Primary ciliary dyskinesia

Did You Know?

• The classic symptom combination was first described in 1904 by A. K. Siewert, while Manes Kartagener published his first report on the subject in 1933.
• Future promising avenues for functional replacement of cilia involve antisense, gene editing via CRISPR-Cas9, and mRNA therapies.

Signs and symptoms

Primary ciliary dyskinesia often announces itself right after birth: about four out of five babies with the condition have breathing trouble within their first day. Many also have a collapsed lung lobe and dangerously low blood oxygen that calls for supplemental oxygen. Within a few months, a chronic, mucus-heavy cough and a runny nose become the norm. The root problem is that the cilia can’t clear mucus from the lungs, leaving the airways wide open for repeated infections like sinusitis, bronchitis, pneumonia, and ear infections. This sets off a cycle of progressive damage, including bronchiectasis that starts in early childhood and sinus disease that can turn severe in adults. Despite these clear early signs, diagnosis is often delayed. In males, sperm that can’t move often cause infertility, though in vitro fertilization can help, and some men do have motile sperm. In females with Kartagener’s syndrome, the fallopian tubes’ cilia don’t work right, which also cuts fertility. Many patients lose some hearing and have middle ear infections that may or may not improve with ear tubes. Sense of smell can be poor, likely because of heavy sinus mucus, though some people say their smell and taste are normal or even sharper. The disease’s course varies widely; in severe cases, a lung transplant becomes necessary. Catching it early makes a big difference: it can sharply cut the risk of infections. Chest physiotherapy, done regularly, has been shown to lower lung infection rates and slow bronchiectasis. Early, aggressive treatment of sinus disease is thought to limit long-term sinus damage, though solid proof is still lacking. And a full-court press—clearing mucus, preventing infections, and treating bacterial overgrowth—has been observed to slow lung decline. The condition affects about 1 in every 7,500 people.

Genetics

Primary ciliary dyskinesia is a genetic condition that impairs motile cilia, structures built from about 250 proteins. In roughly 90% of cases, defects occur in the outer or inner dynein arms, which enable cilia movement. About 38% of these defects stem from mutations in DNAI1 or DNAH5, genes for outer dynein arm proteins. Over 50 genes, including GAS2L2, are linked to this disorder.

Pathophysiology

Primary ciliary dyskinesia is a genetic disorder passed down through families. The tiny hair-like structures called cilia are built from components like inner and outer dynein arms, the central apparatus, and radial spokes. When these parts are missing or broken, the axoneme—the core of the cilium—cannot move. Sometimes the structure looks fine, but chemical problems still stop the cilia from working properly. This malfunction starts affecting the body during embryonic development. A special type of cilium, the nodal monocilium, is key here. Unlike typical motile cilia, it lacks central microtubules and spins clockwise instead of beating back and forth. In the embryo’s primitive node, these cilia are tilted backward, tracing a D-shaped path rather than a perfect circle. In mouse and chick embryos, this creates a steady leftward flow that pushes a protein to the left side, triggering normal left-right body asymmetry. In some people with PCD, mutations likely in the gene for left-right dynein (lrd) stop these nodal cilia from spinning. Without that flow, the protein moves randomly, and about half of those affected develop situs inversus, where internal organs are mirrored, sometimes with dextrocardia. This combination is called Kartagener syndrome. But not all PCD mutations cause this: at least 6% of people with PCD have situs ambiguus, or heterotaxy, where organ placement is a mix of normal and reversed. Splenic issues like polysplenia, asplenia, and complex heart defects are more common in this group, as they are in anyone with situs ambiguus.

Prognosis

There is no reliable estimate of life expectancy for people with PCD, but evidence indicates it is a life-altering, life-shortening multi-system condition, with some people progressing to lung transplant. Decline in lung function has been observed in most studies, with FEV1 decline causing deterioration in health and reducing quality of life. With such a genetically and phenotypically heterogeneous group, observation of median or mean decline in lung function risks regression to the mean, missing groups with significantly worse lung function masked by those with milder phenotypes. Recent published data from clinicians in the United Kingdom, Europe, North America, Canada, and Israel indicate that PCD morbidity and mortality appear to have been underestimated by the medical community. Children with PCD typically have similar or worse lung function than those with cystic fibrosis, and poor lung function is repeatedly observed in children with PCD, with some developing bronchiectasis during childhood.