An adolescent with Wolfram syndrome and central sleep apnea

Abstract

Wolfram syndrome is a rare autosomal recessive disorder affecting approximately 1 in 500,000 individuals. The disorder is most commonly caused by mutations in the WFS1 gene, which encodes an endoplasmic reticulum protein, wolframin, which is thought to protect against endoplasmic reticulum stress-related apoptosis. The major clinical findings of Wolfram syndrome are diabetes mellitus and optic atrophy, both of which usually appear before 16 years of age. Common additional findings include sensorineural hearing impairment, central diabetes insipidus, nonautoimmune hypothyroidism, delayed puberty, neurogenic bladder, cerebellar ataxia, and psychiatric disorders. Central sleep apnea is an uncommon but serious feature of Wolfram syndrome. However, the clinical details of this manifestation have not been documented. Herein, we report an adolescent with recently diagnosed Wolfram syndrome who demonstrated severe central sleep apnea on polysomnography testing.

Citation:

Harris JC, Kenkare JD, Schramm CM. An adolescent with Wolfram syndrome and central sleep apnea. J Clin Sleep Med. 2024;20(7):1205–1208.

REPORT OF CASE

A 14-year-old Asian female with a history of type 1 diabetes, optic atrophy, iron deficiency anemia, and depression was admitted to the nephrology service for obstructive uropathy causing severe hydronephrosis and acute kidney injury (blood urea nitrogen 50 mg/dl and creatinine 4.2 mg/dl), as well as secondary hypocalcemia, hyperparathyroidism, and diabetes insipidus. Routine admission viral testing was positive for influenza A, and although she did not report respiratory symptoms other than an infrequent cough she was treated with oseltamavir. Electrolyte derangements were corrected with replacement, low-dose desmopressin was started to target nephrogenic diabetes insipidus, and postobstructive uropathy was alleviated with catheter diuresis. Her creatinine down-trended to 1.4 to 1.6 mg/dl and resulted in an estimated glomerular filtration rate of 39–41 ml⋅min⁻¹⋅1.73 m⁻² (reference ≥ 60). She was found to have a component of central diabetes insipidus with a response to DDAVP during a water deprivation test but also an appropriate copeptin level consistent with a distal tubular defect from chronic kidney disease/postobstruction. Thyroid function (thyroid-stimulating hormone and free thyroxine) levels were normal. This investigation also demonstrated high-frequency hearing impairments. These clinical findings suggested the possibility of Wolfram syndrome (WS). Genetic analysis revealed the homozygous presence of a variant in the WFS1 gene [c.397 G>A, p.(Ala133Thr)], which has been identified in several individuals heterozygous for another variant in the WFS1 gene and with symptoms of a WFS1-related disorder.¹ The cranial magnetic resonance imaging (MRI) scan was normal, showing no atrophy or myelination of the sulcation abnormalities.

During her 8-day hospitalization, the patient was noted to have intermittent hypoxemia and apneas, both awake and asleep. Prior to hospitalization, her only sleep-related symptom at home was daytime fatigue. She had a normal chest radiograph and awake capillary blood gas. Her electrocardiogram and echocardiogram results were normal. A chest computed tomography scan showed mildly decreased lung volumes and subtle ground-glass opacities that were attributed to subsegmental atelectasis. Supplemental oxygen was initiated both awake and nocturnally; the awake need was initially attributed to neurodegenerative disorder causing central apneas.

