Skip to main content
SpringerLink
Log in

Review of neuropsychological outcomes in isolated methylmalonic acidemia: recommendations for assessing impact of treatments

  • Review Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Methylmalonic acidemia (MMA) due to methylmalonyl-CoA mutase deficiency (OMIM #251,000) is an autosomal recessive disorder of organic acid metabolism associated with life-threatening acute metabolic decompensations and significant neuropsychological deficits. “Isolated” MMA refers to the presence of excess methylmalonic acid without homocysteine elevation. Belonging to this class of disorders are those that involve complete deficiency (mut0) and partial deficiency (mut−) of the methylmalonyl-CoA mutase enzyme and other disorders causing excess methylmalonic acid excretion. These other disorders include enzymatic subtypes related to cobalamin A defect (cblA) (OMIM #25,110), cobalamin B defect (cblB) (OMIM #251,110) and related conditions. Neuropsychological attributes associated with isolated MMA have become more relevant as survival rates increased following improved diagnostic and treatment strategies. Children with this disorder still are at risk for developmental delay, cognitive difficulties and progressive declines in functioning. Mean IQ for all types apart from cblA defect enzymatic subtype is rarely above 85 and much lower for mut0 enzymatic subtype. Identifying psychological domains responsive to improvements in biochemical status is important. This review suggests that processing speed, working memory, language, attention, and quality of life may be sensitive to fluctuations in metabolite levels while IQ and motor skills may be less amenable to change. Due to slower developmental trajectories, Growth Scale Values, Projected Retained Ability Scores and other indices of change need to be incorporated into clinical trial study protocols. Neuropsychologists are uniquely qualified to provide a differentiated picture of cognitive, behavioral and emotional consequences of MMA and analyze benefits or shortcomings of novel treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Data availability

All works discussed in this review have been published and are available to the public.

Code availability

Not applicable.

Abbreviations

MMA:

Methylmalonic acidemia

mut0:

Methylmalonyl CoA mutase enzyme, complete deficiency

mut − :

Methylmalonyl CoA mutase enzyme, partial deficiency

cblA:

Cobalamin A defect

cblB:

Cobalamin B defect

B12:

Vitamin B12 (adenosyl cobalamin)

IQ:

Intelligence quotient

μmol/L:

Micromoles/liter

MRI:

Magnetic resonance imaging

T2:

Time constant for the decay of transverse magnetization

WPPSI-IV:

Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition

WASI-II:

Wechsler Abbreviated Scale of Intelligence, Second Edition

WISC-V:

Wechsler Intelligence Scale for Children, Fifth Edition

WAIS-IV:

Wechsler Adult Intelligence Scale, Fourth Edition

NIH:

National Institutes of Health

CANTAB:

Cambridge Automated Neuropsychological Test Battery

PROMIS:

Patient Reported Outcomes Measurement Information System

BASC-3:

Behavior Assessment System for Children, Third Edition

GSV:

Growth Scale Values

PAS:

Personal Ability Scores

PRAS:

Projected Retained Ability Score

MDRI:

Multi-Domain Responder Index

References

  • Almási T, Guey LT, Lukacs C, Csetneki K, Vokó Z, Zelei T (2019) Systematic literature review and meta-analysis on the epidemiology of methylmalonic acidemia (MMA) with a focus on MMA caused by methylmalonyl-CoA mutase (Mut) deficiency. Orphanet J Rare Dis 14(1):84. https://doi.org/10.1186/s13023-019-1063-z

    Article  PubMed  PubMed Central  Google Scholar 

  • Amaral AU, Cecatto C, Castilho RF, Wajner M (2016) 2-Methylcitric acid impairs glutamate metabolism and induces permeability transition in brain mitochondria. J Neurochem 137(1):62–75. https://doi.org/10.1111/jnc.13544

    Article  CAS  PubMed  Google Scholar 

  • Basner M, Hermosillo E, Nasrini J, Saxena S, Dinges DF, Moore TM, Gur RC (2020) Cognition test battery: Adjusting for practice and stimulus set effects for varying administration intervals in high performing individuals. J Clin Exp Neuropsychol. 2020 Jul;42(5):516–529. https://doi.org/10.1080/13803395.2020.1773765. Epub 2020 Jun 15. Erratum in: J Clin Exp Neuropsychol. 2020 Jun 24:1

  • Baumgarter ER, Viardot C (1995) Long-term follow-up of 77 patients with isolated methylmalonic acidaemia. J Inherit Metab Dis 18(2):138–142. https://doi.org/10.1007/BF00711749

