Vici syndrome is a rare congenital multisystem disorder due to recessive mutations in the key autophagy regulator EPG5. Vici syndrome is characterized by agenesis of the corpus callosum, hypopigmentation, immunodeficiency, cataracts, and cardiomyopathy, with variable additional multisystem involvement. Here we report on a 5-year-old girl who presented with global developmental delay, seizures, callosal agenesis, cataracts, sensorineural hearing loss, hypopigmentation, and immunodeficiency with a low CD4 count and recurrent infections. EPG5 sequencing (prompted by suggestive clinical features) revealed a homozygous missense mutation, c.1007A>G (p.Gln336Arg). The patient was referred to our center for evaluation of nocturnal apnea. Overnight polysomnography showed severe central sleep apnea (CSA) with an overall apnea-hypopnea index of 100.5 events per hour of sleep (central apnea index of 97.5, mixed apnea index of 2, and obstructive hypopnea index of 1). The patient responded to bilevel positive airway pressure therapy with a backup rate with normalization of the apnea-hypopnea index and maintenance of oxygen saturation >90%. Despite successful control of the severe CSA, the patient was eventually started on nocturnal oxygen therapy due to excessive upper airway secretions and the high risk of possible aspiration with positive airway pressure therapy. This is the first report of EPG5-related Vici syndrome associated with CSA. We discuss the polysomnographic findings in our patient in the context of a brief literature review of the reported sleep abnormalities in Vici syndrome.
- CSA —
- central sleep apnea
- OSA —
- obstructive sleep apnea
- REM —
- rapid eye movement
- TST —
- total sleep time
Vici syndrome (Online Mendelian Inheritance in Man 242840) is a rare congenital syndrome with extensive multisystem involvement due to recessive mutations in EPG5 on chromosome 18q12.3, encoding the key autophagy regulator ectopic P-granules protein 5 (EPG5).1 Vici syndrome was originally described in 1988 by Dionisi-Vici and co-workers in 2 brothers, but with <30 cases reported to date, the phenotypical spectrum is still evolving.1–3
A 5-year-old girl diagnosed with Vici syndrome presented to our sleep center for evaluation of frequent short episodes of witnessed non–life-threatening nocturnal apnea. She was born via cesarean delivery at 37 weeks’ gestation to consanguineous first-cousin parents. Delivery was complicated by meconium aspiration. Her birth weight was 2.27 kg (less than the third percentile), length was 49.5 cm (57th percentile), and occipital frontal circumference was 34.3 cm (62nd percentile). She had a history of global developmental delay, seizures, bilateral cataracts, sensorineural hearing loss, biopsy-proven myopathy, and immunodeficiency with a low CD4 count complicated by recurrent respiratory infections. She also had a transient dilated cardiomyopathy during an acute illness at the age of 1 year. Her mother had a history of obstructive sleep apnea (OSA) and 2 first-trimester spontaneous abortions; an older sibling was healthy.
Previous investigations included analysis of the oculocutaneous albinism type 2 (OCA2) gene, revealing no mutations, and an examination of peripheral blood smears, requested under the suspicion of Chediak-Higashi syndrome but not showing any of the giant neutrophil granules suggestive of the latter. Brain MRI showed findings consistent with Vici syndrome, including agenesis of corpus callosum, colpocephaly, and atrophy of the optic nerves, pons, medulla, cerebellum, and cerebral hemispheres (Fig 1). Further genetic testing prompted by suggestive clinical features revealed homozygosity for the EPG5 c.1007A>G (p.Gln336Arg) missense mutation, previously reported by Cullup et al.1 Key clinical and genetic features from our patient have been previously reported.1
On examination at presentation to our center, the patient’s height was 104 cm (22nd percentile) and weight was 15.5 kg (13th percentile). She was unable to speak. There was generalized hypotonia and the patient could not walk or sit without support. She had evidence of generalized hypopigmentation of the eyes, hair, and skin (Fig 2) and had a gastrostomy tube in place because of feeding difficulties. Oral examination revealed a normal tongue; Mallampati class IV, grade 2 tonsils; and a high, arched palate with no micrognathia or maxillary retrusion.