After discharge, she underwent polysomnography testing, initially without supplemental oxygen to achieve a full baseline evaluation. The study was scored using the standard pediatric scoring criteria.² Sleep was characterized by a short latency (9.5 minutes), high efficiency (96.4%), and significant fragmentation (awakening/arousal index of 20.1 events/h). Sleep staging revealed 52.5% stage 1/2 sleep, 10.6% slow-wave sleep, and 36.9% rapid eye movement (REM) sleep. An electrocardiogram showed normal sinus rhythm with an average rate of 83 beats/min and no bradycardia (minimum rate 70 beats/min). There was severe central sleep apnea (CSA) with a central apnea index of 25.2 events/h (Figure 1) and mild obstructive sleep apnea (OSA) with an obstructive apnea-hypopnea index of 4.7 events/h. A “short amount of soft snoring” was reported by the attendant sleep technologist. Sleep-stage dependence was seen in both CSA and OSA parameters, with central apnea index being greater in non-REM sleep and apnea-hypopnea index being greater in REM sleep (Table 1). The central apneas were primarily spontaneous or clustered in 7 episodes of periodic breathing occurring during non-REM sleep (defined by 3 or more recurrent central apneas separated by ≤ 20 seconds of normal breathing and did not show the crescendo–decrescendo respiratory pattern typical of Cheyne–Stokes breathing).³ None of the central apneas in non-REM or REM sleep exceeded 20 seconds in duration (average duration 9.0 seconds; longest 17.5 seconds) or induced bradycardias. Average oxygenation and ventilation were normal during both stages of sleep. Desaturations were frequent but mild, with an oxygen desaturation index of 29.0 events/h but with only 3.1 minutes (0.7% of sleep time) spent at saturations below 90%. Respirations averaged 15.5/min during quiet sleep.

Figure 1. Grouped central apneas on a 5-minute clip from overnight polysomnography.

Table 1.

Comparison of respiratory parameters in rapid eye movement (REM) and non-REM sleep.

	Total Sleep	Non-REM Sleep	REM Sleep
Time (minutes)	447.0	282.0	165.0
Central apneas	188	137	51
Post arousal/sigh (%)	19.1%	20.4%	15.7%
Spontaneous (%)	51.6%	39.4%	84.3%
Periodic breathing (%)	29.3%	28.8%	0.0%
Central apnea index (events/h)	25.2	28.9	18.5
Periodic breathing (minutes)	25.0	25.0	0
Obstructive apneas/hypopneas	0/35	0/14	0/21
Obstructive AHI (events/h)	4.7	3.0	7.6
Average saturation	96.2%	96.2%	96.1%
Nadir saturation	87%	85%	87%
Average ETCO2 (torr)	40.0	40.4	39.3

AHI = apnea-hypopnea index, ETCO₂ = end-tidal CO₂.

The patient was discharged on nasal cannula oxygen; therefore, a subsequent polysomnography compared the efficacy of nasal cannula oxygen and noninvasive ventilation in controlling her central and obstructive apnea. Ventilation was delivered using a ResMed S9 VPAP Tx Lab System via a full-face mask (ResMed, San Diego, California). The first half of the study was performed on bilevel support with spontaneous/timed rate (noninvasive ventilation), and the second half on nasal cannula oxygen (O₂) (275.5 and 204.5 sleep minutes, respectively). O₂ at 1 l/min eliminated the periodic breathing and the CSA, with central apnea indexes of 0.5 and 1.9 events/h in non-REM and in REM sleep, respectively. However, obstructive sleep apnea was largely unchanged (apnea-hypopnea index 3.8 events/h of sleep). The average and nadir saturations were 98.6% and 89%, respectively, and the average transcutaneous CO₂ was 46.2 torr. In comparison, noninvasive ventilation at 13/7 cmH₂O and spontaneous/timed rate 14/min controlled both CSA and OSA (central apnea index 0.0 events/h; apnea-hypopnea index 0.6 events/h), with average and nadir saturations of 98.0% and 95%, and with average transcutaneous CO₂ 44.6 torr. After discussing each treatment option, the patient’s family elected to start noninvasive ventilation.

DISCUSSION

The present report documents an adolescent with Wolfram-like syndrome who was found to have severe CSA based on serendipitously observed sleeping desaturations during a recent hospitalization for obstructive nephropathy due to a neurogenic bladder. CSA was more pronounced in non-REM sleep than in REM sleep and was associated with periodic breathing in non-REM sleep. However, despite its severity, the CSA was not associated with significant gas exchange abnormalities. Mild OSA was also present, which was somewhat worse in REM sleep than in non-REM sleep and was not associated with prominent snoring. Our patient did not have physical examination findings that correlated to these polysomnography findings; she was fit without the obesity that is often seen in WS and she did not have craniofacial abnormalities or adenotonsillar hypertrophy. OSA is frequent in children with WS, found in 4 of 4 patients aged 12 years or younger in one series³; however, CSA in children with WS has not been reported previously.

