REVIEW ARTICLE
pii: jc-00231-14 http://dx.doi.org/10.5664/jcsm.4212
Sleep Disorders Associated with Primary Mitochondrial Diseases Ryan J. Ramezani, B.S.1; Peter W. Stacpoole, Ph.D., M.D.1,2
Department of Medicine and 2Division of Endocrinology, Metabolism and Diabetes, and Department of Biochemistry and Molecular Biology, University of Florida, College of Medicine, Gainesville, FL
1
Study Objectives: Primary mitochondrial diseases are caused by heritable or spontaneous mutations in nuclear DNA or mitochondrial DNA. Such pathological mutations are relatively common in humans and may lead to neurological and neuromuscular complication that could compromise normal sleep behavior. To gain insight into the potential impact of primary mitochondrial disease and sleep pathology, we reviewed the relevant English language literature in which abnormal sleep was reported in association with a mitochondrial disease. Design: We examined publications reported in Web of Science and PubMed from February 1976 through January 2014, and identified 54 patients with a proven or suspected primary mitochondrial disorder who were evaluated for sleep disturbances. Measurements and Results: Both nuclear DNA and mitochondrial DNA mutations were associated with abnormal sleep patterns. Most subjects who underwent polysomnography had central sleep apnea, and only 5 patients had obstructive sleep apnea. Twenty-four patients showed decreased ventilatory drive in response to hypoxia
and/or hypercapnia that was not considered due to weakness of the intrinsic muscles of respiration. Conclusions: Sleep pathology may be an underreported complication of primary mitochondrial diseases. The probable underlying mechanism is cellular energy failure causing both central neurological and peripheral neuromuscular degenerative changes that commonly present as central sleep apnea and poor ventilatory response to hypercapnia. Increased recognition of the genetics and clinical manifestations of mitochondrial diseases by sleep researchers and clinicians is important in the evaluation and treatment of all patients with sleep disturbances. Prospective population-based studies are required to determine the true prevalence of mitochondrial energy failure in subjects with sleep disorders, and conversely, of individuals with primary mitochondrial diseases and sleep pathology. Keywords: sleep apnea, mitochondrial disease, congenital lactic acidosis Citation: Ramezani RJ, Stacpoole PW. Sleep disorders associated with primary mitochondrial diseases. J Clin Sleep Med 2014;10(11):1233-1239.
“P
rimary” mitochondrial diseases are heritable or spontaneous inborn errors of metabolism in which the conversion of substrate fuels into energy is perturbed by loss-of-function mutations in genes encoded by either nuclear or mitochondrial DNA (nDNA; mtDNA). In turn, these mutations give rise to functional defects in mitochondrial enzymes crucial to aerobic metabolism and oxidative phosphorylation (Figure 1). Elevation of blood and/or cerebrospinal fluid lactate is a non-diagnostic, but prevalent, biomarker of mitochondrial disorders. The commonest cause of congenital lactic acidosis (CLA; Table 1) is deficiency of the nuclear-encoded pyruvate dehydrogenase complex (PDC). PDC is located in the mitochondrial matrix and irreversibly decarboxylates pyruvate to acetyl CoA. Thus, PDC functions as a gate-keeper enzyme, linking glycolysis in the cytoplasm to the tricarboxylic acid (TCA) cycle in mitochondria.1,2 Deficiencies in pyruvate carboxylase and certain TCA cycle enzymes can very rarely cause CLA. However, most other etiologies are due to one or more deficiencies in Complexes I – V of the respiratory chain that ultimately reduce molecular oxygen to water and synthesize ATP from ADP and inorganic phosphate. All nucleated eukaryotic cells contain mitochondria and, hence, are subject to inherited or spontaneous mutations in these enzymes of energy metabolism. Consequently, it is not surprising that such primary mitochondrial diseases exhibit protean clinical complications, in which lactic acidosis is a frequent biomarker of 1233
local or systemic energy failure. Because neurons and myocytes rely primarily on mitochondrial glucose oxidation to meet their high energy demands, mitochondrial disorders typically manifest clinically as progressive neurological and neuromuscular degeneration, although any tissue and organ system can be affected.3-6 Most summaries of the natural history of primary mitochondrial diseases do not include sleep disturbances in the clinical spectrum or evaluation and treatment strategies.2,5,7,8 However, the dependency of normal sleep on both neurological and neuromuscular integrity infers a strong relationship between mitochondrial dysfunction and sleep pathology. To address this issue, we critically reviewed literature associating sleep disturbances with the clinical presentation and course of primary mitochondrial diseases. We propose that this pathophysiological relationship be considered in future mechanistically oriented research on sleep and in the clinical assessment of sleep disturbances in the general population.
METHODS We used Web of Science and PubMed to identify all English language publications from February 1976 through January 2014 that described patients who were diagnosed with a primary mitochondrial disease associated with sleep-related problems and/or in whom polysomnography (PSG) was performed. Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
RJ Ramezani and PW Stacpoole
Figure 1
A
B
Major pathways of cellular energy metabolism (A). Glycolysis in the cytoplasm is linked to the tricarboxylic acid (TCA) cycle in mitochondria by the multicomponent pyruvate dehydrogenase complex (PDC), which irreversibly decarboxylates pyruvate acetyl CoA, an intermediate that is also formed as a product of the β-oxidation of long-chain fatty acyl CoAs (LCF acyl CoAs). Alternatively, pyruvate is carboxylated by pyruvate carboxylase to oxaloacetate. Reducing equivalents (nicotinamide adenine dinucleotide NADH; flavin adenine dinucleotide, FADH2) are generated by reactions catalyzed by the PDC and the TCA cycle and donate electrons (e −) that enter the respiratory chain (B) at NADH ubiquinone-oxidoreductase (Complex I) or at succinate-ubiquinone oxidoreductase (Complex II). Electrons from Complexes I and II are transferred via coenzyme Q10 to ubiquinol-cytochrome c reductase (Complex III). Cytochromic oxidase (Complex IV) catalyses the reduction of molecular oxygen to water. Electron transfer at Complex I, III, and IV is coupled to the pumping of protons (H+) from the mitochondrial matrix to the inter-mitochondrial space. These protons are utilized by ATP synthase (Complex V) to generate ATP from ADP, thus completing the process of oxidative phosphorylation. All the enzymes of the PDC, the β-oxidation pathway and the TCA cycle are encoded by nuclear DNA (nDNA). Of the approximately 97 subunits comprising the respiratory chain complexes, only 13 are encoded by mitochondrial DNA, and the rest are nuclear-encoded (mtDNA:nDNA): Complex I (7:~46); Complex II (0:4); Complex III (1:10); Complex IV (3:10); and Complex V (2:14). Panel B from reference5 (used with permission).
Key terminologies we employed were deficiency of any of the respiratory chain complexes and various names and acronyms (see Results) denoting specific mitochondrial diseases or syndromes, coupled with different combinations of sleep disorder terms, such as central or obstructive sleep apnea and PSG. We found 18 publications in which 54 patients were described. The patients and their clinical findings were grouped, when possible, Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
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by disease or syndrome, according to modern biochemical and/ or molecular genetic diagnostic criteria.9-13
RESULTS Table 2 summarizes the diagnostic and clinical characteristics of 54 subjects with a proven or probable primary
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Table 1—Terminology used in this review. Alpers syndrome
Autosomal recessive due to mutations in mtDNA polymerase γ. Onset in youth. Widespread neurodegeneration, seizures, hepatopathy.
PEO (Progressive external ophthalmoplegia)
Maternally transmitted (mtDNA). Onset variable. Ptosis is commonly first sign. Often part of KSS.
POLG (Polymerase gamma)
Encodes for catalytic subunit of mtDNA polymerase. Onset variable for pathological mutations. May be causative for Alpers syndrome, Leigh syndrome, PEO, other severe mt diseases.
