GALOP syndrome: case report with 7-year follow-up.

Abstract: An elderly woman complaining of a gait disorder was found to have the GALOP syndrome (gait ataxia, late-onset polyneuropathy). She exhibited mild distal weakness and sensory loss in the legs, a positive Romberg, and an unsteady gait. Serum immunofixation disclosed a monoclonal IgM-[kappa] protein. There was specific IgM binding to galopin, a central nervous system white matter antigen. Periodic treatment with intravenous immunoglobulin has alleviated her neurologic symptoms. She has now been followed for 7 years and maintained significant improvement in neurologic symptoms and signs.

Key Words: GALOP syndrome, late-onset polyneuropathy, monoclonal gammopathy

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There are only two reports (1,2) and one review (3) describing a total of 15 patients who exhibited the GALOP syndrome (gait ataxia late-onset polyneuropathy). The characteristic clinical presentation is an elderly individual, usually from 60 to 85 years of age, who has an unsteady gait that is often associated with falling and develops insidiously over months to years. There is mild distal sensory loss and weakness, but the gait disorder exceeds what might be expected from these deficits. The gait is often ataxic, and the patient requires extra steps when turning. The sensory loss involves both small and large fibers so that all sensory testing frequently elicits abnormal findings. Electrophysiological testing shows axonal or demyelinating features and serologic studies disclose high titers of serum IgM binding to galopin, a central nervous system antigen. Immunomodulating treatment may significantly improve the gait and ameliorate the sensory complaints. This report outlines the clinical course of a single patient followed for 7 years.

Case Reports

An 82-year-old woman was seen in neurologic consultation in November of 1996 because of a 1-month history of difficulty walking due to poor balance; she also reported "freezing feet," and tingling of the fingertips. Simultaneously she noted weakness of the right foot, especially the right big toe. The symptoms were worse late in the day, when she felt that her feet became "awkward." Her walking endurance was reduced from four miles to one mile per day.

Neurologic examination disclosed mild to moderate distal weakness in the feet, right more than left, and mild weakness of the left interossei and triceps muscles. Romberg test was positive, and she walked with a slight right-foot drop. She had a short stride, took an extra step when turning and could not walk on her heels. Reflexes were absent at the ankles and in the right arm, but 1 + otherwise. She had absent vibratory perception at the toes, and made occasional position sense errors at the left toes. Responses to pain, temperature, and light touch were normal.

Pertinent laboratory findings were a serum protein electrophoresis disclosing a peak in the gamma region. The total gamma globulins were 10.9 g/L. Serum immunofixation revealed a monoclonal IgM-[kappa] protein. The IgM was 7.81 g/L, IgA 1.44 g/L and IgG 7.63 g/L. A summary of the nerve conduction studies is given in Table 1.

Cerebrospinal fluid examination disclosed one white cell per [micro]L, and total protein was 0.93 g/L. A skeletal survey showed demineralization and mild compression of T12. Cryoglobulins, anti-GM1 and anti-MAG autoantibodies were absent. Antinuclear antibody was positive, 1:2,560, and an anti-DNA was negative. A human immunodeficiency virus screen, complement studies, and tests for anti-Ro and anti-La antibodies were negative. GALOP autoantibody screen five months after the patient was first seen disclosed specific IgM binding to the GALOP antigen with a titer of 69,000.

Needle Examination

Anterior tibialis, medial gastrocnemius, first dorsal interosseus, biceps, and lumbar paraspinal muscles disclosed 1+ to 2+ fibrillations at rest. Trains of positive sharp waves occurred on needle insertion in the same musculature except the biceps muscle. There was mildly increased amplitude and duration of motor unit potentials. There was moderate to markedly reduced motor unit recruitment pattern in distal musculature.

In summary, the electromyographic examination revealed abnormalities most consistent with a primary axonloss sensorimotor polyneuropathy. The prolonged F-wave latencies and proximal denervation suggested a polyradiculopathy.

A sural nerve biopsy disclosed a moderately severe depopulation of myelinated nerve fibers. There was segmental demyelination on teased nerve preparation. A milder axonal process was supported by the presence of degenerated axons and myelin digestion chambers. There was no inflammation or vasculitis (Fig. 1).

Clinical Course

The patient has been followed for seven years. She was treated daily with intravenous immunoglobulin (IVIg) at 0.5 g/kg for four days in April 1997. Immediately after treatment, strength of ankle dorsiflexion improved. Vibration was perceived briefly at the toes, position sense was intact, and gait became nearly normal.

In July 1997 the patient returned with complaints of cold, numb feet, a sense of shriveling of her fingers, and weakness of the feet. There was mild weakness of interossei, wrist extensors, gastrocnemius, and anterior tibialis. Vibration and position sense were impaired at the toes bilaterally. She had a positive Romberg test and walked unsteadily. She was again treated daily with IVIg at 1 g/kg over two days. Position sense and gait returned to normal. The patient returned every one to four months with similar symptoms and findings between August 1997 and mid-December 1999. A summary of the patient's autoantibody study results is given in Table 2. Each time she was treated daily with IVIg at 1 g/kg for two days. She exhibited allodynia to vibration, intermittent position sense loss and a positive Romberg test. Occasionally she had mild subjective distal sensory loss to pain. For the next 30 months, IVIg was not required and gabapentin provided symptomatic relief.

