Pearls & Oy-sters: ATX-FGF14 Mimicking Autoimmune Pathology

Case 1

A 68-year-old man was referred to the autoimmune neurology clinic for evaluation of 8 months of episodic dysarthria, dizziness, and imbalance. Episodes occurred every other day, with each episode lasting 30 minutes. He had no preceding febrile illness or reported stressors. The symptoms progressed, and at the time of consultation, the patient experienced several attacks daily, each lasting a few hours. He also reported 10 years of progressive difficulty writing with his dominant left hand. Neurologic examination revealed mild dysarthria, downbeat nystagmus, esotropia, and dysmetria. Strength, sensation, and reflexes were normal. Serologic testing 8 months before the referral showed elevated antidouble stranded DNA antibody (236 IU/mL; normal range: <100 IU/mL), antithyroid peroxidase (TPO) antibody (84.3 IU/mL, normal range 0–4 IU/mL), and thyroglobulin antibody levels (4.6 IU/mL, normal range 0–3.9 IU/mL). The patient had no symptoms of thyroid disease. Other laboratory screening was unremarkable, including thyroid-stimulating hormone, autoimmune (Sjogren's syndrome [SS] A and SSB antibody), infectious (HIV, varicella-zoster virus [VZV], herpes simplex virus [HSV], and rapid plasma reagin), metabolic/toxic (copper, vitamin B1, vitamin B12, and vitamin E), and paraneoplastic evaluation (NMDA receptor, leucine-rich glioma inactivated 1, amphiphysin, contactin-associated protein-like 2, CV2/collapsin response mediator protein 5, Hu, Ri, Yo, Ma1, Ma-2/Ta, Zic4, and glutamic acid decarboxylase 65 antibody in both serum and CSF). CSF analysis showed normal cell count, protein, glucose, and immunoglobulin (Ig) G index. CSF oligoclonal band (OCB) analysis detected 2 unique IgG bands. Routine EEG and contrast MRI of the brain were normal. Whole-body PET/CT scan was normal. He was treated empirically for an autoimmune neurologic condition with high-dose intravenous methylprednisolone therapy for 3 days, followed by prednisone 60 mg, which was slowly tapered to 15 mg at the time of referral. He had also received intravenous immunoglobulin (IVIg) therapy for 2 g/kg over 5 days, 2 months before the referral. During the IVIg, he developed venous thromboembolism and was started on warfarin. No substantial improvement was observed with immunotherapies. At the time of consultation, the patient reported no significant family history.

Additional laboratory evaluation after the referral revealed antinuclear antibody titer of 1:40 (both speckled and nucleolar patterns) and elevated beta-2 glycoprotein-1 (B2GP1) IgM of 24 (normal range: 0–20 SMU) and anticardiolipin IgM of 17 (normal range: 0–12 MPL). B2GP1 IgG, anticardiolipin IgG, and lupus anticoagulant were negative. Repeat MRI demonstrated mild but age-appropriate cerebellar volume loss (Figure 1, A and B). A diagnosis of antiphospholipid syndrome (APS) was considered, but the repeat APS work-up after 12 weeks was negative. At the follow-up, his episodic symptoms continued to increase in duration, lasting 30 minutes to 6 hours. The spells improved in both duration and frequency on acetazolamide. Three years later, he also noted weakness and shaking in his legs during these events. Four years after the first clinic visit, while revisiting family history, the patient noted that his niece (case 2) had recently developed neurologic symptoms.

Case 2

A 49-year-old woman with a history of insulin-dependent diabetes and hypothyroidism presented to the autoimmune neurology clinic for evaluation of progressive ataxia and tremor. The patient reported 3 years of action tremors and word-finding difficulties. MRI of the brain obtained at that time was unremarkable (Figure 1, C and D). Six months after symptom onset, she started experiencing episodes of body shaking lasting for minutes without loss of consciousness or confusion. She subsequently developed progressive gait instability, vertigo, and oscillopsia. Neurologic examination revealed downbeat nystagmus, esotropia, hypermetric saccades, dysmetria in the bilateral upper extremities, impaired rapid alternating movements, and a wide base gait. Strength, sensation, and reflexes were intact.

Work-up at the time of symptom onset was negative for infectious, metabolic/toxic, and autoimmune etiology, except for elevated anti-TPO antibody at 226.3 IU/mL. CSF analysis showed pleocytosis of 164 (99% lymphocytes). CSF glucose, protein, IgG index, and OCB were unremarkable. CSF cryptococcus antigen, VZV, HSV, and leukemia/lymphoma phenotyping were negative. Autoimmune/paraneoplastic encephalopathy-associated antibodies in CSF were negative, similar to case 1. Whole-body CT was unremarkable. Thirty months before her visit, the patient was diagnosed with presumed seronegative autoimmune encephalitis and was initiated on 40 mg of prednisone, which was titrated off after 6 weeks. She was also started on rituximab 24 months before consultation (1 g IV on day 1, day 14, 6 months, and 1 year). One year before the visit, she was initiated on IVIg 0.4 g/kg every 4 weeks. She demonstrated no improvement with immunotherapies. She also started acetazolamide twice a day, which helped with spells of body shaking. On initial evaluation at the autoimmune neurology clinic, she was not on immunotherapy.

On detailed questioning, the patient reported that her father, who died at age 74 years due to prostate cancer, had chronic ataxia and dysarthria and that her paternal grandmother frequently fell owing to imbalance. Repeat CSF analysis was unremarkable. Given the now substantial family history of neurologic symptoms, genetic counseling and subsequent genetic testing were undertaken. Whole genome sequencing with genome-wide structural variant analysis at Variantyx¹ revealed a heterozygous 235.50-kb deletion in the 13q33.1 region intersecting the fibroblast growth factor 14 (FGF14) gene (GRCh38/hg38 13q33.1 chr13:101776915-102012410×1). The patient was diagnosed with ATX-FGF14. Her paternal uncle’s (case 1) genetic testing was performed at Invitae,² where FGF14 sequencing and deletion/duplication analysis also revealed deletion of FGF14 exon 1–3. Although this sequencing was unable to determine the breakpoints of this deletion, both identified deletions encompassed exons 1–3 of the FGF14 gene. A pedigree chart (Figure 2) shows dysarthria, nystagmus, tremor, gait instability, and cognitive disorder across generations, suggesting a neurogenetic etiology.

Figure 2 Four-Generation Pedigree Chart

Six family members exhibited neurologic symptoms. Cases 1 and 2 are indicated by arrows.