CSA reflects a heterogeneous group of disorders that can be segregated into 2 general phenotypes: hypercapnic and nonhypercapnic. The hypercapnic group includes patients with congenital and late-onset central hypoventilation syndrome, neurological syndrome, and impaired respiratory mechanics. These patients have blunted hypercapnic ventilator responses and their awake partial pressure of carbon dioxide (P_aCO₂) is often high. In contrast, nonhypercapnic patients chronically hyperventilate in response to increased hypercapnic ventilatory drives.⁴ By doing so, they maintain P_aCO₂ levels close to the apnea threshold. During sleep, respiratory control becomes solely dependent on autonomic regulation. The incursion of a larger tidal volume in sleep following brief arousal can drive the P_aCO₂ below the apneic threshold and trigger posthyperventilatory central apnea. Desaturation accompanying this apnea can then amplify the postapneic hyperventilatory response, again reducing P_aCO₂ and resulting in a new central apnea.⁵ Repetition of this sequence can lead to a bout of periodic breathing, as observed in our patient. Breaking the hypoxemic contribution to this process likely contributes to the therapeutic efficacy of supplemental oxygen in treating nonhypercapnic patients with CSA,⁶ as was also seen in our patient. We suspected that our patient’s daytime supplemental oxygen requirement was due to P_aCO₂ levels near the apneic threshold and preventing desaturations by using nocturnal supplemental oxygen inhibited the repeat hyperventilatory responses, providing her better reserves to wean off awake oxygen.

CSA has also been reported in patients with WS. In Barrett’s series,⁷ presented before molecular confirmation of the diagnosis was possible, CSA occurred in 5 of 45 patients. Their age, clinical symptoms, and other polysomnographic findings were not documented. One of the 5 patients had “central respiratory failure,” presumably with hypercapnia; the ventilatory status of the other 4 patients was not stated. Cranial MRI scans of the 5 patients showed severe brainstem atrophy. Neurologic abnormalities were present in 62% of the patients, with a mean age of 30 years and an age range of 5–44 years.⁷ Neurological findings are progressive in WS, typically becoming symptomatic by the fourth decade of life, but with presymptomatic onset between the first and second decades of life.⁷ Cranial MRI changes can also be seen in adolescence⁸; however, our patient’s MRI findings were normal.

In the absence of MRI-detectable abnormalities, our patient’s CSA is presumably due to neurodegenerative abnormalities affecting respiratory control centers in her brainstem, potentially heightening her responsiveness to CO₂ before later blunted responsiveness and hypoventilation may occur with progressive involvement. Enhanced chemosensitivity has also been reported in adults with end-stage renal disease,⁹ in whom CSA has been linked to pulmonary congestion.¹⁰ Although our patient had some renal impairment related to obstructive uropathy, she was not in a state of renal failure or volume overload.

In summary, we report the case of a 14-year-old girl with Wolfram-like syndrome who was found to have significant CSA associated with periodic breathing but no hypercapnia, as well as mild OSA. Sleep fragmentation due to CSA may have contributed to daytime fatigue, which is the only sleep-related symptom. We present this case to contribute to the knowledge of respiratory control abnormalities in this rare disorder and with the hope that control of her CSA with noninvasive ventilation will improve her sleep and thus her daytime well-being. Better understanding of central apnea characteristics in WS may add to our future understanding of respiratory control during sleep due to the disorder’s rarity.

DISCLOSURE STATEMENT

The authors report no conflicts of interest.

ABBREVIATIONS

CSA

central sleep apnea

MRI

magnetic resonance imaging

OSA

obstructive sleep apnea

REM

rapid eye movement

WS

Wolfram syndrome