The patient underwent an overnight diagnostic polysomnography (Table 1) with the use of a Respironics Alice system (Pittsburgh, PA). The polysomnography and sleep-associated events were scored according to American Academy of Sleep Medicine scoring guidelines.4 The patient had a total of 769 respiratory events, including 746 central apneas, 15 mixed apneas, and 8 hypopneas with an overall apnea-hypopnea index of 100.5 events per hour of sleep (central apnea index of 97.5, mixed apnea index of 2, and obstructive hypopnea index of 1) (Fig 3).
The minimum oximetry value was 54%, and the total time spent with oxygen saturation <89% was 111.7 minutes. Transcutaneous carbon dioxide monitoring showed a mean Paco2 of 46 mm Hg. Paco2 was elevated above 50 mm Hg for almost 20% of total sleep time (TST). The patient was not receiving any narcotics, and her cardiac echocardiography revealed normal cardiac anatomy and function with no evidence of pulmonary hypertension. High-resolution chest computed tomography showed no evidence of interstitial lung disease.
Subsequently, the patient underwent an overnight titration study (Table 1). At bilevel positive airway pressure settings of 14/7 cm H2O in spontaneous/timed mode with a backup rate of 12 breaths per minute, the apnea-hypopnea and arousal indices were normalized and oxygen saturation was maintained at >90%. It was difficult for the patient to use positive airway pressure therapy due to excessive upper airway secretions, despite treatment with glycopyrrolate, and the high risk of aspiration. After extensive discussion with the parents and considering the patient’s overall prognosis, a palliative management approach was chosen, including nocturnal oxygen at 1.5 L/minute to keep her saturation >90%. Unfortunately, our patient died at the age of 6 years as a consequence of recurrent infections. An autopsy was not performed.
Vici syndrome is a rare and severe congenital multisystem disorder with markedly reduced life expectancy. In the largest cohort study in patients with Vici syndrome and with confirmed EPG5 mutations, only half of them were alive at the time of the last follow-up.1 The most common identifiable causes of death were progressive cardiac failure and recurrent infections secondary to the associated combined immunodeficiency.1
Sleep abnormalities in Vici syndrome remain to be elucidated. Actigraphy and polysomnography were performed in 2 siblings with Vici syndrome. The actogram revealed a delay in the circadian rhythm in 1 patient, possibly due to severe visual impairment. The polysomnography in both patients showed impaired phasic rapid eye movement (REM) sleep parameters in the setting of preserved percentage of REM sleep and increased muscle atonia during non-REM sleep. In both patients, brain MRI showed corpus callosum agenesis, mild cerebral atrophy, and opercular hypoplasia but no brain stem lesions.5
In patients with Vici syndrome, the reported facial abnormalities, hypotonia, and laryngomalacia can all predispose to OSA.6 Despite these reported anomalies, only 1 case of Vici syndrome with OSA and mild desaturations was described. The patient’s brain MRI revealed corpus callosum agenesis, pontine, and cerebellar hypoplasia.7
To our knowledge, this is the first case of Vici syndrome featuring CSA. Severe neurologic involvement that included both the pons and medulla in our patient, as evidenced by brain MRI, is a plausible cause in the pathogenesis of the CSA, but the exact mechanism cannot be extrapolated from a single case. In addition to the absence of corpus callosum, additional central nervous system abnormalities were reported in 19 of 27 patients diagnosed with Vici syndrome. These abnormalities included cerebellar and pontine hypoplasia, ventricular dilatation with white matter atrophy, heterotopias, abnormal septum pellucidum, and schizencephaly.1,3 In the absence of sleep studies in most of the patients with Vici syndrome reported, sleep-related breathing disorders including CSA cannot be excluded.
