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Function of vitamin B12 in the central nervous system as revealed by congenital defects
1Research and Medical Services, Veterans Administration Medical Center, Albany, New York 12208.
Insights
Methylcobalamin deficiency in infants causes developmental delay, seizures, and brain injury. Early treatment with cobalamin can improve symptoms, but myelination may remain impaired.
Area of Science:
- Neuroscience
- Biochemistry
- Pediatrics
Background:
- Methylcobalamin (MeCbl) deficiency in infants leads to severe neurological issues, including developmental delay, seizures, hypotonia, lethargy, and microcephaly.
- Central nervous system (CNS) injury typically manifests within the first six months of postnatal life.
- Similar symptoms are observed in acquired cobalamin (Cbl) deficiency in infants.
Purpose of the Study:
- To investigate the neurological impact of methylcobalamin deficiency in infants.
- To understand the role of Cbl-dependent methyltransferase in infant brain development and function.
Main Methods:
- Clinical observation of 13 infants with MeCbl deficiency.
- Neurological examination and assessment of developmental status.
- Magnetic Resonance Imaging (MRI) to evaluate brain myelination in two cases.
Main Results:
- All 13 infants presented with developmental delay; most experienced seizures, hypotonia, lethargy, and microcephaly.
- MRI revealed delayed myelination, particularly in the cerebrum, in two treated cases.
- Infants showed rapid improvement in hypotonia, lethargy, and responsiveness within 24-48 hours of Cbl treatment, suggesting a distinct CNS effect beyond myelination.
Conclusions:
- A functioning Cbl-dependent methyltransferase is essential for normal human brain development and function.
- Isolated MeCbl deficiency, resulting from cblE and G mutations, impairs brain myelination due to failure of the methionine synthase reaction.
- While Cbl treatment can lead to psychomotor improvement, the delayed myelination may explain incomplete recovery in some cases.
Abstract:
The 13 cases of methylcobalamin (MeCbl) deficiency presenting in early infancy have all been developmentally delayed, and the majority have had seizures, hypotonia, lethargy, and microcephaly. The CNS injury appears to occur during the first 6 months of postnatal life. The same symptoms are seen in acquired cobalamin (Cbl) deficiency in the same age group. MRI performed at age 18-19 months and after 13-14 months of large amounts of Cbl, in two cases showed delayed myelination, most pronounced in the cerebrum. Isolated MeCbl deficiency is the consequence of cblE and G mutations where the lesion is of a single Cbl-dependent enzyme, the methyltransferase. One effect of a deficiency of MeCbl, and of the associated failure of the methionine synthase reaction, is, therefore, an impairment of myelination of the brain of the newborn. The slow, but usually incomplete, improvement in psychomotor status after years of treatment with Cbl may be related to the eventual myelination. However, the hypotonia, lethargy, and impaired responsiveness react to treatment with Cbl within 24-48 hours, which suggests an expression of MeCbl deficiency on the CNS distinct from the delayed myelination. Although there is much to be learned, it is now clear that a normally functioning Cbl-dependent methyl transferase is required for development and function of the human brain.