Abstract
Methylmalonic aciduria (MMA-uria) is seen in several inborn errors of metabolism (IEM) affecting intracellular cobalamin pathways. Methylmalonyl-CoA epimerase (MCE) is an enzyme involved in the mitochondrial cobalamin-dependent pathway generating succinyl-CoA. Homozygous mutations in the corresponding MCEE gene have been shown in children to cause MCE deficiency with isolated MMA-uria and a variable clinical phenotype. We describe a 78-year-old man with Parkinson’s disease, dementia and stroke in whom elevated serum levels of methylmalonic acid had been evident for many years. Metabolic work-up revealed intermittent MMA-uria and increased plasma levels of propionyl-carnitine not responsive to treatment with high-dose hydroxycobalamin. Whole genome sequencing was performed, with data analysis targeted towards genes known to cause IEM. Compound heterozygous mutations were identified in the MCEE gene, c.139C>T (p.Arg47X) and c.419delA (p.Lys140fs), of which the latter is novel. To our knowledge, this is the first report of an adult patient with MCEE mutations and MMA-uria, thus adding novel data to the possible phenotypical spectrum of MCE deficiency. Although clinical implications are uncertain, it can be speculated whether intermittent hyperammonemia during episodes of metabolic stress could have precipitated the patient’s ongoing neurodegeneration attributed to Parkinson’s disease.
Highlights
Following cellular uptake into the lysosome, cobalamin is converted to adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) through two separate pathways
Stroke affecting the basal ganglia, movement disorders and cognitive decline have been described in the context of isolated methylmalonic acid (MMA)-uria [3]
We describe an adult patient with highly elevated plasma MMA and mild MMA-uria likely causeWd ebydaenscurinbdeearlnyiandguMltCpEatdieefintciwenicthy dhuigehtloycoelmevpaotuenddphlaestemroazMygMouAs manudtamtioinlds iMn MtheAM-uCriEaEligkeenlye. cCaeullsueldarbcyoamnpulenmdeenrltyaitniognMstCuEdidesefainciden[1c4yCd] uperotpoioconmatpeoinucnodrphoertaetriooznyagsosuasysmwuetaretionnost pinertfhoermMeCdEiEn gtheinsep.atCieenlltu. lHarowceovmepr,loenmeeonftathtieomn usttautidoiness, ca.1n3d9C[>14TC](p.pArorgp4i7oXn)a,ties ainncoonrspeonrsaetimonutaatsiosanytshawt hearsebeneont psheorfwonrmtoedcaiunsethMisCEpadteiefincti.enHcyowinehveorm, ooznyegooufstshteatem, uantadtitohneso, tch.e1r39isCa>Tfra(mp.eAshrgif4t7mXu),taitsioan ncaounssienngsea pmruemtaatitounretshtaotphcaosdobne.enBosthhomwuntattoiocnasuasree tMhuCsEprdeedfiicctieednctyo riensuhlot minotzhyegsoyunsthsetsaitseo, fatnrudntchaetedotvheerrsiiosnas forfatmheesMhiCftEmpurtoatteiionn, scuaupspionrgtiangpraenmuantudreerlsytionpgcModCoEnd
Summary
Following cellular uptake into the lysosome, cobalamin is converted to adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) through two separate pathways. Methylmalonic aciduria (MMA-uria) is present in several inborn errors of metabolism (IEM) affecting different steps of these intracellular cobalamin pathways. Disruption of AdoCbl, and by extension MUT, is known to cause isolated MMA-uria [2]. Stroke affecting the basal ganglia, movement disorders and cognitive decline have been described in the context of isolated MMA-uria [3]. S Behavioral symptoms ensued, including hallucinations, anxiety and delusions, causing the patient to be moved to a nursing home. 2019, 20, 2631 ensued, including hallucinations, anxiety and delusions, causing the patient to be moved to a nursing home. The second mutation, c.419delA (p.Lys140fs), causes a frameshift introducing a premature stop codon that has not been described before in the context of MCE deficiency (Figure 2). Shhaeentteegrreoorzzyyseggqoouuuessncccaairrnrrgiieerorssf oothff eoonnMeeCeeaaEccEhhgooeffnttheh,eeippnrrogobebnaanondmd’’siscmmDuuNttaaAttiiooinsnossl..ated from blood, revealed the sons as
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