CLA (Congenital lactic acidosis)
Multiple etiologies. Onset in youth.
Heteroplasmy
A mixture of mutant and wild-type sequences in mtDNA that can be present in different proportions in different tissues. When the proportion of mutated mtDNA reaches a so-called “threshold effect” in the cells of a given tissue or organ, a new clinical phenotype appears (e.g., onset of dementia or diabetes in a patient with MELAS).
KSS (Kearns-Sayre syndrome)
First multisystem mitochondrial disorder to be defined clinically. Large-scale mtDNA deletions. Onset in youth. Retinitis pigmentosa, external ophthalmoplegia, complete heart block, ataxia, ± lactic acidosis, among many other signs and symptoms.
Leigh syndrome
Also called subacute necrotizing encephalomyopathy. Primarily involves basal ganglia and brainstem. Common to many nDNA (e.g., PDC deficiency) and mtDNA mutations. Onset usually in youth. Seizures, blindness, hearing loss, dementia, ataxia, hypotonia, ± lactic acidosis.
Mitochondrial myopathy
Multiple etiologies. Nonspecific term emphasizing skeletal muscle as disease target. Onset variable, RRFs common, hypotonia, ± lactic acidosis.
MELAS (Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes)
Maternally transmitted (mtDNA). Onset throughout life. Seizures, migraines, diabetes, hearing loss, psychiatric problems, dementia.
NARP (Peripheral neuropathy, ataxia and retinitis pigmentosa):
Maternally transmitted (mtDNA). Onset in youth, sensory neuropathy, seizures, dementia, ± lactic acidosis.
PDC deficiency (Pyruvate Dehydrogenase Complex deficiency)
All components nDNA-encoded, most are X-linked spontaneous mutations; most others are autosomal recessive. Onset in youth. Hypotonia, psychomotor retardation, seizures, lactic acidosis.
LHON (Leber’s hereditary optic neuropathy)
Maternally transmitted (mtDNA). Neuroretinal degeneration causing acute loss of central vision, especially in young men. Most prevalent mt disease, ± lactic acidosis.
RRF (Ragged red fibers)
Histochemical hallmark of mitochondrial muscle pathology, showing segmental accumulations of (usually morphologically abnormal) mitochondria in subsarcolemmal and intermyofibrillar muscle regions.
From 1,5
mitochondrial disease.14-31 All patients were diagnosed with a sleep disorder and/or had complaints of abnormal sleep, based on family report or self-report. Two patients had PDC deficiency. Patient 1, a 7-year-old boy with biochemically proven PDC deficiency, was diagnosed with central type sleep apnea syndrome, following radiological, electrophysiological, and pulmonary function criteria requiring tracheostomy and assisted ventilation.14 Patient 2 was a 13-month-old girl with classical radiological evidence of Leigh syndrome (Table 1) and cortical atrophy whose clinical picture included psychomotor retardation and hypotonia, both typical manifestations of the enzyme defect.15 Further evaluation of this child at age 7 years disclosed progressive disturbance in both auditory and somatosensory evoked potentials, coupled with polysomnographic evidence of abnormalities in both the tonic and phasic components of sleep during REM. Patient 3 was a 27-year-old woman with biochemically proven complex IV (cytochrome c oxidase) deficiency in whom PSG showed no apneic episodes despite significant desaturation during sleep, consistent with a state of hypoventilation.16 Molecular genetic testing resulted in the definitive diagnosis of a mitochondrial disease in subjects 4-14. Biopsied skeletal muscle from patient 4, an obese 23-year-old woman who had
a history of loud snoring, revealed 91% heteroplasmy for the mtDNA NARP mutation (nucleotide 8993).17 PSG showed severe obstructive sleep apnea, hypopnea, and central apnea. Patient 5 was a 37-year-old man with diabetes who had the most common mtDNA point mutation for MELAS, an A→ G tRNA leu(UUR) substitution at amino acid position 3243.18 Of interest is that this individual had none of the symptomatology typically associated with MELAS (Table 1). However, he suffered from chronic, often extreme, insomnia and was diagnosed with delayed sleep phase syndrome. Patient 6, a 21-year-old man with the identical A3243G mutation manifested gait and visual disturbance and other typical signs and symptoms of MELAS (headaches, dizziness, vomiting and stroke-like episodes). He also presented with hypoxic ventilatory depression and chronic hypoventilation of uncertain etiology.19 Following experimental exposure to hypoxia, his respiratory rate decreased, but tidal volume did not change. Sleep PSG was not performed. Patient 7 was a 48-year-old man with mitochondrial myopathy and the presence on muscle biopsy of multiple mtDNA mutations: A5466G; GA7912A and T10601C. His PSG revealed central sleep apnea, with 19 apneic episodes/hour.20 Subjects 8-15 had Leigh syndrome and demonstrated both diversity in their molecular genetic etiologies and sleep
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RJ Ramezani and PW Stacpoole
Table 2—Summary of patients and findings. Patient
Age/Sex
Diagnosis
Sleep Findings
Reference
1
7/M
PDC deficiency
Central hypoventilation syndrome
14
2
13m/F
Leigh’s syndrome; neuroradiological findings
Obstructive sleep apnea
15
3
27/F
Complex IV Deficiency
Polysomnograph revealed respiratory muscle weakness that was not limited to sleep (sleep apnea was ruled out)
16
4
23/F
NARP 8993
Obstructive sleep apnea
17
5
37/M
MELAS (A3243G)
Delayed sleep phase syndrome
18
6
21/M
MELAS
Hypoxic ventilator depression
19
7
48/M
Multiple novel mtDNA mutations
Central sleep apnea
20
8
3/F
Leigh syndrome/molecular genetic diagnosis
Central sleep apnea
21
9
1/M
Leigh syndrome/molecular genetic diagnosis
Central sleep apnea
21
10
19/F
Leigh syndrome/molecular genetic diagnosis
Hiccup apnea **
21
11
10/F
Leigh syndrome/molecular genetic diagnosis
Central/obstructive sleep apnea
21
12
12/F
MERRF/Leigh overlap syndrome/molecular genetic diagnosis (A8344g)
Central sleep apnea
21
13
2/M
Alpers/Leigh overlap syndrome/molecular genetic diagnosis (T8993G)
Severe apnea, polysomnograph could not confirm whether these apneas were central or obstructive
21
14
17/F
Leigh syndrome/neuro-radiological findings
Obstructive sleep apnea
22
15
24/M
Leigh syndrome/Brainstem encephalomyopathy of subacute onset
Obstructive sleep apnea
23
16
31/F
Ragged Red Fibers/Muscle Biopsy
Depressed ventilatory drive response to hypoxia
24
17
65/F
Ragged Red Fibers/Muscle Biopsy
Depressed ventilatory drive response to hypoxia
24
18
37/F
Ragged Red Fibers/Muscle Biopsy
Depressed ventilatory drive response to hypoxia/ hypercapnia (elevated CO2)
24
19
29/F
Kearns-Sayre/muscle biopsy ragged red fibers
Depressed ventilatory drive response to hypoxia/ hypercapnia (elevated CO2)
25
20
21/F
Kearns-Sayre/muscle biopsy, biochemical diagnosis
Depressed ventilatory drive response to hypoxia/ hypercapnia (elevated CO2)
25
21
13/M
Kearns-Sayre/muscle biopsy, biochemical diagnosis
Depressed ventilatory drive response to hypoxia/ hypercapnia (elevated CO2)
25
22
25/F
Kearns-Sayre, muscle biopsy, muscle biopsy/biochemical
Depressed ventilatory drive response to hypoxia/ hypercapnia (elevated CO2)
25
23
34/F
PEO (mt DNA deletion)
*
26
24
14/F
PEO (mt DNA deletion)
*
26
25
17/F
PEO (mt DNA deletion)
*
26
26
17/F
PEO (mt DNA deletion)
*
26
27
32/F
PEO (mt DNA deletion)
*
26
* Sleep findings for individual patients 23-42 not reported in Smits et al.26 CSA denotes central sleep apnea. See Table 1 for other abbreviations. Table 2 continues on the following page
