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.

Introduction

“All the things my body once did by itself, it does now only by special order … A single moment of inattention and I forget to breathe” laments the cursed, and unfaithful, husband of water sprite Ondine in Jean Giradoux's play by the same name.¹ So is derived “Ondine's curse” indicating an apparently spontaneous failure of automatic respiratory drive. An affected individual must make a conscious effort to breathe and suffers hypoventilation during sleep. It is typically seen in congenital central hypoventilation syndrome, but may be acquired. Based on two patients with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17) described here, and two cases by others,², ³ we propose Ondine's curse is an uncommon part of the phenotype associated with microtubule association protein tau (MAPT) variants.

FTDP‐17 is clinically, pathologically and genetically diverse. Early descriptions of FTDP‐17 described autosomal dominant transmission with executive dysfunction, language impairment, behavioral change, parkinsonism and late amyotrophy. Our understanding of the genetic variants underlying FTDP‐17 has evolved,⁴ and variants in MAPT on chromosome 17q21.31 are known to cause most forms of FTDP‐17 (FTDP‐17t).⁵ More than 50 disease‐causing MAPT variants have been described⁴, ⁶ giving rise to diverse phenotypes. Together, C9ORF72, progranulin and MAPT variants account for >80% of hereditary frontotemporal lobar degeneration (FTLD), with MAPT variants responsible for almost all hereditary tau‐positive FTLD (FTLD‐tau).⁷

We present the clinical‐radiological‐pathological findings in two patients with FTDP‐17t who developed fatal Ondine's curse (central hypoventilation syndrome).

Patient 1

A 36‐year‐old Irish woman, with a family history of frontotemporal dementia, was first seen as part of a research study when asymptomatic (subject IV 2;(8)). Genetic testing confirmed a then novel familial intronic variant c.915 + 15A > C at the exon 10/intron 10 boundary of MAPT.⁸

At onset (age 37 years) the patient noticed a subtle deterioration in her walking, mild arm tremor and she recalled falling off her bicycle without explanation. Initially, signs were subtle but clinical examinations over 4 years revealed eyelid opening apraxia with sensory trick, parkinsonism with slow, shuffling gait, reduced right arm swing, postural instability, mild resting upper limb tremor, mild rigidity and bradykinesia. She had facial impassivity and positive palmomental reflexes. Later, pyramidal signs emerged with generalized spasticity, symmetrically brisk reflexes, Hoffman's signs, and bilateral ankle clonus but with flexor plantars and normal power. She developed a weak cough and sneeze with brisk jaw jerk. Eye movements were normal. Neck movements hinted at cervical dystonia. Her jaw was tremulous when open and distressing oromandibular dystonia caused dental deformities.

In the first 3 years she performed consistently well in all domains of cognitive testing without personality change. She experienced a reactive depression with anxiety following her genetic diagnosis. Over time she developed apathy. Unfortunately, her condition relentlessly deteriorated. Poor saliva control, marked anterocollis, severe oromandibular dystonia that interfered with oral intake, recurrent aspiration pneumoniae and progressive decline in short term memory along with emotional lability, emerged as prominent issues. Imaging performed over the course of her illness is shown (Fig. 1).

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.

Family astutely noted while in hospital that “her carbon dioxide would climb to a certain level, her breathing seemed to stop and oxygen levels plummet.” At onset of an episode, she would become flushed with associated rhinorrhoea and diaphoresis, possibly attributable to carbon dioxide retention. Sleep studies confirmed nocturnal hypercarbia associated with increasingly frequent periods of apnoea. She was diagnosed with central hypoventilation and ultimately required a tracheostomy and prolonged invasive ventilation. Her worsening anterocollis and oromandibular dystonia posed challenges to maintaining ventilation via tracheostomy. Her anterocollis deteriorated and at times her chin covered the tracheostomy, with some response however to botulinum toxin. She remained ventilator‐dependent at home and cared for by her family. She died aged 39 from respiratory infection approximately 35 months after initial presentation.

