Article Figures & Data
Figures
- Figure 1
- Mitochondrial iron-sulfur cluster assembly: all involved proteins are written in their genetic names. Yellow circle presents sulfur and red circle presents iron. Numbers indicate the steps of the process; number 1 and 2 include the core components of the process. Proteins associated with known medical conditions are underlined. Ala - Alanine, BOLA3 - bolA family member 3, Cys - Cysteine, FDX2 - Ferredoxin 2, FDXR - Ferredoxin reductase, FXN - Frataxin, GLRX5 - glutaredoxin 5, GRPEL1 - GrpE like 1, GSH - tripeptide glutathione, HSCB - HscB mitochondrial iron-sulfur cluster cochaperone, HSPA9 - heat shock protein family A (Hsp70) member 9, IBA57 - iron-sulfur cluster assembly factor for biotin synthase- and aconitase-like mitochondrial proteins, with a mass of 57kDa, ISCA1 - iron-sulfur cluster assembly 1, ISCA2 - iron-sulfur cluster assembly 2, ISCU - Iron–sulfur cluster scaffold homolog, LIAS - lipoic acid synthetase, LYRM4 - LYR motif containing 4, NFS - Cysteine desulfurase, NFU1 - NFU1 iron-sulfur cluster scaffold, NUBPL - nucleotide binding protein like, SDH - succinate dehydrogenase.
- Figure 2
- Lipoic Acid Synthetase (LIAS) biosynthesis and function, LIAS is essential in the maturation of lipoic acid (LA) which acts as cofactor for many enzymes. lipoic acid is bound to E2 and E3 subunits of the mitochondrial a-ketoacid dehydrogenase complex family (Pyruvate dehydrogenase, oxoglutarate (a ketoglutarate) dehydrogenase and branched chain ketoacid dehydrogenase, 2-oxoadipate dehydrogenase). lipoic acid is also bound to protein H in the Glycine cleavage system (GCS). Diseases which cause inhibition of any of ISC assembly step 3 proteins (shown in red and underlined) will affect the synthesis of the target apoprotein LIAS and subsequently the end product LA. As a result, all the biological process which include lipoic acid will be affected; the activity of a-ketoacid dehydrogenase complex family will decrease and the GCS activity will decrease which result in hyperglycinemia. ISC - Iron–sulfur clusters, 5,10-MTHF - 5, 10 methylene tetrahydrofolate, GCS - Glycine Cleavage System, THF - tetrahydrofolate
Tables
Variables Frataxin (FXN) ISD11 (LYRM4) NFS1 ISCU FDX1L GLRX5 NFU1 BOLA3 IBA57 ISCA2 NUBPL ABCB7 HSPA9 OMIM# 22930 615595 603485 255125 614585 616860 and 616859 605711 614299 615330 616370 613621 301310 616854 Disease Friedreich ataxia (FRDA) Combined oxidative phosphorylation deficiency 19 Infantile complex II/III deficiency (IMC23D) Myopathy with lactic acidosis, hereditary mitochondrial muscle myopathy 616860: Anemia, sideroblastic, 3, pyridoxine-616859: refractory Spasticity, childhood- Multiple mitochondrial dysfunctions syndrome 1 Multiple mitochondrial dysfunctions syndrome 2 Multiple mitochondrial dysfunctions syndrome 3 Multiple mitochondrial dysfunctions syndrome 4 Mitochondrial complex I deficiency Sidroblastic anemia with ataxia Even-plus syndrome Year 1996 2013 2014 2008 2014 2007 and 2011 2011 2011 2013 2015 2010 1999 2015 Pathway defect Core [Fe-S] assembly Core [Fe-S] assembly Core [Fe-S] assembly Core [Fe-S] assembly Core [Fe-S] assembly [Fe-S] transfer to specific recipients [Fe-S] transfer to specific recipients [Fe-S] transfer to specific recipients [Fe4-S4] assembly [Fe4-S4] assembly Mitochondrial translation; complex I assembly Mitochondrial export Mitochondrial iron import Number of patients/Prevalence 1:50000 2 3 25 1 5 20 3 2 6 7 22 3 Age of onset Childhood-Adult (usually 2nd decade) Neonatal Infantile Childhood Childhood Adult and childhood neonatal and infantile Infantile Neonatal Infantile Infantile Childhood Prenatal Origin Panethnic Lebanon and Syria Canada Sweden and Norway Morocco Italy and China Mexico, Germany, Serbia, Romania, Pakistan India, Australia, Africa Morocco Saudi Argentina, Germany, Canada, Australia, Netherlands USA Chile and Korea Clinical hints Ataxia, dysarthria, muscle weakness, spasticity in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, and loss of position and vibration sense, cardiomyopathy, DM Hypotonia, respiratory distress Hypotonia, respiratory distress, seizure, multisystem