Apnea and Hyperventilation

Children with Pitt-Hopkins can have periods of very unusual breathing patterns, which has been reported by some parents may be due to anxiety issues. Treatment of anxiety could help reduce apnea and hyperventilation. Usually it manifests between their 5th and 10th year of age, but earlier or much later (sometimes only in early adulthood) has been observed as well. A typical pattern is a few minutes very fast breathing (hyperpnoea), followed by a period during which the child stops breathing completely (apnoea). This pattern can be present repeatedly, also within a short period of time. Both fast breathing or temporarily no breathing can occur separately as well. During sleep breathing is usually normal. During the fast breathing the child swallows a lot more air, which enters the belly and gut, and causes a distended belly.


Sunday , 25 September 2011
Hall 2-32         Session 109        12:50-14:40  


Thematic Poster Session : New insights in paediatric respiratory physiology  
Acetazolamide for severe hyperventilation and apnea in a child with Pitt-Hopkins syndrome

S. Verhulst, W. De Backer (Wilrijk, Belgium)

Case report: We present the case of a 9 year old boy with Pitt-Hopkins syndrome who had severe attacks of hyperventilation followed by apnea and syncope while awake. These episodes occurred on a daily basis. A magnetic resonance scan of the brain at the age of 4 years showed a normal aspect of the brain stem and cerebellum. Figure 1 shows serious oxygen desaturation and hypocapnia.

In view of the hyperventilation, we started the patient on 250 mg of acetazolamide once daily. The patient was reevaluated one and a half month later. The clinical picture was markedly improved: long lasting apneas and episodes of syncope were no longer observed. A blood gas showed a pH of 7.35 with a pCO2 of 32.9 mmHg and a base excess of -6.5 mmol/L. Polygraphic monitoring showed the presence of several short central apneas but with preserved oxygen saturation and a more stable CO2 curve.
Discussion: Pitt-Hopkins syndrome is due to de novo mutations at the TCF4 locus and is characterised by distinct facial features, mental retardation and episodic hyperventilation with apnea while awake. Both the pathogenesis of these hyperventilation episodes as its treatment are unknown. This is the first report on the positive effect of acetazolamide on daytime hyperventilation and apnea in this syndrome. In this view; it would also be interesting to study the effects of acetazolamide in patients with similar syndromes including Rett and Joubert syndrome.


TCF4 deletions or mutations and apnea

Samiya Ahmad, MD and Jannine D. Cody, PhD
20 August 2012

There have been two recent reports about the treatment of apnea in children with Pitt Hopkins syndrome. We wanted to explain the findings in hopes that it could help guide families struggling with this issue.

The first paper (Verhulst et al., 2012) reported on two patients with Pitt Hopkins syndrome. One patient (a 21 year old male) had a mutation in the TCF4 gene and the other patient (A 9 year old male) had a deletion of the gene. The first was diagnosed with central apnea and both patients would daily hyperventilate followed by fainting. The first patient was also on valproate for epilepsy. Both were started on 250 mg of acetazolamide and both had considerable improvement in oxygen saturation during sleep and the decreased frequency of apnea episodes.

A second report (Maini et al., 2012) described a single patient (7 year old female) with Pitt Hopkins syndrome caused by a TCF4 mutation. She was shown to have central apnea during both wakefulness and sleep. She was treated with diazepam (0.25 mg/kg/d) and showed no improvement. She was then started on slowly increasing doses of valproate until she reached a dose of 25 mg/kg/d. This decreased, though did not eliminate, the incidence of apneas, and improved oxygen saturations.

Acetazolamide is not a typical treatment for apnea. It is used for acute altitude sickness and central apnea caused by high altitude in adults. The safety and effectiveness in children is unknown. Valproate is typically used for epilepsy and migraine headache prophylaxis. It has the potential for liver damage and should be used cautiously with close medical monitoring. Given that all medicines can have side effects, especially when used long-term, and these are case reports of a total of 3 patients, it is prudent to proceed cautiously. The first step if your child has hyperventilation episodes and/or possible sleep apnea, is to have a sleep study (polysomnography) performed and interpreted by a certified sleep specialist. Sleep specialists can be from a neurology, pulmonology, otolaryngology (ENT) or medicine/pediatric background. If central apnea is confirmed, then the use of a positive pressure device (BiPAP with back-up rate) is the least risky treatment. If that is ineffective or not tolerated, then the use of drug therapy could be pursued and your sleep physician could use these papers as a guide.

Verhulst SL, De Dooy J, Ramet J, Bockaert N, Van Coster R, Ceulemans B, De Backer W. (2012). Acetazolamide for seere apnea in Pitt-Hopkins syndrome. Am J Med Genet Part A 158A:932-934.

Maini I, Cantalupo G, Turco EC, De Paolis F, Magnani C, Parrino L Terzano MG, Pisani F. (2012). Clinical and polygraphic improvement of breathing abnormalities after valproate in a case of Pitt-Hopkins syndrome. J Clin Child Neurol Feb 28.


A new treatment for breathing problems in children with Rett syndrome may hold promise for children with Pitt Hopkins syndrome: Researchers from Bristol’s School of Physiology & Pharmacology announced that they have successfully discovered ways to stop breath holding episodes in people who are affected by Rett Syndrome. Their claim is that, through the use of existing drugs, they can alter the body’s levels of γ-Aminobutyric acid (GABA), which is a neurotransmitter in the nervous system. Augmenting GABA markedly improves the respiratory phenotype. In addition, a serotonin 1a receptor agonist that depresses expiratory neuron activity also reduces apnea, corrects the irregular breathing pattern, and prolongs survival in MeCP2 null males. Combining a GABA reuptake blocker with a serotonin 1a agonist in heterozygous females completely corrects their respiratory defects. (pnas.org)  See link to article: http://reverseautismnow.org/researchers-discover-how-to-stop-breath-holding-in-girls-with-rett-syndrome.html