Patient 2

Our second patient was the proband (III:39) in an Irish‐American family with Disinhibition‐Dementia‐Parkinsonism‐Amyotrophy complex⁹, ¹⁰ (subsequently renamed FTDP‐17) associated with a splice site +14C > T exon10/intron10 boundary variant in MAPT.⁴, ⁹, ¹¹ A 41‐year‐old Irishman complained of a deterioration in walking. Within a year he suffered further decline with generalized stiffness, poor cough, and difficulty swallowing. He attended the Neurological Institute, New York and clinical assessment revealed symmetric bradykinesia, rigidity, rest tremor, postural instability, shuffling gait and masked facies along with positive glabellar tap, snout reflex, palilalia and tachyphemia. Family members had suffered various combinations of parkinsonism and dementia,⁹ suggestive of an autosomal dominant neurodegenerative condition.

Collateral history confirmed insidious personality and behavioral change over the preceding decade. Previously fastidious about his appearance, he began to wear sweat‐pants to dances. He displayed hypersexual behaviors. Later, he became increasingly stubborn and intractable in his thinking. Family reported a decline in memory, a deterioration in writing with difficulty retrieving appropriate letters and his behavior deteriorated further from a childish disinhibition to a withdrawn state with emotional blunting. He developed a sweet tooth.

He avoided sleep and reported breathing was no longer automatic. Electroencephalogram, lumbar puncture and computed tomography of brain were normal. He was diagnosed with central neurogenic hypoventilation on the basis of carbon dioxide (CO₂) retention (particularly related to sleep) with abnormal ventilatory response to CO₂, normal pulmonary function tests and normal phrenic nerve conduction studies. Phrenic nerve stimulation plus intermittent respirator use via tracheostomy, were required to maintain adequate ventilatory support. Disability accrued and he developed dementia. At 45 years he was noted to have fasciculations and EMG confirmed diffuse denervation. He had developed hyperreflexia, bilateral ankle clonus, Hoffman's signs with an absent gag reflex and weak cough. He suffered a prolonged nocturnal cardiorespiratory arrest and remained in a vegetative state on ventilatory support for a further 7 months until his death approximately 5 years after initial presentation to hospital.

Pathological Findings

Neuropathology Patient 1

Macroscopic examination demonstrated no significant fronto‐temporal atrophy. The basal ganglia and thalamus appeared normal, however the substantia nigra was depigmented. Histologically, there was no cortical spongiosis nor significant neuronal loss or gliosis within the cortex, basal ganglia, amygdala, or thalamus. Immunohistochemical staining with phospho‐Tau demonstrated frequent neurofibrillary tangles, neuropil threads and glial inclusions within the basal ganglia and lateral geniculate nucleus, with similar findings in the medial temporal lobe (Fig. 2). Alpha‐synuclein and Beta‐A4 were negative.

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.

The periaqueductal gray matter (PAG) and substantia nigra showed significant neuronal loss and gliosis, the latter with associated pigment incontinence. Several residual neurons showed distended cytoplasm with refractile basophilic inclusions.

Extensive 4 repeat (4R) predominant Tau‐pathology was seen in the periaqueductal gray matter, midline raphe nuclei, substantia nigra, pontine and medullary tegmentum and more lateral medulla including the nucleus of the solitary tract as well as the reticular formation. Alpha‐synuclein and Beta‐A4 were negative. The spinal cord demonstrated large numbers of neuropil threads and neurofibrillary tangles throughout the spinal cord gray matter, particularly within the anterior horns. Staining for TDP‐43 was negative.

Neuropathology Patient 2 (Reported in Part Previously)

Post‐mortem examination was performed months after a cardiopulmonary arrest and prolonged ventilation due to a vegetative state, thus superimposed anoxic effects were seen.¹⁰ The brain revealed mild to moderate atrophy of both temporal poles. The basal ganglia were symmetrically decreased in size, with cavitation and light discoloration of the medial aspect of both substantia nigra.

Histologically, there were varying degrees of neuronal loss and gliosis within all lobes, most marked in the superior frontal gyri. The basal ganglia, substantia nigra and cerebellum were also affected Other brainstem structures appeared intact. Lewy bodies were not seen.

The spinal cord showed severe degeneration of the lateral funiculi, with moderate loss of lumbar anterior horn cells.

