Cobalamin/Propionate/Homocysteine Metabolism Related Disorders Panel

Cobalamin/Propionate/Homocysteine Metabolism Related Disorders Panel, Sequencing and Deletion/Duplication 2011157
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Confirm suspected cobalamin (vitamin B12)/propionate/homocysteine metabolism-related disorder in individuals with clinical symptoms and/or biochemical findings. Should not be ordered to assess vitamin B12 level.

For tests to consider before ordering genetic testing, see Related Tests.

Disorders of cobalamin (vitamin B12)/propionate/homocysteine metabolism result from defects in the vitamin B12 metabolic pathway. Age of disease onset ranges from the perinatal period to adulthood. Multiple organ systems are affected. Molecular testing is used to confirm suspected cobalamin/propionate/homocysteine metabolism-related disorder in individuals with clinical symptoms and/or biochemical findings.

Disease Overview

Findings

  • Cardiovascular
  • Gastrointestinal
  • Hematological
  • Immunological
  • Neurological
  • Neuromuscular/skeletal
  • Ocular
  • Renal
  • Respiratory
  • Dysmorphic features
  • Failure to thrive
  • Metabolic decompensation

Etiology

  • Defects of absorption, transport, and intracellular metabolism of cobalamin/propionate/homocysteine lead to accumulation of methylmalonic acid, methionine, and/or homocysteine in blood and urine.
  • Elevated propionylcarnitine level and/or propionyl/acetylcarnitine ratio are usually detected in plasma, and increased methylmalonic acid is detected in blood, despite normal or elevated vitamin B12 levels.

Prevalence

  • Methylmalonic aciduria from all causes – 1/48,000-61,000 in North America
  • Isolated methylmalonic acidemia – 1/50,000-100,000
  • Combined malonic/methylmalonic aciduria – ~1/30,000
  • Methylmalonic aciduria, vitamin B12-responsive, cblA type – 1/50,000-100,000
  • Methylmalonic aciduria, vitamin B12-responsive, cblB type – 1/50,000-100,000
  • Methylmalonic aciduria and homocystinuria, cblC type – up to 1/67,000
  • Methylmalonic aciduria, and homocystinuria, cblD type – 1/50,000-100,000
  • Methylmalonic aciduria, mut (0) type – 1/50,000-100,000
  • Methylmalonyl-CoA epimerase deficiency – 1/50,000-100,000
  • Homocystinuria due to cystathionine beta-synthase deficiency – 1/1,800 in Qatar; 1/6,400 in Norway; 1/17,800 in Germany

  • Methionine adenosyltransferase deficiency – 1/22,000 in Spain; 1/26,000 in Portugal

  • Homocystinuria, B6-responsive and nonresponsive types, combined – 1/58,000-1,000,000

  • Propionic acidemia – 1/50,000-100,000; 1/1,000-2,000 in Inuit in Greenland; 1/5,000 in Saudi Arabia

  • Rare for other disorders included in the panel

Inheritance

Autosomal recessive for all genes tested, except for HCFC1 (X-linked) and MAT1A (autosomal dominant or autosomal recessive)

Genotype-Phenotype Correlation

  • Variants in multiple genes cause overlapping and highly variable phenotypes.

  • Other genetic and/or biochemical/dietary factors may influence severity of clinical phenotype.

  • Clinical features and age of onset are highly variable.

Test Description

See Genes Tested table for genes included in the panel.

Clinical Sensitivity

Variable, dependent on condition

Limitations

  • A negative result does not exclude a heritable form of cobalamin metabolism disorders.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the targeted genes
    • Regulatory region variants and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Deletions/duplications in the ADK, AHCY, and GNMT genes
    • Non-coding transcripts
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Deletions/duplications less than 1 kb in the targeted genes by array
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
    • Single exon deletions/duplications in the following exons:
      • ABCD4 (NM_005050) 1; HCFC1 (NM_005334) 26; MTHFR (NM_001330358) 1; PCCB (NM_001178014) 4; SUCLA2 (NM_003850) 11

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

100

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

100

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Genes Tested

Gene Alias Symbol(s) MIM Number Disorder Inheritance

ABCD4

PXMP1L, PMP69, P70R, EST352188

603214

Methylmalonic aciduria and homocystinuria, cblJ type

AR

ACSF3

 

614245

Combined malonic and methylmalonic aciduria

AR

ADK

AK

102750

Hypermethioninemia due to adenosine kinase deficiency

AR

AHCY

SAHH

180960

Hypermethioninemia with

S-adenosylhomocysteine hydrolase deficiency

AR

AMN

amnionless

605799

Megaloblastic anemia 1, Norwegian type

AR

CBLIF (GIF)