    Article  CAS  PubMed  Google Scholar 

  • Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, Huemer M, Hochuli M, Assoun M, Ballhausen D, Burlina A, Fowler B, Grünert SC, Grünewald S, Honzik T, Merinero B, Pérez-Cerdá C, Scholl-Bürgi S, Skovby F, Wijburg F, MacDonald A, Martinelli D, Sass JO, Valayannopoulos V, Chakrapani A (2014) Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis 2(9):130. https://doi.org/10.1186/s13023-014-0130-8

    Article  Google Scholar 

  • Bayley N, Alyward GP (2019) Bayley scales of infant and toddler development—fourth edition: administration manual. Pearson Corp Inc, New York, NY

    Google Scholar 

  • Beglinger LJ, Gaydos B, Tangphao-Daniels O, Duff K, Kareken DA, Crawford J, Fastenau PS, Siemers ER (2005) Practice effects and the use of alternate forms in serial neuropsychological testing. Arch Clin Neuropsychol 20(4):517–529. https://doi.org/10.1016/j.acn.2004.12.003

    Article  PubMed  Google Scholar 

  • Budimirovic DB, Berry-Kravis E, Erickson CA, Hall SS, Hessl D, Reiss AL, King MK, Abbeduto L, Kaufmann WE (2017) Updated report on tools to measure outcomes of clinical trials in fragile X syndrome. J Neurodev Disord 12(9):14. https://doi.org/10.1186/s11689-017-9193-x.PMID:28616097;PMCID:PMC5467057

    Article  Google Scholar 

  • Busch RM, Lineweaver TT, Ferguson L, Haut JS (2015) Reliable change indices and standardized regression-based change score norms for evaluating neuropsychological change in children with epilepsy. Epilepsy Behav 47: 45–54

  • Cabrera-Pastor A, Taoro-Gonzalez L, Felipo V (2016) Hyperammonemia alters glycinergic neurotransmission and modulation of the glutamate-nitric oxide-cGMP pathway by extracellular glycine in cerebellum in vivo. J Neurochem 137(4):539–548. https://doi.org/10.1111/jnc.13579

    Article  CAS  PubMed  Google Scholar 

  • Chakrapani A, Sivakumar P, McKiernan PJ, Leonard JV (2002) Metabolic stroke in methylmalonic acidemia five years after liver transplantation. J Pediatr 140(2):261–263. https://doi.org/10.1067/mpd.2002.121698

    Article  PubMed  Google Scholar 

  • Chapman KA, Gramer G, Viall S, Summar ML (2018) Incidence of maple syrup urine disease, propionic acidemia, and methylmalonic aciduria from newborn screening data. Mol Genet Metab Rep 5(15):106–109. https://doi.org/10.1016/j.ymgmr.2018.03.011

    Article  CAS  Google Scholar 

  • Chen K, Didsbury M, van Zwieten A, Howell M, Kim S, Tong A, Howard K, Nassar N, Barton B, Lah S, Lorenzo J, Strippoli G, Palmer S, Teixeira-Pinto A, Mackie F, McTaggart S, Walker A, Kara T, Craig JC, Wong G (2018) Neurocognitive and educational outcomes in children and adolescents with CKD: a systematic review and meta-analysis. Clin J Am Soc Nephrol 13(3):387–397. https://doi.org/10.2215/CJN.09650917

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen PW, Hwu WL, Ho MC, Lee NC, Chien YH, Ni YH, Lee PH (2010) Stabilization of blood methylmalonic acid level in methylmalonic acidemia after liver transplantation. Pediatr Transplant 14(3):337–341. https://doi.org/10.1111/j.1399-3046.2009.01227.x

    Article  CAS  PubMed  Google Scholar 

  • Chu TH, Chien YH, Lin HY, Liao HC, Ho HJ, Lai CJ, Chiang CC, Lin NC, Yang CF, Hwu WL, Lee NC, Lin SP, Liu CS, Hu RH, Ho MC, Niu DM (2019) Methylmalonic acidemia/propionic acidemia - the biochemical presentation and comparing the outcome between liver transplantation versus non-liver transplantation groups. Orphanet J Rare Dis 14(1):73. https://doi.org/10.1186/s13023-019-1045-1

    Article  PubMed  PubMed Central  Google Scholar 

  • Coelho D, Suormala T, Stucki M, Lerner-Ellis JP, Rosenblatt DS, Newbold RF, Baumgartner MR, Fowler B (2008) Gene identification for the cblD defect of vitamin B12 metabolism. N Engl J Med 358(14):1454–1464. https://doi.org/10.1056/NEJMoa072200

    Article  CAS  PubMed  Google Scholar 

  • Cosson MA, Benoist JF, Touati G, Déchaux M, Royer N, Grandin L, Jais JP, Boddaert N, Barbier V, Desguerre I, Campeau PM, Rabier D, Valayannopoulos V, Niaudet P, de Lonlay P (2009) Long-term outcome in methylmalonic aciduria: a series of 30 French patients. Mol Genet Metab 97(3):172–178. https://doi.org/10.1016/j.ymgme.2009.03.006

    Article  CAS  PubMed  Google Scholar 

  • Costanzo M, Caterino M, Cevenini A, Jung V, Chhuon C, Lipecka J, Fedele R, Guerrera IC, Ruoppolo M (2020) Proteomics reveals that methylmalonyl-CoA mutase modulates cell architecture and increases susceptibility to stress. Int J Mol Sci 21(14):4998. https://doi.org/10.3390/ijms21144998

    Article  CAS  PubMed Central  Google Scholar 

  • DeRoche K, Welsh M (2008) Twenty-five years of research on neurocognitive outcomes in early-treated phenylketonuria: intelligence and executive function. Dev Neuropsychol 33(4):474–504. https://doi.org/10.1080/87565640802101482

    Article  PubMed  Google Scholar 

  • Dionisi-Vici C, Deodato F, Röschinger W, Rhead W, Wilcken B (2006) 'Classical' organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis 29(2–3):383–9. https://doi.org/10.1007/s10545-006-0278-z

  • Duff K, Westervelt HJ, McCaffrey RJ, Haase RF (2001) Practice effects, test-retest stability, and dual baseline assessments with the California Verbal Learning Test in an HIV sample. Arch Clin Neuropsychol 16(5):461–476

    CAS  PubMed  Google Scholar 

  • Elliott CD (2007) Differential abilities scale, second edition. San Antonio, TX: Harcourt Assessment

  • Falleti MG, Maruff P, Collie A, Darby DG (2006) Practice effects associated with the repeated assessment of cognitive function using the CogState battery at 10-minute, one week and one month test-retest intervals. J Clin Exp Neuropsychol 28(7):1095–1112. https://doi.org/10.1080/13803390500205718

    Article  PubMed  Google Scholar 

  • Farmer CA, Kaat AJ, Thurm A, Anselm I, Akshoomoff N, Bennett A, Berry L, Bruchey A, Barshop BA, Berry-Kravis E, Bianconi S, Cecil KM, Davis RJ, Ficicioglu C, Porter FD, Wainer A, Goin-Kochel RP, Leonczyk C, Guthrie W, Koeberl D, Love-Nichols J, Mamak E, Mercimek-Andrews S, Thomas RP, Spiridigliozzi GA, Sullivan N, Sutton VR, Udhnani MD, Waisbren SE, Miller JS (2020) Person ability scores as an alternative to norm-referenced scores as outcome measures in studies of neurodevelopmental disorders. Am J Intellect Dev Disabil 125(6):475–480. https://doi.org/10.1352/1944-7558-125.6.475

    Article  PubMed  Google Scholar 

  • Fenton WA, Gravel RA, Rosenblatt DS (2001) Disorders of propionate and methylmalonate metabolism. In Scriver CR, Beaudet AL, Sly WS, Valle, D (eds) The metabolic and molecular bases of inherited disease. 2165–2193

  • Feuchtbaum L, Carter J, Dowray S, Currier RJ, Lorey F (2012) Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet Med 14(11):937–945. https://doi.org/10.1038/gim.2012.76

    Article  PubMed  Google Scholar 

  • Fray PJ, Robbins TW (1996) CANTAB battery: proposed utility in neurotoxicology. Neurotoxicol Teratol. 18(4):499–504. https://doi.org/10.1016/0892-0362(96)00027-x

  • Gershon RC, Wagster MV, Hendrie HC, Fox NA, Cook KF, Nowinski CJ (2013) NIH toolbox for assessment of neurological and behavioral function. Neurology 80(11 Suppl 3):S2-6. https://doi.org/10.1212/WNL.0b013e3182872e5f

    Article  PubMed  PubMed Central  Google Scholar 

  • Haijes HA, Jans JJM, Tas SY, Verhoeven-Duif NM, van Hasselt PM (2019) Pathophysiology of propionic and methylmalonic acidemias. Part 1: Complications. J Inherit Metab Dis. 42(5):730–744. https://doi.org/10.1002/jimd.12129

  • Haijes HA, Molema F, Langeveld M, Janssen MC, Bosch AM, van Spronsen F, Mulder MF, Verhoeven-Duif NM, Jans JJM, van der Ploeg AT, Wagenmakers MA, Rubio-Gozalbo ME, Brouwers MCGJ, de Vries MC, Langendonk JG, Williams M, van Hasselt PM (2020) Retrospective evaluation of the Dutch pre-newborn screening cohort for propionic acidemia and isolated methylmalonic acidemia: What to aim, expect, and evaluate from newborn screening? J Inherit Metab Dis 43(3):424–437. https://doi.org/10.1002/jimd.12193

  • Han B, Nie W, Sun M, Liu Y, Cao Z (2020) Clinical presentation, molecular analysis and follow-up of patients with mut methylmalonic acidemia in Shandong province. China Pediatr Neonatol 61(2):148–154. https://doi.org/10.1016/j.pedneo.2019.07.004

    Article  PubMed  Google Scholar 

  • Heringer J, Valayannopoulos V, Lund AM, Wijburg FA, Freisinger P, Barić I, Baumgartner MR, Burgard P, Burlina AB, Chapman KA, I Saladelafont EC, Karall D, Mühlhausen C, Riches V, Schiff M, Sykut-Cegielska J, Walter JH, Zeman J, Chabrol B, Kölker S; additional individual contributors of the E-IMD consortium (2016) Impact of age at onset and newborn screening on outcome in organic acidurias. J Inherit Metab Dis 39(3):341–353. https://doi.org/10.1007/s10545-015-9907-8

  • Heuberger K, Bailey HJ, Burda P, Chaikuad A, Krysztofinska E, Suormala T, Bürer C, Lutz S, Fowler B, Froese DS, Yue WW, Baumgartner MR (2019) Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. Biochim Biophys Acta Mol Basis Dis 1865(6):1265–1272. https://doi.org/10.1016/j.bbadis.2019.01.021

  • Howieson D (2019) Current limitations of neuropsychological tests and assessment procedures. Clin Neuropsychol 33(2):200–208. https://doi.org/10.1080/13854046.2018.1552762

    Article  PubMed  Google Scholar 

  • Hörster F, Baumgartner MR, Viardot C, Suormala T, Burgard P, Fowler B, Hoffmann GF, Garbade SF, Kölker S, Baumgartner ER (2007) Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB). Pediatr Res 62(2):225–230. https://doi.org/10.1203/PDR.0b013e3180a0325f

    Article  PubMed  Google Scholar 

  • Hörster F, Garbade SF, Zwickler T, Aydin HI, Bodamer OA, Burlina AB, Das AM, De Klerk JBC, Dionisi-Vici C, Geb S, Gökcay G, Guffon N, Maier EM, Morava E, Walter JH, Schwahn B, Wijburg FA, Lindner M, Grünewald S, Baumgartner MR, Kölker S (2009) Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters. J Inherit Metab Dis 32(5):630. https://doi.org/10.1007/s10545-009-1189-6. Epub 2009 Jul 31. Erratum in: J Inherit Metab Dis. 2009 Dec;32(6):762–3

  • Hörster F, Tuncel AT, Gleich F, Plessl T, Froese SD, Garbade SF, Kölker S, Baumgartner MR; Additional Contributors from E-IMD (2021) Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut. J Inherit Metab Dis 44(1):193–214. https://doi.org/10.1002/jimd.12297

  • Jiang YZ, Sun LY (2019) The value of liver transplantation for methylmalonic acidemia. Front Pediatr. 2019 Mar 21;7:87. https://doi.org/10.3389/fped.2019.00087. Erratum in: Front Pediatr. 2020 Apr 02;8:126

  • Kang L, Liu Y, Shen M, Liu Y, He R, Song J, Jin Y, Li M, Zhang Y, Dong H, Liu X, Yan H, Qin J, Zheng H, Chen Y, Li D, Wei H, Zhang H, Sun L, Zhu Z, Liang D, Yang Y (2020) A study on a cohort of 301 Chinese patients with isolated methylmalonic acidemia. J Inherit Metab Dis 43(3):409–423. https://doi.org/10.1002/jimd.12183

    Article  CAS  PubMed  Google Scholar 

  • Kaplan P, Ficicioglu C, Mazur AT, Palmieri MJ, Berry GT (2006) Liver transplantation is not curative for methylmalonic acidopathy caused by methylmalonyl-CoA mutase deficiency. Mol Genet Metabol 88:322–326. https://doi.org/10.1016/j.ymgme.2006.04.003

    Article  CAS  Google Scholar 

  • Khanna A, Gish R, Winter SC, Nyhan WL, Barshop BA (2016) Successful domino liver transplantation from a patient with methylmalonic acidemia. JIMD Rep 25:87–94. https://doi.org/10.1007/89042015480

    Article  CAS  PubMed  Google Scholar 

  • Ktena YP, Paul SM, Hauser NS, Sloan JL, Gropman A, Manoli I, Venditti CP (2015) Delineating the spectrum of impairments, disabilities, and rehabilitation needs in methylmalonic acidemia (MMA). Am J Med Genet A 167A(9):2075–2084. https://doi.org/10.1002/ajmg.a.37127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kronenberger WG, Harrington M, Yee KS (2021) Projected retained ability score (PRAS): a new methodology for quantifying absolute change in norm-based psychological test scores over time. Assessment. 2021 Mar;28(2):367–379. https://doi.org/10.1177/1073191119872250

  • Kölker S, Burgard P, Sauer SW, Okun JG (2013) Current concepts in organic acidurias: understanding intra- and extracerebral disease manifestation. J Inherit Metab Dis 36(4):635–644. https://doi.org/10.1007/s10545-013-9600-8

    Article  CAS  PubMed  Google Scholar 

  • Kölker S, Garcia-Cazorla A, Valayannopoulos V, Lund AM, Burlina AB, Sykut-Cegielska J, Wijburg FA, Teles EL, Zeman J, Dionisi-Vici C, Barić I, Karall D, Augoustides-Savvopoulou P, Aksglaede L, Arnoux JB, Avram P, Baumgartner MR, Blasco-Alonso J, Chabrol B, Chakrapani A, Chapman K, I Saladelafont EC, Couce ML, de Meirleir L, Dobbelaere D, Dvorakova V, Furlan F, Gleich F, Gradowska W, Grünewald S, Jalan A, Häberle J, Haege G, Lachmann R, Laemmle A, Langereis E, de Lonlay P, Martinelli D, Matsumoto S, Mühlhausen C, de Baulny HO, Ortez C, Peña-Quintana L, Ramadža DP, Rodrigues E, Scholl-Bürgi S, Sokal E, Staufner C, Summar ML, Thompson N, Vara R, Pinera IV, Walter JH, Williams M, Burgard P (2015) The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis 38(6):1041–57. https://doi.org/10.1007/s10545-015-9839-3

  • Ledley FD, Levy HL, Shih VE, Benjamin R, Mahoney MJ (1984) Benign methylmalonic aciduria. N Engl J Med 311(16):1015–1018. https://doi.org/10.1056/NEJM198410183111604

    Article  CAS  PubMed  Google Scholar 

  • Leonard JV (1995) The management and outcome of propionic and methylmalonic acidaemia. J Inherit Metab Dis 18(4):430–434. https://doi.org/10.1007/BF00710054

    Article  CAS  PubMed  Google Scholar 

  • Li D, McDonald CM, Elfring GL, Souza M, McIntosh J, Kim DH, Wei LJ (2020) Assessment of treatment effect with multiple outcomes in 2 clinical trials of patients with Duchenne muscular dystrophy. JAMA Netw Open 3(2):e1921306. https://doi.org/10.1001/jamanetworkopen.2019.21306

    Article  PubMed  PubMed Central  Google Scholar 

  • Manoli I, Sloan JL, Venditti CP (2005) Isolated methylmalonic acidemia. 2005 Aug 16 [updated 2016 Dec 1]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. PMID: 20301409

  • Manoli I, Myles JG, Sloan JL, Shchelochkov OA, Venditti CP (2016) A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias. Genet Med. 2016 Apr;18(4):386–95. https://doi.org/10.1038/gim.2015.102

  • Marcotte K, Graham NL, Fraser KC, Meltzer JA, Tang-Wai DF, Chow TW, Freedman M, Leonard C, Black SE, Rochon E (2017) White matter disruption and connected speech in non-fluent and semantic variants of primary progressive aphasia. Dementia and Geriatric Cognitive Disorders Extra 7(1):52–73. https://doi.org/10.1159/000456710

    Article  PubMed  PubMed Central  Google Scholar 

  • Matsui SM, Mahoney MJ, Rosenberg LE (1983) The natural history of the inherited methylmalonic acidemias. N Engl J Med 308:857–861. https://doi.org/10.1056/NEJM198304143081501

    Article  CAS  PubMed  Google Scholar 

  • McArdle JJ, Grimm KJ, Hamagami F, Bowles RP, Meredith W (2009) Modeling life-span growth curves of cognition using longitudinal data with multiple samples and changing scales of measurement. Psychol Methods 14(2):126–149. https://doi.org/10.1037/a0015857

    Article  PubMed  PubMed Central  Google Scholar 

  • Molema F, Williams M, Langendonk J, Darwish-Murad S, van de Wetering J, Jacobs E, Onkenhout W, Brusse E, van der Eerden A, Wagenmakers M (2020) Neurotoxicity including posterior reversible encephalopathy syndrome after initiation of calcineurin inhibitors in transplanted methylmalonic acidemia patients: Two case reports and review of the literature. JIMD Rep 51(1):89–104. https://doi.org/10.1002/jmd2.12088

    Article  PubMed  PubMed Central  Google Scholar 

  • Melo DR, Kowaltowski AJ, Wajner M, Castilho RF (2011) Mitochondrial energy metabolism in neurodegeneration associated with methylmalonic acidemia. J Bioenerg Biomembr 43(1):39–46. https://doi.org/10.1007/s10863-011-9330-2

    Article  CAS  PubMed  Google Scholar 

  • Morioka D, Kasahara M, Horikawa R, Yokoyama S, Fukuda A, Nakagawa A (2007) Efficacy of living donor liver transplantation for patients with methylmalonic acidemia. Am J Transplant 7(12):2782–2787. https://doi.org/10.1111/j.1600-6143.2007.01986.x

    Article  CAS  PubMed  Google Scholar 

  • Mueller KD, Koscik RL, Hermann BP, Johnson SC, Turkstra LS (2018) Declines in connected language are associated with very early mild cognitive impairment: results from the wisconsin registry for alzheimer’s prevention. Front Aging Neurosci 9(9):437. https://doi.org/10.3389/fnagi.2017.00437

    Article  PubMed  PubMed Central  Google Scholar 

  • Nicolaides P, Leonard J, Surtees R (1998) Neurological outcome of methylmalonic acidaemia. Arch Dis Child 78(6):508–512. https://doi.org/10.1136/adc.78.6.508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niemi AK, Kim IK, Krueger CE, Cowan TM, Baugh N, Farrell R, Bonham CA, Concepcion W, Esquivel CO, Enns GM (2015) Treatment of methylmalonic acidemia by liver or combined liver-kidney transplantation. J Pediatr 166(6):1455–61.e1. https://doi.org/10.1016/j.jpeds.2015.01.051

    Article  PubMed  Google Scholar 

  • Nizon M, Ottolenghi C, Valayannopoulos V, Arnoux JB, Barbier V, Habarou F, Desguerre I, Boddaert N, Bonnefont JP, Acquaviva C, Benoist JF, Rabier D, Touati G, de Lonlay P (2013) Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias. Orphanet J Rare Dis 23(8):148. https://doi.org/10.1186/1750-1172-8-148

    Article  Google Scholar 

  • Nyhan WL, Gargus JJ, Boyle K, Selby R, Koch R (2002) Progressive neurologic disability in methylmalonic acidemia despite transplantation of the liver. Eur J Pediatr 161(7):377–379. https://doi.org/10.1007/s00431-002-0970-4

    Article  PubMed  Google Scholar 

  • O’Shea CJ, Sloan JL, Wiggs EA, Pao M, Gropman A, Baker EH, Manoli I, Venditti CP, Snow J (2012) Neurocognitive phenotype of isolated methylmalonic acidemia. Pediatrics 129(6):e1541–e1551. https://doi.org/10.1542/peds.2011-1715

    Article  PubMed  PubMed Central  Google Scholar 

  • Pascoal C, Brasil S, Francisco R, Marques-da-Silva D, Rafalko A, Jaeken J, Videira PA, Barros L, Dos Reis FV (2018) Patient and observer reported outcome measures to evaluate health-related quality of life in inherited metabolic diseases: a scoping review. Orphanet J Rare Dis 13(1):215. https://doi.org/10.1186/s13023-018-0953-9

    Article  PubMed  PubMed Central  Google Scholar 

  • Payne JM, Hearps SJC, Walsh KS, Paltin I, Barton B, Ullrich NJ, Haebich KM, Coghill D, Gioia GA, Cantor A, Cutter G, Tonsgard JH, Viskochil D, Rey-Casserly C, Schorry EK, Ackerson JD, Klesse L, Fisher MJ, Gutmann DH, Rosser T, Packer RJ, Korf B, Acosta MT, North KN; NF Clinical Trials Consortium (2019) Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1. Ann Clin Transl Neurol 6(12):2555–2565. https://doi.org/10.1002/acn3.50952

  • Pillai NR, Stroup BM, Poliner A, Rossetti L, Rawls B, Shayota BJ, Soler-Alfonso C, Tunuguntala HP, Goss J, Craigen W, Scaglia F, Sutton VR, Himes RW, Burrage LC (2019) Liver transplantation in propionic and methylmalonic acidemia: A single center study with literature review. Mol Genet Metab 128(4):431–443. https://doi.org/10.1016/j.ymgme.2019.11.001

  • Prada CE, Al Jasmi F, Kirk EP, Hopp M, Jones O, Leslie ND, Burrow TA (2011) Cardiac disease in methylmalonic acidemia. J Pediatr 159(5):862–864. https://doi.org/10.1016/j.jpeds.2011.06.005

