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INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

IN THIS issue of the ARCHIVES, Manschot and coauthors¹ describe 3 families with polyneuropathy associated with monoclonal gammopathy and anti–myelin-associated glycoprotein (anti-MAG) antibodies. The patients would have been assumed to have hereditary neuropathy if it were not for the IgM monoclonal gammopathies. The distinction is important because immune-mediated neuropathies are responsive to drug therapy, whereas hereditary neuropathies are not, and hereditary neuropathies can be passed on to future generations. Other than that, the article raises important issues regarding the diagnosis of hereditary and demyelinating neuropathies, the significance of monoclonal gammopathies and autoantibodies, and the genetics of lymphoproliferative and autoimmune diseases.

In practice, patients are presumed to have hereditary neuropathy if other family members are affected, if they have a diagnostic DNA test, or, occasionally, if they have a characteristic phenotype. The condition is probably overdiagnosed, and in some instances justified merely by a distant family member with high arches or painful feet. Before the availability of antibody and DNA testing, for example, many patients with anti-MAG antibodies were diagnosed as having Charcot-Marie-Tooth disease type 1 (CMT1) because of their similar phenotype. Neuropathy is sufficiently common so that more than one family member can be coincidentally affected, and familial disposition to certain diseases such as diabetes or autoimmunity can increase the chances of developing neuropathy. The diagnosis of hereditary neuropathy is often uncertain in diseases for which DNA testing is still not available, and should not be made lightly. The diagnosis is impossible to disprove, and can have severe emotional and social consequences. The patients remain untreated, are often distraught, and have to inform their families that they may have inherited the disease. In the cases described, the negative DNA test results and presence of an alternative explanation for the neuropathy enabled the physicians to make the correct diagnosis.

The presence of a monoclonal gammopathy in a patient with neuropathy may alert the physician to the possible occurrence of an associated autoimmune or lymphoproliferative disease. Most monoclonal gammopathies are nonmalignant, but those of the IgG type can be associated with myeloma, the POEMS (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome, or amyloidosis. The IgM monoclonal gammopathies are sometimes associated with Waldenström macroglobulinemia, chronic lymphocytic leukemia or lymphoma, cryoglobulinemia, or autoantibody activity to peripheral nerves. However, monoclonal gammopathies are also nonspecifically increased in chronic inflammatory or infectious diseases and in old age, and can occur in chronic inflammatory demyelinating polyneuropathy (CIDP), so that their presence could be coincidental. In the cases reported by Manschot et al,¹ 3 of the 6 patients expressed IgM anti-MAG antibodies, which can cause neuropathy, confirming their role in the disease. It is not clear whether the other patients were not tested for or did not have detectable autoantibody activity, but other possible causes for neuropathy in patients with IgM monoclonal gammopathies include neurolymphomatosis, cryoglobulinemia, amyloidosis, or antibodies to GD1b or GM1 ganglioside, or sulfatide. In cases where no cause can be found, the monoclonal gammopathy might be coincidental or directed at an as yet unidentified nerve antigen.²

The association of IgM monoclonal gammopathy and peripheral neuropathy in multiple members of the same family has also been reported by other groups, and is probably not coincidental.³ Some families exhibit a predisposition to the development of IgM monoclonal gammopathies or Waldenström macroglobulinemia,⁴ and since up to 50% of patients with IgM monoclonal gammopathies can develop neuropathy, there is a finite probability that both conditions can occur in more than one family member. The development of IgM monoclonal gammopathies in susceptible family members is probably a consequence of both genetic and environmental factors, and since IgM monoclonal gammopathies arise from the B1 or CD5⁺ B-cell population, which is also responsible for expression of anti-MAG antibodies,^{5, 6} environmental factors or infections that activate these cells could result in the secretion of monoclonal gammopathies that cause neuropathy. It would have been of interest to know how many other members of the same families had monoclonal gammopathies, with or without autoantibody activity.