pathologies on PSG.21-23 Patient 8, a 3-year-old girl with the pathological mtDNA mutation A8334G, had central sleep apnea. Patient 9, a 1-year-old boy with the T8993G mutation, also had central sleep apnea by PSG, while the PSG of patient 10, a 19-year-old girl with the T9176C mutation, showed obstructive sleep apnea. In contrast, mixed central and obstructive sleep apnea was diagnosed in a 10-year-old-girl with the same pathological mutation (Patient 11). Patient 12 year a 12-year-old girl with a MERRF/Leigh overlap syndrome caused by an A8344G Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
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mtDNA mutation. Patient 13 was a 2-year-old boy with Alpers/Leigh overlap syndrome due to an A8993G substitution in mtDNA who had severe apneic breathing, although PSG could not differentiate between central or obstructive pathology.21 Patient 14, a 17-year-old girl, had Leigh syndrome of undetermined etiology, myopathy, obesity, and obstructive sleep apnea.22 Seventeen cases demonstrated clinical and/or muscle biopsy findings consistent with a primary mitochondrial disease
Sleep Disorders in Mitochondrial Diseases
Table 2 (continued )—Summary of patients and findings. Patient
Age/Sex
Diagnosis
Sleep Findings
Reference
28
11/M
PEO (mt DNA deletion)
*
26
29
25/M
PEO (mt DNA deletion)
*
26
30
14/M
PEO (mt DNA deletion)
*
26
31
12/F
PEO (A3243G)
*
26
32
12/M
PEO (A3243G)
*
26
33
36/M
PEO (G12315A)
*
26
34
30/M
PEO (T5709C)
*
26
35
48/M
PEO (A4267G)
*
26
36
21/M
POLG
*
26
37
4/M
POLG
*
26
38
13/F
POLG
*
26
39
23/M
POLG
*
26
40
39/M
POLG
*
26
41
53/M
POLG
*
26
42
24/F
POLG
*
26
43
46/M
Mitochondrial Encephalomyopathy/muscle biopsy
Central sleep apnea
27
44
40/M
LHON (G3460A)
Central sleep apnea
28
45
34/M
Mt encephalopathy; MRI consistent with Leigh syndrome
Hypnic
29
46
30/F
Ophthalmoplegia plus (Kearns Sayre), ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Reduced ventilatory response to inhaled CO2 as compared to normal values
30
47
41/M
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Reduced ventilatory response to inhaled CO2 as compared to normal values, no sleep apnea episodes
30
48
62/F
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Desaturation during sleep irrespective of breathing rhythm, reduced ventilatory response to inhaled CO2 as compared to normal values, no sleep apnea episodes
30
49
51/F
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Mainly CSA, reduced ventilatory response to inhaled CO2 as compared to normal values
30
50
42/M
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Reduced ventilatory response to inhaled CO2 as compared to normal values, no sleep apnea episodes
30
51
55/M
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Mainly CSA; reduced ventilatory response to inhaled CO2 as compared to normal values
30
52
55/M
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically
Mainly CSA; reduced ventilatory response to inhaled CO2 as compared to normal values
30
53
52/F
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Mainly CSA; reduced ventilatory response to inhaled CO2 as compared to normal values
30
54
34/F
Leigh’s syndrome, histochemical diagnosis
CSA
31
* Sleep findings for individual patients 23-42 not reported in Smits et al.26 CSA denotes central sleep apnea. See Table 1 for other abbreviations.
etiology without definitive biochemical or molecular genetic proof of an enzymatic defect or pathological nDNA or mtDNA mutation. Patient 15 was a 24-year-old male with encephalomyopathy who was diagnosed with Leigh syndrome in view of clinical and neuroradiological findings, although genetic testing did not identify a causative mutation.23 Patients 16-18 showed depressed ventilatory response to hypoxia; patient 16, a 31-year-old woman with RRF found on muscle biopsy, also exhibited depressed ventilatory drive to 1237
hypercapnia.24 PSG was not performed in these subjects and the investigators surmised that their sleep abnormalities were attributable to a defect in central and/or peripheral chemoreceptor function, rather than to an intrinsic weakness in the muscles of respiration. Patients 19-35 were diagnosed with PEO or Kearns-Sayre syndrome on the basis of clinical findings and muscle biopsy studies that showed the presence of RRFs and/or other myopathic changes.25,26 Subjects 19-22 exhibited depressed Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
RJ Ramezani and PW Stacpoole
ventilatory drive in response to hypoxia and hypercapnia that was not considered due to weakness of respiratory muscles. Thirteen patients had PEO due either to a point mutation or a deletion of mtDNA, and patients 36-42 had a mutation in POLG, causing disruption in mtDNA replication. Patients 23-42 underwent extensive evaluation at a single Dutch neuromuscular center,26 and despite differences in the etiology of their mitochondrial disease, shared several common clinical features relevant to sleep pathology. Fifteen of the 20 patients had subjective nocturnal sleep dysfunction, as indicated by a Pittsburgh Sleep Quality Index score > 5, while 6 subjects reported excessive daytime sleepiness (Epworth Sleepiness Scale score > 10) and 14 patients had symptoms of depression and/or anxiety (Hospital Anxiety and Depression Scale). Disruptive sleep architecture in these patients was variably manifested by decreased sleep efficiency, duration of wakefulness after sleep onset and increased frequencies of stage 1 sleep and arousal index. Cognitive impairment, proximal myopathy, ataxia, restless leg syndrome, dysarthria, and polyneuropathy were also common features. One subject had a mild obstructive component to sleep apnea, while at least 20% of the patients had central sleep apnea. However, subjective nocturnal sleep dysfunction did not predict PSG results. Patient 43 was a 46-year-old man who had PSG evidence of central sleep apnea, and mitochondrial encephalomyopathy, based on muscle biopsy.27 He also had an abnormally elevated blood lactate-pyruvate response during exercise and elevated lactate and pyruvate concentrations in cerebrospinal fluid. This patient’s respiratory disturbance was determined to be primarily due to brainstem involvement, based on high-signal intensity lesions from midbrain to medulla seen on magnetic resonance imaging (MRI) and on tests of both somatosensory and brainstem auditory evoked potentials. Phrenic nerve conduction velocity was also prolonged, which could contribute to the patient’s disturbed respiration. Patient 44 had LHON due to a common point mutation, whose central sleep apnea was associated with excessive daytime sleepiness and oxygen desaturation up to 72% SpO2 during sleep.28 Patient 45 had an undefined mitochondrial encephalopathy and MRI findings consistent with Leigh syndrome, whose abnormal sleep architecture was characterized by hypnic myoclonus, prolonged sleep onset, and reduced sleep efficiency.29 Patients 46-54 had ophthalmoplegia and RRFs on muscle biopsy, and all but patient 52 were reported to have complex IV deficiency in skeletal muscle.30 PSG revealed that all patients had reduced ventilatory response to inhaled carbon dioxide. Patients 47, 48, and 50 exhibited no apneic episodes during sleep, although patient 48 desaturated during sleep irrespective of breathing rhythm. Patients 49 and 51-53 had mainly centraltype sleep apnea. Patient 54 was a 34-year-old woman with Leigh syndrome, whose PSG also revealed central sleep apnea.31 The patient breathed normally while awake; however, immediately after the onset of sleep, her respiratory rate and tidal volume became irregular. Her oxygen saturation averaged 78% during NREM sleep and 45% during REM sleep. Central apneas (72/h of sleep) usually last 10 to 15 seconds, but reached a maximum of 35 seconds of REM sleep. Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
