Abstract
Objective/context: We describe the second patient presenting the combination of two homoallelic homozygous nonsense mutations in two genes distant from 1.8 Mb in the chromosome 2p13-3, the methylmalonyl-CoA epimerase gene (MCEE) and the sepiapterin reductase gene (SPR).
Case report: The patient was born from consanguineous parents. He has presented a moderate but constant methylmalonic acid (MMA) excretion in urine associated with a mental retardation. The first homozygous mutation was identified in the MCEE gene (c.139C>T; p.Arg47*). Progressive dystonia and cataplexy narcolepsy led to diagnose the second homozygous mutation in the SPR gene: c.751A>T; p.Lys251*. Sepiapterin reductase deficiency (SRD) was characterized by a defect in tetrahydrobiopterin (BH4), the cofactor of several hydroxylases needed for the synthesis of neurotransmitters. A treatment with l-DOPA/carbidopa and 5-HTP dramatically improved the dystonic posture, the mood and the hypersomnia, proving that the pathogenesis was due to SRD. A supplementation with BH4 did not induce additional clinical benefit, although HVA and HIAA increased in CSF. The polyunsaturated fatty acids were measured in CSF as the markers of the neuronal stress. We have shown that DHA and its precursor EPA were high before and during the time course of the different treatments.
In conclusion: The patient has inherited two copies of the two mutations from his consanguineous parents in the MCEE and SPR genes in the chromosome 2p13-3. DHA and EPA increased in CSF as a response to the neuronal stress induced by the defect in neurotransmitters or the altered metabolism of the odd-chain fatty acids and cholesterol.
Keywords
Competing interests: None declared
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Abbreviations
- 5-HIAA:
-
5-Hydroxyindoleacetic acid
- 5-HT:
-
5-Hydroxytryptamine/serotonin
- 5-HTP:
-
5-Hydroxytryptophan
- BH2:
-
Dihydrobiopterin
- BH4:
-
Tetrahydrobiopterin
- BP:
-
Biopterin
- CSF:
-
Cerebrospinal fluid
- DA:
-
Dopamine
- DHA:
-
Docosahexaenoic acid (22:6n-3)
- EPA:
-
Eicosapentaenoic acid (20:5n-3)
- GC-MS:
-
Gas chromatography-mass spectrometry
- HGH:
-
Human growth hormone
- HVA:
-
Homovanillic acid
- l-DOPA:
-
3,4-Dihydroxyphenylalanine
- MCEE :
-
Methylmalonyl-CoA epimerase gene
- MMA:
-
Methylmalonic acid
- MTHF:
-
Methyltetrahydrofolate
- NOS:
-
Nitric oxide synthase
- OMD:
-
3-Orthomethyl-Dopa or 3-methoxytyrosine
- PUFA:
-
Polyunsaturated fatty acid
- RV:
-
Reference value
- SPR :
-
Sepiapterin reductase gene
- SRD:
-
Sepiapterin reductase deficiency
References
Abeling NG, Duran M, Bakker HD, Stroomer L, Thony B, Blau N, Booij J, Poll-The BT (2006) Sepiapterin reductase deficiency an autosomal recessive DOPA-responsive dystonia. Mol Genet Metab 89:116–120
Bauer I, Crewther S, Pipingas A, Sellick L, Crewther D (2014) Does omega-3 fatty acid supplementation enhance neural efficiency? A review of the literature. Hum Psychopharmacol 29:8–18. doi:10.1002/hup.2370
Bazan NG (2006) Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends Neurosci 29:263–271. doi:10.1016/j.tins.2006.03.005
Bikker H, Bakker HD, Abeling NG, Poll-The BT, Kleijer WJ, Rosenblatt DS, Waterham HR, Wanders RJ, Duran M (2006) A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria. Hum Mutat 27:640–643. doi:10.1002/humu.20373
Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37:911–917
Clot F, Grabli D, Cazeneuve C, Roze E, Castelnau P, Chabrol B, Landrieu P, Nguyen K, Ponsot G, Abada M, Doummar D, Damier P, Gil R, Thobois S, Ward AJ, Hutchinson M, Toutain A, Picard F, Camuzat A, Fedirko E, San C, Bouteiller D, LeGuern E, Durr A, Vidailhet M, Brice A (2009) Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia. Brain 132:1753–1763. doi:10.1093/brain/awp084
Crawford JR, Garthwaite PH (2007) Comparison of a single case to a control or normative sample in neuropsychology: development of a Bayesian approach. Cogn Neuropsychol 24:343–372. doi:10.1080/02643290701290146
Engstrom K, Saldeen AS, Yang B, Mehta JL, Saldeen T (2009) Effect of fish oils containing different amounts of EPA, DHA, and antioxidants on plasma and brain fatty acids and brain nitric oxide synthase activity in rats. Ups J Med Sci 114:206–213. doi:10.3109/03009730903268958
Fonteh AN, Chiang J, Cipolla M, Hale J, Diallo F, Chirino A, Arakaki X, Harrington MG (2013) Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer’s disease. J Lipid Res 54:2884–2897. doi:10.1194/jlr.M037622
Fonteh AN, Cipolla M, Chiang J, Arakaki X, Harrington MG (2014) Human cerebrospinal fluid fatty acid levels differ between supernatant fluid and brain-derived nanoparticle fractions, and are altered in Alzheimer’s disease. PLoS One 9:e100519. doi:10.1371/journal.pone.0100519
Friedman J, Hyland K, Blau N, MacCollin M (2006) Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurology 67:2032–2035. doi:10.1212/01.wnl.0000247274.21261.b4