The diffuse cortical changes without focal distribution argued against all changes being from the anoxic episode. Post‐mortem findings favored a diffuse, degenerative gray matter disease, with secondary changes in the white matter. The spinal cord changes were deemed largely secondary (descending tracts) but some lumbar anterior horn nerve degeneration was probably part of the disease.

Discussion

There is phenotypic and pathologic heterogeneity associated with MAPT variants.¹⁰, ¹² The clinical syndrome spans behavioral, psychiatric, cognitive, and motor deficits. We first described central hypoventilation in the DDPAC proband (Patient 2) due to splice site c.915 + 14C > T exon10/intron10 boundary variant in MAPT.⁹, ¹⁰, ¹¹ Omoto and colleagues² subsequently described a sibling pair also with the intronic 10 + 14 splice site variant in MAPT; their syndrome was one of psychiatric disturbance, parkinsonism, pyramidal signs and central hypoventilation in a sibling. Nicholl et al³ detail a sibling pair born of consanguineous parents with a homozygous, recessive transition of C1291T of the MAPT mRNA within exon 12 (S352L). One sibling presented following a seizure and respiratory arrest. Her brother developed stridor and recurrent central apnoea when awake and asleep, impaired ocular saccades, and parkinsonism. Neither Omoto nor Nicholl commented upon our earlier report of central hypoventilation in the DDPAC pedigree.⁹

Ondine's curse, or failure of central respiratory drive, occurs in a number of conditions including the well‐documented congenital central hypoventilation syndrome and in acquired cases secondary to structural brainstem insults and neurodegenerative disorders, including multiple systems atrophy, the rare Perry syndrome,¹³ a case report of progressive supranuclear palsy¹⁴ and anti‐IgLON5‐associated tauopathy.¹⁵ Our two patients suggest that central hypoventilation is part of the phenotypic spectrum of MAPT variants, specifically FTDP‐17t, and suggest that central respiratory centres are vulnerable to toxic tau aggregation or dysfunction.

The bilateral pontomedullary respiratory network is responsible for central neural control of respiration and is influenced by afferents from lung mechanoreceptors and peripheral chemoreceptors, transmitted by the nucleus of the solitary tract, as well as central chemoreceptors thought to be located in the ventral medulla (retrotrapezoid nucleus).¹⁶ The pre‐Botzinger nucleus of the ventral respiratory column is an important collection of neurons for respiratory rhythm generation. Lesions along this complex network, may lead to impaired chemosensitivity and thus impaired central responses to hypercapnic and acidic states, causing central hypoventilation. We found significant medullary tau pathology in patient 1 and the medullary tegmentum was also implicated in the kindred described by Nicholl et al.³ Moreover, the pre‐Botzinger complex was affected by 4R tau deposition in the Japanese case.² Patient 1 also had tau pathology, neuronal loss and astrocytic gliosis of periaqueductal gray matter (PAG), an area thought to act as a relay point in chemoreception with connections to the ventral respiratory group, the rostral ventrolateral medulla and hypothalamus.¹⁷ Unlike patients with congenital central hypoventilation syndrome and Perry syndrome we did not observe more widespread autonomic dysfunction.