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DISCUSSION These data indicate that, of 54 subjects with proven or suspected mitochondrial disease, 47 had PSG recordings, and 12 of these individuals exhibited central sleep apnea. Twenty-four patients showed depressed ventilatory drive in response to hypoxia and/or hypercapnia that investigators did not attribute to weakness of the intrinsic muscles of respiration. Only five patients, at least two of whom were obese, showed signs of obstructive sleep apnea. Two practical questions begged by these findings pertain to the frequency of their occurrence relative to the prevalence of primary mitochondrial diseases in the general population and whether a family or personal history of mitochondrial diseases should be included in the initial evaluation of any person with suspected sleep pathology. This retrospective analysis can only hint at the true associations between mitochondrial disease and abnormal sleep. However, at least 1:200 ostensibly healthy humans are reported to harbor at least one pathological mtDNA mutation potentially capable of causing disease in the offspring of female carriers.32 Although most such carriers are unlikely to ever exhibit clinical signs or symptoms, up to 1:5000 people in the general population will ultimately clinically manifest a mtDNA disease.33,34 In addition, all the PDC components and the vast majority of the subunits of the respiratory chain are nuclear encoded. Thus, nDNA and mtDNA mutations in genes encoding enzymes of mitochondrial fuel metabolism are common causes of human morbidity. Furthermore, because highly oxidative tissues, such as the nervous system and muscle, are so vulnerable to disruption of mitochondrial energetics, it is reasonable to assume that disordered sleep may be one sign of dysfunction affecting these organ systems. Indeed, chronic fatigue and diminished exercise tolerance are common complications or primary mitochondrial diseases2,5 that could reflect, at least in part, abnormal sleep patterns unrecognized by affected individuals, their families and their healthcare providers. What underlying mechanisms beyond energy failure might contribute to sleep pathology in mitochondrial disease? Neuromuscular degeneration and hypotonia are also classic clinical manifestations of mitochondrial diseases and were highly represented in the patients described in this review. Because even healthy subjects experience some loss of respiratory muscle tone during REM sleep, it would follow that mitochondrial disease patients have increased susceptibility to REM-associated hypotonia and hypoxemia, as occurs in patients with other forms of neurodegenerative disease.27 Although weakness of respiratory and upper airway muscles would contribute to sleep-disordered breathing, an additional potentially important contributing factor could be brainstem involvement that is particularly common in patients with Leigh syndrome or following stroke-like episodes in patients with MELAS.18 Others have observed characteristic respiratory patterns in individuals with Leigh syndrome, including post-sigh apnea, hiccup, and apneusis that could reflect compromise of dorsal root ganglion neurons proximate to the solitary tract nucleus.20 We conclude from this retrospective review that abnormal sleep patterns may be underreported complications of patients with primary mitochondrial disorders. The basic underlying mechanism of cellular energy failure results in both
Sleep Disorders in Mitochondrial Diseases
central neurological and peripheral neuromuscular degenerative changes that are reflected, to variable degrees, as central sleep apnea and poor ventilatory responses to hypercapnia. In turn, disordered sleep in affected patients contributes to a vicious cycle of progressive daytime fatigue, hypotonia, and exercise intolerance. This self-perpetuating pattern is similar to the positive feedback loop experienced by many other individuals whose sleep disturbances are not known to be caused by a primary mitochondrial disease. However, it is this very similarity in clinical presentation and course that has masked the true prevalence and underlying mechanisms of sleep pathology in primary mitochondrial diseases, which can only be satisfactorily addressed by prospective, population-based studies. There are no proven treatments for any primary mitochondrial disease, so traditional interventions are supportive, yet anecdotal. Treatment of sleep disturbances may be one of the few options to improve the quality of life of affected patients. Thus, we suggest that increased attention by sleep researchers to a patient’s family history of maternally transmitted disorders and awareness of the multisystem clinical features of mitochondrial diseases may be critical to the differential diagnosis of all patients with sleep disturbances.
REFERENCES 1. Stacpoole PW, Gilbert LR. Pyruvate dehydrogenase complex deficiency. In: Glew RH, Rosenthal MD, eds. Clinical studies in medical biochemistry. 3rd ed. New York: Oxford University Press, 2007:77-88. 2. Patel KP, O’Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab 2012;106:385-94. 3. Stacpoole PW. Lactic acidosis and other mitochondrial disorders. Metabolism 1997;46:306-21. 4. Skladal D, Sudmeier C, Konstantopoulou V, et al. The clinical spectrum of mitochondrial disease in 75 pediatric patients. Clin Pediatr (Phila) 2003;42:70310. 5. DiMauro S, Hirano M, Schon EA, eds. Mitochondrial Medicine. Abingdon, Oxfordshire, UK: Informa Healthcare, 2006. 6. Gibson K, Halliday JL, Kirby DM, Yaplito-Lee J, Thorburn DR, Boneh A. Mitochondrial oxidative phosphorylation disorders presenting in neonates: clinical manifestations and enzymatic and molecular diagnoses. Pediatrics 2008;122:1003-8. 7. Kisler JE, Whittaker RG, McFarland R. Mitochondrial diseases in childhood: a clinical approach to investigation and management. Dev Med Child Neurol 2010;52:422-33. 8. Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N, Cohen BH. Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 2007;120:1326-33. 9. Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 2002;59:1406-11. 10. Wolf NI, Smeitink JA. Mitochondrial disorders: a proposal for consensus diagnostic criteria in infants and children. Neurology 2002;59:1402-5. 11. Haas RH, Parikh S, Falk MJ, et al. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab 2008;94:16-37. 12. Kerr D, Grahame G, Nakouzi G. Assays of pyruvate dehydrogenase complex and pyruvate carboxylase activity. In: Wong LJ, ed. Mitochondrial disorders: biochemical and molecular analysis. Clifton, NJ: Humana/Springer, 2012:93-119. 13. Stacpoole PW, deGrauw TJ, Feigenbaum AS, et al. Design and implementation of the first randomized controlled trial of coenzyme CoQ10 in children with primary mitochondrial diseases. Mitochondrion 2012;12:623-9. 14. Johnston K, Newth CJ, Sheu KF, et al. Central hypoventilation syndrome in pyruvate dehydrogenase complex deficiency. Pediatrics 1984;74:1034-40. 15. Araki S, Hayashi M, Yasaka A, Maruki K. Electrophysiological brainstem dysfunction in a child with Leigh disease. Pediatr Neurol 1997;16:329-33.
