Respiration

Disturbed regulation of respiration is one of the main criteria of PTHS. It is most probably part of the general dysautonomia that occurs in PTHS. Dysautonomia means that all processes which are automatically steered by your nervous system are no longer regulated well. This means it might also show in characteristics such as dilated pupils with sluggish response to light, instability of temperature, decrease circulation in hands and feet, constipation, or not emptying urine completely from the bladder urinary retention.
Respiration problems can start at a variable age. We gathered data on 256 children and adults with PTHS and found that 123 (48%) had hyperbreathing which started at a mean age of 6 years, but it could start as early as 3 months or as late as 37 years. The true frequency of a disturbed respiration may well be higher, as affected individuals may have been reported at an age where they may not yet have developed the abnormal breathing. When checking this for each age group the incidence of respiration problems was 20% before 2 years of age, 23% between 3 and 5 years, 22% between 6 and 10 years, 69% between 11 and 15 years, and present in over 90% of older individuals. Rarely, hyperbreathing has started to occur in a young child and then, after months or even years, disappeared again for several years. We did not see a relation between the change in the gene and the occurrence of hyperbreathing.
The typical breathing pattern consists of rapid breathing, sometimes regular sometimes irregular, followed by a pause in breathing. It usually takes 2 to 5 minutes. It may occur several times per hour to a few times per year. The spells are not reported during sleep. Apnoea’s and hyperbreathing may also occur independent of each other. Periods of hyperbreathing may be triggered by excitement, stress, or anxieties, but may also occur without clear issues that makes it arise. A period of apnoea may be followed by cyanosis (blue discoloration of lips and pale blue skin) and rarely loss of consciousness. Oxygen saturation (the amount of oxygen in the blood) may be decreased during a spell of abnormal breathing.  We are not aware of any instance that the heart stopped beating provoked by a spell of apnoea (R11). Sometimes the epilepsy occurs first and after months or years the breathing abnormalities follow, but the reverse occurs as well, but only infrequently a spell is followed immediately by a seizure. Many affected individuals develop clubbing of fingers (broadening of the tips of the fingers) within a few years after the start of the breathing irregularities. Clubbing was present in 9 of 49 individuals with PTHS in whom the hands were evaluated during the 2018 PTHS World Conference. In some the clubbing had been noted before the hyperbreathing had started but it is more likely the hyperbreathing had gone unnoticed before.
Other consequences of the abnormal breathing are excessive burping and swelling of the abdomen. Breathing spells may cause anxieties in a child or adult with PTHS and appear quite concerning, but many do not seem to be disturbed and remain comfortable. Others stop what they are doing, some sit down to prevent a fall, and in a minority loss of consciousness occurs. Infrequently, irregular breathing at night and catathrenia (an apnoea at the end of inhaling air and groaning when exhaling, both during sleep) has been reported. Parasomnias (unusual behaviour during sleep like nightmares and sleepwalking) were reported in 10 of the attendees of the 2018 PTHS World Conference. Although polysomnographies are not available for evaluation, it has been suggested that the breathing problems at night may also have a different cause and be obstructive in nature (R12).
There is a report from Belgium on two children with PTHS and marked spells of hyperbreathing which decreased in number and duration when using acetazolamide, and in another adult it did work too. Acetazolamide is a carbonic anhydrase inhibitor and is used in acute mountain sickness which resembles the breathing problems in PTHS to some extent. However, how it may work in PTHS is still uncertain. A major side effect may be low potassium levels which has been a reason to stop the medication in several children and adults with PTHS. In individuals without PTHS, other medications such as triazolam and zolpidem have been used for central sleep apnoea, but we must assume the effect in PTHS to be low due to the different origin of the respiratory problems in PTHS. In a mouse model of another syndrome, Rett syndrome, in which breathing problems also occur, sarizotan has been shown to reduce the incidence of apnoea and hyperbreathing, and a clinical trial is now underway. If successful it may hold promise for the breathing problems in PTHS.

Recommendations
R11 It should be explained to caregivers that spells of hyperbreathing, despite being disturbing to witnesses, are unlikely to be harmful.

R12 If breathing disturbances occur at night, polysomnography should be considered in individuals with PTHS to exclude obstructive sleep apnoea.