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Myopathy, lactic acidosis, and sideroblastic anemia 1(MLASA1)

MedGen UID:
1634824
Concept ID:
C4551958
Disease or Syndrome
Synonym: MLASA1
 
Gene (location): PUS1 (12q24.33)
 
Monarch Initiative: MONDO:0024553
OMIM®: 600462

Definition

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). [from OMIM]

Clinical features

From HPO
Exercise intolerance
MedGen UID:
603270
Concept ID:
C0424551
Finding
A functional motor deficit where individuals whose responses to the challenges of exercise fail to achieve levels considered normal for their age and gender.
Scapular winging
MedGen UID:
66822
Concept ID:
C0240953
Anatomical Abnormality
Abnormal protrusion of the scapula away from the surface of the back.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hypopituitarism
MedGen UID:
9386
Concept ID:
C0020635
Disease or Syndrome
A condition of diminution or cessation of secretion of one or more hormones from the anterior pituitary gland. This may result from surgical or radiation ablation, non-secretory pituitary neoplasms, metastatic tumors, infarction, pituitary apoplexy, infiltrative or granulomatous processes, and other conditions.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hypochromic anemia
MedGen UID:
8065
Concept ID:
C0002884
Disease or Syndrome
A type of anemia characterized by an abnormally low concentration of hemoglobin in the erythrocytes.
Sideroblastic anemia
MedGen UID:
8067
Concept ID:
C0002896
Disease or Syndrome
Sideroblastic anemia results from a defect in the incorporation of iron into the heme molecule. A sideroblast is an erythroblast that has stainable deposits of iron in cytoplasm (this can be demonstrated by Prussian blue staining).
Erythroid hyperplasia
MedGen UID:
4536
Concept ID:
C0014800
Disease or Syndrome
Increased count of erythroid precursor cells, that is, erythroid lineage cells in the bone marrow.
Pappenheimer bodies
MedGen UID:
137696
Concept ID:
C0333814
Finding
A type of erythrocyte inclusion characterized by basophilic stippling of erythrocytes, that is, by numerous very small coarse or fine blue granules within the cytoplasm with the additional stipulation that the stippled particles are due to iron granules (demonstrable by the Prussian blue stain).
Microcytic anemia
MedGen UID:
1673948
Concept ID:
C5194182
Disease or Syndrome
A kind of anemia in which the volume of the red blood cells is reduced.
Hyperlordosis
MedGen UID:
9805
Concept ID:
C0024003
Finding
Abnormally increased curvature (anterior concavity) of the lumbar or cervical spine.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Gowers sign
MedGen UID:
65865
Concept ID:
C0234182
Finding
A phenomenon whereby patients are not able to stand up without the use of the hands owing to weakness of the proximal muscles of the lower limbs.
Progressive muscle weakness
MedGen UID:
68704
Concept ID:
C0240421
Finding
Generalized limb muscle atrophy
MedGen UID:
333018
Concept ID:
C1838114
Disease or Syndrome
Generalized (unlocalized) atrophy affecting muscles of the limbs in both proximal and distal locations.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Ragged-red muscle fibers
MedGen UID:
477048
Concept ID:
C3275417
Finding
An abnormal appearance of muscle fibers observed on muscle biopsy. Ragged red fibers can be visualized with Gomori trichrome staining as irregular and intensely red subsarcolemmal zones, whereas the normal myofibrils are green. The margins of affect fibers appear red and ragged. The ragged-red is due to the accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber, leading to the appearance of a red rim and speckled sarcoplasm.
Cytochrome C oxidase-negative muscle fibers
MedGen UID:
867360
Concept ID:
C4021724
Finding
An abnormally reduced activity of the enzyme cytochrome C oxidase in muscle tissue.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Restrictive ventilatory defect
MedGen UID:
478856
Concept ID:
C3277226
Finding
A functional defect characterized by reduced total lung capacity (TLC) not associated with abnormalities of expiratory airflow or airway resistance. Spirometrically, a restrictive defect is defined as FEV1 (forced expiratory volume in 1 second) and FVC (forced vital capacity) less than 80 per cent. Restrictive lung disease may be caused by alterations in lung parenchyma or because of a disease of the pleura, chest wall, or neuromuscular apparatus.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Increased circulating ferritin concentration
MedGen UID:
69130
Concept ID:
C0241013
Finding
Increased concentration of ferritin in the blood circulation.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Depressed nasal ridge
MedGen UID:
334631
Concept ID:
C1842876
Finding
Lack of prominence of the nose resulting from a posteriorly-placed nasal ridge.
Pallor
MedGen UID:
10547
Concept ID:
C0030232
Finding
Abnormally pale skin.
Distichiasis
MedGen UID:
98074
Concept ID:
C0423848
Anatomical Abnormality
Double rows of eyelashes.
Delayed puberty
MedGen UID:
46203
Concept ID:
C0034012
Pathologic Function
Passing the age when puberty normally occurs with no physical or hormonal signs of the onset of puberty.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Pigmentary retinopathy
MedGen UID:
1643295
Concept ID:
C4551715
Disease or Syndrome
An abnormality of the retina characterized by pigment deposition. It is typically associated with migration and proliferation of macrophages or retinal pigment epithelial cells into the retina; melanin from these cells causes the pigmentary changes. Pigmentary retinopathy is a common final pathway of many retinal conditions and is often associated with visual loss.
Decreased activity of mitochondrial complex I
MedGen UID:
393796
Concept ID:
C2677650
Finding
A reduction in the activity of the mitochondrial respiratory chain complex I, which is part of the electron transport chain in mitochondria.
Decreased activity of mitochondrial complex IV
MedGen UID:
866520
Concept ID:
C4020800
Finding
A reduction in the activity of the mitochondrial respiratory chain complex IV, which is part of the electron transport chain in mitochondria.

