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.

Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene

“…One patient presented with acute metabolic decompensation; an older sibling had developmental delay attributable to co-existing hydrocephalus, but was otherwise asymptomatic [5] . Two unrelated patients had progressive neurological symptoms; however, each was also affected by a second inherited disorder, sepiapterin reductase deficiency, which fully explained the clinical course [6] , [7] , [8] . All four patients presented with methylmalonic aciduria which was persistent but usually mild or moderate.…”

Genetic, structural, and functional analysis of mutations causing methylmalonyl-CoA epimerase deficiency

“…Thus far, 11 cases of MMAuria have been identified due to mutations in the MCEE gene (1)(2)(3)(4)(5)(6). We screened fibroblast cell lines taken from 150 patients with mild but clear MMAuria who could not be assigned to a cobalamin class of defect.…”

“…Isolated methylmalonic aciduria (MMAuria), an inborn error of organic acid metabolism, is typically caused by deficiency of MUT or by a defect in the transport or processing of its organometallic cofactor, adenosylcobalamin. However, mutations in the human MCEE gene (OMIM #251120) have been identified in eleven cases of atypical MMAuria (1)(2)(3)(4)(5)(6). For two patients, coincidental mutations in the SPR gene causing sepiapterin reductase deficiency sufficiently explained their clinical symptoms (2,4), while two others have been described as asymptomatic (3), leaving the clinical importance of MCEE deficiency in doubt.…”

“…However, mutations in the human MCEE gene (OMIM #251120) have been identified in eleven cases of atypical MMAuria (1)(2)(3)(4)(5)(6). For two patients, coincidental mutations in the SPR gene causing sepiapterin reductase deficiency sufficiently explained their clinical symptoms (2,4), while two others have been described as asymptomatic (3), leaving the clinical importance of MCEE deficiency in doubt. The majority of patients with MCEE deficiency (seven including those with sepiapterin reductase deficiency) are homozygous for the stop-gain nonsense mutation c.139C>T (p.Arg47*)(1-6); the missense mutations p.Lys60Gln and p.Arg143Cys (3) and a splicing mutation (c.379-644A>G) (5) have also been identified, but the functional relevance of these missense mutations remains unclear.…”

Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency

“…Isolated methylmalonic aciduria (MMAuria), an inborn error of organic acid metabolism, is typically caused by deficiency of MUT or by a defect in the transport or processing of its organometallic cofactor, adenosylcobalamin. However, pathogenic variations in the human MCEE gene (OMIM # 251120 ) have been identified in eleven cases of atypical MMAuria [ [1] , [2] , [3] , [4] , [5] , [6] ]. For two patients, coincidental variations in the SPR gene causing sepiapterin reductase deficiency sufficiently explained their clinical symptoms [ 2 , 4 ], while two others have been described as asymptomatic [ 3 ], leaving the clinical importance of MCEE deficiency in doubt.…”