Table 2.

Molecular Genetic Testing Used in Isolated Methylmalonic Acidemia

Gene 1, 2Proportion of Isolated MMA Attributed to Mutation of Gene 3Proportion of Pathogenic Variants 4 Detected by Method
Sequence analysis 5Gene-targeted deletion/duplication analysis 6
MCEE Rare25 probands/families 7Unknown, none reported 8
MMAA 25%97% 9Unknown, one large deletion reported 8, 10
MMAB 12%98% 11Unknown, none reported 8
MMADHC Rare9 probands/families 12Unknown, none reported 8
MMUT 60% (75%-78% mut0 enzymatic subtype, 20%-22% mut– enzymatic subtype)96% 13, 14~1% 8
Unknown 15RareNA

NA = not applicable

1.

Genes are listed in alphabetic order.

2.
3.

Based on Worgan et al [2006], Hörster et al [2007], Hörster et al [2009], Forny et al [2016], Forny et al [2021], Hörster et al [2021]. Depending on the definition of B12 responsiveness these percentages vary in different reports and populations [Yu et al 2021].

4.

See Molecular Genetics for information on allelic variants detected in this gene.

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.
8.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

9.
10.
11.
12.
13.
14.

For individuals of Hispanic descent, targeted exon 2 analysis for the MMUT c.322C>T pathogenic variant may be considered (see Molecular Genetics).

15.

Some individuals with isolated MMA remain undiagnosed despite extensive genome and RNA sequencing, suggesting that additional genetic causes of isolated or combined subtypes of MMA may be identified with future research [Abdrabo et al 2020].

From: Isolated Methylmalonic Acidemia

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