16. O’Brien A, Blaivas M, Albers J, Wald J, Watts C. A case of respiratory muscle weakness due to cytochrome c oxidase enzyme deficiency. Eur Respir J 1998;12:742-4. 17. Sembrano E, Barthlen GM, Wallace S, Lamm C. Polysomnographic findings in a patient with the mitochondrial encephalomyopathy NARP. Neurology 1997;49:1714-7. 18. Suzuki Y, Taniyama M, Hata T, Miyaoka H, Atsumi Y, Matsuoka K. Sleepwake dysrhythm in mitochondrial diabetes mellitus. Diabetes Res Clin Pract 2007;35:61-2. 19. Osanai S, Takahashi T, Enomoto H, et al. Hypoxic ventilatory depression in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes. Respirology 2001;6:163-6. 20. Sakaue S, Ohmuro J, Mishina T, et al. A case of diabetes, deafness, cardiomyopathy, and central sleep apnea: novel mitochondrial DNA polymorphisms. Tohoku J Exp Med 2002;196:203-11. 21. Yasaki E, Saito Y, Nakano K, et al. Characteristics of breathing abnormality in Leigh and its overlap syndromes. Neuropediatrics 2001;32:299-306. 22. Tan ALW, Goy R. Anaesthetic management of a patient with Leigh’s syndrome with central hypoventilation and obstructive sleep apnoea. Singapore Med J 2013;54:e250-3. 23. Mermigkis C, Bouloukaki I, Mastorodemos V, et al. Medical treatment with thiamine, coenzyme Q, vitamins E and C, and carnitine improved obstructive sleep apnea in an adult case of Leigh disease. Sleep Breath 2013;17:1129-35. 24. Barohn RJ, Clanton T, Sahenk Z, Mendell JR. Recurrent respiratory insufficiency and depressed ventilatory drive complicating mitochondrial myopathies. Neurology 1990;40:103-6. 25. Carroll JE, Zwillich C, Weil JV, Brooke MH. Depressed ventilator response in oculocraniosomatic neuromuscular disease. Neurology 1976;26:140-6. 26. Smits BW. Westeneng HJ, van Hal MA, van Engelen BG, Overeem S. Sleep disturbances in chronic progressive external ophthalmoplegia. Eur J Neurol 2012;19:176-8. 27. Tatsumi C, Takahashi M, Yorifuji S, Kitaguchi M, Tarui S. Mitochondrial encephalomyopathy and sleep apnea. Eur Neurol 1988;28:64-9. 28. Vetrugno R, Valentino ML, La Morgia C, et al. Sleep-related periodic respiration with central sleep apnea in Leber Hereditary Optic Neuropathy (LHON). Sleep Med 2010;11:426-7. 29. Pincherle A, Mantoani L, Villani F, Confalonieri P, Erbetta A. Excessive fragmentary hypnic myoclonus in a patient affected by a mitochondrial encephalomyopathy. Sleep Med 2006;7:663. 30. Manni R, Piccolo G, Banfi P, et al. Respiratory patterns during sleep in mitochondrial myopathies with ophthalmoplegia. Eur Neurol 1991;31:12-7. 31. Cumminskey J, Guilleminault C, Davis R, Duncan K, Golder J. Automatic respiratory failure: sleep studies and Leigh’s disease (case report). Neurology 1987;37:1876-8. 32. Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF. Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet 2008;83:254-60. 33. Schaefer AM, McFarland R, Blakely EL, et al. Prevalence of mitochondrial DNA disease in adults. Ann Neurol 2008;63:35-9. 34. Skladal D, Halliday J, Thorburn DR. Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 2003;126(Pt 8):1905-12.
ACKNOWLEDGMENTS The authors thank Drs. Brian Fuehrlein, Paul Carney and Richard Berry for helpful comments and Ms. Candace Caputo for editorial assistance.
SUBMISSION & CORRESPONDENCE INFORMATION Submitted for publication June, 2014 Submitted in final revised form July, 2014 Accepted for publication August, 2014 Address correspondence to: Peter W. Stacpoole, Ph.D., M.D., PO Box 100226, Gainesville, FL 32610-0226; E-mail: [email protected]
DISCLOSURE STATEMENT This was not an industry supported study. The authors have indicated no financial conflicts of interest.
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Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
pii: jc-00231-14 http://dx.doi.org/10.5664/jcsm.4212
Sleep Disorders Associated with Primary Mitochondrial Diseases Ryan J. Ramezani, B.S.1; Peter W. Stacpoole, Ph.D., M.D.1,2
Department of Medicine and 2Division of Endocrinology, Metabolism and Diabetes, and Department of Biochemistry and Molecular Biology, University of Florida, College of Medicine, Gainesville, FL
1
Study Objectives: Primary mitochondrial diseases are caused by heritable or spontaneous mutations in nuclear DNA or mitochondrial DNA. Such pathological mutations are relatively common in humans and may lead to neurological and neuromuscular complication that could compromise normal sleep behavior. To gain insight into the potential impact of primary mitochondrial disease and sleep pathology, we reviewed the relevant English language literature in which abnormal sleep was reported in association with a mitochondrial disease. Design: We examined publications reported in Web of Science and PubMed from February 1976 through January 2014, and identified 54 patients with a proven or suspected primary mitochondrial disorder who were evaluated for sleep disturbances. Measurements and Results: Both nuclear DNA and mitochondrial DNA mutations were associated with abnormal sleep patterns. Most subjects who underwent polysomnography had central sleep apnea, and only 5 patients had obstructive sleep apnea. Twenty-four patients showed decreased ventilatory drive in response to hypoxia
and/or hypercapnia that was not considered due to weakness of the intrinsic muscles of respiration. Conclusions: Sleep pathology may be an underreported complication of primary mitochondrial diseases. The probable underlying mechanism is cellular energy failure causing both central neurological and peripheral neuromuscular degenerative changes that commonly present as central sleep apnea and poor ventilatory response to hypercapnia. Increased recognition of the genetics and clinical manifestations of mitochondrial diseases by sleep researchers and clinicians is important in the evaluation and treatment of all patients with sleep disturbances. Prospective population-based studies are required to determine the true prevalence of mitochondrial energy failure in subjects with sleep disorders, and conversely, of individuals with primary mitochondrial diseases and sleep pathology. Keywords: sleep apnea, mitochondrial disease, congenital lactic acidosis Citation: Ramezani RJ, Stacpoole PW. Sleep disorders associated with primary mitochondrial diseases. J Clin Sleep Med 2014;10(11):1233-1239.
“P
rimary” mitochondrial diseases are heritable or spontaneous inborn errors of metabolism in which the conversion of substrate fuels into energy is perturbed by loss-of-function mutations in genes encoded by either nuclear or mitochondrial DNA (nDNA; mtDNA). In turn, these mutations give rise to functional defects in mitochondrial enzymes crucial to aerobic metabolism and oxidative phosphorylation (Figure 1). Elevation of blood and/or cerebrospinal fluid lactate is a non-diagnostic, but prevalent, biomarker of mitochondrial disorders. The commonest cause of congenital lactic acidosis (CLA; Table 1) is deficiency of the nuclear-encoded pyruvate dehydrogenase complex (PDC). PDC is located in the mitochondrial matrix and irreversibly decarboxylates pyruvate to acetyl CoA. Thus, PDC functions as a gate-keeper enzyme, linking glycolysis in the cytoplasm to the tricarboxylic acid (TCA) cycle in mitochondria.1,2 Deficiencies in pyruvate carboxylase and certain TCA cycle enzymes can very rarely cause CLA. However, most other etiologies are due to one or more deficiencies in Complexes I – V of the respiratory chain that ultimately reduce molecular oxygen to water and synthesize ATP from ADP and inorganic phosphate. All nucleated eukaryotic cells contain mitochondria and, hence, are subject to inherited or spontaneous mutations in these enzymes of energy metabolism. Consequently, it is not surprising that such primary mitochondrial diseases exhibit protean clinical complications, in which lactic acidosis is a frequent biomarker of 1233
local or systemic energy failure. Because neurons and myocytes rely primarily on mitochondrial glucose oxidation to meet their high energy demands, mitochondrial disorders typically manifest clinically as progressive neurological and neuromuscular degeneration, although any tissue and organ system can be affected.3-6 Most summaries of the natural history of primary mitochondrial diseases do not include sleep disturbances in the clinical spectrum or evaluation and treatment strategies.2,5,7,8 However, the dependency of normal sleep on both neurological and neuromuscular integrity infers a strong relationship between mitochondrial dysfunction and sleep pathology. To address this issue, we critically reviewed literature associating sleep disturbances with the clinical presentation and course of primary mitochondrial diseases. We propose that this pathophysiological relationship be considered in future mechanistically oriented research on sleep and in the clinical assessment of sleep disturbances in the general population.
