Characteristics of Breathing Abnormality in Leigh and its Overlap Syndromes

Abstract

In this report we describe the respiratory patterns of six patients with Leigh syndrome, including two individual cases with accompanying clinical phenotypes of Alpers disease and mitochondrial encephalopathy with ragged red fibers. In five cases where sleep apnea was monitored, each one showed isolated or post-sigh central apnea, hiccup, apneusis-like breathing and obstructive apnea in various combinations. The remaining patient with Alpers/Leigh overlap syndrome showed an apneusis-like pattern of dyspnea. The sleep structure was examined in three patients. Two patients with brainstem lesions showed a decrease in the deep sleep stages and an absence of REM sleep. Medullary lesions were found in four patients by magnetic resonance imaging or at autopsy and involved predominantly the dorsal respiratory group (DRG) of medullary neurons. The role of DRG lesions in the pathophysiology of respiratory symptoms in Leigh syndrome is discussed.

Fatal breathing dysfunction in a mouse model of Leigh syndrome

“…We noted previously (23) that KO mice resemble humans with LS with regard to a large range of phenotypes and we now extend that to breathing. Respiratory abnormalities affect many LS patients (8,9,35,36) and virtually all patients with mutations in the NDUFS4 gene (16-21, 37); however, the link between mitochondrial dysfunction and breathing could not be investigated without an animal model.…”

Sleep apnea in pediatric neurological conditions

“…In a case series of adults with Alexander disease with brainstem (mainly medullary) involvement, OSA was common [53]. Mitochondrial disorders generally show a mixed pattern of obstructive and central events from brainstem involvement, phrenic nerve involvement, or diaphragmatic and intercostals muscle weakness; they can be life-threatening, especially during exacerbations [54]. Decreased sleep effi ciency and more awakenings were noted commonly in adults with multiple sclerosis with high subtentorial lesion burden, especially during exacerbations [55].…”

Outpatient Anesthesia for Oral Surgery in a Juvenile With Leigh Disease

“…Magnetic resonance imaging or computed tomography often reveals symmetrical necrotic lesions along the brainstem, diencephalon, and basal ganglion. 6,7 Lesions also occur frequently on the cerebellum and spinal cord but with less definitive histologic features. 8 The necrosis shows no partiality between gray and white matter, particularly on the brainstem, and the brainstem tegmentum is the structure most frequently damaged.…”

“…9 The lesions may be contemporaneous with optic demyelination and instances of spongiform cavitation. 7 Leigh disease is thought to be attributable to disorders of energy metabolism, specifically, mitochondrial respiratory chain defects and deficiencies of the pyruvate dehydrogenase complex. 10 These abnormalities elevate pyruvate levels in the serum and cerebrospinal fluid and also instigate lactic acidosis, all of which are defining clinical characteristics of the disease.…”

“…2,10 Recurring focal lesions suggest increasingly insufficient energy supply at these areas as the disease progresses. 7 A study by Howell et al 11 reports that a mutation of mitochondrial DNA may be causatively associated with the presentation of the disease.…”