Ondine's Curse in Frontotemporal Dementia with Parkinsonism Linked to Chromosome 17 Caused by MAPT Variants

Abstract

Background: "Ondine's curse" or central hypoventilation, induces an apparently spontaneous failure of automatic respiratory drive, henceforth necessitating a conscious effort to breathe and sleep induced hypoventilation. It is typically seen in congenital central hypoventilation syndrome, but may be acquired.

Objectives: To highlight Ondine's curse as part of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) secondary to microtubule associated protein tau (MAPT) variants.

Methods: We describe the clinical and neuropathological findings in two patients with fatal Ondine's curse associated with FTDP-17 and secondary to MAPT variants (FTDP-17t). We discuss neuroanatomical correlates. We review two prior reports of central hypoventilation associated with MAPT variants suggesting that Ondine's curse occurs uncommonly in FTDP-17t.

Results: Despite variants affecting different regions of MAPT and a degree of heterogeneity in pathological findings, the patients reviewed all experienced central hypoventilation during their disease course.

Conclusion: Tauopathy should be considered in patients with adult-onset Ondine's curse.

Keywords: Ondine's curse; central hypoventilation; frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17); frontotemporal lobar degeneration (FTLD); microtubule associated protein tau (MAPT).

FIG. 1

Neuroimaging of patient 1 over course of FTDP17t illness. (A) MRI brain without significant lobar atrophy, performed within the first year of symptom onset. (B) Two representative cuts from patient 1's Dopamine transporter imaging (¹²³IFT‐CIT‐DAT), performed within her first year of symptoms, demonstrating moderate to severe reduction in the striatum bilaterally. Right caudate specific ratio 0.91, left caudate specific ratio 1.23; right putamen specific ration 0.45, left putamen specific ratio 0.49 (values < 2.0 considered abnormal). (C) F18 Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) scan of brain, 2 years after first symptoms, revealed symmetrical, bilateral anterior temporal cortical metabolism in the low normal range. Basal ganglia tracer uptake was in the normal range with caudate nucleus uptake low normal bilaterally. Frontal cortical metabolic activity was normal.

FIG. 2

Neuropathological findings from patient 1. (A) Periaqueductal gray matter (PAG) (× 20 magnifications). Blue arrows indicate reactive astrocytes. Yellow arrows indicate residual neurons. (B) Reactive gliosis in the PAG (glial fibrillary acid protein immunohistochemistry; × 10 magnifications). (C) Substantia Nigra (× 20 magnifications) demonstrating significant neuronal loss. Blue arrows indicate reactive astrocytes. Yellow arrow indicates a residual pigmented neuron. Red arrow indicated pigment incontinence. (D) PAG (× 40 magnifications) 4 repeat tau immunohistochemistry. The red arrow indicates a globose neurofibrillary tangle. The yellow arrow indicates neuropil threads. Blue arrow indicates a coiled glial cytoplasmic inclusion.