METHODS We used Web of Science and PubMed to identify all English language publications from February 1976 through January 2014 that described patients who were diagnosed with a primary mitochondrial disease associated with sleep-related problems and/or in whom polysomnography (PSG) was performed. Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
RJ Ramezani and PW Stacpoole
Figure 1
A
B
Major pathways of cellular energy metabolism (A). Glycolysis in the cytoplasm is linked to the tricarboxylic acid (TCA) cycle in mitochondria by the multicomponent pyruvate dehydrogenase complex (PDC), which irreversibly decarboxylates pyruvate acetyl CoA, an intermediate that is also formed as a product of the β-oxidation of long-chain fatty acyl CoAs (LCF acyl CoAs). Alternatively, pyruvate is carboxylated by pyruvate carboxylase to oxaloacetate. Reducing equivalents (nicotinamide adenine dinucleotide NADH; flavin adenine dinucleotide, FADH2) are generated by reactions catalyzed by the PDC and the TCA cycle and donate electrons (e −) that enter the respiratory chain (B) at NADH ubiquinone-oxidoreductase (Complex I) or at succinate-ubiquinone oxidoreductase (Complex II). Electrons from Complexes I and II are transferred via coenzyme Q10 to ubiquinol-cytochrome c reductase (Complex III). Cytochromic oxidase (Complex IV) catalyses the reduction of molecular oxygen to water. Electron transfer at Complex I, III, and IV is coupled to the pumping of protons (H+) from the mitochondrial matrix to the inter-mitochondrial space. These protons are utilized by ATP synthase (Complex V) to generate ATP from ADP, thus completing the process of oxidative phosphorylation. All the enzymes of the PDC, the β-oxidation pathway and the TCA cycle are encoded by nuclear DNA (nDNA). Of the approximately 97 subunits comprising the respiratory chain complexes, only 13 are encoded by mitochondrial DNA, and the rest are nuclear-encoded (mtDNA:nDNA): Complex I (7:~46); Complex II (0:4); Complex III (1:10); Complex IV (3:10); and Complex V (2:14). Panel B from reference5 (used with permission).
Key terminologies we employed were deficiency of any of the respiratory chain complexes and various names and acronyms (see Results) denoting specific mitochondrial diseases or syndromes, coupled with different combinations of sleep disorder terms, such as central or obstructive sleep apnea and PSG. We found 18 publications in which 54 patients were described. The patients and their clinical findings were grouped, when possible, Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
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by disease or syndrome, according to modern biochemical and/ or molecular genetic diagnostic criteria.9-13
RESULTS Table 2 summarizes the diagnostic and clinical characteristics of 54 subjects with a proven or probable primary
Sleep Disorders in Mitochondrial Diseases
Table 1—Terminology used in this review. Alpers syndrome
Autosomal recessive due to mutations in mtDNA polymerase γ. Onset in youth. Widespread neurodegeneration, seizures, hepatopathy.
PEO (Progressive external ophthalmoplegia)
Maternally transmitted (mtDNA). Onset variable. Ptosis is commonly first sign. Often part of KSS.
POLG (Polymerase gamma)
Encodes for catalytic subunit of mtDNA polymerase. Onset variable for pathological mutations. May be causative for Alpers syndrome, Leigh syndrome, PEO, other severe mt diseases.
CLA (Congenital lactic acidosis)
Multiple etiologies. Onset in youth.
Heteroplasmy
A mixture of mutant and wild-type sequences in mtDNA that can be present in different proportions in different tissues. When the proportion of mutated mtDNA reaches a so-called “threshold effect” in the cells of a given tissue or organ, a new clinical phenotype appears (e.g., onset of dementia or diabetes in a patient with MELAS).
KSS (Kearns-Sayre syndrome)
First multisystem mitochondrial disorder to be defined clinically. Large-scale mtDNA deletions. Onset in youth. Retinitis pigmentosa, external ophthalmoplegia, complete heart block, ataxia, ± lactic acidosis, among many other signs and symptoms.
Leigh syndrome
Also called subacute necrotizing encephalomyopathy. Primarily involves basal ganglia and brainstem. Common to many nDNA (e.g., PDC deficiency) and mtDNA mutations. Onset usually in youth. Seizures, blindness, hearing loss, dementia, ataxia, hypotonia, ± lactic acidosis.
Mitochondrial myopathy
Multiple etiologies. Nonspecific term emphasizing skeletal muscle as disease target. Onset variable, RRFs common, hypotonia, ± lactic acidosis.
MELAS (Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes)
Maternally transmitted (mtDNA). Onset throughout life. Seizures, migraines, diabetes, hearing loss, psychiatric problems, dementia.
NARP (Peripheral neuropathy, ataxia and retinitis pigmentosa):
Maternally transmitted (mtDNA). Onset in youth, sensory neuropathy, seizures, dementia, ± lactic acidosis.
PDC deficiency (Pyruvate Dehydrogenase Complex deficiency)
All components nDNA-encoded, most are X-linked spontaneous mutations; most others are autosomal recessive. Onset in youth. Hypotonia, psychomotor retardation, seizures, lactic acidosis.
LHON (Leber’s hereditary optic neuropathy)
Maternally transmitted (mtDNA). Neuroretinal degeneration causing acute loss of central vision, especially in young men. Most prevalent mt disease, ± lactic acidosis.
RRF (Ragged red fibers)
Histochemical hallmark of mitochondrial muscle pathology, showing segmental accumulations of (usually morphologically abnormal) mitochondria in subsarcolemmal and intermyofibrillar muscle regions.
From 1,5
mitochondrial disease.14-31 All patients were diagnosed with a sleep disorder and/or had complaints of abnormal sleep, based on family report or self-report. Two patients had PDC deficiency. Patient 1, a 7-year-old boy with biochemically proven PDC deficiency, was diagnosed with central type sleep apnea syndrome, following radiological, electrophysiological, and pulmonary function criteria requiring tracheostomy and assisted ventilation.14 Patient 2 was a 13-month-old girl with classical radiological evidence of Leigh syndrome (Table 1) and cortical atrophy whose clinical picture included psychomotor retardation and hypotonia, both typical manifestations of the enzyme defect.15 Further evaluation of this child at age 7 years disclosed progressive disturbance in both auditory and somatosensory evoked potentials, coupled with polysomnographic evidence of abnormalities in both the tonic and phasic components of sleep during REM. Patient 3 was a 27-year-old woman with biochemically proven complex IV (cytochrome c oxidase) deficiency in whom PSG showed no apneic episodes despite significant desaturation during sleep, consistent with a state of hypoventilation.16 Molecular genetic testing resulted in the definitive diagnosis of a mitochondrial disease in subjects 4-14. Biopsied skeletal muscle from patient 4, an obese 23-year-old woman who had
