Effect of genetically caused excess of brain gamma-hydroxybutyric acid and GABA on sleep.
BACKGROUND
Exogenous gamma-hydroxybutyrate (GHB) increases slow-wave sleep and reduces daytime sleepiness and cataplexy in patients with primary narcolepsy.


OBJECTIVE
To examine nighttime sleep and daytime sleepiness in a 13-year-old girl homozygous for succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare recessive metabolic disorder that disrupts the normal degradation of 4-aminobutyric acid (GABA), and leads to an accumulation of GHB and GABA within the brain.


METHODS
Sleep interview, nighttime polysomnography, Multiple Sleep Latency Tests, and continuous 24-hour in-lab recordings in the patient; overnight polysomnography in her recessive mother and in a 13-year-old female control.


RESULTS
During quiet wakefulness, background electroencephalographic activity was slow and composed of 7-Hz activity. Sleep stage 3/4 was slightly increased (28.1% of total sleep period, norms 15%-28%), and the daytime mean sleep latency was short in the patient (3 minutes 42 seconds, norms > 8 minutes). Stage 2 spindles were infrequent in the child (0.18/minute, norms: 1.2-9.2/minute) and her mother (0.65/minute) but normal (4.6/minute) in the control. At the beginning of the second night, a tonic-clonic seizure occurred, followed by a dramatic increase in stage 3/4 sleep, that lasted 46.3 % of the total sleep period, double the normal value. The mother showed a reduced total sleep time and rapid eye movement sleep percentage.


CONCLUSIONS
This suggests that a chronic excess of GABA and GHB induces subtle sleep abnormalities, whereas increased slow-wave sleep evoked by a sudden event (here an epileptic seizure) may be caused by a supplementary increase in GABA and GHB.
Arnulf
Isabelle
I
Fédération des Pathologies du Sommeil, Hôpital Pitié-Salpêtrière. arnulf@stanford.edu
Konofal
Eric
E
Gibson
K Michael
KM
Rabier
Daniel
D
Beauvais
Pierre
P
Derenne
Jean-Philippe
JP
Philippe
Anne
A
D000293:Adolescent; D001921:Brain / Q000378:metabolism*; D020739:Brain Diseases, Metabolic, Inborn / Q000097:blood / Q000201:enzymology / Q000235:genetics; D006970:Disorders of Excessive Somnolence / Q000175:diagnosis* / Q000503:physiopathology*; D004569:Electroencephalography; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology; D043586:Methylmalonyl-CoA Decarboxylase / Q000097:blood; D017286:Polysomnography; D012890:Sleep / Q000502:physiology*; D012894:Sleep Stages / Q000502:physiology; D012978:Sodium Oxybate / Q000378:metabolism* / Q000652:urine; D050644:Succinate-Semialdehyde Dehydrogenase / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D014851:Wakefulness / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000235:genetics* / Q000378:metabolism* / Q000652:urine
D005680:gamma-Aminobutyric Acid; D012978:Sodium Oxybate; D050644:Succinate-Semialdehyde Dehydrogenase; D043586:Methylmalonyl-CoA Decarboxylase