Abstract
Costeff syndrome (CS) is a rare autosomal-recessive neurological disorder, which is known almost exclusively in patients of Iraqi Jewish descent, manifesting in childhood with optic atrophy, ataxia, chorea and spastic paraparesis. Our aim was to study the clinical spectrum of CS and natural history using a cross-sectional study design. Consecutive patients with CS were recruited to the study. Patients were diagnosed based on clinical features, along with elevated urinary levels of methylglutaconic and methylglutaric acid, and by identification of the disease-causing mutation in the OPA3 gene in most. All patients were examined by a neurologist and signs and symptoms were rated. 28 patients with CS (16 males, 21 families, age at last observation 28.6 ± 16.1 years, range 0.5–68 years) were included. First signs of neurological deficit appeared in infancy or early childhood, with delayed motor milestones, choreiform movements, ataxia and visual disturbances. Ataxia and chorea were the dominant motor features in childhood, but varied in severity among patients and did not seem to worsen with age. Pyramidal dysfunction appeared later and progressed with age (r = 0.71, p < 0.001) leading to spastic paraparesis and marked gait impairment. The course of neurological deterioration was slow and the majority of patients could still walk beyond the fifth decade. While visual acuity seemed to deteriorate, it did not correlate with age. CS is a rare neurogenetic disorder that causes serious disability and worsens with age. Spasticity significantly increases over the years and is the most crucial determinant of neurological dysfunction.
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Costeff H, Elpeleg O, Apter N, Divry P, Gadoth N (1993) 3-Methylglutaconic aciduria in “optic atrophy plus”. Ann Neurol 33:103–104
Elpeleg ON, Costeff H, Joseph A, Shental Y, Weitz R, Gibson KM (1994) 3-Methylglutaconic aciduria in the Iraqi-Jewish ‘optic atrophy plus’ (Costeff) syndrome. Dev Med Child Neurol 36(2):167–172
Costeff H, Gadoth N, Apter N, Prialnic M, Savir H (1989) A familial syndrome of infantile optic atrophy, movement disorder, and spastic paraplegia. Neurology 39:595–597
Zeharia A, Elpeleg ON, Mukamel M, Weitz R, Ariel R, Mimouni M (1992) 3-Methylglutaconic aciduria: a new variant. Pediatrics 89(6 Pt 1):1080–1082
Gonzalez IL (2005) Barth syndrome: tAZ gene mutations, mRNAs, and evolution. Am J Med Genet A 134(4):409–414
Neuwald AF (1997) Barth syndrome may be due to an acyltransferase deficiency. Curr Biol 7:465–466
Wortmann SB, Duran M, Anikster Y, Barth PG, Sperl W, Zschocke J, Morava E, Wevers RA (2013) Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature. J Inherit Metab Dis 36(6):923–928
Davey KM, Parboosingh JS, McLeod DR, Chan A, Casey R, Ferreira P, Snyder FF, Bridge PJ, Bernier FP (2006) Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition. J Med Genet 43(5):385–393
Su B, Ryan RO (2014) Metabolic biology of 3-methylglutaconic acid-uria: a new perspective. J Inherit Metab Dis 37(3):359–368
Nystuen A, Costeff H, Elpeleg ON, Apter N, Bonné-Tamir B, Mohrenweiser H, Haider N, Stone EM, Sheffield VC (1997) Iraqi-Jewish kindreds with optic atrophy plus (3-methylglutaconic aciduria type 3) demonstrate linkage disequilibrium with the CTG repeat in the 3′ untranslated region of the myotonic dystrophy protein kinase gene. Hum Mol Genet 6(4):563–569
Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O (2001) Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am J Hum Genet 69(6):1218–1224
Pei W, Kratz LE, Bernardini I, Sood R, Yokogawa T, Dorward H, Ciccone C, Kelley RI, Anikster Y, Burgess HA, Huizing M, Feldman B (2010) A model of Costeff syndrome reveals metabolic and protective functions of mitochondrial OPA3. Development 137(15):2587–2596
Ryu SW, Jeong HJ, Choi M, Karbowski M, Choi C (2010) Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation. Cell Mol Life Sci 67(16):2839–2850
Hauser SL, Dawson DM, Lehrich JR, Beal MF, Kevy SV, Propper RD, Mills JA, Weiner HL (1983) Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Engl J Med 308:173–180
Saneto RP, Friedman SD, Shaw DW (2008) Neuroimaging of mitochondrial disease. Mitochondrion 8(5–6):396–413
Archer SL (2013) Mitochondrial dynamics—mitochondrial fission and fusion in human diseases. N Engl J Med 369(23):2236–2251
Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C et al (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26:207–210
Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battaloglu E, Polyakov AV, Timmerman V, Schröder JM, Vance JM (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36:449–451
Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60(5):748–766
Zsurka G, Kunz WS (2013) Mitochondrial involvement in neurodegenerative diseases. IUBMB Life 65(3):263–272
Costeff H, Apter N, Elpeleg ON, Prialnic M, Böhles HJ (1998) Ineffectiveness of oral coenzyme Q10 supplementation in 3-methylglutaconic aciduria, type 3. Brain Dev 20(1):33–35
Enns GM, Kinsman SL, Perlman SL, Spicer KM, Abdenur JE, Cohen BH, Amagata A, Barnes A, Kheifets V, Shrader WD, Thoolen M, Blankenberg F, Miller G (2012) Initial experience in the treatment of inherited mitochondrial disease with EPI-743. Mol Genet Metab 105(1):91–102
Sadun AA, Chicani CF, Ross-Cisneros FN, Barboni P, Thoolen M, Shrader WD, Kubis K, Carelli V, Miller G (2012) Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Arch Neurol 69(3):331–338
Martinelli D, Catteruccia M, Piemonte F, Pastore A, Tozzi G, Dionisi-Vici C, Pontrelli G, Corsetti T, Livadiotti S, Kheifets V, Hinman A, Shrader WD, Thoolen M, Klein MB, Bertini E, Miller G (2012) EPI-743 reverses the progression of the pediatric mitochondrial disease—genetically defined Leigh syndrome. Mol Genet Metab 107(3):383–388
Blankenberg FG, Kinsman SL, Cohen BH, Goris ML, Spicer KM, Perlman SL, Krane EJ, Kheifets V, Thoolen M, Miller G, Enns GM (2012) Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease. Mol Genet Metab 107(4):690–699
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The authors are deeply in debt to the patients and families for their participation.
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On behalf of all authors, the corresponding author states that there is no conflict of interest.
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This study was carried in accordance with ethical standards as set out in the Declaration of Helsinki.
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415_2014_7481_MOESM1_ESM.tif
Supplemental Figure A: Additional 11 pedigrees of families with CS. Detailed are the pedigrees of families H, J, S, N, M, O, F, K, P, A and R. Full signs designate affected individuals, index patients are designated with arrows. Of note, several families exhibit additional Costeff-suspected patients who were not included in the study cohort. Consanguinity can be noted in families S and O. (TIFF 6998 kb)
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Yahalom, G., Anikster, Y., Huna-Baron, R. et al. Costeff syndrome: clinical features and natural history. J Neurol 261, 2275–2282 (2014). https://doi.org/10.1007/s00415-014-7481-x
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DOI: https://doi.org/10.1007/s00415-014-7481-x