Info

MMA/tHcy

Intracellular defects of cobalamin

Normal

Severe disease, T MMA/tHcy

Abbreviations: NA, neurologic abnormalities; MMA, methylmalonic acid; tHcy, total homocysteine; T, increased.

Abbreviations: NA, neurologic abnormalities; MMA, methylmalonic acid; tHcy, total homocysteine; T, increased.

Adenosylcobalamin Deficiency CblA (OMIM 251100) and CblB (OMIM 251110) Diseases

Deficiencies of adenosylcobalamin synthesis lead to impaired methylmalonyl CoA mutase activity and result in methylmalonic acidemia. Cobalamin-responsive methylmalonic aciduria characterizes both CblA and CblB diseases. Intact cells from both CblA and CblB patients fail to synthesize adenosylcobalamin. However, cell extracts from CblA patients can synthesize adenosylcobalamin when provided with an appropriate reducing system, whereas extracts from CblB patients cannot. The defect in CblA may be related to a deficiency of a mitochondrial nicotinamide adenine dinucleotide phosphate (NADPH)-linked aquacobalamin reductase. The defect in CblB affects adenosyltransferase, which is involved in the final step in adenosyl-cobalamin synthesis. This group of patients presents with:

• Life-threatening or fatal ketoacidosis in the first few weeks or months of life

• Hypoglycemia and hyperglycinemia

• Failure to thrive or developmental retardation (may be a consequence of the aci-dosis and reversed by relief of the ketoacidosis)

• Normal serum cobalamin concentrations.

Both CblA and CblB are autosomal recessive diseases. Studies of these patients have shown that intact cells fail to oxidize propionate normally. Methylmalonyl CoA arises chiefly through the carboxylation of propionate, which in turn derives largely from degradation of valine, isoleucine, methionine, and threonine.

Treatment

Ninety percent of CblA patients respond to therapy with systemic hydroxocobal-amin or cyanocobalamin, whereas only 40% of CblB patients respond to this therapy. Only 30% have long-term survival.

Deficiency of Methylmalonyl-CoA Mutase (mut°, mut-)

Defects in methylmalonyl CoA mutase apoenzyme formation can occur and result in methylmalonic aciduria, which is accompanied by life-threatening or fatal ketoaci-dosis, unresponsive to vitamin B12.

Protein feeding induces symptoms rapidly. Symptoms include lethargy, failure to thrive, muscular hypotonia, respiratory distress, and recurrent vomiting and dehydration. Children normally excrete <15-20 ng of methylmalonic acid per gram of creatinine, whereas patients with methylmalonyl CoA mutase deficiency excrete >100 mg up to several grams daily. Patients may have elevated levels of ketones, glycine, and ammonia in the blood and urine. Many also have hypoglycemia, leukopenia, and thrombocytopenia.

Treatment

Treatment involves protein restriction using a formula deficient in valine, isoleucine, methionine, and threonine, with the goal of limiting amino acids that use the propi-onate pathway. Therapy with carnitine has been advocated for those patients who are carnitine deficient. Lincomycin and metronidazole have been used to reduce enteric propionate production by anaerobic bacteria. These patients do not respond well to vitamin B12 therapy. Despite therapy, a number of patients have experienced basal ganglia infarcts, tubulointerstitial nephritis, acute pancreatitis, and cardiomy-opathy as complications. Liver transplantation has been attempted.

Cultures of patients' fibroblasts show two classes of mutase deficiency: those having no detectable enzyme activity are designated mut°, whereas those with residual activity, which can be stimulated by high levels of cobalamin, are termed mut-. Some mut° cell lines synthesize no detectable protein.

Methylcobalamin Synthesis Deficiency: CblE (OMIM 236270) and CblG (OMIM 250940) Diseases

Abnormalities in methylcobalamin synthesis result in reduced N5-methyltetrahydro-folate:homocysteine methyltransferase and consequently lead to homocystinuria with hypomethioninemia. Thus, homocystinuria and hypomethioninemia, usually without methylmalonic aciduria, characterize functional methionine synthase deficiency (CblE, CblG), although one CblE patient had transient methylmalonic aciduria. Fibroblasts from CblE and CblG patients show a decreased accumulation of methylcobalamin with a normal accumulation of adenosylcobalamin after incubation with cyanocobalamin. Their fibroblasts show decreased incorporation of labeled methyltetrahydrofolate as well. Cyanocobalamin uptake and binding to both cobal-amin-dependent enzymes is normal in CblE fibroblasts and in most CblG fibroblasts.

