Severe Central Sleep Apnea in ViciSyndromeKarim El-Kersh, MDa, Heinz Jungbluth, MD, PhDb,c,d, Paul Gringras, MDe, Egambaram Senthilvel, MD, FRCSEdf

abstract Vici syndrome is a rare congenital multisystem disorder due to recessivemutations in the key autophagy regulator EPG5. Vici syndrome ischaracterized by agenesis of the corpus callosum, hypopigmentation,immunodeficiency, cataracts, and cardiomyopathy, with variable additionalmultisystem involvement. Here we report on a 5-year-old girl who presentedwith global developmental delay, seizures, callosal agenesis, cataracts,sensorineural hearing loss, hypopigmentation, and immunodeficiency witha low CD4 count and recurrent infections. EPG5 sequencing (prompted bysuggestive clinical features) revealed a homozygous missense mutation,c.1007A.G (p.Gln336Arg). The patient was referred to our center forevaluation of nocturnal apnea. Overnight polysomnography showed severecentral sleep apnea (CSA) with an overall apnea-hypopnea index of 100.5events 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 bilevelpositive airway pressure therapy with a backup rate with normalization of theapnea-hypopnea index and maintenance of oxygen saturation .90%. Despitesuccessful control of the severe CSA, the patient was eventually started onnocturnal oxygen therapy due to excessive upper airway secretions and thehigh risk of possible aspiration with positive airway pressure therapy. This isthe first report of EPG5-related Vici syndrome associated with CSA. We discussthe polysomnographic findings in our patient in the context of a briefliterature review of the reported sleep abnormalities in Vici syndrome.

Vici syndrome (Online MendelianInheritance in Man 242840) is a rarecongenital syndrome with extensivemultisystem involvement due torecessive mutations in EPG5 onchromosome 18q12.3, encoding thekey autophagy regulator ectopicP-granules protein 5 (EPG5).1 Vicisyndrome was originally described in1988 by Dionisi-Vici and co-workers in2 brothers, but with ,30 casesreported to date, the phenotypicalspectrum is still evolving.1–3

CASE REPORT

A 5-year-old girl diagnosed with Vicisyndrome presented to our sleepcenter for evaluation of frequentshort episodes of witnessed non–life-

threatening nocturnal apnea. She wasborn via cesarean delivery at 37 weeks’gestation to consanguineous first-cousinparents. Delivery was complicated bymeconium aspiration. Her birth weightwas 2.27 kg (less than the thirdpercentile), length was 49.5 cm (57thpercentile), and occipital frontalcircumference was 34.3 cm (62ndpercentile). She had a history of globaldevelopmental delay, seizures, bilateralcataracts, sensorineural hearing loss,biopsy-proven myopathy, andimmunodeficiency with a low CD4count complicated by recurrentrespiratory infections. She also hada transient dilated cardiomyopathyduring an acute illness at the age of 1year. Her mother had a history of

Departments of aPulmonary, Critical Care, and SleepDisorders Medicine and fPediatrics, Division of SleepMedicine, University of Louisville, Louisville, Kentucky;bDepartment of Paediatric Neurology and eChildren’s SleepMedicine, Evelina Children’s Hospital, Guy’s & St. Thomas’Hospital NHS Foundation Trust, London, United Kingdom;and cRandall Division for Cell and Molecular Biophysics,Muscle Signalling Section, and dDepartment of Basic andClinical Neuroscience Division, The Institute of Psychiatry,Psychology & Neuroscience, King’s College, London, UnitedKingdom

Dr El-Kersh drafted the initial manuscript;Dr Jungbluth provided results of genetic testing,contributed in editing the manuscript, and reviewedand revised the manuscript; Dr Gringrascontributed in editing the manuscript and reviewedand revised the manuscript; Dr Senthilvelcontributed in drafting the initial manuscript andreviewed and revised the manuscript; and allauthors approved the final manuscript assubmitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2015-0297

DOI: 10.1542/peds.2015-0297

Accepted for publication Jun 25, 2015

Address correspondence to Karim El-Kersh, MD,Department of Pulmonary, Critical Care and SleepDisorders Medicine, Ambulatory Care Building, 550South Jackson St, Louisville, KY 40202. E-mail: karim.elkersh@louisville.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,1098-4275).

Copyright © 2015 by the American Academy ofPediatrics

FINANCIAL DISCLOSURE: The authors have indicatedthey have no financial relationships relevant to thisarticle to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors haveindicated they have no potential conflicts of interestto disclose.

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obstructive sleep apnea (OSA) and 2first-trimester spontaneous abortions;an older sibling was healthy.

