Table 1.

Diseases caused by mitochondrial iron-sulfur cluster biogenesis.

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