Clinical findings

• In most patients, illness within the first 2 years of life, but a number of patients have been diagnosed in adulthood

• Megaloblastic anemia

• Various neurologic deficits including developmental delay, cerebral atrophy, EEG abnormalities, nystagmus, hypotonia, hypertonia, seizures, blindness, and ataxia

Treatment

Hydroxocobalamin is administered systemically, daily at first, then once or twice weekly. Usually this corrects the anemia and the metabolic abnormalities. Betaine supplementation may be helpful to reduce the homocysteine further. The neurologic findings are more difficult to reverse once established, particularly in CblG disease. There has been successful prenatal diagnosis of CblE disease in amniocytes, and the mother with an affected fetus can be treated with twice weekly hydroxocobalamin after the second trimester.

Combined Adenosylcobalamin and Methylcobalamin Deficiency CblC (OMIM 277400), CblD (OMIM 277410), and CblF (OMIM 277380) Diseases

These disorders result in failure of cells to synthesize both methylcobalamin (resulting in homocystinuria and hypomethioninemia) and adenosylcobalamin (resulting in methylmalonic aciduria) and, accordingly, deficient activity of methylmalonyl

CoA mutase and N5-methyltetrahydrofolate: homocysteine methy¡transferase. Fibroblasts from CblC and CblD patients accumulate virtually no adenosylcobal-amin or methylcobalamin when incubated with labeled cyanocobalamin. In contrast, fibroblasts from CblF patients accumulate excess cobalamin, but it is all unmetabo-lized cyanocobalamin, nonprotein bound, and localized to lysosomes. In CblC and CblD, the defect is believed to involve cob(III)alamin* reductase or reductases, whereas in CblF, the defect involves the exit of cobalamin from the lysosome. Partial deficiencies of cyanocobalamin beta-ligand transferase and microsomal cob(III)alamin reduc-tase have been described in CblC and CblD fibroblasts as well. These patients present in the first year of life with:

• Poor feeding, failure to thrive, and lethargy

• Macrocytosis, hypersegmented neutrophils, thrombocytopenia, and megaloblas-tic anemia

• Developmental retardation

• Spasticity, delirium, and psychosis (in older children and adolescents)

• Hydrocephalus, cor pulmonale, and hepatic failure, as well as a pigmentary retinopathy with perimacular degeneration

• Methylmalonic acid levels that are lower than in methylmalonyl CoA mutase deficiency, but greater than in defects of cobalamin transport.

In addition, many patients with the onset of symptoms in the first month of life die, whereas those with a later onset have a better prognosis.

CblC, CblD, and CblF diseases can be differentiated using cultured fibroblasts. Failure of uptake of labeled cyanocobalamin distinguishes CblC and CblD from all other cbl mutations. There is reduced incorporation of propionate and methyltet-rahydrofolate into macromolecules in all three disorders and reduced synthesis of adenosylcobalamin and methylcobalamin. Complementation analysis between an unknown cell line and previously defined groups establishes the specific diagnosis. Prenatal diagnosis has been successfully accomplished in CblC disease using chori-onic villus biopsy material and cells.

Treatment

The treatment of CblC disease can be difficult. Daily therapy with oral betaine and twice weekly injections of hydroxocobalamin improve lethargy, irritability, and failure to thrive; reduce methylmalonic aciduria; and return serum methionine and homocysteine concentrations to normal. There has been incomplete reversal of the neurologic and retinal findings. Surviving patients usually have moderate to severe developmental delay, even with good metabolic control.

Acquired

In protein malnutrition (kwashiorkor, marasmus) and liver disease, impaired utilization of vitamin B12 has been reported. Certain drugs are associated with impaired absorption or utilization of vitamin B12 (see Table 4-2).

Was this article helpful?

0 0

Post a comment