Friedman J, Roze E, Abdenur JE, Chang R, Gasperini S, Saletti V, Wali GM, Eiroa H, Neville B, Felice A, Parascandalo R, Zafeiriou DI, Arrabal-Fernandez L, Dill P, Eichler FS, Echenne B, Gutierrez-Solana LG, Hoffmann GF, Hyland K, Kusmierska K, Tijssen MA, Lutz T, Mazzuca M, Penzien J, Poll-The BT, Sykut-Cegielska J, Szymanska K, Thony B, Blau N (2012) Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann Neurol 71:520–530. doi:10.1002/ana.22685
Gradinger AB, Belair C, Worgan LC, Li CD, Lavallee J, Roquis D, Watkins D, Rosenblatt DS (2007) Atypical methylmalonic aciduria: frequency of mutations in the methylmalonyl CoA epimerase gene (MCEE). Hum Mutat 28:1045. doi:10.1002/humu.9507
Hong SH, Belayev L, Khoutorova L, Obenaus A, Bazan NG (2014) Docosahexaenoic acid confers enduring neuroprotection in experimental stroke. J Neurol Sci 338:135–141. doi:10.1016/j.jns.2013.12.033
Jiang LH, Shi Y, Wang LS, Yang ZR (2009) The influence of orally administered docosahexaenoic acid on cognitive ability in aged mice. J Nutr Biochem 20:735–741. doi:10.1016/j.jnutbio.2008.07.003
Kearney H.M., Kearney J.B., Conlin L.K. (2011) Diagnostic implications of excessive homozygosity detected by SNP-based microarrays: consanguinity, uniparental disomy, and recessive single-gene mutations. Clin Lab Med 31:595-613, ix. DOI: 10.1016/j.cll.2011.08.003.
Kim HY (2007) Novel metabolism of docosahexaenoic acid in neural cells. J Biol Chem 282:18661–18665. doi:10.1074/jbc.R700015200
Koht J, Rengmark A, Opladen T, Bjornara KA, Selberg T, Tallaksen CM, Blau N, Toft M (2014) Clinical and genetic studies in a family with a novel mutation in the sepiapterin reductase gene. Acta Neurol Scand Suppl 7–12. doi:10.1111/ane.12230
Lavialle M, Champeil-Potokar G, Alessandri JM, Balasse L, Guesnet P, Papillon C, Pevet P, Vancassel S, Vivien-Roels B, Denis I (2008) An (n-3) polyunsaturated fatty acid-deficient diet disturbs daily locomotor activity, melatonin rhythm, and striatal dopamine in Syrian hamsters. J Nutr 138:1719–1724
Montgomery JA, Mamer OA, Scriver CR (1983) Metabolism of methylmalonic acid in rats. Is methylmalonyl-coenzyme a racemase deficiency symptomatic in man? J Clin Invest 72:1937–1947. doi:10.1172/JCI111158
Ormazabal A, Garcia-Cazorla A, Fernandez Y, Fernandez-Alvarez E, Campistol J, Artuch R (2005) HPLC with electrochemical and fluorescence detection procedures for the diagnosis of inborn errors of biogenic amines and pterins. J Neurosci Methods 142:153–158
Pottala JV, Yaffe K, Robinson JG, Espeland MA, Wallace R, Harris WS (2014) Higher RBC EPA+DHA corresponds with larger total brain and hippocampal volumes: WHIMS-MRI study. Neurology 82:435–442. doi:10.1212/WNL.0000000000000080
Zorzi G, Redweik U, Trippe H, Penzien JM, Thony B, Blau N (2002) Detection of sepiapterin in CSF of patients with sepiapterin reductase deficiency. Mol Genet Metab 75:174–177
Acknowledgements
We thank Clotilde Robin for correcting the English language. Claude Wolf for helpful discussions about PUFA and Rafel Laboissiere for statistical advising.
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Communicated by: Nenad Blau, PhD
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Take-Home Message
We present a complete description of the medical and the genetic history for the patient with a combination of the two rare MCEE/SPR homozygous mutations, and we present the first investigation of the level of DHA and EPA in CSF for metabolic diseases.
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Michel Mazzuca, Marie-Anne Maubert, Léna Damaj, Fabienne Clot, Marylène Cadoudal, Christele Dubourg, Sylvie Odent, Jean François Benoit, Nadia Bahi-Buisson, Laurence Christa and Pascale de Lonlay declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.
Details of the Contributions of Individual Authors
For medical care of the patient: Michel Mazzuca, Léna Damaj, Nadia Bahi-Buisson and Pascale de Lonlay were the referring physicians.
For biochemical analysis: Marie-Anne Maubert (PUFA analysis) and Marylène Cadoudal and Laurence Christa (neurotransmitter analysis) designed and performed the experiments.
For molecular genetic analysis: Fabienne Clot, Christele Dubourg, Sylvie Odent and Jean François Benoit designed and performed the experiments.
Conduct and reporting of the work described in the article: Michel Mazzuca, Sylvie Odent, Laurence Christa and Pascale de Lonlay analysed the data and wrote the manuscript.
All these authors equally contributed to this work.
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Mazzuca, M. et al. (2015). Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under l-DOPA, 5-HTP and BH4 Trials. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 22. JIMD Reports, vol 22. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_410
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DOI: https://doi.org/10.1007/8904_2015_410
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