Neurology -- Correspondence for Nemni et al., 62 (11) 2101-2102

Correspondence published:

Stiff person syndrome does not always occur with maternal passive transfer of GAD65 antibodies: Ted M. Burns, Lawrence H. Phillips, H. Royden Jones (26 July 2004)

Reply to Burns et al: Raffaello Nemni, Luisa M. Caniatti, Maira Gironi, Elena Bazzigaluppi, and Domenico De Grandis. (26 July 2004)

Stiff person syndrome does not always occur with maternal passive transfer of GAD65 antibodies 26 July 2004

Ted M. Burns,
University of Virginia
Hospital Drive, Charlottesville, VA,
Lawrence H. Phillips, H. Royden Jones
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Re: Stiff person syndrome does not always occur with maternal passive transfer of GAD65 antibodies

tmb8r{at}virginia.edu Ted M. Burns, et al.

Nemni et al’s recent study reporting high anti-GAD65 antibody titers in a mother with stiff-person syndrome (SPS) and in her two asymptomatic children is of special interest. [1] Recently, we reported a similar experience in a symptomatic mother and her asymptomatic infant. [2] In our family, the mother (and grandfather) had symptomatic SPS with markedly elevated GAD65 antibodies, whereas the infant was asymptomatic in spite of elevated GAD65 antibody titers. The baby’s antibody titers dropped markedly during the first year of life (72.7 nmol/L at birth, 6.65 nmol/L at 3 months, 0.65 nmol/L at 7 months). This suggested transplacental passage of antibodies.
We felt that the absence of abnormal neurologic symptoms or signs in the infant suggested that GAD65 antibodies may lack pathogenicity and rather be a biomarker, as has been demonstrated with the type 1 Purkinje cell cytoplasmic antibody marker of cerebellar ataxia. [3] However, we acknowledged that this question is far from settled for many reasons. Nemni et al also correctly pointed out that their observations don’t exculpate GAD65antibodies in SPS. A different, better-studied disease that is also caused by transplacental antibody transfer directed at an intracellular antigen target illustrates the need for caution before deriving too many conclusions from our and Nemni’s clinical observations.
In congenital heart block (CHB) caused by maternal antibodies, anti-SSA/Ro or anti-SSB/La antibodies are found in greater than 85% of mothers who have CHB fetuses, but the risk of CHB in the fetus is only 2% when mothers have these antibodies. [4] As may be true for neonatal myasthenia gravis, differences in the fine specificity of the antibodies may explain some of the differences. [5] However, the recurrence rate of CHB is under 20% in subsequent pregnancies, and the concordance rates in twin gestations is low, and thus it must take more than just cognate autoantibodies to cause disease in the progeny.
Regarding SPS, Nemni et al also point out that the infants’ functional blood-brain barrier may have contributed to disease resistance. There are currenlythree examples of infants receiving high levels of GAD65 antibodies by transplacental passage who did not develop disease. But the “absence of evidence is not evidence of the absence” of a pathogenic role for GAD65 antibodies. If the converse were to ever occur—transplacental transfer of SPS to an infant—the weight of evidence would shift toward antibody-mediated pathogenicity.
Lastly, Nemni et al also observed that the mother did not breastfeed the infants. They postulate that this may have conferred some resistance to disease development, a phenomenon that has been demonstrated in mice with maternal ovarian autoantibodies. In our family, the mother did breastfeed the infant throughout the first year of life, which suggests to us that breastfeeding may not be a critical factor in these cases.
References
1. Nemni R, Caniatti LM, Gironi M, Bazzigaluppi E, De Grandis D. Stiff person syndrome does not always occur with maternal passive transfer of GAD65 antibodies. Neurology 2004;62:2101-2102.
2. Burns TM, Jones HR, Phillips LH, Bugawan TL, Erlich HA, Lennon VA. Clinically disparate stiff-person syndrome with GAD65 autoantibody in a father and daughter. Neurology 2003;61:1291-1293.
3. Albert ML, Darnell JC, Bender A, et al. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med 1998;4:1321-1324.
4. Buyon JP, Clancy RM. Maternal autoantibodies and congenital heart block: mediators, markers, and therapeutic approach. Seminars Arthritis Rheumatism 2003;33:140-154.
5. Gardnerova M, Eymard B, Morel E, et al. The fetal/adult acetylcholine receptor antibody ratio in mothers with myasthenia gravis as a marker for transfer of the disease to the newborn. Neurology 1997;48:50-54.

Reply to Burns et al 26 July 2004

Raffaello Nemni,
Don C. Gnocchi Foundation, University of Milan, Italy
Don C. Gnocchi Foundation, University of Milan, Capecelatro 66, 20148 Milan, Italy,
Luisa M. Caniatti, Maira Gironi, Elena Bazzigaluppi, and Domenico De Grandis.
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Re: Reply to Burns et al

raffaello.nemni{at}unimi.it Raffaello Nemni, et al.

We thank Burns et al for their comments on our article [1] and the opportunity to further clarify the role played by autoantibodies to glutamic acid decarboxylase (anti-GAD65) in the pathogenesis of stiff- person syndrome (SPS).
Burns et al reported an asymptomatic infant with transplacental passage of anti-GAD65 from a symptomatic mother. This confirms the hypothesis that multiple coexisting factors are required to develop stiff-person syndrome (SPS) and that autoantibodies to glutamic acid decarboxylase (anti-GAD65) may play a critical but not unambiguous role in the pathogenesis of SPS. Burns et al, after suggesting that GAD65 may lack pathogenicity, note that the easiest answer is not always correct, especially in immunology and urge caution in drawing conclusions from observations made in other diseases caused by transplacental antibody transfer. [4,5]
As Burns et al correctly pointed out, fine specificity of the autoantibodies may explain the different phenotypic expression of anti- GAD65-related syndromes and possibly the lack of pathogenicity of anti-GAD65.
We are following an adult patient with high titer anti-GAD65 and no signs of anti-GAD65-related disease. Nevertheless, higher anti-GAD65 titer and recognition of a linear terminal epitope in the autoantigen GAD65 distinguish SPS from type 1 diabetes mellitus, suggesting that titer and fine specificity of anti-GAD65 are related to different phenotypic expression of anti-GAD65-related syndromes.
Concerning the failure of the natural passive transfer in SPS, it has to be considered that self antigen accessibility could vary among individuals in different periods of life. An epitope easily accessible during adult life could be secluded during fetal life and infancy. Moreover, a specific HLA aplotype could account for a preferential presentation to circulating-cognate antibodies.
Cellular reactivity to GAD65 might be crucial for developing SPS 3. Accordingly, different antigen processing mechanisms, HLA aplotypes involved in antigen presentation, and factors possibly contributing to disease resistance or susceptibility should be considered to clarify the pathogenesis of SPS.