title: 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).
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neurometabolism Department, Reference Center for Inherited Metabolic Diseases, Assistance Publique des Hôpitaux de Paris et Université, Necker, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Mazzuca
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Maubert
authors.forename: Léna
authors.initials: L
authors.lastname: Damaj
authors.forename: Fabienne
authors.initials: F
authors.lastname: Clot
authors.forename: Marylène
authors.initials: M
authors.lastname: Cadoudal
authors.forename: Christele
authors.initials: C
authors.lastname: Dubourg
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.forename: Jean François
authors.initials: JF
authors.lastname: Benoit
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
authors.forename: Laurence
authors.initials: L
authors.lastname: Christa
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay