Details of Disease

General Information of Disease (ID: DISHY8VB)

• Disease Name: Methylmalonic acidemia
• Synonyms: methylmalonic aciduria, vitamin B12-responsive, due to defect in synthesis of adenosylcobalamin, cblB type; methylmalonic aciduria, vitamin B12-responsive, due to defect in synthesis of adenosylcobalamin, cblA type; methylmalonic aciduria, mut type; methylmalonic aciduria type cblB; methylmalonic aciduria type cblA; methylmalonic aciduria mut type; methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency; methylmalonic aciduria cblB type; methylmalonic acidemia, cblB type; methylmalonic acidemia, cblA type; METHYLMALONICACIDURIA, vitamin B12-responsive, due to defect in synthesis of adenosylcobalamin--Cbl B; METHYLMALONICACIDURIA, vitamin B12-responsive, due to defect in synthesis of adenosylcobalamin--Cbl A; METHYLMALONICACIDURIA due to methylmalonic CoA mutase deficiency; methylmalonic aciduria
• Disease Class: 5C50: Metabolism inborn error
• Definition: A rare autosomal recessive inherited disorder caused by mutations of the MUT, MMAA, MMAB, MMADHC, and MCEE genes. It is characterized by abnormalities in the metabolism of lipids and proteins. Signs and symptoms usually appear early in life and vary from mild to life threatening. They include vomiting, dehydration, hypotonia, developmental delays, hepatomegaly, lethargy, intellectual disabilities, and chronic kidney disease.
• Disease Hierarchy:
  DISB7ID3: Inborn organic aciduria
  DISHY8VB: Methylmalonic acidemia
• ICD Code: ICD-11: ICD-11: 5C50.E0
• Disease Identifiers:
  MONDO ID: MONDO_0002012
  MESH ID: C537358
  UMLS CUI: C0268583
  MedGen ID: 120654
  HPO ID: HP:0002912
  SNOMED CT ID: 42393006

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 5 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
HST5040	DM13Y55	Phase 2	NA	[1]
mRNA-3705	DMQZ62O	Phase 2	mRNA	[2]
HLB-001	DMMJDG6	Phase 1/2	NA	[3]
mRNA-3704	DME7PBN	Phase 1/2	mRNA therapy	[4]
BBP-671	DMR9XMZ	Phase 1	Small molecule	[5]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 2 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
MVK	TT5DFHW	Limited	Biomarker	[6]
CD320	TT0KV32	Strong	Genetic Variation	[7]

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC22A5	DT3HUVD	Limited	Genetic Variation	[8]

This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
NAGS	DEGI1A9	Strong	Genetic Variation	[9]

This Disease Is Related to 20 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
CAVIN1	OTFO915U	Limited	Biomarker	[10]
CRABP2	OTY01V9G	Limited	Biomarker	[10]
CYCS	OTBFALJD	Limited	Biomarker	[10]
GPD2	OTV232Y7	Limited	Biomarker	[10]
KCTD10	OT5HFZXU	Limited	Genetic Variation	[6]
SEPTIN11	OTX2O0ZX	Limited	Biomarker	[10]
SEPTIN2	OT3G33TM	Limited	Biomarker	[10]
SUCLG2	OT0KHLY2	Limited	Biomarker	[10]
MMADHC	OTP0UPL2	Disputed	Genetic Variation	[11]
MCEE	OTTJP3GM	moderate	Genetic Variation	[12]
MMACHC	OTX0TT3W	moderate	Genetic Variation	[13]
ACSF3	OT3WZW8S	Strong	Biomarker	[14]
ALDH6A1	OT8LCZCT	Strong	Genetic Variation	[15]
CDKL5	OTGL5HRV	Strong	Biomarker	[16]
MMAA	OTMAVZVO	Strong	Genetic Variation	[17]
MMAB	OTOWOEJN	Strong	CausalMutation	[18]
MMD	OTB5I4OC	Strong	Genetic Variation	[19]
SUCLA2	OTMZD4PW	Strong	Genetic Variation	[20]
SUCLG1	OTDCSPXH	Strong	Genetic Variation	[21]
MCCD1	OTLS95WO	Definitive	Biomarker	[22]

