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

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.

Competing interests: None declared

Appendices

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.

Disclosure

The authors have nothing to disclose.

Compliance with Ethics Guidelines

Conflict of Interest

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.