Recent clinical studies

Etiology

Kothari SS, Shah J, Sharma V, Charaniya R, Parikh R, Vaniawala SN
BMC Med Genomics 2024 Aug 15;17(1):213. doi: 10.1186/s12920-024-01983-8. PMID: 39148116Free PMC Article
Tesarova M, Vondrackova A, Stufkova H, Veprekova L, Stranecky V, Berankova K, Hansikova H, Magner M, Galoova N, Honzik T, Vodickova E, Stary J, Zeman J
Pediatr Blood Cancer 2019 Apr;66(4):e27591. Epub 2018 Dec 26 doi: 10.1002/pbc.27591. PMID: 30588737
Riley LG, Cooper S, Hickey P, Rudinger-Thirion J, McKenzie M, Compton A, Lim SC, Thorburn D, Ryan MT, Giegé R, Bahlo M, Christodoulou J
Am J Hum Genet 2010 Jul 9;87(1):52-9. doi: 10.1016/j.ajhg.2010.06.001. PMID: 20598274Free PMC Article

Diagnosis

Sommerville EW, Ng YS, Alston CL, Dallabona C, Gilberti M, He L, Knowles C, Chin SL, Schaefer AM, Falkous G, Murdoch D, Longman C, de Visser M, Bindoff LA, Rawles JM, Dean JCS, Petty RK, Farrugia ME, Haack TB, Prokisch H, McFarland R, Turnbull DM, Donnini C, Taylor RW, Gorman GS
JAMA Neurol 2017 Jun 1;74(6):686-694. doi: 10.1001/jamaneurol.2016.4357. PMID: 28395030Free PMC Article
Alfadhel M, Nashabat M, Abu Ali Q, Hundallah K
Neurosciences (Riyadh) 2017 Jan;22(1):4-13. doi: 10.17712/nsj.2017.1.20160542. PMID: 28064324Free PMC Article
Metodiev MD, Assouline Z, Landrieu P, Chretien D, Bader-Meunier B, Guitton C, Munnich A, Rötig A
Eur J Hum Genet 2015 Jun;23(6):880-2. Epub 2014 Sep 17 doi: 10.1038/ejhg.2014.192. PMID: 25227147Free PMC Article
Shahni R, Wedatilake Y, Cleary MA, Lindley KJ, Sibson KR, Rahman S
Am J Med Genet A 2013 Sep;161A(9):2334-8. Epub 2013 Aug 5 doi: 10.1002/ajmg.a.36065. PMID: 23918765Free PMC Article