organ failure Muscle weakness, exercise intolerance and cardiomyopathy Severe proximal lower limb weakness and muscle cramps 616860: Sideroblastic anemia, hepatosplenomegaly and jaundice 616859: Spastic paraplegia, spinal lesion, and optic atrophy Hypotonia, respiratory distress, seizure, Neurologic regression pulmonary hypertension, lethargy, poor feeding, White matter lesions seen on brain imaging Hypotonia, respiratory distress, seizure, Neurologic regression, lethargy, poor feeding, optic atrophy, white matter lesions seen on brain imaging Severe hypotonia, generalized muscle weakness, absent primitive reflexes, microcephaly and dysmorphic features (retrognathia, high palate, widely spaced nipples, arthrogryposis, cerebral atrophy and polymicrogyria on Brain MRI Neuroregression, developmental delay, nystagmus with optic atrophy and diffuse white matter disease of the brain and spine Hypotonia, muscle weakness, muscle atrophy exercise intolerance Muscle biopsy shows abnormal mitochondria, developmental delay, neuroregression, seizure, white matter lesions seen on brain imaging Sidroblastic anemia and ataxia EVEN-PLUS syndrome is characterized by short stature, vertebral and epiphyseal changes, microtia, midface hypoplasia with flat nose and triangular nares, cardiac malformations, and other findings including anal atresia, hypodontia, and aplasia cutis. The features overlap those reported in patients with CODAS syndrome Biochemical hints None Lactic acidosis, metabolic acidosis, high liver enzymes low complexes I-IV in the muscle Lactic acidosis, metabolic acidosis, high CK level and high liver enzymes, DIC picture, low complexes II and III in the muscle Lactic acidosis, Myoglobinuria Histopathology showed succinate dehydrogenase and cytochrome c oxidase (COX) deficienc Lactic acidosis, myoglobinuria and low complexes I, II and III in the muscle 616860: hypochromic microcytic anemia, increase ferritin level, ringed sideroblasts on bone marrow aspirate Hyperglycinemia, metabolic acidosis, lactic acidosis, Increased urinary 2-hydroxybutyrate, Decreased activity of pyruvate dehydrogenase complex, low complexes I and II in the muscle same as NFU1 gene defect Hyperglycinemia, metabolic acidosis, lactic acidosis Hyperglycinemia, metabolic acidosis, lactic acidosis hypoglycemia, lactic acidosis, low complex I in the muscle Increased free erythrocyte protoporphyrin, hypochromic microcytic anemia, ringed sideroblasts on bone marrow aspirate Not specific Mutation reported 90 % have expanded GAA repeat in intron 1 of FXN gene* Missense mutation c.203G>T, p.Arg68Lys Missense mutation c.251G>A, p.Arg72Gln Splicing defect IVS5 + 382G>C, heterozygosity for the splicing defect and the missense mutation c.149G>A, p.Gly50Glu homozygous mutation c.1A>T 616860: A> G homozygous transition 616859: Homozygous deletion c.151_153delAAG, p.K51del or compound heterozygosity for p.K51del and 8bp insertion A homozygous missense mutation, c.545G>A(p.Arg182Gln), compound heterozygous for aforementioned mutation and a splice-site (c.545+5G>A) mutation, compound heterozygous mutation (g.69400462C>A, p.Gly208Cys); g.69592691_ 69648327del, [?]) compound heterozygous mutation (c.544C>T, [?], p.Arg182Trp);[?]), (c. 565G>A, p. Gly189Arg);[568G>A],;[Gly190 Arg]), (c.[544C>T];[?], p.[Arg182Trp];[?]), homozygous frameshift mutation c.302+3A>G (p.Val56Glyfs*9), compound heterozygous mutation (c.62G>C, p.Arg21Pro); (c.622G>T, p.Gly208Cys) (c.136C4T, p.R46X) (c.941A > C, p.Gln314Pro) (c.229G>A, p.Gly77Ser) Homozygous missense mutation (c.166G>A, p.Gly56Arg), intronic mutation: c.815-27T>C or compound heterozygous for (c.166G>A, p.Gly56Arg) and other mutation Homozygous missense mutation(c.1200T>G(p.Ile400Met), Other several mutations near to or in transmembrane domains of the ABC transporter Compound hgetrozygous mutation (c.383A > G (p.Y128C) and c.882_883delAG (p.V296*), homozygous missense mutation (c.376C > T;p.Arg126Trp). Mortality The average age of death was at 37.5 years (range, 5–71 years) 1/2 2/3 None None None 20/20 3/3 2/2 4/6 None None None
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