Blindness Caused by a Junk Food Diet
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Blindness Caused by a Junk Food Diet. Ann Intern Med.2019;171:859-861. [Epub 30 September 2019]. doi:10.7326/L19-0361
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Comment
We would like to caution the authors regarding their diagnosis of nutritional optic neuropathy. They make this diagnosis given elevated levels of homocysteine (Hcy) and methylmalonic acid (MMA) in the context of a history of a vitamin B12 (cobalamin) level in the lower range of normal. While metabolism of both Hcy and MMA are B12 dependent, and elevations can indicate deficiency, these values should normalize following B12 supplementation.1 There are other aetiologies to explain the patient’s biochemical and clinical phenotype that were not explored by the authors.
Both MMA and Hcy are elevated in many inborn errors of cobalamin metabolism.2 In particular, the authors should exclude a diagnosis of transcobalamin II (TCII) deficiency, caused by mutations in the TCN2 gene. It is characterized by elevated MMA and Hcy, and a low or normal B12 level. Although normally detected in infancy, late presentations have been described. Furthermore, partially treated patients can have normal neurological function but present with visual abnormalities including retinopathy.3 Symptoms are progressive, but treatment with intramuscular hydroxycobalamin would represent optimal therapy.
Consideration should also be given to disorders of intracellular B12 processing, such as cobalamin C, D, F and J deficiencies (caused by mutations in MMACHC, MMADHC, LMBRD1, and ABCD4 respectively). These disorders can present across the lifespan with variable symptoms including megaloblastic anemia and optic neuropathy.4 Late presentation with a range of symptoms as well as asymptomatic patients have been described.5 Biochemically, these disorders also present with low or normal levels of B12 in conjunction with elevated total Hcy and MMA. Most importantly, all of these disorders are progressive but treatable. Optimum therapy includes intramuscular hydroxycobalamin with oral folic acid and betaine. Cobalamin X deficiency, due to mutations in HCFC1, ZNF143 and THAP11, can present with similar biochemical findings but is clinically less likely in this case as more severe neurological issues have been reported in the rare number of cases to date.4
On the basis of the information presented we suggest that the patient have further work-up to exclude inborn errors of metabolism. Specifically, we would recommend molecular genetic testing of the genes mentioned above, and/or enzymatic studies if required. Identification of such a disease would inform the patient’s treatment whereas exclusion of these diseases would support the authors’ hypothesis that his optic neuropathy is truly nutritional.
1. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med. 2013; 368:149-60.
2. Watkins D, Rosenblatt DS. Inborn errors of cobalamin absorption and metabolism. Am J Med Genet Part C Semin Med Genet. 2011; 157:33–44.
3. Trakadis YJ, Alfares A, Bodamer OA et al. Update on transcobalamin deficiency: clinical presentation, treatment and outcome. J Inherit Metab Dis. 2014;37(3):461-73.
4. Sloan JL, Carrillo N, Adams D, et al. Disorders of Intracellular Cobalamin Metabolism. 2008 Feb 25 [Updated 2018 Sep 6]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1328/
5. M. Huemer, S. Scholl-Bürgi, K. Hadaya, et al. Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy. Orphanet J. Rare Dis. 2014;9:161.
Response
Total homocysteine (Hcy) and methylmalonic acid (MMA) levels were measured to understand the significance of our patient’s low-normal vitamin B12 level and clinical history of poor diet; both were mildly elevated. In a targeted strategy to investigate causes of homocystinuria, we use Hcy level as a guide to the likely cause1. Inherited metabolic disorders (IMDs) are rare, generally present in early infancy or childhood and are normally associated with Hcy levels >100µmol/L1. The Hcy level in our case was <50µmol/L at presentation, and the most common causes are delayed sample separation (<1mol/L/hour); hypothyroidism; low-normal or deficient levels of vitamin B6 (pyridoxine), B9 (folate) and B12 (cobalamin); renal impairment; and certain medications1. Hcy levels 50-100µmol/L may occur from the same aetiologies but can be investigated further with plasma amino acids and urine organic acids if the clinical history is suggestive of an IMD.
