Reasons why I think that the lack of Folic Acid during the periconceptional period is an etiological factor for the Joint Hypermobility Syndrome.

For most authors, the Joint Hypermobility Syndrome (JHS) is a forme fruste of the classic Hereditary Diseases of Connective Tissues (HDCT), like Ehlers-Danlos (EDS), Marfan Syndrome (MFS) and Osteogenesis Imperfecta (OI). It is a condition that appears to be due to a genetic mutation, the frequency of which has increased around the world and apparently more so in Chile. Its cause and the reason of the apparent increase in frequency, in the last several years, are unknown. In this article I plan to discuss possible causes, which I have thought after the clinical observation of more than 1000 of these patients. I see them daily in my adult rheumatological practice and diagnose them using the Brighton Criteria¹.

The finding that the lack of a vitamin, such as FA, can cause gene alterations and thus congenital malformations (CMF), is impressive. It is well known that Neural Tube Defects (NTD) are caused by lack of Folic Acid (FA) during the periconceptional period ². Similarly, I think that myelomeningocele is the result from an alteration of the collagen of the meninges, bone and skin.

FA is necessary for cellular replication and growth, since it is essential in the synthesis of DNA and RNA, which are needed for protein synthesis in all cells. Furthermore, folates decrease the level of homocysteine (Hmc), a toxic metabolite, converting it to methionine, which is essential in protein synthesis. Therefore rapid growing tissues, like the fetus, erythrocytes, and immunologic system have a higher need of FA. It is quite possible then, that the lack of FA during the periconceptional period could cause mutations leading to JHS, like they have been proven to cause other congenital malformations. “Genetic malformations, secondary to lack of FA, are frequent in nutritional deficient states, and have been found around the world, in all the population studies done”³.

What mutagenic factor could be common to all countries? Smog, insecticides or radiations, could not be the reason, since they would affect only certain groups of people. Consanguinity, that is a known factor in the genesis of CMF, a condition that has existed in Chile for many years, does not appear to play an important role in the genesis of JHS, since it is more important in Autosomal recessive inheritance than in Autosomal dominant inheritance, which is the case of most of the HDCT.

It is my impression that an important factor could be the consumption of flour and specially bread, that is the most important staple food in the world, more so than rice or maize, and that arrives to all corners of the globe. Flour consumption had an explosive increase with the discovery of the power mills in 1870. The excessive consumption of bread without FA enrichment, in disproportion with the “protector foods” (food with FA, iron, and other vitamins), would have produced, in my belief, an increase in the frequency of JHS, as well as other CMF, including the NTD. Worldwide, 3% of the newborns have CMF, which translates into 4 million newborns with CMF a year, of which 500.000 are NTD. Chile, with a 96 Kg. average per capita bread consumption per year, is the second largest bread consumer in the world, second only to Germany. It is important to highlight that bread enriched by a legal mandate in Chile only since January 2000. This could be one explanation why the prevalence of JHS appears to be higher in Chile. There is also a related genetic factor that is very important in this context. There is a high frequency of the polymorphism of the Methylenetetrahydrofolate Reductase (MTHFR) in Latin populations. This mutation reduces this enzyme’s activity by 50%, elevating the homocysteine (Hmc) blood level slightly, thus significantly increasing the requirements of FA. We have termed this condition as “folate resistance”. Jugessur ⁴ thinks that this mutation could cause a CMF increase. Nitsche ⁵ has reported the presence of the polymorphism of the C677T of the MTHFR in 40% of the women in Chile and Spain, as compared to 10% in most other non-Latin origin countries. This could make CMF and especially NTD to be more prevalent in these populations. This polymorphism has also a high frequency in the Hispanic population of Baja California⁵, where coincidentally there is a higher NTD prevalence. Interestingly enough, Feuchtbaum ⁶ reported that the frequency increase in NTD between 1990 and 1994 in the state of California, was 40% higher in Hispanics than in Americans, Caucasians and Color people. The latter ethnic group in the USA have this MTHFR polymorphism in only 11%, and have a low rate of NTD ³, on the other hand in Mexico, where this mutation exists in 34.8%, the rate of NTD is very high ⁷. It is interesting to note that the high prevalence of JHS that has been published in Chile and Spain (34.6% and 25% respectively) ^8,9 coincides with the higher frequency of the MTHFR polymorphism in Latin populations.

Higher prevalence of Down syndrome and Cleft Palate has been found in populations with higher levels of MTHFR polymorphisms ¹⁰, this would indicate that they are also related to a lack of FA.

In 107 patients with Marfan syndrome, Giusti noted aortic dissection in association to elevated homocysteine, in patients with MTHFR polymorphism¹¹. In Homocistinuria, that is also a connective tissue disease, that has a very similar phenotype to MFS and like it, is due to a fibrillin alteration, it has been noted that the elevation of the Hmc level is associated with osteoporosis ¹². Noteworthy is the fact that in Homocistinuria both coronary problems and venous thrombosis are frequent. It has been reported that the higher cardiovascular risk of SLE is due to the Hmc elevation¹³

The demonstration that there is a deleterious action of elevated Hmc on collagen tissues of the vessels and bones, tends to support the idea that it also could do the same in JHS.

