Page 632 - Williams Hematology ( PDFDrive )

606 Part VI: The Erythrocyte Chapter 41: Folate, Cobalamin, and Megaloblastic Anemias 607

Transcobalamin Deficiency TC deficiency is an autosomal TABLE 41–6. Cobalamin Mutant Class Syndromes
recessive disorder causing a flagrant megaloblastic anemia that gen-
erally presents in early infancy. The disease is dangerously deceptive Methylmalonic Megaloblastic
395
because it results from a very severe deficiency of tissue cobalamin, Syndrome Aciduria Homocystinuria Anemia
usually with serum cobalamin levels in the normal range because most cblA, cblB, + – –
of the plasma cobalamin is bound to HC resulting in a misleading test cblH
result if reliance is placed simply on serum cobalamin measurement. cblE, cblC – + +
Undiagnosed TC deficiency causes irreversible CNS damage. Patients
397
are healthy at birth but over the next few weeks develop signs and symp- cblC, cblD, + + ±
toms of cobalamin deficiency, such as rapidly progressive pancytopenia, cblF
mouth ulcers, vomiting, and diarrhea. Recurrent bacterial infections
may occur. Neurologic findings are not prominent in the early stages or production of its cofactor, AdoCbl. The cblH variant appears to rep-
395
of the disease. 397 resent an interallelic variant of cblA. Patients present in infancy with
405
Serum folate and cobalamin are normal (the latter because most acidosis because they cannot catabolize methylmalonic acid. Symptoms
cobalamin is carried by HC). Homocysteine and/or methylmalonic acid include lethargy and failure to thrive, vomiting, and neurologic prob-
levels are elevated in the plasma. The marrow is megaloblastic and the lems. Mental retardation is not prominent, and megaloblastic anemia
398
cobalamin absorption is usually but not always abnormal and is not cor- is absent. Most patients respond to 1000 mcg/day of OHCbl or CnCbl,
rected by intrinsic factor. The diagnosis is made by measuring plasma although muto and mut– patients are unresponsive.
399
TC. Prenatal diagnosis is possible. Serum should be obtained prior
389
400
to treatment because TC levels in normal individuals drop sharply after Homocystinuria Only (Cble and Cblg)
cobalamin is given. TC deficiency is treated with cobalamin doses suffi- In these disorders, N -methyltetrahydrofolate-homocysteine meth-
5
ciently large to force enough vitamin into the cells to allow normal func- yltransferase is defective and lacks the capacity to produce MeCbl.
406
tion. Initial therapy can consist of oral CnCbl or OHCbl 500 to 1000 mcg In patients with cblG, methionine synthase is missing or defective.
407
twice a week, or IM OHCbl 1000 mcg/week. Blood counts and symp- cblE results from failure to reactivate methionine synthase that was
toms should be monitored and doses adjusted upward if necessary. inactivated by oxidation of its bound cobalamin. Patients present in
408
Several single nucleotide polymorphisms in the TC gene have infancy with vomiting, mental retardation, and megaloblastic anemia.
been described and the allele frequency of the most common form (776 They have marked homocystinuria and hyperhomocysteinemia without
C>G) is high in certain populations. 401,402 HoloTC levels are lower and methylmalonic aciduria or methylmalonic acidemia. They respond well
methylmalonate levels are higher in individuals homozygous for the G to CnCbl 1000 mcg/day or 1000 mcg/week. Infants diagnosed prena-
allele, 401,402 suggesting that this genotype may be associated with less- tally and treated from birth usually show normal development. On rare
favorable cobalamin status. 64 occasions, this disorder may first become apparent in adult life.
Haptocorrin Deficiency Congenital deficiency is not associated
with clinically manifested cobalamin deficiency, although the plasma Methylmalonic Aciduria and Homocystinuria (Cblc, Cbld, and
or serum cobalamin levels are well below normal, and this is how
345
the condition is recognized. The absence of morbidity in these patients Cblf)
indicates that HCs are not essential for health. In these disorders, the defect in Cbl transformation affects AdoCbl
+
++
True Juvenile Pernicious Anemia True PA, with gastric atrophy and MeCbl, probably because reduction of cobalt from Co to Co is
and a defect in intrinsic factor secretion, is exceedingly rare in child- defective. These patients have both hyperhomocysteinemia and meth-
hood. Patients usually present in their teens with cobalamin defi- ylmalonic acidemia. The age at initial presentation ranges from early
403
ciency. Serum antiintrinsic factor antibodies usually are present. The infancy to adolescence. In addition to lethargy and failure to thrive,
265
diagnosis and treatment are the same as for PA in adults. affected infants present with serious neurologic difficulties. Older
patients present with psychological problems, progressive dementia,
and motor signs and symptoms. cblC disease is the most common of
INBORN ERRORS OF COBALAMIN the cobalamin inborn errors. In cblF the defect lies in an inability to
409
METABOLISM release cobalamin from lysosomes. Megaloblastic anemia occurs
in about half the cases. Patients respond partially to 1000 mcg/day of
Cobalamin is converted to AdoCbl and MeCbl by a complex series of OHCbl or CnCbl.
transformations involving several steps. 388,398,404 Eight disorders affecting A tentative diagnosis of a cobalamin mutation can be made by
this cobalamin transformation pathway have been described, one for demonstrating methylmalonic aciduria and/or homocystinuria in a
each of the steps. Because the molecular causes of these disorders have patient with the clinical findings described above in “Methylmalonic
not yet been fully characterized, the disorders themselves are not named Aciduria Only” or “Homocystinuria Only,” respectively. Establishing
for a defective protein but instead are designated by sequential capi- a diagnosis requires a specialized laboratory equipped to do cultured
tal letters preceded by a cbl prefix. The disorders can be grouped into fibroblast complementation studies. In a patient suspected of having
388
three broad clinical syndromes based on the abnormal metabolites in a cobalamin mutation, treatment should be started pending the test
the patient’s urine (Table 41–6). These disorders are usually discovered results because early high-dose cobalamin treatment is risk-free and
during investigation of infants with unexplained developmental delay, may reduce the chance of damage to the CNS. Fetuses with these dis-
acidosis, anemia, or unexplained neurologic difficulties. Typically they eases have been successfully treated in utero with very large doses of
have normal plasma cobalamin levels. CnCbl given parenterally to the mother. 410
Methylmalonic Aciduria Only (cblA, cblB, and cblH)
In cblA and cblB, AdoCbl production is impaired but MeCbl produc- INBORN ERRORS OF FOLATE METABOLISM
tion is normal. This may result either from an abnormal methylmalonyl Megaloblastic anemia in infancy has been described in three inherited
CoA mutase (designated muto or mut–) or from a defect in activation disorders of folate metabolism. 30,389,411

Kaushansky_chapter 41_p0583-0616.indd 607 9/17/15 6:24 PM