a history of loud snoring, revealed 91% heteroplasmy for the mtDNA NARP mutation (nucleotide 8993).17 PSG showed severe obstructive sleep apnea, hypopnea, and central apnea. Patient 5 was a 37-year-old man with diabetes who had the most common mtDNA point mutation for MELAS, an A→ G tRNA leu(UUR) substitution at amino acid position 3243.18 Of interest is that this individual had none of the symptomatology typically associated with MELAS (Table 1). However, he suffered from chronic, often extreme, insomnia and was diagnosed with delayed sleep phase syndrome. Patient 6, a 21-year-old man with the identical A3243G mutation manifested gait and visual disturbance and other typical signs and symptoms of MELAS (headaches, dizziness, vomiting and stroke-like episodes). He also presented with hypoxic ventilatory depression and chronic hypoventilation of uncertain etiology.19 Following experimental exposure to hypoxia, his respiratory rate decreased, but tidal volume did not change. Sleep PSG was not performed. Patient 7 was a 48-year-old man with mitochondrial myopathy and the presence on muscle biopsy of multiple mtDNA mutations: A5466G; GA7912A and T10601C. His PSG revealed central sleep apnea, with 19 apneic episodes/hour.20 Subjects 8-15 had Leigh syndrome and demonstrated both diversity in their molecular genetic etiologies and sleep
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RJ Ramezani and PW Stacpoole
Table 2—Summary of patients and findings. Patient
Age/Sex
Diagnosis
Sleep Findings
Reference
1
7/M
PDC deficiency
Central hypoventilation syndrome
14
2
13m/F
Leigh’s syndrome; neuroradiological findings
Obstructive sleep apnea
15
3
27/F
Complex IV Deficiency
Polysomnograph revealed respiratory muscle weakness that was not limited to sleep (sleep apnea was ruled out)
16
4
23/F
NARP 8993
Obstructive sleep apnea
17
5
37/M
MELAS (A3243G)
Delayed sleep phase syndrome
18
6
21/M
MELAS
Hypoxic ventilator depression
19
7
48/M
Multiple novel mtDNA mutations
Central sleep apnea
20
8
3/F
Leigh syndrome/molecular genetic diagnosis
Central sleep apnea
21
9
1/M
Leigh syndrome/molecular genetic diagnosis
Central sleep apnea
21
10
19/F
Leigh syndrome/molecular genetic diagnosis
Hiccup apnea **
21
11
10/F
Leigh syndrome/molecular genetic diagnosis
Central/obstructive sleep apnea
21
12
12/F
MERRF/Leigh overlap syndrome/molecular genetic diagnosis (A8344g)
Central sleep apnea
21
13
2/M
Alpers/Leigh overlap syndrome/molecular genetic diagnosis (T8993G)
Severe apnea, polysomnograph could not confirm whether these apneas were central or obstructive
21
14
17/F
Leigh syndrome/neuro-radiological findings
Obstructive sleep apnea
22
15
24/M
Leigh syndrome/Brainstem encephalomyopathy of subacute onset
Obstructive sleep apnea
23
16
31/F
Ragged Red Fibers/Muscle Biopsy
Depressed ventilatory drive response to hypoxia
24
17
65/F
Ragged Red Fibers/Muscle Biopsy
Depressed ventilatory drive response to hypoxia
24
18
37/F
Ragged Red Fibers/Muscle Biopsy
Depressed ventilatory drive response to hypoxia/ hypercapnia (elevated CO2)
24
19
29/F
Kearns-Sayre/muscle biopsy ragged red fibers
Depressed ventilatory drive response to hypoxia/ hypercapnia (elevated CO2)
25
20
21/F
Kearns-Sayre/muscle biopsy, biochemical diagnosis
Depressed ventilatory drive response to hypoxia/ hypercapnia (elevated CO2)
25
21
13/M
Kearns-Sayre/muscle biopsy, biochemical diagnosis
Depressed ventilatory drive response to hypoxia/ hypercapnia (elevated CO2)
25
22
25/F
Kearns-Sayre, muscle biopsy, muscle biopsy/biochemical
Depressed ventilatory drive response to hypoxia/ hypercapnia (elevated CO2)
25
23
34/F
PEO (mt DNA deletion)
*
26
24
14/F
PEO (mt DNA deletion)
*
26
25
17/F
PEO (mt DNA deletion)
*
26
26
17/F
PEO (mt DNA deletion)
*
26
27
32/F
PEO (mt DNA deletion)
*
26
* Sleep findings for individual patients 23-42 not reported in Smits et al.26 CSA denotes central sleep apnea. See Table 1 for other abbreviations. Table 2 continues on the following page
pathologies on PSG.21-23 Patient 8, a 3-year-old girl with the pathological mtDNA mutation A8334G, had central sleep apnea. Patient 9, a 1-year-old boy with the T8993G mutation, also had central sleep apnea by PSG, while the PSG of patient 10, a 19-year-old girl with the T9176C mutation, showed obstructive sleep apnea. In contrast, mixed central and obstructive sleep apnea was diagnosed in a 10-year-old-girl with the same pathological mutation (Patient 11). Patient 12 year a 12-year-old girl with a MERRF/Leigh overlap syndrome caused by an A8344G Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
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mtDNA mutation. Patient 13 was a 2-year-old boy with Alpers/Leigh overlap syndrome due to an A8993G substitution in mtDNA who had severe apneic breathing, although PSG could not differentiate between central or obstructive pathology.21 Patient 14, a 17-year-old girl, had Leigh syndrome of undetermined etiology, myopathy, obesity, and obstructive sleep apnea.22 Seventeen cases demonstrated clinical and/or muscle biopsy findings consistent with a primary mitochondrial disease
Sleep Disorders in Mitochondrial Diseases
Table 2 (continued )—Summary of patients and findings. Patient
Age/Sex
Diagnosis
Sleep Findings
Reference
28
11/M
PEO (mt DNA deletion)
*
26
29
25/M
PEO (mt DNA deletion)
*
26
30
14/M
PEO (mt DNA deletion)
*
26
31
12/F
PEO (A3243G)
*
26
32
12/M
PEO (A3243G)
*
26
33
36/M
PEO (G12315A)
*
26
34
30/M
PEO (T5709C)
*
26
35
48/M
PEO (A4267G)
*
26
36
21/M
POLG
*
26
37
4/M
POLG
*
26
38
13/F
POLG
*
26
39
23/M
POLG
*
26
40
39/M
POLG
*
26
41
53/M
POLG
*
26
42
24/F
POLG
*
26
43
46/M
Mitochondrial Encephalomyopathy/muscle biopsy
Central sleep apnea
27
44
40/M
LHON (G3460A)
Central sleep apnea
28
45
34/M
Mt encephalopathy; MRI consistent with Leigh syndrome
Hypnic
29
46
30/F
Ophthalmoplegia plus (Kearns Sayre), ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Reduced ventilatory response to inhaled CO2 as compared to normal values
30
47
41/M
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Reduced ventilatory response to inhaled CO2 as compared to normal values, no sleep apnea episodes
30
48
62/F
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Desaturation during sleep irrespective of breathing rhythm, reduced ventilatory response to inhaled CO2 as compared to normal values, no sleep apnea episodes
30
49
51/F
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Mainly CSA, reduced ventilatory response to inhaled CO2 as compared to normal values
30
50
42/M
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Reduced ventilatory response to inhaled CO2 as compared to normal values, no sleep apnea episodes
30
51
55/M
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Mainly CSA; reduced ventilatory response to inhaled CO2 as compared to normal values
30
52
55/M
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically
Mainly CSA; reduced ventilatory response to inhaled CO2 as compared to normal values
30
53
52/F
Ophthalmoplegia plus, ragged red fibers by electron microscopy/histochemically, cytochrome c oxidase defect
Mainly CSA; reduced ventilatory response to inhaled CO2 as compared to normal values
30
54
34/F
Leigh’s syndrome, histochemical diagnosis
CSA
31
* Sleep findings for individual patients 23-42 not reported in Smits et al.26 CSA denotes central sleep apnea. See Table 1 for other abbreviations.