Recently, in January 2004, Lucock showed that elevated Hmc (due to the lack of FA) can change the properties of copper (chelate) and inhibit an enzyme called lysyl-oxidase, which alters collagen and elastin crosslinks, producing the weakness of collagen tissues This would explain why low FA can induce osteoporosis, and could also be a physiopathological explanation of what we have theorized from clinical observations ^{8 , 14}.

Due to the fact that FA prevents chromosomic alterations, by facilitating DNA replication, it is not rare that FA deficiency could be the base of a big number of diseases and alterations of normal development (Fenech) ¹⁵ including NTD, development of depressions (Alpert) ¹⁶ as well as mental retardation, among others.

After examining more than 600 patients with JHS, in the last 4 years, we have concluded that they frequently have CMF such as, spondylolisthesis, transitional vertebra, spina bifida occulta, scoliosis, flat feet and hip displacia. Spina bifida occulta, a relatively frequent finding in patients with JHS is a lesser degree of the worrisome open spina bifida that occurs in NTD, suggesting that both could be caused by the lack of FA. In the Prune-Belly Syndrome, which has renal malformations, cryptorquidea and absence of abdominal wall, the association of CMF and collagen fiber alterations is evident. Other authors, such as Czeizel ¹⁷, think that NTD are associated with other CMF. All this makes us conclude that the same cause of other CMF is probably the cause of the JHS genetic mutations.

It is probable that the same agent can produce different CMF by acting over different genes at the same time or at different times. As an example, Down Syndrome associated to cardiac malformations and later tendency to leukemia and neoplasia; NTD associated to cardiac alterations; Malformations of the kidneys and urinary tract, associated to absence of abdominal wall, in the Prune-Belly Syndrome.

Recently, importance has been given to the lack of FA not only during the periconceptional period, but also during people’s lives. Rimm ¹⁸ in a study of 60.000 nurses, noted significantly less coronary problems in the ones that took FA and Pyridoxine (B-6). Tice ¹⁹ suggests adults to take FA and Cyanocobalamin (B-12), since they reduce the tendency to Pernicious Anemia, insanity and other manifestations of the lack of these vitamins. Toole ²⁰ suggests taking FA daily starting at age 40, to prevent vascular accidents.

The lack of FA can produce collagen fiber alterations. It is known that if FA is not added to Methotrexate treatment, oral ulcers and subcutaneous nodules are more frequent. An increase in Homocysteine has been described in Behçet, which would be the cause of the vascular complications²⁰. Behçet is also a collagen disease, characterized by arthritis associated to vascular problems, oral and genital ulcers, which suggest that a lack of FA may be a factor in the pathogenesis of this condition.

All this makes us think that patients with alteration of the collagen fibers could benefit by taking FA, which could also prevent other problems, such as coronary or cerebral arteriosclerosis, Alzheimer and certain types of cancer. Two recent population studies of the Rotterdam and Framingham communities, including more than 2,000 people each, showed significant associations in the increase of Hmc blood levels with osteoporotic fractures ^21,22. The author’s explanation is that the elevated Hmc would weaken the bones by altering collagen crosslinks.

We have also noticed in our clinical practice, that the elevated JHS prevalence in Chile, affects indiscriminately people from different ethnic groups. It is well known that this condition is seen around the world, but appears to be more prevalent in Chile and Spain ^7,8. Thus it is likely that the etiologic factor is not only genetical, but could also be nutritional (lack of folic acid). Lately there have been reports of the presence of folate receptor auto-antibodies ²³, which would increase the FA intake requirement.

Unfortunately, it is of no use now to check serum FA or erythrocyte folate (which would be more reliable since it tells us about tissue levels) in patients with JHS, since with flour fortification these values are now normal. We have focused our discussion only on FA, but it is possible that the cause of the genetic mutations causing JHS could be due to the lack of several vitamins including FA, B-12 (Cyanobalamine) and B-6 (Pyridoxine).

Future genetic, biochemical and animal experimental studies would most likely elucidate what, so far, are just theories based in clinical observations.

References

1.- Grahame R. Brighton Diagnosis Criteria for the Benign Joint Hypermobility Syndrome. Br. J Rheumatol 2000 ; 27 : 1777-1779.

2.- Mulinare J, Cordero JF, Erickson JD, Berry RT. Periconceptional Use of Multivitamins and the Occurrence of Neural Tube Defects. JAMA 1988;260:3141.

3.- Schneider, JA, Rees DC, Liu Y-T and Clegg JB. Worldwide Distribution of a Common Methylenetetrahydrofolate Reductase Mutation Am. J. Hum. Genet. 1998, 62:1258-60,.

