Abnormal cobalamin-dependent transmethylation in AIDS-associated myelopathy

Rocco, Alessandro Di; Bottiglieri, Teodoro; Werner, P.; Geraci, Anthony; Simpson, David M.; Godbold, James; Morgello, Susan

doi:10.1212/wnl.58.5.730

Cited by 53 publications

(24 citation statements)

References 32 publications

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“…In this regard, "functional" deficiency of Cbl has recently been suggested in the pathogenesis of both Alzheimer disease and AIDS myelopathy. 43,44 Moreover, pharmacologic doses of methylcobalamin can improve measures of both cardiac autonomic dysfunction and peripheral neuropathy in diabetic subjects, [45][46][47] and high doses of methylcobalamin also accelerate nerve regeneration in rats with acrylamide neuropathy. 48 The observation that methylcobalamin can serve as a methyl donor in vitro in the DNA methylase reaction provides one possible mechanism for a pharmacologic effect of Cbl therapy.…”

Section: Discussionmentioning

confidence: 99%

Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing

Solomon

2005

Blood

136

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IntroductionWhile cobalamin (Cbl) deficiency classically causes macrocytic anemia, anemia can occur without macrocytosis, and both neurologic and cognitive dysfunction often develop in the absence of hematologic changes. 1-5 Symptoms consistent with Cbl deficiency, including paresthesias, unsteady gait, fatigue, and impaired memory, are commonly encountered in the ambulatory care setting, and early recognition of Cbl deficiency is important to prevent progressive, irreversible neurologic and cognitive impairment. 6,7 Although treatment with Cbl is often initiated after the finding of a low serum Cbl level, many patients with low Cbl levels are not Cbl deficient. 8,9 As a result, measurements of the Cbl-dependent metabolites, methylmalonic acid (MMA) and homocysteine (HCys), have recently been used to confirm the presence of Cbl deficiency. Retrospective studies of patients at academic medical centers with low serum Cbl levels and clinically overt Cbl deficiency found MMA and/or HCys levels more than 3 standard deviations (SD) above the normal mean in almost all patients. 8,10-12 Thus, algorithms for the diagnosis of Cbl deficiency were developed that suggest initial measurement of serum Cbl followed by determination of MMA and HCys when Cbl levels are intermediate or when suspicion of clinically significant Cbl deficiency is high. 8,[13][14][15][16][17][18][19][20] However, because little attention has been given to the study of patients with clinical findings consistent with Cbl deficiency but normal vitamin and metabolite levels, the negative predictive value of these tests is uncertain. Indeed, Cbl levels are normal in some patients with overt deficiency, 11 and currently available Cbl assay kits may not be reliable. 21,22 Moreover, because studies from academic centers usually employed special diagnostic or research laboratory facilities, their findings may not be representative of those obtainable in other ambulatory care settings.Thus, a retrospective review of patients evaluated for Cbl deficiency during a 10-year period at a staff model HMO utilizing a national commercial laboratory was performed. Initially, only patients with low serum Cbl levels or elevated metabolite levels received therapeutic trials of Cbl. However, in the seventh year of the study period, one patient with total absence of vibratory sensation in the iliac crest, knees, and ankles had complete recovery following 2 months of Cbl therapy despite normal Cbl, MMA, and HCys levels. Thereafter, therapy was offered to all patients with hematologic or neurologic abnormalities consistent with Cbl deficiency regardless of the results of screening studies. Patients, materials, and methods Laboratory methodsSerum Cbl was measured by the ADVIA Centaur chemiluminescence assay (Bayer Diagnostics, Tarrytown, NY). Normal Cbl values were 200 to 1100 pg/mL, but higher reference ranges have been suggested, 11,13,16,17,20,23,24 and the statement "patients with values less than 300 pg/mL may experience unexplained neuropsychiatric or hematologic abnormali...

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Section: Discussionmentioning

confidence: 99%

Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing

Solomon

2005

Blood

136

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“…The mean duration of illness was 11.4 (0.25-50) months. Their median education level was 14 (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) years. 31 patients were vegetarian and 2 occasional non-vegetarian (< 1/week); only 4 of these patients consumed milk > 500 ml/day.…”

Section: Resultsmentioning

confidence: 99%

“…Rapidly progressive cognitive impairment, myelopathy and cranial MRI abnormalities found in our patients simulated HIV encephalomyelopathy. The myelopathy in HIV clinically and pathologically simulate subacute combined degeneration as both produce patchy or diffuse vacuolar demyelination affecting posterior and pyramidal tract [4]. Subcortical white matter T2 hyperintensity followed by cortical atrophy has been described in HIV encephalopathy.…”

Section: Discussionmentioning

confidence: 99%

“…All our patients were negative for HIV and they improved following B12 therapy. The association of B12 deficiency in various neurological diseases such as multiple sclerosis [19], Alzheimer's disease [30] and HIV [4] although postulated have yet to be confirmed in view of a lack of improvement following B12 therapy. Routine measure of cognitive function by MMSE often fails to detect executive cognitive dysfunction; moreover MMSE is education and age dependent [22].…”

Section: Discussionmentioning

confidence: 99%

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Vitamin B12 deficiency neurological syndromes: correlation of clinical, MRI and cognitive evoked potential

Kalita

Misra

2008

J Neurol

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“…Vacuolar myelopathy is characterised pathologically by the presence of intramyelinic and periaxonal vacuoles, containing foamy macrophages, in the lateral and posterior columns of the thoracic portion of the spinal cord. A deficiency of the B 12 -dependent transmethylation pathway rather than direct HIV infection seems to be the pathological explanation for vacuolar myelopathy [8]. Clinically, vacuolar myelopathy manifests itself late in the course of HIV infection.…”

Section: Vacuolar Myelopathymentioning

confidence: 99%

The neurological manifestations of HIV infection

2003

Swiss Arch Neurol Psychiatr

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Abnormal cobalamin-dependent transmethylation in AIDS-associated myelopathy

Abstract: AM is associated with an abnormality of the vitamin B(12)-dependent transmethylation pathway.

Cited by 53 publications

References 32 publications

Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing

Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing

Vitamin B12 deficiency neurological syndromes: correlation of clinical, MRI and cognitive evoked potential

The neurological manifestations of HIV infection

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