Table 1

Diseases caused by mitochondrial iron-sulfur cluster biogenesis.

VariablesFrataxin (FXN)ISD11 (LYRM4)NFS1ISCUFDX1LGLRX5NFU1BOLA3IBA57ISCA2NUBPLABCB7HSPA9
OMIM#22930615595603485255125614585616860 and 616859605711614299615330616370613621301310616854
DiseaseFriedreich ataxia (FRDA)Combined oxidative phosphorylation deficiency 19Infantile complex II/III deficiency (IMC23D)Myopathy with lactic acidosis, hereditarymitochondrial muscle myopathy616860: Anemia, sideroblastic, 3, pyridoxine-616859: refractory Spasticity, childhood-Multiple mitochondrial dysfunctions syndrome 1Multiple mitochondrial dysfunctions syndrome 2Multiple mitochondrial dysfunctions syndrome 3Multiple mitochondrial dysfunctions syndrome 4Mitochondrial complex I deficiencySidroblastic anemia with ataxiaEven-plus syndrome
Year199620132014200820142007 and 20112011201120132015201019992015
Pathway defectCore [Fe-S] assemblyCore [Fe-S] assemblyCore [Fe-S] assemblyCore [Fe-S] assemblyCore [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] assemblyMitochondrial translation; complex I assemblyMitochondrial exportMitochondrial iron import
Number of patients/Prevalence1:50000232515203267223
Age of onsetChildhood-Adult (usually 2nd decade)NeonatalInfantileChildhoodChildhoodAdult and childhoodneonatal and infantileInfantileNeonatalInfantileInfantileChildhoodPrenatal
OriginPanethnicLebanon and SyriaCanadaSweden and NorwayMoroccoItaly and ChinaMexico, Germany, Serbia, Romania, PakistanIndia, Australia, AfricaMoroccoSaudiArgentina, Germany, Canada, Australia, NetherlandsUSAChile and Korea
Clinical hintsAtaxia, dysarthria, muscle weakness, spasticity in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, and loss of position and vibration sense, cardiomyopathy, DMHypotonia, respiratory distressHypotonia, respiratory distress, seizure, multisystem organ failureMuscle weakness, exercise intolerance and cardiomyopathySevere proximal lower limb weakness and muscle cramps616860: Sideroblastic anemia, hepatosplenomegaly and jaundice 616859: Spastic paraplegia, spinal lesion, and optic atrophyHypotonia, respiratory distress, seizure, Neurologic regression pulmonary hypertension, lethargy, poor feeding, White matter lesions seen on brain imagingHypotonia, respiratory distress, seizure, Neurologic regression, lethargy, poor feeding, optic atrophy, white matter lesions seen on brain imagingSevere hypotonia, generalized muscle weakness, absent primitive reflexes, microcephaly and dysmorphic features (retrognathia, high palate, widely spaced nipples, arthrogryposis, cerebral atrophy and polymicrogyria on Brain MRINeuroregression, developmental delay, nystagmus with optic atrophy and diffuse white matter disease of the brain and spineHypotonia, muscle weakness, muscle atrophy exercise intolerance Muscle biopsy shows abnormal mitochondria, developmental delay, neuroregression, seizure, white matter lesions seen on brain imagingSidroblastic anemia and ataxiaEVEN-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 hintsNoneLactic acidosis, metabolic acidosis, high liver enzymes low complexes I-IV in the muscleLactic acidosis, metabolic acidosis, high CK level and high liver enzymes, DIC picture, low complexes II and III in the muscleLactic acidosis, Myoglobinuria Histopathology showed succinate dehydrogenase and cytochrome c oxidase (COX) deficiencLactic acidosis, myoglobinuria and low complexes I, II and III in the muscle616860: hypochromic microcytic anemia, increase ferritin level, ringed sideroblasts on bone marrow aspirateHyperglycinemia, metabolic acidosis, lactic acidosis, Increased urinary 2-hydroxybutyrate, Decreased activity of pyruvate dehydrogenase complex, low complexes I and II in the musclesame as NFU1 gene defectHyperglycinemia, metabolic acidosis, lactic acidosisHyperglycinemia, metabolic acidosis, lactic acidosishypoglycemia, lactic acidosis, low complex I in the muscleIncreased free erythrocyte protoporphyrin, hypochromic microcytic anemia, ringed sideroblasts on bone marrow aspirateNot specific
Mutation reported90 % have expanded GAA repeat in intron 1 of FXN gene*Missense mutation c.203G>T, p.Arg68LysMissense mutation c.251G>A, p.Arg72GlnSplicing defect IVS5 + 382G>C, heterozygosity for the splicing defect and the missense mutation c.149G>A, p.Gly50Gluhomozygous mutation c.1A>T616860: A> G homozygous transition 616859: Homozygous deletion c.151_153delAAG, p.K51del or compound heterozygosity for p.K51del and 8bp insertionA 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 mutationHomozygous missense mutation(c.1200T>G(p.Ile400Met), Other several mutations near to or in transmembrane domains of the ABC transporterCompound hgetrozygous mutation (c.383A > G (p.Y128C) and c.882_883delAG (p.V296*), homozygous missense mutation (c.376C > T;p.Arg126Trp).
MortalityThe average age of death was at 37.5 years (range, 5–71 years)1/22/3NoneNoneNone20/203/32/24/6NoneNoneNone