TCN3, IF, IFMH, INF

609342

Intrinsic factor deficiency

AR

CBS

HIP4

613381

Homocystinuria due to cystathionine beta-synthase deficiency

AR

CD320

8D6, 8D6A

606475

Methylmalonic aciduria, transient, due to transcobalamin receptor defect

AR

CUBN

MGA1, IFCR, gp280

602997

Megaloblastic anemia 1, Finnish type

AR

GNMT

 

606628

Glycine N-methyltransferase deficiency

AR

HCFC1

HFC1, MRX3, HCF-1, HCF1, CFF, VCAF, MGC70925, PPP1R89

300019

Methylmalonic acidemia and homocysteinemia, cblX type; intellectual disability, X-linked 3

XL

LMBRD1

C6orf209, FLJ11240, bA810I22.1, cblF

612625

Methylmalonic aciduria and homocystinuria, cblF type

AR

MAT1A

MAT, SAMS, MATA1, SAMS1

610550

Methionine adenosyltransferase I/III deficiency

AD and AR

MCEE

GLOD2

608419

Methylmalonyl-CoA epimerase deficiency

AR

MMAA

cblA

607481

Methylmalonic aciduria, B12 responsive, cblA type

AR

MMAB

cblB, CFAP23

607568

Methylmalonic aciduria, cblB type

AR

MMACHC

DKFZP564I122, cblC

609831

Methylmalonic aciduria and homocystinuria, cblC type

AR

MMADHC

C2orf25, CL25022, cblD

611935

Mmethylmalonic aciduria and homocystinuria, cblD type

AR

MMUT (MUT)

MCM

609058

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, mut (0) type

AR

MTHFR

 

607093

Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate

AR

MTR

cblG

156570

Homocystinuria-megaloblastic anemia, cblG complementation type

AR

MTRR

cblE

602568

Homocystinuria-megaloblastic anemia, cblE complementation type

AR

PCCA

 

232000

Propionic acidemia

AR

PCCB

 

232050

Propionic acidemia

AR

SUCLA2

 

603921

Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria)

AR

SUCLG1

 

611224

Mitochondrial dna depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria)

AR

TCN1

TCI, TC1

189905

Transcobalamin I deficiency

AR

TCN2

D22S676, D22S750, TC2

613441

Transcobalamin II deficiency

AR

AD, autosomal dominant; AR, autosomal recessive; XL, X-linked
References 

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. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014; 9: 130. PubMed

Cusmano-Ozog K, Levine S, Martin M, Packman S, Rosenblatt D, Cederbaum S, Cowan T, Enns G. Cobalamin C disease identified by newborn screening: the California experience. In: Program and abstracts for the SIMD annual meeting. Mol Genet Metab. 2007:227-65. [Accessed: Nov 2018]

Manoli I, Sloan J, Venditti C. Isolated Methylmalonic Acidemia. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Revision: Dec 2016; Accessed: Nov 2018]

Martins E, Marcão A, Bandeira A, Fonseca H, Nogueira C, Vilarinho L. Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands. JIMD Rep. 2012; 6: 107-12. PubMed

Rosenblatt D, Watkins D. Methylmalonic acidemia without homocystinuria. Orphanet. [Last Update: Mar 2012; Accessed: Nov 2018]

Sacharow S, Picker J, Levy H. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: May 2017; Accessed: Nov 2018]

Skovby F, Gaustadnes M, Mudd SH. A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency. Mol Genet Metab. 2010 Jan;99(1):1-3. PubMed

Sloan J, Carrillo N, Adams D, Venditti C. Disorders of Intracellular Cobalamin Metabolism. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Sep 2018; Accessed: Nov 2018]

Sloan JL, Johnston JJ, Manoli I, Chandler RJ, Krause C, Carrillo-Carrasco N, Chandrasekaran SD, Sysol JR, O'Brien K, Hauser NS, Sapp JC, Dorward HM, Huizing M; NIH Intramural Sequencing Center Group, Barshop BA, Berry SA, James PM, Champaigne NL, de Lonlay P, Valayannopoulos V, Geschwind MD, Gavrilov DK, Nyhan WL, Biesecker LG, Venditti CP. Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nat Genet. 2011 Aug 14;43(9):883-6. PubMed

Weisfeld-Adams JD, Morrissey MA, Kirmse BM, Salveson BR, Wasserstein MP, McGuire PJ, Sunny S, Cohen-Pfeffer JL, Yu C, Caggana M, Diaz GA. Newborn screening and early biochemical follow-up in combined methylmalonic aciduria and homocystinuria, cblC type, and utility of methionine as a secondary screening analyte. Mol Genet Metab. 2010; 99(2): 116-23. PubMed

Last Update: January 2019