4.- Jugessur A, Wilcox AJ, Lie RT, Murray JC, Taylor JA et al. Exploring the Effects of Methylenetetrahydrofolate Reductase Gene Variants C6771 and A1298C on the Risk of Orofacial Clefts in 261 Norwegian Case-Parent Triads. Am J Epidemiol 2003;157:1083-91.

5.- Nitsche F, Alliende M, Santos JL, Pérez F, Santa María L, Herttrampf E y Cortes F. Frecuencia del polimorfismo C677T de la 5,10-metilentetradehidrofolato reductasa (MTHFR) en mujeres chilenas madres de afectados con espina bífida y en controles normales. Rev Méd Chile 2003;131:1399-04.

6.- Feuchtbaum LB, Currier RJ, Riggle S, Roberson M, Lorey FW, Cunningham GC. Neural Tube Defect Prevalence in California (1990-1994): Eliciting Patterns by Type of Defect and Maternal Race/Ethnicity. Genet Test 1999;3: 265-72

7.- Mutchinick OM, López MA, Luna L, Waxman J, Babinsky VE. High Prevalence of the Thermolabile Methylenetetrahydrofolate Reductasa Variant in Mexico: a country with a very high prevalence of neural tube defects. Mol Genet Metab. 1999 ;68(4):461-67.

8.- Bravo JF. Malformaciones congénitas y administración de ácido fólico en mujeres en edad fértil. Bol Hosp SJ de Dios 2004; 51 (2): 64-69.

9.- Guma M, Olivé A, Holgado S, Casado E, Roca J, Forcada J, Duró JC y Tena X. Una estimación de la laxitud articular en la consulta externa. Rev Esp Reumatol 2001; 28: 298-00.

10.- O´Leary BV, Parle-McDermontt A, Molloy MA, Kirke NP, Johnson Z, Conley M, et al. MTRR and MTHFR Polymorphism: link to Down syndrome ? Am J Med Genet 2002;107:151-55.

11.- Giusti B, Porciani MC, Brunelli T, Evangelisti L, Fedi S, Gensini GF, et al. Phenotype Variability of Cardiovascular Manifestations in Marfan Syndrome. Possible Role of Hyperhomocysteinemia and C677T MTHFR Gene Polymorphism. Eur Heart J 2003;24(22):2038-45.

12.- Van Meurs J, Dhonukshe-Rutten R, Pluijm S, et al. Homocysteine Levels and the Risk of Osteoporotic Fracture. NEJM 2004; 350: 2033-41.

13.- Bruce IN, Urowitz MB, Gladman DD, Steiner G. Risks Factors for Coronary Heart Disease in Women with Systemic Lupus Erythematosus: The Toronto Risk Factor Study. Arth Rheum 2003;48:3159-67.

14.- Lucock M. Is Folic Acid the Ultimate Functional Food Component for Disease Prevention ? BMJ 2004;328:211-14.

15.- Fenech M. The Role of Folic Acid and Vitamin B12 in Genomic Stability of Human Cells. Mutat Res. 2001;475:57-67.

16.- Alpert, JE and Fava M. Nutrition and Depression: the role of folate. Nutrition Reviews 1997; 55:145-49.

17.- Czeizel AE. Primary Prevention of Neural Tube Defects and Some Other Major Congenital Abnormalities: Recommendations for the Appropriate use of Folic Acid During Pregnancy. Pediatr Drugs 2000;2: 437-49.

18.- Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, et al. Folate and Vitamin B6 From Diet Supplements in Relation to Risk of Coronary Heart Disease Among Women. JAMA 1998;279:359-64.

19.- Tice JA, Ross E, Coxson PG, Rosenberg I, Weinstein MC, Hunink MGM, et al. Cost-effectiveness of Vitamin Therapy to Lower Plasma Homocysteine Levels for the Prevention of Coronary Heart Disease. JAMA 2001;286:936-943.

20.- Spence JD, Howard VJ, Chambless LE, Malinow MR, Pettigrew LC, Stampfer MR, Toole JF for the VISP Investigators. Vitamin intervention for stroke prevention (VISP) Trial: Rationale and Design. Neuroepidemiology 2001;20:16-25.

21.- Evereklioglu Her, Cumurcu T, Turköz Y, et al. Serum Homocysteine Level is Increased and Correlated with Endothelin-1 and Nitric Oxide in BeHmcet´s Disease. J Ophthatmol 2002;86:653-57.

22.- McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a Predictive Factor for Hip Fracture in Older Persons. NEJM 2004; 350: 2042-49.

23.- Rothenberg SP, Da Costa MP, Sequeira JM, Cracco J, Roberts JL, Weedon J, Quadros EV. Autoantibodies Against Folate Receptors in Women With a Pregnancy Complicated by a Neural Tube Defect. NEJM 2004; 350: 134-42.

Jaime F Bravo MD

December 28th, 2004

Updated: September 8th, 2006