The differential diagnosis of demyelinating sensorimotor neuropathies includes hereditary neuropathy, CIDP, anti-MAG neuropathy, and osteosclerotic myeloma. Electrophysiological studies can help distinguish between the different types, as in CMT1 there is uniform slowing of nerve conduction velocities; in CIDP the abnormalities are nonuniform, asymmetric, and include conduction block and temporal dispersion; and anti-MAG neuropathy is typically associated with markedly prolonged distal latencies.⁷ However, many patients present atypically, there is significant overlap of abnormalities between the different groups, and nonuniform conduction abnormalities including conduction blocks can also be seen in hereditary neuropathy with predisposition to pressure palsy. To complicate matters, patients with hereditary neuropathies can also develop CIDP or monoclonal gammopathies, which are amenable to immune therapy.^{8, 9} Anti-MAG neuropathy and osteosclerotic myeloma can be diagnosed using serological and radiologic tests respectively, but there is no reliable test for CIDP, and DNA testing can identify or rule out most but not all hereditary demyelinating neuropathies. That EGR2 gene mutations can cause the CMT1 phenotype, for example, was only recently discovered.¹⁰ The evaluation and treatment of peripheral neuropathies is becoming increasingly complex, requiring a more sophisticated understanding of laboratory testing in addition to the more traditional clinical skills.

 
 
Author/Article Information

 
Norman Latov, MD, PhD
Department of Neurology
Columbia University
710 W 168th St
New York, NY 10032




 
 

REFERENCES

1.
Manschot SM, Notermans NC, van den Berg LH, Verschuuren JJGM, Lokhorst HM.
Three families with polyneuropathy associated with monoclonal gammopathy.
Arch Neurol.
2000;57:740-742.
ABSTRACT  |  FULL TEXT  |  PDF  |  MEDLINE
 

2.
Gordon P, Brannagan T, Latov N.
Neurological manifestations of paraproteinemia and cryoglobulinemia.
In: Vinken PJ, Bruyn GW, Aminoff MJ, Goetz CG, eds. Handbook of Clinical Neurology: Systemic Diseases III. Amsterdam, the Netherlands: Elsevier; 1999:430-462.

 

3.
Jensen TS, Schroder HD, Onssonu I, et al.
IgM monoclonal gammopathy and neuropathy in 2 siblings.
J Neurol Neurosurg Psychiatry.
1988;51:1308-1315.
MEDLINE
 

4.
Renier G, Ifrah N, Chevailler A, Saint-Andre JP, Boasson M, Hurez D.
Four brothers with Waldenström's macroglobulinemia.
Cancer.
1989;64:1544-1559.

 

5.
Van Arkel C, Hopstaken CM, Bos NA, et al.
Monoclonal gammopathies in aging u,x-transgenic mice: involvement of the B-1 cell lineage.
Eur J Immunol.
1997;27:2436-2440.
MEDLINE
 

6.
Lee KW, Inghirami G, Spatz L, Knowles DM, Latov N.
The B cells that express anti-MAG antibodies in neuropathy and non-malignant IgM monoclonal gammopathy belong to the CD5 subpopulation.
J Neuroimmunol.
1991;31:82-88.

 

7.
Kadu DA, England JD, Sumner AJ.
Distal accentuation of conduction slowing in polyneuropathy associated with antibodies to myelin-associated glycoprotein and sulfated glucuronyl paragloboside.
Brain.
1994;117:941-947.
MEDLINE
 

8.
Gregory R, Thomas PK, King RHM, et al.
Coexistence of hereditary motor and sensory neuropathy type Ia and IgM paraproteinemic neuropathy.
Ann Neurol.
1993;33:649-652.
MEDLINE
 

9.
Briani C, Brannagan TH, Trojaborg W, Latov N.
Chronic inflammatory demyelinating polyneuropathy.
Neuromuscul Disord.
1996;6:311-325.
MEDLINE
 

10.
Warner LE, Mancias P, Butler IJ, et al.
Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies.
Nat Genet.
1998;18:382-384.
MEDLINE