etiology without definitive biochemical or molecular genetic proof of an enzymatic defect or pathological nDNA or mtDNA mutation. Patient 15 was a 24-year-old male with encephalomyopathy who was diagnosed with Leigh syndrome in view of clinical and neuroradiological findings, although genetic testing did not identify a causative mutation.23 Patients 16-18 showed depressed ventilatory response to hypoxia; patient 16, a 31-year-old woman with RRF found on muscle biopsy, also exhibited depressed ventilatory drive to 1237
hypercapnia.24 PSG was not performed in these subjects and the investigators surmised that their sleep abnormalities were attributable to a defect in central and/or peripheral chemoreceptor function, rather than to an intrinsic weakness in the muscles of respiration. Patients 19-35 were diagnosed with PEO or Kearns-Sayre syndrome on the basis of clinical findings and muscle biopsy studies that showed the presence of RRFs and/or other myopathic changes.25,26 Subjects 19-22 exhibited depressed Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
RJ Ramezani and PW Stacpoole
ventilatory drive in response to hypoxia and hypercapnia that was not considered due to weakness of respiratory muscles. Thirteen patients had PEO due either to a point mutation or a deletion of mtDNA, and patients 36-42 had a mutation in POLG, causing disruption in mtDNA replication. Patients 23-42 underwent extensive evaluation at a single Dutch neuromuscular center,26 and despite differences in the etiology of their mitochondrial disease, shared several common clinical features relevant to sleep pathology. Fifteen of the 20 patients had subjective nocturnal sleep dysfunction, as indicated by a Pittsburgh Sleep Quality Index score > 5, while 6 subjects reported excessive daytime sleepiness (Epworth Sleepiness Scale score > 10) and 14 patients had symptoms of depression and/or anxiety (Hospital Anxiety and Depression Scale). Disruptive sleep architecture in these patients was variably manifested by decreased sleep efficiency, duration of wakefulness after sleep onset and increased frequencies of stage 1 sleep and arousal index. Cognitive impairment, proximal myopathy, ataxia, restless leg syndrome, dysarthria, and polyneuropathy were also common features. One subject had a mild obstructive component to sleep apnea, while at least 20% of the patients had central sleep apnea. However, subjective nocturnal sleep dysfunction did not predict PSG results. Patient 43 was a 46-year-old man who had PSG evidence of central sleep apnea, and mitochondrial encephalomyopathy, based on muscle biopsy.27 He also had an abnormally elevated blood lactate-pyruvate response during exercise and elevated lactate and pyruvate concentrations in cerebrospinal fluid. This patient’s respiratory disturbance was determined to be primarily due to brainstem involvement, based on high-signal intensity lesions from midbrain to medulla seen on magnetic resonance imaging (MRI) and on tests of both somatosensory and brainstem auditory evoked potentials. Phrenic nerve conduction velocity was also prolonged, which could contribute to the patient’s disturbed respiration. Patient 44 had LHON due to a common point mutation, whose central sleep apnea was associated with excessive daytime sleepiness and oxygen desaturation up to 72% SpO2 during sleep.28 Patient 45 had an undefined mitochondrial encephalopathy and MRI findings consistent with Leigh syndrome, whose abnormal sleep architecture was characterized by hypnic myoclonus, prolonged sleep onset, and reduced sleep efficiency.29 Patients 46-54 had ophthalmoplegia and RRFs on muscle biopsy, and all but patient 52 were reported to have complex IV deficiency in skeletal muscle.30 PSG revealed that all patients had reduced ventilatory response to inhaled carbon dioxide. Patients 47, 48, and 50 exhibited no apneic episodes during sleep, although patient 48 desaturated during sleep irrespective of breathing rhythm. Patients 49 and 51-53 had mainly centraltype sleep apnea. Patient 54 was a 34-year-old woman with Leigh syndrome, whose PSG also revealed central sleep apnea.31 The patient breathed normally while awake; however, immediately after the onset of sleep, her respiratory rate and tidal volume became irregular. Her oxygen saturation averaged 78% during NREM sleep and 45% during REM sleep. Central apneas (72/h of sleep) usually last 10 to 15 seconds, but reached a maximum of 35 seconds of REM sleep. Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
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DISCUSSION These data indicate that, of 54 subjects with proven or suspected mitochondrial disease, 47 had PSG recordings, and 12 of these individuals exhibited central sleep apnea. Twenty-four patients showed depressed ventilatory drive in response to hypoxia and/or hypercapnia that investigators did not attribute to weakness of the intrinsic muscles of respiration. Only five patients, at least two of whom were obese, showed signs of obstructive sleep apnea. Two practical questions begged by these findings pertain to the frequency of their occurrence relative to the prevalence of primary mitochondrial diseases in the general population and whether a family or personal history of mitochondrial diseases should be included in the initial evaluation of any person with suspected sleep pathology. This retrospective analysis can only hint at the true associations between mitochondrial disease and abnormal sleep. However, at least 1:200 ostensibly healthy humans are reported to harbor at least one pathological mtDNA mutation potentially capable of causing disease in the offspring of female carriers.32 Although most such carriers are unlikely to ever exhibit clinical signs or symptoms, up to 1:5000 people in the general population will ultimately clinically manifest a mtDNA disease.33,34 In addition, all the PDC components and the vast majority of the subunits of the respiratory chain are nuclear encoded. Thus, nDNA and mtDNA mutations in genes encoding enzymes of mitochondrial fuel metabolism are common causes of human morbidity. Furthermore, because highly oxidative tissues, such as the nervous system and muscle, are so vulnerable to disruption of mitochondrial energetics, it is reasonable to assume that disordered sleep may be one sign of dysfunction affecting these organ systems. Indeed, chronic fatigue and diminished exercise tolerance are common complications or primary mitochondrial diseases2,5 that could reflect, at least in part, abnormal sleep patterns unrecognized by affected individuals, their families and their healthcare providers. What underlying mechanisms beyond energy failure might contribute to sleep pathology in mitochondrial disease? Neuromuscular degeneration and hypotonia are also classic clinical manifestations of mitochondrial diseases and were highly represented in the patients described in this review. Because even healthy subjects experience some loss of respiratory muscle tone during REM sleep, it would follow that mitochondrial disease patients have increased susceptibility to REM-associated hypotonia and hypoxemia, as occurs in patients with other forms of neurodegenerative disease.27 Although weakness of respiratory and upper airway muscles would contribute to sleep-disordered breathing, an additional potentially important contributing factor could be brainstem involvement that is particularly common in patients with Leigh syndrome or following stroke-like episodes in patients with MELAS.18 Others have observed characteristic respiratory patterns in individuals with Leigh syndrome, including post-sigh apnea, hiccup, and apneusis that could reflect compromise of dorsal root ganglion neurons proximate to the solitary tract nucleus.20 We conclude from this retrospective review that abnormal sleep patterns may be underreported complications of patients with primary mitochondrial disorders. The basic underlying mechanism of cellular energy failure results in both
Sleep Disorders in Mitochondrial Diseases
central neurological and peripheral neuromuscular degenerative changes that are reflected, to variable degrees, as central sleep apnea and poor ventilatory responses to hypercapnia. In turn, disordered sleep in affected patients contributes to a vicious cycle of progressive daytime fatigue, hypotonia, and exercise intolerance. This self-perpetuating pattern is similar to the positive feedback loop experienced by many other individuals whose sleep disturbances are not known to be caused by a primary mitochondrial disease. However, it is this very similarity in clinical presentation and course that has masked the true prevalence and underlying mechanisms of sleep pathology in primary mitochondrial diseases, which can only be satisfactorily addressed by prospective, population-based studies. There are no proven treatments for any primary mitochondrial disease, so traditional interventions are supportive, yet anecdotal. Treatment of sleep disturbances may be one of the few options to improve the quality of life of affected patients. Thus, we suggest that increased attention by sleep researchers to a patient’s family history of maternally transmitted disorders and awareness of the multisystem clinical features of mitochondrial diseases may be critical to the differential diagnosis of all patients with sleep disturbances.
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ACKNOWLEDGMENTS The authors thank Drs. Brian Fuehrlein, Paul Carney and Richard Berry for helpful comments and Ms. Candace Caputo for editorial assistance.
SUBMISSION & CORRESPONDENCE INFORMATION Submitted for publication June, 2014 Submitted in final revised form July, 2014 Accepted for publication August, 2014 Address correspondence to: Peter W. Stacpoole, Ph.D., M.D., PO Box 100226, Gainesville, FL 32610-0226; E-mail: [email protected]
DISCLOSURE STATEMENT This was not an industry supported study. The authors have indicated no financial conflicts of interest.
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