While it’s true that some IMDs, e.g. remethylation or cobalamin (Cbl) pathway mutations, can be associated with Hcy levels <100µmol/L, the authors cite examples with very different phenotypes2-4. Transcobalamin II (TCII) deficiency presents before age 2 with failure to thrive or haematological abnormalities, e.g. pancytopenia, and those with visual abnormalities have retinopathy, not optic neuropathy3. Disorders of intracellular B12 processing can present in adolescence and adults (CblC and CblD, not CblF or CblJ), but the phenotype is again different2,4. One case of late-onset CblC deficiency had hypertensive retinopathy from malignant hypertension, whereas early-onset cases of CblC deficiency have pigmentary retinopathy, not optic neuropathy4. Likewise, CblF and CblJ deficiencies present in early infancy or childhood, and one case with CblJ deficiency presenting as a neonate had retinal dystrophy, not optic neuropathy2.
IMDs, including disorders of the Cbl pathway, were considered in our patient in light of the elevated Hcy and MMA results. However, the levels of Hcy and MMA in conjunction with the clinical history and response to vitamin supplementation made an IMD unlikely. We do not believe that our patient’s visual loss was due to vitamin B12 deficiency alone, but from the combined deficiencies of multiple nutrients, specifically copper and the B vitamin group, many of which have close inter-relationships in the remethylation and folate cycles of the CNS5. While an IMD would not explain our patient’s low vitamin D, bone mineral density, copper and selenium levels, his poor diet provides an explanation for all of his abnormalities.
References
1. Refsum H, Smith AD, Ueland PM, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004;50:3-32.
2. Sloan JL, Carrillo N, Adams D, Venditti CP. Disorders of Intracellular Cobalamin Metabolism. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews((R)). Seattle (WA)1993.
3. Trakadis YJ, Alfares A, Bodamer OA, et al. Update on transcobalamin deficiency: clinical presentation, treatment and outcome. J Inherit Metab Dis 2014;37:461-73.
4. Huemer M, Scholl-Burgi S, Hadaya K, et al. Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy. Orphanet J Rare Dis 2014;9:161.
5. Sechi G, Sechi E, Fois C, Kumar N. Advances in clinical determinants and neurological manifestations of B vitamin deficiency in adults. Nutrition reviews 2016;74:281-300.
comment
Low copper is diagnostic of deficiency according the Oxford Textbook of Medicine (2, 3). This deficiency may explain some seemingly unrelated phenomena that have been reviewed (2-5).
Decreased myelination of optic nerves has been found in copper deficient rodents(5). Rats, mice and people low in copper have poor hearing; a patient with hearing loss improved with a copper supplement (4). There can be no medical doubt that copper deficiency can cause osteoporosis in people; two double-blind, placebo-controlled trials reveal that supplements including copper improved bone mineral density in women (2). Rats deficient in copper have high homocysteine; copper supplementation lowers homocysteine in men (3).
Descriptions of ocular lesions and results of treatment in copper deficiency are minimal (5). It is not clear whether neurological stabilization without cure is from insufficient supplementation or from severe and irreversible deficiency; nerves grow slowly and re-myelination also may be slow (5).
Copper deficiency explains more abnormalities of the patient than other possible, concomitant deficiencies. Their description of the retinal abnormalities may be the most extensive yet published; his visual stabilization is similar to other cases. There is no well-defined regimen of copper replacement therapy regarding chemical form, dose, duration or route of administration. Four mg of oral copper daily (as gluconate) may be effective over some months.
1. Harrison R, Warburton V, Lux A, Atan D. Blindness Caused by a Junk Food Diet. Ann Intern Med. 2019.
2. Klevay LM. Copper. In: Coates PM, Betz, J.M., Blackman,M.R., Cragg, G.M., Levine,M., Moss, J., White, J.D., ed. Encyclopedia of Dietary Supplements. 2 ed. London: Informa Healthcare; 2010:175-84.
3. Klevay LM. Ischaemic heart disease from copper deficiency: a unified theory. Nutr Res Rev. 2016;29:172-9.
4. Klevay LM. Copper deficiency and neuropathology related to the petrous bone. Ann Epidemiol. 2014;24:488-9.
5. Klevay LM. Ocular lesions from copper deficiency. Indian J Med Res. 2017;146:430-1.
Junk food is not cheap