Prognosis

Tesarova M, Vondrackova A, Stufkova H, Veprekova L, Stranecky V, Berankova K, Hansikova H, Magner M, Galoova N, Honzik T, Vodickova E, Stary J, Zeman J
Pediatr Blood Cancer 2019 Apr;66(4):e27591. Epub 2018 Dec 26 doi: 10.1002/pbc.27591. PMID: 30588737
Sommerville EW, Ng YS, Alston CL, Dallabona C, Gilberti M, He L, Knowles C, Chin SL, Schaefer AM, Falkous G, Murdoch D, Longman C, de Visser M, Bindoff LA, Rawles JM, Dean JCS, Petty RK, Farrugia ME, Haack TB, Prokisch H, McFarland R, Turnbull DM, Donnini C, Taylor RW, Gorman GS
JAMA Neurol 2017 Jun 1;74(6):686-694. doi: 10.1001/jamaneurol.2016.4357. PMID: 28395030Free PMC Article
Dingerdissen H, Weaver DS, Karp PD, Pan Y, Simonyan V, Mazumder R
Biol Direct 2014 Jun 3;9:9. doi: 10.1186/1745-6150-9-9. PMID: 24894379Free PMC Article
Nakajima J, Eminoglu TF, Vatansever G, Nakashima M, Tsurusaki Y, Saitsu H, Kawashima H, Matsumoto N, Miyake N
J Hum Genet 2014 Apr;59(4):229-32. Epub 2014 Jan 16 doi: 10.1038/jhg.2013.143. PMID: 24430573
Fernandez-Vizarra E, Berardinelli A, Valente L, Tiranti V, Zeviani M
J Med Genet 2007 Mar;44(3):173-80. Epub 2006 Oct 20 doi: 10.1136/jmg.2006.045252. PMID: 17056637Free PMC Article

Clinical prediction guides

Kothari SS, Shah J, Sharma V, Charaniya R, Parikh R, Vaniawala SN
BMC Med Genomics 2024 Aug 15;17(1):213. doi: 10.1186/s12920-024-01983-8. PMID: 39148116Free PMC Article
Wang B, Shi D, Yang S, Lian Y, Li H, Cao M, He Y, Zhang L, Qiu C, Liu T, Wen W, Ma Y, Shi L, Cheng T, Shi L, Yuan W, Chu Y, Shi J
Blood 2024 Aug 8;144(6):657-671. doi: 10.1182/blood.2023022004. PMID: 38635773
Sommerville EW, Ng YS, Alston CL, Dallabona C, Gilberti M, He L, Knowles C, Chin SL, Schaefer AM, Falkous G, Murdoch D, Longman C, de Visser M, Bindoff LA, Rawles JM, Dean JCS, Petty RK, Farrugia ME, Haack TB, Prokisch H, McFarland R, Turnbull DM, Donnini C, Taylor RW, Gorman GS
JAMA Neurol 2017 Jun 1;74(6):686-694. doi: 10.1001/jamaneurol.2016.4357. PMID: 28395030Free PMC Article
Dingerdissen H, Weaver DS, Karp PD, Pan Y, Simonyan V, Mazumder R
Biol Direct 2014 Jun 3;9:9. doi: 10.1186/1745-6150-9-9. PMID: 24894379Free PMC Article
Fernandez-Vizarra E, Berardinelli A, Valente L, Tiranti V, Zeviani M
J Med Genet 2007 Mar;44(3):173-80. Epub 2006 Oct 20 doi: 10.1136/jmg.2006.045252. PMID: 17056637Free PMC Article

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