Previous investigations includedanalysis of the oculocutaneousalbinism type 2 (OCA2) gene, revealingno mutations, and an examination ofperipheral blood smears, requestedunder the suspicion of Chediak-Higashi syndrome but not showingany of the giant neutrophil granulessuggestive of the latter. Brain MRIshowed findings consistent with Vicisyndrome, including agenesis ofcorpus callosum, colpocephaly, andatrophy of the optic nerves, pons,medulla, cerebellum, and cerebralhemispheres (Fig 1). Further genetictesting prompted by suggestiveclinical features revealedhomozygosity for the EPG5 c.1007A.G (p.Gln336Arg) missense mutation,previously reported by Cullup et al.1

Key clinical and genetic features fromour patient have been previouslyreported.1

On examination at presentation toour center, the patient’s height was104 cm (22nd percentile) and weight

was 15.5 kg (13th percentile). Shewas unable to speak. There wasgeneralized hypotonia and the patientcould not walk or sit without support.She had evidence of generalizedhypopigmentation of the eyes, hair,and skin (Fig 2) and hada gastrostomy tube in place becauseof feeding difficulties. Oralexamination revealed a normaltongue; Mallampati class IV, grade 2tonsils; and a high, arched palate withno micrognathia or maxillaryretrusion.

The patient underwent an overnightdiagnostic polysomnography(Table 1) with the use ofa Respironics Alice system(Pittsburgh, PA). Thepolysomnography and sleep-associated events were scoredaccording to American Academy ofSleep Medicine scoring guidelines.4

The patient had a total of 769respiratory events, including 746central apneas, 15 mixed apneas, and8 hypopneas with an overall apnea-hypopnea index of 100.5 events perhour of sleep (central apnea index of

97.5, mixed apnea index of 2, andobstructive hypopnea index of 1)(Fig 3).

The minimum oximetry value was54%, and the total time spent withoxygen saturation ,89% was 111.7minutes. Transcutaneous carbondioxide monitoring showed a meanPaCO2 of 46 mmHg. PaCO2 waselevated above 50 mmHg for almost20% of total sleep time (TST). Thepatient was not receiving anynarcotics, and her cardiacechocardiography revealed normalcardiac anatomy and function with noevidence of pulmonary hypertension.High-resolution chest computedtomography showed no evidence ofinterstitial lung disease.

Subsequently, the patient underwentan overnight titration study (Table 1).At bilevel positive airway pressuresettings of 14/7 cmH2O inspontaneous/timed mode witha backup rate of 12 breaths perminute, the apnea-hypopnea andarousal indices were normalized andoxygen saturation was maintained at.90%. It was difficult for the patient

FIGURE 1Brain MRI sagittal T1-weighted images reveal agenesis of the corpus callosum (A; arrow), colpocephaly (B; *), and marked atrophy of the pons, medulla,cerebellum, and cerebral hemispheres.

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to use positive airway pressuretherapy due to excessive upperairway secretions, despite treatmentwith glycopyrrolate, and the high riskof aspiration. After extensivediscussion with the parents andconsidering the patient’s overallprognosis, a palliative managementapproach was chosen, includingnocturnal oxygen at 1.5 L/minute tokeep her saturation .90%.Unfortunately, our patient died at theage of 6 years as a consequence ofrecurrent infections. An autopsy wasnot performed.

DISCUSSION

Vici syndrome is a rare and severecongenital multisystem disorder withmarkedly reduced life expectancy. In

the largest cohort study in patientswith Vici syndrome and withconfirmed EPG5 mutations, only halfof them were alive at the time of thelast follow-up.1 The most commonidentifiable causes of death wereprogressive cardiac failure andrecurrent infections secondary to theassociated combinedimmunodeficiency.1

Sleep abnormalities in Vici syndromeremain to be elucidated. Actigraphyand polysomnography wereperformed in 2 siblings with Vicisyndrome. The actogram revealeda delay in the circadian rhythm in 1patient, possibly due to severe visualimpairment. The polysomnography inboth patients showed impaired phasicrapid eye movement (REM) sleepparameters in the setting of

preserved percentage of REM sleepand increased muscle atonia duringnon-REM sleep. In both patients,brain MRI showed corpus callosumagenesis, mild cerebral atrophy, andopercular hypoplasia but no brainstem lesions.5

In patients with Vici syndrome, thereported facial abnormalities,hypotonia, and laryngomalacia can allpredispose to OSA.6 Despite thesereported anomalies, only 1 case ofVici syndrome with OSA and milddesaturations was described. Thepatient’s brain MRI revealed corpuscallosum agenesis, pontine, andcerebellar hypoplasia.7

To our knowledge, this is the firstcase of Vici syndrome featuring CSA.Severe neurologic involvement thatincluded both the pons and medullain our patient, as evidenced by brainMRI, is a plausible cause in thepathogenesis of the CSA, but the exactmechanism cannot be extrapolatedfrom a single case. In addition to theabsence of corpus callosum,additional central nervous systemabnormalities were reported in 19 of27 patients diagnosed with Vicisyndrome. These abnormalitiesincluded cerebellar and pontinehypoplasia, ventricular dilatationwith white matter atrophy,heterotopias, abnormal septumpellucidum, and schizencephaly.1,3 Inthe absence of sleep studies in mostof the patients with Vici syndromereported, sleep-related breathingdisorders including CSA cannot beexcluded.