    Article  PubMed  Google Scholar 

  • Proctor EC, Turton N, Boan EJ, Bennett E, Philips S, Heaton RA, Hargreaves IP (2020) The effect of methylmalonic acid treatment on human neuronal cell coenzyme Q10 status and mitochondrial function. Int J Mol Sci 21(23):9137. https://doi.org/10.3390/ijms21239137

    Article  CAS  PubMed Central  Google Scholar 

  • Reynolds CR, Kamphaus RW (2015) Behavior assessment system for children, Third Edition. Bloomington, MN: Pearson

  • Ristl R, Urach S, Rosenkranz G, Posch M (2019) Methods for the analysis of multiple endpoints in small populations: A review. J Biopharm Stat 29(1):1–29. https://doi.org/10.1080/10543406.2018.1489402

    Article  PubMed  Google Scholar 

  • Sakamoto R, Nakamura K, Kido J, Matsumoto S, Mitsubuchi H, Inomata Y, Endo F (2016) Improvement in the prognosis and development of patients with methylmalonic acidemia after living donor liver transplant. Pediatr Transplant 20(8):1081–1086. https://doi.org/10.1111/petr.12804

    Article  CAS  PubMed  Google Scholar 

  • Shapiro E, Bernstein J, Adams HR, Barbier AJ, Buracchio T, Como P, Delaney KA, Eichler F, Goldsmith JC, Hogan M, Kovacs S, Mink JW, Odenkirchen J, Parisi MA, Skrinar A, Waisbren SE, Mulberg AE (2016) Neurocognitive clinical outcome assessments for inborn errors of metabolism and other rare conditions. Mol Genet Metab 118(2):65–9. https://doi.org/10.1016/j.ymgme.2016.04.006

  • Sheikhmoonesi F, Shafaat A, Moarefian S, Zaman T (2013) Affective disorder as the first manifestation of methylmalonic acidemia: a case report. Iran J Pediatr 23(2):245–6

  • Shevell MI, Matiaszuk N, Ledley FD, Rosenblatt DS (1993) Varying neurological phenotypes among mut0 and Mut- patients with methylmalonylCoA mutase deficiency. Am J Med Genet 45(5):619–624. https://doi.org/10.1002/ajmg.1320450521

    Article  CAS  PubMed  Google Scholar 

  • Sloan JL, Manoli I, Venditti CP (2015) Liver or combined liver-kidney transplantation for patients with isolated methylmalonic acidemia: who and when? J Pediatr 166(6):1346–1350. https://doi.org/10.1016/j.jpeds.2015.03.026

    Article  PubMed  Google Scholar 

  • Smith PJ, Need AC, Cirulli ET, Chiba-Falek O, Attix DK (2013) A comparison of the Cambridge automated neuropsychological test battery (CANTAB) with “traditional” neuropsychological testing instruments. J Clin Exp Neuropsychol 35(3):319–328. https://doi.org/10.1080/13803395.2013.771618

    Article  PubMed  Google Scholar 

  • Sniderman LC, Lambert M, Giguère R, Auray-Blais C, Lemieux B, Laframboise R, Rosenblatt DS, Treacy EP (1999) Outcome of individuals with low-moderate methylmalonic aciduria detected through a neonatal screening program. J Pediatr 134(6):675–680

    Article  CAS  PubMed  Google Scholar 

  • Spada M, Calvo PL, Brunati A, Peruzzi L, Dell’Olio D, Romagnoli R, Porta F (2015) Early liver transplantation for neonatal-onset methylmalonic acidemia. Pediatrics 136(1):e252–e256. https://doi.org/10.1542/peds.2015-0175

    Article  PubMed  Google Scholar 

  • Sparrow SS, Cicchetti DV, Saulnier CA (2016) Vineland adaptive behavior scales, Third edition (Vineland-3). NCS Pearson, Bloomington

    Google Scholar 

  • Splinter K, Niemi AK, Cox R, Platt J, Shah M, Enns GM, Kasahara M, Bernstein JA (2016) Impaired health-related quality of life in children and families affected by methylmalonic acidemia. J Genet Couns 25(5):936–944. https://doi.org/10.1007/s10897-015-9921-x

    Article  PubMed  Google Scholar 

  • Tandon PK, Kakkis ED (2021) The multi-domain responder index: a novel analysis tool to capture a broader assessment of clinical benefit in heterogeneous complex rare diseases. Orphanet J Rare Dis 16(1):183. https://doi.org/10.1186/s13023-021-01805-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomas MS, Annaz D, Ansari D, Scerif G, Jarrold C, Karmiloff-Smith A (2009) Using developmental trajectories to understand developmental disorders. J Speech Lang Hear Res 52(2):336–358. https://doi.org/10.1044/1092-4388(2009/07-0144)

