Knowledge on rare diseases and orphan drugs

Cystic fibrosis (CF) is the most common genetic disorder among Caucasians. In Europe, the average prevalence at birth is 1/5,000; the average prevalence in the general population is 1/9,000. There is wide variation in both rates depending on geographic location.

CF is chronic and usually progressive. Symptoms often start at birth and involve the lungs and gastrointestinal tract. A common presentation might include thick secretions and chronic infections in the lung, bulky diarrhea and short stature. Abnormal airway secretions, inflammation and infections lead to bronchiectasis and early death. CF-related diabetes (CFRD) occurs at high frequency, rising to nearly 50% of patients surviving to age 50. Male sterility is common. Individuals with mild phenotypes may have mild or absent respiratory symptoms in childhood, but some may have infertility or may develop bronchiectasis or pancreatitis later in life. These individuals are typically diagnosed by newborn screening, but may be diagnosed later in life.

Abnormal chloride channel function causes high salt content sweat and highly viscous mucus secretions. CF is a monogenic autosomal recessive disease caused by CFTR mutations. Among thousands of mutations, less than 300 cause disease when present in a homozygous or compound heterozygous state. About 70% of patients are homozygous for the delta F508 allele; 30 other mutations account for 20% of cases. Genotype and phenotype correlate poorly, but mutations associated with pancreatic insufficiency lead to more severe phenotypes. Mutations permitting residual CFTR function (e.g. R117H) are associated with the milder phenotype. Many factors influence phenotype.

Diagnosis requires a typical clinical syndrome and either laboratory confirmed CFTR protein dysfunction or presence of two disease-causing mutations of CFTR on heteroalleles. Sweat testing confirms protein dysfunction. Newborn screening may presumptively diagnose CF before symptoms.

Any cause of bronchiectasis may mimic CF including primary ciliary dyskinesia, immunodeficiency, autoimmune disease, untreated pneumonia, esophageal reflux, or anatomic limitation to airway clearance such as in scoliosis. Some unusual or rare conditions falsely elevate sweat chloride suggesting CF. Genetic testing helps in these cases.

In at risk pregnancies, mutation analysis of chorionic villus samples after gestation week eight is possible for diagnosis.

The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at risk couples carrying CF mutations (identified by birth of a child with CF, neonatal screening detection of carrier status or family history), informing them that the risk of having an affected child at each pregnancy is 25%.

Treatment is transitioning from addressing symptoms to correcting biochemical defects. The oldest therapies include bronchial drainage and broad spectrum antibiotics for increasingly resistant pathogens. Pancreatic enzyme replacement with vitamin and calorie supplements improve digestion and nutrition. Insulin replacement for CFRD addresses lack of insulin release not seen in other types of diabetes. New CFTR modulators partly restore chloride channel function in about 90% of patients. However, they do not treat absent, truncated or severely malformed proteins.

Lung disease is the main driver of morbidity and mortality. However, non-specific treatments improved the expectation of life at birth to more than 35 years, and with the advent of CFTR modulator therapy life expectancy has increased to nearly 50 years. Prognosis for newborns with CF may soon approach that of general populations. However, aging CF patients may be more vulnerable to disease associated with aging than the general population.

Last update: October 2020 - Expert reviewer(s): Dr Theodore LIOU