Although the awake respiratory ratewas lower than expected for age, ourpatient maintained awake PaCO2levels ,50 mmHg with no elevationof serum bicarbonate levels. Duringsleep, there was a further reductionin the respiratory rate with periods ofhypercapnia. Although this findingcan represent an element of sleep-related hypoventilation, the totalduration spent with PaCO2 .50 mmHg was ,25% of the TST that isrequired to score pediatric sleep-related

TABLE 1 Sleep Architecture During the Diagnostic and the Titration Studies

Parameter Diagnostic Study Titration Study

Recording time, min 520 486TST, min 459 411.5Sleep efficiency, % 88 84Stage, %N1 0 0N2 0.8 3.2N3 98.9 96.8REM 0 0

Highest tcpco2, mm Hg 59 46

tcpco2, transcutaneous carbon dioxide.

FIGURE 2The patient at the age of 3 years. (Consent was obtained from the parents.)

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hypoventilation according to AmericanAcademy of Sleep Medicine scoringguidelines.4

Another observation was thepredominance of stage N3 non-REMsleep. Our patient spent 98.8% and96.8% of her TST in stage N3 non-REMsleep during the diagnostic and thetitration studies, respectively. Subjectswith corpus callosum agenesis tend tohave more slow-wave sleep, lessinterhemispheric EEG coherence, andultradian rhythm disturbances.8

Despite these findings in acallosalsubjects, slow-wave sleeppredominance was not previouslydescribed among the polysomnographicfindings in Vici syndrome.5,7

Although our patient was notreceiving any REM sleep-suppressantmedications, she also did not haveany REM sleep during the diagnosticor the titration study. It is plausiblethat the absence of REM sleep in ourpatient could have been related to herpontine atrophy, considering that thepons plays an essential role in thegeneration of REM sleep duringwhich the central nervous system

cholinergic activity predominates.9

Absence of REM sleep may suggest animpairment of the central nervoussystem cholinergic system as well.Although REM sleep percentage wasreported to be preserved in 2 siblingswith Vici syndrome, both of them didnot have evidence of brain steminvolvement on brain MRI, in contrastto our patient.5

Pitt-Hopkins syndrome and familialagenesis of the corpus callosum are 2conditions in which apneic spellswere described in association withcallosal agenesis. In both syndromes,there was evidence of respiratoryrhythm disturbances.10,11 In Pitt-Hopkins syndrome the apneic spellswere confirmed to be central apneasvia polygraphic recording in 1 patientwho did not have signs of brain stemabnormalities on imaging.10 Infamilial callosal agenesis, the apneicspells were clinically described andpostmortem examination showedmarked brain stem spongiosis, amongother findings.11 The apneic spells inthese syndromes can be related toepisodes of hyperventilation(posthyperventilation apnea) in

Pitt-Hopkins syndrome or to brainstem involvement in familial callosalagenesis.10,11 Although animalstudies suggested a possible role forthe corpus callosum in functionalintegration of respiratory centers onboth sides, the clinical implication ofthis observation in acallosal subjectsis yet to be elucidated.12

The potential for CSA to worsen heartfailure in patients with Vici syndromewith undiagnosed central apneas isnot to be underestimated. Thepathophysiologic consequences ofCSA adversely affect left ventricularstructure and function and canworsen heart failure via severalmechanisms that include increasingexpression of proinflammatory andvasoconstrictor genes, augmentingnocturnal sympathetic activity, andvia changes in intrathoracic pressurethat can increase the afterload andoxygen consumption on an alreadycompromised left ventricle. 13–16

Although there are short-termsuggestions that treatment of CSAmight improve cardiac function, thereare, however, no robust studies toshow the long-term impact of

FIGURE 3A 2-minute polysomnographic recording during stage N3 non-REM sleep reveals central apneas (red arrows) (transcutaneous PaCO2 shows PaCO2 levels,50 mm Hg).

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treatment, particularly in childrenwith rare disorders.

In conclusion, we describe the firstcase of CSA associated with EPG5-related Vici syndrome. Ourobservations suggest that, in additionto the associated cardiomyopathy andcombined immunodeficiency, CSA hasto be considered as another importantand potentially treatable cause ofmorbidity and mortality in EPG5-related Vici syndrome. More studiesare needed to further investigate sleepabnormalities in EPG5-related Vicisyndrome and their consequences.Finally, our observations suggest anintriguing link between certain sleepdisorder phenotypes andneurodevelopmental disordersinvolving structural abnormalities ofthe corpus callosum and the pons.

ABBREVIATIONS

CSA: central sleep apneaOSA: obstructive sleep apneaREM: rapid eye movementTST: total sleep time

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DOI: 10.1542/peds.2015-0297 originally published online October 19, 2015; 2015;136;e1390Pediatrics 

Karim El-Kersh, Heinz Jungbluth, Paul Gringras and Egambaram SenthilvelSevere Central Sleep Apnea in Vici Syndrome

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DOI: 10.1542/peds.2015-0297 originally published online October 19, 2015; 2015;136;e1390Pediatrics 

Karim El-Kersh, Heinz Jungbluth, Paul Gringras and Egambaram SenthilvelSevere Central Sleep Apnea in Vici Syndrome

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