Despite the common phenotypic link of central hypoventilation, these cases stem from different variants in MAPT and there is neuropathological variation. Neuronal and glial 4R tau deposits predominated in patient 1 and in the patient described by Omoto.² This is typical for gene variants affecting exon/intron 10.⁶ In contrast, Nicholl et al³ reported central hypoventilation in a patient with an exon 12 variant in MAPT, with predominance of 3R tau exhibiting relatively reduced affinity for microtubules and a predisposition to enhanced filament formation.⁶ While we understand the effects of specific MAPT variants on tau isoform ratio, and note the segregation of tau isoforms with specific pathological subtypes, clinical and pathological heterogeneity exist for MAPT variants, even within families carrying the same variant, extending to rates of degeneration and anatomical hierarchical spread.¹⁸, ¹⁹ However, data from imaging and neuropathological studies indicate that the most frequently reported disease trajectory involves preferential early degeneration of entorhinal cortex and amygdala with anterior temporal lobe particularly vulnerable, and later involvement of subcortical, brainstem nuclei and anterior horn cells; mirroring the most commonly reported presentation of behavioral variants followed by later development of parkinsonism and amyotrophy.⁶ This hierarchical spread however is far from universal.⁶, ¹⁰, ¹² We describe individuals with both 4R and 3R tau isoform predominant pathology, who developed central hypoventilation, implying degeneration of a common anatomic network rather than an isoform‐specific molecular process. In our own cases, Ondine's curse manifested at different disease stages. Patient 2 exhibited many of the neuropathological features consistent with advanced disease, however patient 1 had no significant cortical atrophy, absence of frontotemporal cortical spongiosis, and the characteristic neurohistologic features associated with FTDP‐17t were most prominent in basal ganglia (with tau pathology seen but no significant atrophy, neuronal loss or gliosis), inferior hippocampus and brainstem structures rather than diffuse frontotemporal cortical change and basal ganglia atrophy. This suggests differences in regional and cellular vulnerability that predispose to protein aggregation, and at different disease stages. MAPT expression, splicing and genetic regulation has been shown to differ across brain regions.²⁰ It has also been hypothesized that differential MAPT splicing in astrocyte subpopulations may effect disease expression²¹—selective vulnerability of chemosensitive retrotrapezoid nucleus astrocytes could thus be plausible. Cellular variation in posttranslational modification of tau may also play a role in the spatiotemporal distribution of tau pathology.²² Understanding regional and cellular vulnerability is an exciting area involving new molecular techniques (eg single nucleus RNA sequencing) and evolving knowledge in selectively neuronal vulnerabity in neurodegeneration,²³, ²⁴, ²⁵ certainly warrants further investigation in MAPT‐associated disorders with the potential to greatly enhance our understanding of sporadic and heritable FTD.¹⁹

The development of central hypoventilation was ultimately life‐shortening with survival of approximately 2.5 and 5 years from presentation for patients 1 and 2. “Unfortunately, post‐mortem examination in patient 2 was complicated by hypoxic‐ischaemic changes post cardiac arrest and prolonged ventilation. Autopsy also pre‐dated the availability of tau immunohistochemical staining and we currently cannot access the specimens, thus, although unlikely given the identified familial MAPT variant and similar autopsy findings of amyotrophy in an affected family member,¹⁰ co‐existent TDP‐43 pathology cannot be excluded. Tissue from patient 2 was subsequently included, along with specimens from family members, in a publication on the neuropathological findings identified in his pedigree, which reported the general findings of “ballooned neurons stained positive for phosphorylated filaments and variably positive for ubiquitin and tau.”¹⁰

We describe Ondine's curse therefore, occurring in two patients with FTDP‐17t but with varying degree and distribution of neuropathological changes. Despite variants affecting different regions of MAPT and a degree of heterogeneity in pathological findings, the patients discussed all experienced central hypoventilation during their disease course. This suggests Ondine's curse is an uncommon part of the spectrum of disease caused by MAPT variants. Neurologists should be mindful of the potential for respiratory dysfunction as a complication of neurodegenerative disease and of the mechanisms and localisation of such dysfunction in order to anticipate care needs.

Here we describe two patients, from different kindreds, who suffered the ultimately life‐shortening complication of central hypoventilation in association with FTDP‐17 due to MAPT variants, thus expanding the phenotype. We recommend tauopathy to be included in the differential diagnosis of adult patients with central hypoventilation.

Author Roles

(1) Research Project: A Conception, B Organization; (2) Manuscript: A Writing of first draft, B Review and Critique

L.W.: 1A, 1B, 2A

D.O.: 1B, 2B

C.F.: 2B

B.M.: 1B, 2B

A.M.: 1B, 2B

L.R.: 1B

R.M.: 2B

R.P.: 2B

S.F.: 1A, 2B

A.B.: 1B, 2B

T.L.: 1A, 2B

Disclosures

Ethical Compliance Statement

The authors confirm that the approval of an institutional review board was not required for this work. Informed consent was obtained from the patients reported above for publication. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest

The authors declare that there are no funding sources or conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months

LW, DO, CF, BM, AM, LR, RM, RP and AB have no financial disclosure for the past 12 months. SF has received honoraria from Springer publishers as co‐editor and royalty from Elsevier publishers as book co‐author. TL has received research grant funding from Michael J. Fox Foundation and Irish Health Research Board unrelated to this work.