ABCD4 – Methylmalonic acidemia with homocystinuria, type cblJ

ABCD4 encodes a lysosomal ATP‐binding cassette transporter required for cobalamin export to the cytosol in concert with LMBD1, and biallelic pathogenic variants cause the autosomal recessive disorder methylmalonic acidemia with homocystinuria, type cblJ (MONDO:0013925). Patients present neonatally or in early infancy with methylmalonic aciduria, hyperhomocysteinemia, hypotonia, and feeding difficulties. Early biochemical detection may require supplemental tandem mass spectrometry assays for total homocysteine in dried blood spots.

Two unrelated probands with biallelic ABCD4 variants have been reported. A Chinese patient homozygous for c.423C>G (p.Asn141Lys) exhibited elevated methylmalonic acid and homocysteine levels and was missed by routine newborn screening (PMID:30651581). Separately, a patient presenting at 7 days with hypotonia and methylmalonic aciduria harbored compound heterozygous variants c.1295G>A (p.Arg432Gln) and c.1667_1668delAG (p.Glu556GlyfsTer27) (PMID:28572511).

No extended segregation data are available, and affected relatives have not been systematically reported for either family.

The variant spectrum includes missense changes (e.g., c.423C>G (p.Asn141Lys)) and frameshift alleles (e.g., c.1667_1668delAG (p.Glu556GlyfsTer27)), all consistent with loss of transporter function. No population‐specific founder alleles have been described.

Mechanistic studies demonstrate that ABCD4 forms homodimers and interacts with LMBD1 to mediate lysosomal cobalamin export (PMID:25535791; PMID:27456980). Patient‐derived mutations disrupt the ABCD4–LMBD1 interaction and lysosomal targeting, as shown by live‐cell FRET and rescue assays (PMID:28572511). Reconstitution in liposomes confirmed ATPase‐dependent cobalamin transport by ABCD4 but not by LMBD1 (PMID:33845046), and transmembrane helix 6 was identified as critical for substrate recognition (PMID:38069516).

Collectively, two unrelated patients with compelling biallelic variants and multiple concordant in vitro and cellular assays establish a moderate level of gene‐disease association. Additional segregation studies and in vivo models could further strengthen this link.

Key Take-home: Biallelic ABCD4 variants reliably predict cblJ deficiency, and targeted molecular and biochemical testing enables early diagnosis and management.

References

• Journal of human genetics • 2019 • Patients with cobalamin G or J defect missed by the current newborn screening program: diagnosis and novel mutations. PMID:30651581
• Molecular membrane biology • 2014 • Purification and interaction analyses of two human lysosomal vitamin B12 transporters: LMBD1 and ABCD4. PMID:25535791
• Scientific reports • 2016 • Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum to lysosomes requires the escort protein LMBD1. PMID:27456980
• The Journal of biological chemistry • 2017 • Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B12-trafficking proteins ABCD4 and LMBD1. PMID:28572511
• The Journal of biological chemistry • 2021 • The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro. PMID:33845046
• Journal of inherited metabolic disease • 2024 • Transmembrane helix 6 of ABCD4 is indispensable for cobalamin transport. PMID:38069516

Evidence Based Scoring (AI generated)