    Article  PubMed  Google Scholar 

  • Vakil E (2012) Neuropsychological assessment: principles, rationale, and challenges. J Clin Exp Neuropsychol 34(2):135–150. https://doi.org/10.1080/13803395.2011.623121

    Article  PubMed  Google Scholar 

  • van der Meer SB, Poggi F, Spada M, Bonnefont JP, Ogier H, Hubert P, Depondt E, Rapoport D, Rabier D, Charpentier C et al (1994) Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia. J Pediatr 125(6 Pt 1):903–908. https://doi.org/10.1016/s0022-3476(05)82005-0

    Article  PubMed  Google Scholar 

  • Varvogli L, Repetto GM, Waisbren SE, Levy HL (2000) High cognitive outcome in an adolescent with Mut- methylmalonic acidemia. Am J Med Genet 96(2):192–195

    Article  CAS  PubMed  Google Scholar 

  • Watkins D, Rosenblatt DS (2011) Inborn errors of cobalamin absorption and metabolism. Am J Med Genet C Semin Med Genet 157C(1):33–44. https://doi.org/10.1002/ajmg.c.30288

    Article  CAS  PubMed  Google Scholar 

  • Wechsler D (2011) Wechsler abbreviated scale of intelligence, second edition (WASI-II), San Antonio, TX: NCS Pearson

  • Wechsler D (2008) Wechsler Adult Intelligence Scale--Fourth Edition (WAIS-IV), Bloomington, MN: NCS Pearson

  • Wechsler D (2014) Wechsler intelligence scale for children -fifth edition (WISC-V), Bloomington, MN: NCS Pearson

  • Wechsler D (2012) Wechsler preschool and primary scale of intelligence-fourth edition (WPPSI-IV), Bloomington MN: NCS Pearson

  • Weinfurt KP (2019) Clarifying the meaning of clinically meaningful benefit in clinical research: noticeable change vs valuable change. JAMA 322(24):2381–2382. https://doi.org/10.1001/jama.2019.18496

    Article  PubMed  Google Scholar 

  • Yang L, Guo B, Li X, Liu X, Wei X, Guo L (2020) Brain MRI features of methylmalonic acidemia in children: the relationship between neuropsychological scores and MRI findings. Sci Rep 10(1):13099. https://doi.org/10.1038/s41598-020-70113-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu Y, Shuai R, Liang L, Qiu W, Shen L, Wu S, Wei H, Chen Y, Yang C, Xu P, Chen X, Zou H, Feng J, Niu T, Hu H, Ye J, Zhang H, Lu D, Gong Z, Zhan X, Ji W, Gu X, Han L (2021) Different mutations in the MMUT gene are associated with the effect of vitamin B12 in a cohort of 266 Chinese patients with mut-type methylmalonic acidemia: A retrospective study. Mol Genet Genomic Med 9(11):e1822. https://doi.org/10.1002/mgg3.1822

  • Zeltner NA, Landolt MA, Baumgartner MR, Lageder S, Ouitmann J, Sommer R, Karall D, Mühlhausen C, Schlune A, Scholl-Bürgi S, Huemer M (2017) Living with intoxication-type inborn errors of metabolism: A qualitative analysis of interviews with paediatric patients and their parents. JIMD Rep 31:1–9. https://doi.org/10.1007/8904_2016_545

    Article  PubMed  Google Scholar 

  • Zhang C, Wang X, Hao S, Zhang Q, Zheng L, Zhou B, Liu F, Feng X, Chen X, Ma P, Chen C, Cao Z, Ma X (2020) Mutation analysis, treatment and prenatal diagnosis of Chinese cases of methylmalonic acidemia. Sci Rep 10(1):12509. https://doi.org/10.1038/s41598-020-69565-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou X, Cui Y, Han J (2018) Methylmalonic acidemia: Current status and research priorities. Intractable Rare Dis Res 7(2):73–78. https://doi.org/10.5582/irdr.2018.01026

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author thanks Harvey Levy, MD and Kimberly Chapman, MD for their helpful comments on an earlier draft of this manuscript and Stephanie Sacharow, MD for her careful editing of the final version.

Author information

Authors and Affiliations

  1. Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Susan E. Waisbren

Authors
  1. Susan E. Waisbren
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S. Waisbren reviewed the literature, analyzed the accumulated information, and wrote the manuscript.

Corresponding author

Correspondence to Susan E. Waisbren.

Ethics declarations

Conflicts of interest

S. Waisbren consults to Hemoshear Therapeutics.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Waisbren, S.E. Review of neuropsychological outcomes in isolated methylmalonic acidemia: recommendations for assessing impact of treatments. Metab Brain Dis 37, 1317–1335 (2022). https://doi.org/10.1007/s11011-022-00954-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-022-00954-1

Keywords

Search

Navigation