Although the awake respiratory rate was lower than expected for age, our patient maintained awake Paco2 levels <50 mm Hg with no elevation of serum bicarbonate levels. During sleep, there was a further reduction in the respiratory rate with periods of hypercapnia. Although this finding can represent an element of sleep-related hypoventilation, the total duration spent with Paco2 >50 mm Hg was <25% of the TST that is required to score pediatric sleep-related hypoventilation according to American Academy of Sleep Medicine scoring guidelines.4
Another observation was the predominance of stage N3 non-REM sleep. Our patient spent 98.8% and 96.8% of her TST in stage N3 non-REM sleep during the diagnostic and the titration studies, respectively. Subjects with corpus callosum agenesis tend to have more slow-wave sleep, less interhemispheric EEG coherence, and ultradian rhythm disturbances.8 Despite these findings in acallosal subjects, slow-wave sleep predominance was not previously described among the polysomnographic findings in Vici syndrome.5,7
Although our patient was not receiving any REM sleep-suppressant medications, she also did not have any REM sleep during the diagnostic or the titration study. It is plausible that the absence of REM sleep in our patient could have been related to her pontine atrophy, considering that the pons plays an essential role in the generation of REM sleep during which the central nervous system cholinergic activity predominates.9 Absence of REM sleep may suggest an impairment of the central nervous system cholinergic system as well. Although REM sleep percentage was reported to be preserved in 2 siblings with Vici syndrome, both of them did not have evidence of brain stem involvement on brain MRI, in contrast to our patient.5
Pitt-Hopkins syndrome and familial agenesis of the corpus callosum are 2 conditions in which apneic spells were described in association with callosal agenesis. In both syndromes, there was evidence of respiratory rhythm disturbances.10,11 In Pitt-Hopkins syndrome the apneic spells were confirmed to be central apneas via polygraphic recording in 1 patient who did not have signs of brain stem abnormalities on imaging.10 In familial callosal agenesis, the apneic spells were clinically described and postmortem examination showed marked brain stem spongiosis, among other findings.11 The apneic spells in these syndromes can be related to episodes of hyperventilation (posthyperventilation apnea) in Pitt-Hopkins syndrome or to brain stem involvement in familial callosal agenesis.10,11 Although animal studies suggested a possible role for the corpus callosum in functional integration of respiratory centers on both sides, the clinical implication of this observation in acallosal subjects is yet to be elucidated.12
The potential for CSA to worsen heart failure in patients with Vici syndrome with undiagnosed central apneas is not to be underestimated. The pathophysiologic consequences of CSA adversely affect left ventricular structure and function and can worsen heart failure via several mechanisms that include increasing expression of proinflammatory and vasoconstrictor genes, augmenting nocturnal sympathetic activity, and via changes in intrathoracic pressure that can increase the afterload and oxygen consumption on an already compromised left ventricle. 13–16 Although there are short-term suggestions that treatment of CSA might improve cardiac function, there are, however, no robust studies to show the long-term impact of treatment, particularly in children with rare disorders.
In conclusion, we describe the first case of CSA associated with EPG5-related Vici syndrome. Our observations suggest that, in addition to the associated cardiomyopathy and combined immunodeficiency, CSA has to be considered as another important and potentially treatable cause of morbidity and mortality in EPG5-related Vici syndrome. More studies are needed to further investigate sleep abnormalities in EPG5-related Vici syndrome and their consequences. Finally, our observations suggest an intriguing link between certain sleep disorder phenotypes and neurodevelopmental disorders involving structural abnormalities of the corpus callosum and the pons.
- Accepted June 25, 2015.
- Address correspondence to Karim El-Kersh, MD, Department of Pulmonary, Critical Care and Sleep Disorders Medicine, Ambulatory Care Building, 550 South Jackson St, Louisville, KY 40202. E-mail:
Dr El-Kersh drafted the initial manuscript; Dr Jungbluth provided results of genetic testing, contributed in editing the manuscript, and reviewed and revised the manuscript; Dr Gringras contributed in editing the manuscript and reviewed and revised the manuscript; Dr Senthilvel contributed in drafting the initial manuscript and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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- Copyright © 2015 by the American Academy of Pediatrics