Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype

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Abstract

Rationale:

In primary ciliary dyskinesia (PCD), factors leading to disease heterogeneity are poorly understood.

Objectives:

To describe early lung disease progression in PCD and identify associations between ultrastructural defects and genotypes with clinical phenotype.

Methods:

Prospective, longitudinal (5 years), multicenter, observational study. Inclusion criteria: < 19 years at enrollment; > 2 annual study visits. Linear mixed effects models including random slope and random intercept were used to evaluate longitudinal associations between ciliary defect group (or genotype group) and clinical features (percent predicted FEV1, weight and height z-scores).

Measurements and Main Results:

137 participants completed 732 visits. The group with absent inner dynein arm, central apparatus defects and microtubular disorganization (IDA/CA/MTD; n=41) were significantly younger at diagnosis and in mixed effects models had significantly lower percent predicted FEV1, weight and height z scores than the isolated outer dynein arm (ODA) defect (n=55) group. Participants with CCDC39 or CCDC40 mutations (n=34) had lower percent predicted FEV1, weight and height z-scores than those with DNAH5 mutations (n=36). For the entire cohort, percent predicted FEV1 decline was heterogeneous with a mean (standard error, SE) decline of 0.57 (0.25) percent predicted/year. Rate of decline was different from zero only in the IDA/MTD/CA group (mean (SE) -1.11 (0.48) pp/yr; p=0.02).

Conclusions:

Participants with IDA/MTD/CA defects, which included individuals with CCDC39 or CCDC40 mutations, had worse lung function and growth indices compared to those with ODA defects and DNAH5 mutations, respectively. The only group with a significant lung function decline over time were participants with IDA/MTD/CA defects.

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