INTRODUCTION

Antibodies to glutamic acid decarboxylase (GAD) have been associated with several neurological syndromes, including stiff- person syndrome, cerebellar ataxia and epilepsy. These antibodies were first described in 1988, but several controversies about GAD autoimmunity still remain. No criteria exist to establish when a neurological syndrome is pathogenically linked to GAD antibodies, often leading to the assumption that any syndrome in which these antibodies are present is immune mediated, sometimes resulting in misdiagnosis and unnecessary treatment. Dalamau et al¹ have described recommendations for assessing the association between a neurological syndrome and the presence of GAD antibodies, and critically review the evidence on the pathogenicity of GAD antibodies.

Although the typical age of onset for Huntington’s disease (HD) is in the fourth decade, between 4.4–11.5% of individuals with HD have a late onset (over 60 years of age). Diagnosis of Late onset HD (LoHD) can be missed, due to the perceived low likelihood of HD in the over 60 age group.

We describe a 65-year-old woman with chorea who has associated elevated serum anti-GAD antibodies who was eventually diagnosed with Huntington’s disease.

CASE

A 65-year-old, right-handed Caucasian woman was referred to our Movement Disorder Clinic for the gradual onset and progression of abnormal movements and falls over a 3 year period. These were now affecting her daily living activities. She attributed her falls to the abnormal movements and impairment of balance. She reported an unintentional weight loss of 15 lbs over the last year, despite normal appetite. She denied dysphagia, cognitive impairment, urinary or bowel symptoms, or hallucinations. She denied the use of antidopaminergic medications and was not on hormone replacement therapy. There was no history of diabetes, systemic lupus erythematosus or hypercoagulability. Family history included a diagnosis of schizophrenia in her son. She otherwise denied a family history of neurological, autoimmune or rheumatological disorders.

On examination, she was oriented to time, place and person. She had generalized non-rhythmic, non-stereotypical, flowing movements involving all body regions (suggestive of generalized chorea). Motor impersistence was noted in the tongue and hands with milkmaid’s grip. Gait was broad based with truncal lean to the right. Coordination in the extremities was intact. Plantar reflexes were flexor bilaterally. (View the Video).

Initial work up for blood glucose, thyroid stimulating hormone, parathyroid stimulating hormone, ionized calcium, lupus anticoagulant, antinuclear antibody, erythrocyte sedimentation rate, comprehensive metabolic panel and creatinine kinase were normal. HIV and syphilis screening were negative. Vitamin B12 was low at 166 pg/ml (normal: 280-900 pg/ml). Despite Vitamin B12 injections, her symptoms did not improve. MRI Brain with and without contrast was normal.

Tier 2 work up including labs for lactate, pyruvate, celiac antibodies (anti-gliadin, anti-tissue transglutaminase), anti-SS A, anti-SS B, and serum paraneoplastic panel were normal. Serum anti-GAD was elevated at 20 IU/ml (normal <0.2 IU/ml). Cerebrospinal fluid (CSF) studies including anti-GAD and paraneoplastic panel were normal. Oncologic workup was unremarkable, including a PET scan.

She received IVIG for 5 days with mild transient reduction in her abnormal movements. She was also started on Risperidone 1mg/day for symptomatic control of chorea without improvement.

Given the low elevation of serum anti-GAD levels, poor response to intravenous immunoglobulin (IVIG), normal CSF anti-GAD levels and minimal available literature on anti-GAD induced chorea, we advised Huntingtin gene testing which demonstrated 40 CAG repeats and confirmed a diagnosis of Huntington’s disease.

She was started on Deutetrabenazine 21mg b.i.d. with improvement in symptoms, but was not compliant due to intolerable side effects (depression). Aripiprazole subsequently improved her symptoms.

DISCUSSION

High concentrations of GAD65 antibodies are associated with a limited set of clinically distinct phenotypes, namely: stiff person syndrome disorder, cerebellar ataxia, epilepsy and limbic encephalitis, suggesting some syndrome specificity.^2,3,4,5 Our patient had a clinical phenotype only rarely described in the literature through case reports. O’Toole et al ⁶ described 3 patients with paraneoplastic anti-GAD chorea, and Venker et al ⁷ also described a complex paraneoplastic anti-GAD movement disorder with dystonic movements of the platysma and submandibular muscles, athetotic movements of the upper and lower limbs, body swaying, asymmetric myoclonic jerks, and an ataxia of the trunk and extremities.

In GAD antibody-associated clinically distinctive phenotypes, the serum levels of GAD65 antibodies are greater than 100-fold higher than those in patients with T1DM. Low levels of GAD65 antibodies can be present in up to 8% of healthy individuals and in patients with diverse neurological disorders. ^8,9,10 In the experience of Dalamau et al,¹ positive GAD immunoreactivity in rat brain sections detected with immunohistochemistry or a cell-based assay is indicative of levels of GAD65 antibodies ≥1,800 U/ml if determined with two commercial radioimmunoassay kits (CIS Bio International, Gif- sur- Yvette, France, and CentAK anti- GAD65 M, Medipan GMBH, Berlin, Germany). GAD antibodies were first discovered 32 years ago, making it unlikely that a distinct syndrome associated with low titers of GAD antibodies remains unrecognized. Consequently, when levels of GAD antibodies are low, other possible etiologies must be explored. Our patient had a serum anti-GAD level of 20 IU/ml (considered a mild elevation) which should call into question the diagnosis of anti-GAD chorea.

When a patient has a neurological syndrome associated with high serum levels of GAD antibodies, their CSF should be tested for the presence of GAD65 antibodies. Intrathecal synthesis of GAD antibodies provides the strongest evidence that the neurological syndrome is associated with GAD autoimmunity. ^5,11 In our patient, CSF anti-GAD antibody levels were not elevated. At this point, an alternate etiology for the chorea should be sought.

Given that Tier 1 and Tier 2 testing for causes of chorea were negative, despite the absence of a family history of Huntington’s disease, we performed genetic testing which revealed 40 CAG repeats, confirming the diagnosis of Huntington’s disease.

Late onset Huntington’s disease (LoHD) is defined as symptom onset after age 60. Between 4.4–11.5% of individuals with HD have an age of onset over 60.^12,13,14 In studies where the age of onset is ≥60, the mean CAG repeat length was calculated to be 40.9 with an average age of onset of 65.5. Across all studies, 170/180 reported cases of LoHD had a CAG repeat length of ≤44.15 Lipe et al. ¹⁶ reported that approximately 85% of people had chorea at onset. Family history may also be uninformative in LoHD. Lipe et al. 16 reported that only 32.4% of people with LoHD had a family history.

CONCLUSION

Present data suggest that neurological disorders in which serum levels of GAD65 antibodies are low are unlikely to be autoimmune in nature. The diagnosis of a GAD antibody-associated syndrome must be based on the spectrum of symptoms, serum levels of anti-GAD antibodies, and demonstration of intrathecal antibody synthesis.

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