS1) mutation into adulthood. Eur J Hum Genet 2015;23:880-2.  Back to cited text no. 6
Woods J, Cederbaum S. Myopathy, lactic acidosis and sideroblastic anemia 1 (MLASA1): A 25-year follow-up. Mol Genet Metab Rep 2019;21:100517. doi: 10.1016/j.ymgmr.2019.100517.  Back to cited text no. 7
Cao M, Donà M, Valentino ML, Valentino L, Semplicini C, Maresca A, et al. Clinical and molecular study in a long-surviving patient with MLASA syndrome due to novel PUS1 mutations. Neurogenetics 2016;17:65-70.  Back to cited text no. 8
Bykhovskaya Y, Casas K, Mengesha E, Inbal A, Fischel-Ghodsian N. Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). Am J Hum Genet 2004;74:1303-8.  Back to cited text no. 9
Riley LG, Cooper S, Hickey P, Rudinger-Thirion J, McKenzie M, Compton A, et al. Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome. Am J Hum Genet 2010;87:52-9.  Back to cited text no. 10


  [Table 1], [Table 2]


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