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SNOMEDCT: 237933007; ORPHA: 2967;
Carmel and Herbert (1969) reported 2 adult brothers from a Puerto Rican-Corsican family with decreased serum cobalamin (vitamin B12) due to congenital absence of the R-type binders of cobalamin in serum, saliva, cerebrospinal fluid, gastric juice, and granulocytes. The saliva contained no immunologic R binder, but a small amount of cross-reacting material was found in the serum. Partial deficiency was found in all 3 offspring of the affected males tested. The defect appeared to be clinically benign. Hall and Begley (1977) reported follow-up of the family reported by Carmel and Herbert (1969). One of the brothers had a slowly progressive neurologic disease characterized by spastic paraparesis and dementia, but the authors thought that it was unrelated to the transcobalamin defect as no other family members with R binder deficiency were affected.
Lin et al. (2001) provided further follow-up of the brother followed by Hall and Begley (1977). His neurologic condition had deteriorated despite intermittent cobalamin injections, and he died in 1983 of an unknown cause. Laboratory studies late in his life showed decreased serum cobalamin and borderline low serum iron with no megaloblastic changes. Further laboratory studies confirmed decreased levels of TCN1 (189905) and identified a serum and salivary deficiency of lactoferrin (LTF; 150210), a protein that coexists with R binder in specific granules of neutrophils and in secretions. His son and the son of his older R-deficient brother, both presumptive heterozygotes, also had mild deficiency of both R binder and lactoferrin. None of the patients had a predisposition to infections, as seen in specific granule deficiency (SGD; 245480). In contrast, serum and salivary lactoferrin levels were normal in 4 additional unrelated patients with TCN1 deficiency. Lin et al. (2001) postulated that the deficiencies of both TCN1 and lactoferrin constituted a unique hereditary disorder that was distinct from that of isolated R binder deficiency.
Carmel (1982) reported a 77-year-old man with low serum cobalamin due to transcobalamin I deficiency. In addition, salivary cobalamin R binder protein was virtually undetectable, thus establishing the diagnosis. Laboratory studies showed that almost all of his cobalamin was carried by TCN2 (613441). Megaloblastic anemia was not present and the patient was able to maintain normal serum cobalamin levels while receiving monthly injections. The patient also had chronic anemia, atrophic gastritis, mild congestive heart failure, and mild distal vibratory loss, the last of which the authors attributed to coexisting folate deficiency and alcohol abuse. Carmel (1982) concluded that transcobalamin I deficiency is a benign disorder, in marked contrast to transcobalamin II deficiency (275350).
Carmel (1983) reported a 64-year-old man with decreased serum cobalamin, normal serum folate, and no megaloblastic changes. No methylmalonic acid or homocystine was found in the urine. No R binder was detected in serum, gastric juices, saliva, or granulocytes by radioimmunoassay. The patient had no neurologic dysfunction related to low serum cobalamin.
Sigal et al. (1987) described a previously healthy man with plasma R binder deficiency who was evaluated at 45 years of age for paresthesias in both hands. Paresthesias and numbness gradually developed in his legs and his gait became unsteady. Two years later he had moderate to severe loss of proprioceptive sensation in all limbs, mild loss of perception of pain and touch, hypoactive to absent deep tendon reflexes, but intact strength. Seven years after onset the patient had marked difficulty in manipulating objects with his hands, his gait had become wide-based, and proprioception was absent at the elbows and knees. Pinprick and temperature sensations were slightly reduced at the wrist and ankles, and deep tendon reflexes were absent. By 10 years after onset (age 55), he was confined to a wheelchair. Vitamin B12 appeared to have no therapeutic value. Serum B12 levels were decreased, and serum R binder levels were absent, but low levels of R binder were detectable in saliva.
Adcock and McKnight (2002) reported a 48-year-old woman who was found on routine testing to have decreased serum cobalamin and mildly increased mean corpuscular volume. Serum folate, homocysteine, and methylmalonic acid were normal. Vitamin B12 injections resulted in only transient improvement in serum cobalamin levels. Laboratory findings and the absence of neurologic, gastrointestinal, and hematologic abnormalities suggested TCN1 deficiency. Adcock and McKnight (2002) emphasized the importance of correct diagnosis of TCN1 deficiency in the setting of decreased cobalamin because unnecessary treatment can be avoided.
Exclusion Studies
In 1 of the brothers with TCN1 deficiency originally reported by Carmel and Herbert (1969), Lin et al. (2001) did not identify any mutations in the promoter region of the initial coding sequence of the TCN1 gene (189905). However, shortage of material prevented further sequencing.
Adcock, B. B., McKnight, J. T. Cobalamin pseudodeficiency due to a transcobalamin I deficiency. South. Med. J. 95: 1060-1062, 2002. [PubMed: 12356110]
Carmel, R., Herbert, V. Deficiency of vitamin B12-binding alpha globulin in two brothers. Blood 33: 1-12, 1969. [PubMed: 4178969]
Carmel, R. A new case of deficiency of the R binder for cobalamin, with observations of minor cobalamin-binding proteins in serum and saliva. Blood 59: 152-156, 1982. [PubMed: 7053761]
Carmel, R. R-binder deficiency: a clinically benign cause of cobalamin pseudodeficiency. JAMA 250: 1886-1890, 1983. [PubMed: 6620485] [Full Text: https://doi.org/10.1001/jama.250.14.1886]
Hall, C. A., Begley, J. A. Congenital deficiency of human R-type binding proteins of cobalamin. Am. J. Hum. Genet. 29: 619-626, 1977. [PubMed: 930926]
Lin, J. C., Borregaard, N., Liebman, H. A., Carmel, R. Deficiency of the specific granule proteins, R binder/transcobalamin I and lactoferrin, in plasma and saliva: a new disorder. Am. J. Med. Genet. 100: 145-151, 2001. [PubMed: 11298376] [Full Text: https://doi.org/10.1002/ajmg.1232]
Sigal, S. H., Hall, C. A., Antel, J. P. Plasma R binder deficiency and neurologic disease. New Eng. J. Med. 317: 1330-1332, 1987. [PubMed: 3683461] [Full Text: https://doi.org/10.1056/NEJM198711193172106]