Notes on lysosomal storage disorders and B12, mostly for myself...
Lysosomes are the cell's recycling crew. Large molecules enter lysosomes, and are disassembled by lysosomal enzymes. People with lysosomal storage disorders (LDs) are missing one of these enzymes, so the large molecules enter, but can't be fragmented or ejected. The molecules therefore accumulate in the lysosomes causing dysfunction or death, usually in childhood or young adulthood. There are over 50 types of LDs currently known. Enzyme replacement and gene therapies are being developed, but they have variable efficacy, are difficult to administer, and are very expensive ($800K/yr). In future, as gene sequencing becomes commonplace, the occurrence of LDs may decrease in the population; more people will discover their LD carrier status, and choose preimplantation genetic diagnosis (PGD) to avoid implanting embryos with LDs.
Around 2-3% of the overall population are carriers of an LD, and therefore have half the normal amount of an enzyme used in lysosomal processing. Normally this isn't a problem, but hints are now emerging that LD carriers may have some health effects from their enzyme deficit. For example, in at least one LD (Gaucher's disease) there is a higher incidence of Parkinson's disease among carriers (https://www.gaucherdisease.org/blog...disease-and-parkinsons-disease-podcast-recap/ ).
B12 may also be affected by lysosomal storage disorders, although perhaps not at the carrier level. Some people with Gaucher's appear to have active-B12 changes:
https://journals.sagepub.com/doi/full/10.1177/2326409817692359
"Vitamin B12 metabolism involves various cellular compartments including the lysosome, and a disruption in the lysosomal and endocytic pathways induces functional deficiency of this micronutrient. "
"Vitamin B12 bound to transcobalamin, that is, holo-TC is distributed via systemic circulation to all cells in the body. Cells take up holo-TC via receptor-mediated endocytosis, aided by the transcobalamin receptor (CD320),45,46 which shuttles vitamin B12 into lysosomes. The protein binder TC undergoes degradation in the lysosome, liberating vitamin B12 that is subsequently exported out of this compartment using the transporters LMBR1 Domain Containing 1 (LMBRD1)47,48 and ATP Binding Cassette Subfamily D Member 4 (ABCD4).49,50 Once in the cytosol, newly internalized vitamin B12 undergoes processing and trafficking by proteins, CblC51-57 and CblD,58-63 respectively, to finally reach acceptor proteins, MS in the cytosol and MCM in the mitochondrion.
Insufficient intake and certain inborn errors of metabolism impairing the cellular transport, trafficking, and utilization of vitamin B12 manifest as functional cobalamin deficiency, with either isolated or combined homocystinuria and methylmalonic aciduria. Untreated vitamin B12 deficiency causes hematological abnormalities, subacute combined degeneration of the spinal cord, and polyneuropathy."
Lysosomes are the cell's recycling crew. Large molecules enter lysosomes, and are disassembled by lysosomal enzymes. People with lysosomal storage disorders (LDs) are missing one of these enzymes, so the large molecules enter, but can't be fragmented or ejected. The molecules therefore accumulate in the lysosomes causing dysfunction or death, usually in childhood or young adulthood. There are over 50 types of LDs currently known. Enzyme replacement and gene therapies are being developed, but they have variable efficacy, are difficult to administer, and are very expensive ($800K/yr). In future, as gene sequencing becomes commonplace, the occurrence of LDs may decrease in the population; more people will discover their LD carrier status, and choose preimplantation genetic diagnosis (PGD) to avoid implanting embryos with LDs.
Around 2-3% of the overall population are carriers of an LD, and therefore have half the normal amount of an enzyme used in lysosomal processing. Normally this isn't a problem, but hints are now emerging that LD carriers may have some health effects from their enzyme deficit. For example, in at least one LD (Gaucher's disease) there is a higher incidence of Parkinson's disease among carriers (https://www.gaucherdisease.org/blog...disease-and-parkinsons-disease-podcast-recap/ ).
B12 may also be affected by lysosomal storage disorders, although perhaps not at the carrier level. Some people with Gaucher's appear to have active-B12 changes:
https://journals.sagepub.com/doi/full/10.1177/2326409817692359
"Vitamin B12 metabolism involves various cellular compartments including the lysosome, and a disruption in the lysosomal and endocytic pathways induces functional deficiency of this micronutrient. "
"Vitamin B12 bound to transcobalamin, that is, holo-TC is distributed via systemic circulation to all cells in the body. Cells take up holo-TC via receptor-mediated endocytosis, aided by the transcobalamin receptor (CD320),45,46 which shuttles vitamin B12 into lysosomes. The protein binder TC undergoes degradation in the lysosome, liberating vitamin B12 that is subsequently exported out of this compartment using the transporters LMBR1 Domain Containing 1 (LMBRD1)47,48 and ATP Binding Cassette Subfamily D Member 4 (ABCD4).49,50 Once in the cytosol, newly internalized vitamin B12 undergoes processing and trafficking by proteins, CblC51-57 and CblD,58-63 respectively, to finally reach acceptor proteins, MS in the cytosol and MCM in the mitochondrion.
Insufficient intake and certain inborn errors of metabolism impairing the cellular transport, trafficking, and utilization of vitamin B12 manifest as functional cobalamin deficiency, with either isolated or combined homocystinuria and methylmalonic aciduria. Untreated vitamin B12 deficiency causes hematological abnormalities, subacute combined degeneration of the spinal cord, and polyneuropathy."
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