Because of increasing foot discomfort and unsteadiness, she returned in October of 2002. Her examination disclosed mild anterior tibialis weakness, vibration and position sense loss at the toes, and an unsteady gait. Serum immunofixation revealed a monoclonal IgM-[kappa] protein and total IgM was 9.70 g/L. GALOP autoantibodies were measured at a titer of 77,250. Treatment with IVIg was resumed.

Discussion

This 82-year-old woman complained of difficulty walking because of poor balance, freezing feet, and tingling of the fingertips. The gait difficulty was her most troublesome symptom. She exhibited mild distal weakness in all extremities, absent ankle jerks, impaired vibration and position sense at the toes, a positive Romberg test, and an unsteady gait, especially when turning. Cerebrospinal fluid protein was 0.93 g/L. Serum protein electrophoresis showed a peak in the gamma region with total gamma globulins of 10.9 g/L. Serum immunofixation disclosed a monoclonal IgM Kappa protein. There was specific IgM binding to the GALOP antigen with a titer of 69,000. Electromyography and nerve conduction studies demonstrated abnormalities most consistent with a primary axon loss sensorimotor polyneuropathy. Conversely, the nerve biopsy disclosed a severe depopulation of myelinated nerve fibers, segmental demyelination on teased nerve preparation, and several degenerated axons. Treatment with IVIg at 1 to 4-month intervals over 28 months improved distal strength and gait. Sensory symptoms abated with gabapentin treatment.

[FIGURE 1 OMITTED]

Six years after the patient was initially seen, her symptoms of unsteadyness and foot discomfort recurred. There was a concomitant increase in the GALOP autoantibody levels, which reached a titer of 77,250. Resumption of IVIg treatment significantly lessened her symptoms and has improved her gait.

Long-term immunosuppression may be required to treat this disorder. The mechanism of action by which IVIg is effective has not been clearly elucidated. A major consideration includes binding and neutralization of pathogenic autoantibodies to prevent interaction with the autoantigen. IVIg may supply the anti-idiotypic antibodies which perform this function. (4)

Table 1. Nerve conduction studies (a)

Motor nerves           DL    F-wave     CV     Amplitude

Peroneal             4.5 ms  62.2 m/s  40 m/s    1 mV
Tibial               4.3 ms  62.7 m/s  40 m/s    3.2 mV
Median               4.3 ms  31.9 m/s  52 m/s    2.6 mV
Ulnar                3.4 ms  32.5 m/s  45 m/s    1.6 mV

Sensory Nerves
Sural antidromic   unobtainable                  0
Median antidromic    3.7 ms            42 m/s   10 [micro]V
Ulnar antidromic     3.2 ms            42 m/s    9 [micro]V

(a) DL, distal latency; CV, conduction velocity; mV, millivolts;
[micro]V, microvolts.

Table 2. Autoantibody studies (GSC ELISA IgM ELISA titer) (a)

Date                       Level/findings

March 10, 1997    69,000 GSC-specific (GALOP positive)
August 26, 1997  603,750 polyreactive
August 25, 1998  453,750 polyreactive
October 1, 2002   77,250 GSC-specific (GALOP positive)

Acknowledgments

The assistance of Julie Ansell and Virendrakumar Desai, PhD, in preparation of the manuscript is appreciated.

Accepted December 8, 2003.

Copyright [c] 2004 by The Southern Medical Association 0038-4348/04/9704-0410

Please see Alireza Minagar's editorial on page 333 of this issue.

References

1. Pestronk A, Choksi R, Bieser K, et al. Treatable gait disorders and polyneuropathy associated with high titer serum IgM binding to antigens that copurify with myelin associated glycoprotein. Muscle and Nerve, 1994;17:1293-1300.

2. Pestronk A, Choksi R, Bieser K, et al. GALOP syndrome: a treatable autoimmune gait disorder with late-age onset. Ann Neurol 1993;34:268-269.

3. Pestronk A. Chronic immune polyneuropathies and serum autoantibodies, in Rolak LA and Harati Y: Neuroimmunology for the clinician. Boston, Butterworth-Heinemann, 1997, pp 237-251.

4. Dalakas MC. Mechanism of action of intravenous immunoglobulin and therapeutic considerations in the treatment of autoimmune neurologic diseases. Neurology 1998;51(6 suppl 5):S2-S8.

RELATED ARTICLE: Key Points

* GALOP syndrome is a rare, insidious gait disorder caused by a peripheral sensorimotor neuropathy in elderly patients.

* An IgM monoclonal gammopathy is a characteristic finding.

* There are high titers of serum IgM binding to a central nervous system antigen.

* Immunomodulating treatment is usually effective in alleviating the neurologic deficits.

Jack N. Alpert, MD

From the Department of Neurology, Saint Luke's Episcopal Hospital, Houston, TX.

Reprint requests to Jack N. Alpert, MD, Chief, Department of Neurology, Saint Luke's Episcopal Hospital, Houston, TX 77030.