References

• [1] ClinicalTrials.gov (NCT04732429) A Phase 2 Open-label, Dose Escalation Study of HST5040 in Subjects With Propionic or Methylmalonic Acidemia Followed by a Randomized, Double-blind, Placebo-controlled, 2-period Crossover Study and an Open-label, Long-term Extension Study. U.S.National Institutes of Health.
• [2] ClinicalTrials.gov (NCT05295433) A Phase 1/2, Global, Open-Label, Extension Study to Evaluate the Long-Term Safety and Clinical Activity of mRNA-3705 in Participants Previously Enrolled in the mRNA-3705-P101 Study. U.S.National Institutes of Health.
• [3] ClinicalTrials.gov (NCT04581785) A Phase 1/2 Open-label Clinical Study of hLB-001 Gene Therapy in Pediatric Patients With Methylmalonic Acidemia Characterized by MMUT Mutations. U.S.National Institutes of Health.
• [4] ClinicalTrials.gov (NCT03810690) Open Label Study of mRNA-3704 in Patients With Isolated Methylmalonic Acidemia. U.S. National Institutes of Health.
• [5] ClinicalTrials.gov (NCT04836494) A First-in-human, Randomized, Placebo-controlled, Single and Multiple Ascending Dose Escalation to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BBP-671 in Healthy Subjects and In Patients With Propionic Acidemia or Methylmalonic Acidemia. U.S.National Institutes of Health.
• [6] Association of KCTD10, MVK, and MMAB polymorphisms with dyslipidemia and coronary heart disease in Han Chinese population.Lipids Health Dis. 2016 Oct 4;15(1):171. doi: 10.1186/s12944-016-0348-7.
• [7] Positive newborn screen for methylmalonic aciduria identifies the first mutation in TCblR/CD320, the gene for cellular uptake of transcobalamin-bound vitamin B(12). Hum Mutat. 2010 Aug;31(8):924-9. doi: 10.1002/humu.21297.
• [8] Expanded Newborn Screening for Inborn Errors of Metabolism and Genetic Characteristics in a Chinese Population.Front Genet. 2018 Apr 20;9:122. doi: 10.3389/fgene.2018.00122. eCollection 2018.
• [9] Evaluation of long-term effectiveness of the use of carglumic acid in patients with propionic acidemia (PA) or methylmalonic acidemia (MMA): study protocol for a randomized controlled trial.BMC Pediatr. 2019 Jun 13;19(1):195. doi: 10.1186/s12887-019-1571-y.
• [10] Quantitative analysis of mitochondrial protein expression in methylmalonic acidemia by two-dimensional difference gel electrophoresis.J Proteome Res. 2006 Jul;5(7):1602-10. doi: 10.1021/pr050481r.
• [11] Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism.J Pediatr. 2009 Apr;154(4):551-6. doi: 10.1016/j.jpeds.2008.10.043. Epub 2008 Dec 5.
• [12] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency.Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1265-1272. doi: 10.1016/j.bbadis.2019.01.021. Epub 2019 Jan 22.
• [13] Molecular genetic characterization of cblC defects in 126 pedigrees and prenatal genetic diagnosis of pedigrees with combined methylmalonic aciduria and homocystinuria.BMC Med Genet. 2018 Aug 29;19(1):154. doi: 10.1186/s12881-018-0666-x.
• [14] Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nat Genet. 2011 Aug 14;43(9):883-6. doi: 10.1038/ng.908.
• [15] Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.Orphanet J Rare Dis. 2013 Jul 9;8:98. doi: 10.1186/1750-1172-8-98.
• [16] A male case with CDKL5-associated encephalopathy manifesting transient methylmalonic acidemia.Eur J Med Genet. 2018 Aug;61(8):451-454. doi: 10.1016/j.ejmg.2018.03.003. Epub 2018 Mar 3.
• [17] Mild clinical features of isolated methylmalonic acidemia associated with a novel variant in the MMAA gene in two Chinese siblings.BMC Med Genet. 2018 Jul 11;19(1):114. doi: 10.1186/s12881-018-0635-4.
• [18] Inborn Errors of Metabolism in the United Arab Emirates: Disorders Detected by Newborn Screening (2011-2014).JIMD Rep. 2016;28:127-135. doi: 10.1007/8904_2015_512. Epub 2015 Nov 21.
• [19] Outcome of individuals with low-moderate methylmalonic aciduria detected through a neonatal screening program.J Pediatr. 1999 Jun;134(6):675-80. doi: 10.1016/s0022-3476(99)70280-5.
• [20] Co-occurring Down syndrome and SUCLA2-related mitochondrial depletion syndrome.Am J Med Genet A. 2017 Oct;173(10):2720-2724. doi: 10.1002/ajmg.a.38351. Epub 2017 Jul 27.
• [21] Five novel SUCLG1 mutations in three Chinese patients with succinate-CoA ligase deficiency noticed by mild methylmalonic aciduria.Brain Dev. 2016 Jan;38(1):61-7. doi: 10.1016/j.braindev.2015.05.002. Epub 2015 May 28.
• [22] Expanded Newborn Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry in Suzhou, China: Disease Spectrum, Prevalence, Genetic Characteristics in a Chinese Population.Front Genet. 2019 Oct 29;10:1052. doi: 10.3389/fgene.2019.01052. eCollection 2019.