PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset Central Hypoventilation syndrome

Congenital central hypoventilation syndrome mimicking mitochondrial disease

“…The phenotype of our patient was similar to other patients with LO‐CCHS, which was previously reported in heterozygous 24 PAR 10, 11 and some of 25 PAR 2, 18, 19, 20, 21. Her ascites, pleural effusion, hepatomegaly, as well as pulmonary hypertension, right ventricular hypertrophy, and right atrium enlargement could be explained from pulmonary and cardiac failure.…”

Late onset congenital central hypoventilation syndrome after exposure to general anesthesia

“…The reason for this congenital syndrome becoming apparent only after exposure to general anesthesia is unknown, but it could be explained, at least in part, by variable penetrance and the degree of mutation of the causative gene. 13 Clinically, care should be taken to distinguish LO-CHS from a disorder known as rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD). However, children with ROHHAD present with rapid weight gain (15-20 pounds) from three to ten years of age, and they do not have mutations in PHOX2B.…”

Sensitive Detection of Polyalanine Expansions in PHOX2B by Polymerase Chain Reaction Using Bisulfite-Converted DNA

“…The prevalence of polyalanine expansions, ranging from 5 to 13 residues, in patients with CCHS has been reported. [3][4][5] In a previous study, heterozygous polyalanine triplet expansions were detected in 4 of 10 affected Japanese patients. 6 Amino acid tandem repeats, also known as homopolymeric tracts, are abundant in the human genome.…”

“…The unusually high GC content interferes with direct polymerase chain reaction (PCR) amplification, except for that of relatively large fragments more than 380 bp. 2,4 Even when PCR does operate, the smaller repeat allele is predominant, allowing the possibility that the other fully expanded allele does not undergo successful amplification. 4,8 To avoid technical difficulties arising from high GC contents, a bisulfite treatment for DNA has been developed for Gand C-containing repeat expansions such as that in fragile X syndrome.…”

“…2,4 Even when PCR does operate, the smaller repeat allele is predominant, allowing the possibility that the other fully expanded allele does not undergo successful amplification. 4,8 To avoid technical difficulties arising from high GC contents, a bisulfite treatment for DNA has been developed for Gand C-containing repeat expansions such as that in fragile X syndrome. 9,10 This chemical deamination by bisulfite converts cytosine selectively to uracil on single-stranded DNA, on which conventional PCR potentially operates.…”