Some patients with Gaucher disease type 3c may develop non-calcified lesions in their coronary arteries, as well as tissue scarring affecting the lungs, a report of new cases and a literature review show.
Although these cardiac and pulmonary manifestations could be rare, they may represent an important cause of disease burden and mortality. So researchers stress that coronary and lung disease evaluations should be added to the follow-up routine of Gaucher patients with type 3c disease.
These findings were reported in a study, “Gaucher disease type 3c: New patients with unique presentations and review of the literature,” published in the journal Molecular Genetics and Metabolism.
Gaucher disease is characterized by the accumulation of a fatty compound called glucocerebroside in various organs and tissues in the body. This occurs because of mutations in both copies (one inherited from the mother and one from the father) of the gene GBA, which provides instructions for making the enzyme beta-glucocerebrosidase, which breaks down glucocerebroside.
There are three distinct types of Gaucher disease, distinguished by the absence (type 1) or presence and extent (type 2 or type 3) of neurological complications.
Type 3 patients have both non-neurological and neurological symptoms; however, their neurological manifestations are milder than in patients with type 2 disease. This form of Gaucher is further classified into four subtypes (3a, 3b, 3c, and the less common Norrbottnian variant) based on the predominant symptoms.
In addition to neurological findings, consisting mainly of oculomotor apraxia (inability to move the eyes side to side), other Gaucher-related features, such as reduced number of blood components (pancytopenia) and increased organ size, are usually mild.
Subtype 3c is an atypical variant of Gaucher disease, predominantly characterized by progressive calcification of the heart valves and the aorta — the main artery that carries blood from the heart to the body. This causes them to get harder, thicker, and narrower.
Heart failure is the main cause of disease burden, mostly involving calcifications of the aortic and mitral valves.
Gaucher disease subtype 3c results from two identical mutations — identified as p.Asp448His or D409H — in both copies of the GBA gene. Since the first report of a patient with this disease variant, only 36 additional patients from 19 families have been clinically described worldwide.
Israeli and Spanish researchers have now reported four new cases from three different families who showed unusual manifestations for this disease subtype.
One of the atypical cases was of a women (patient 1b) who had a blockage of the coronary arteries — which supply blood to the heart’s muscle — caused by both calcified and non-calcified lesions.
Only five other reports of non-calcified lesions in type 3c Gaucher patients have been published, consisting of fibrosis (tissue scarring) and/or atherosclerosis (plaques rich in fat and calcium building up inside arteries). Overall, 15% of described cases, including the one newly reported, had non-calcified cardiovascular lesions. “Therefore, this rare phenotypic feature should raise a question of the role of GBA in the [development] of coronary disease,” researchers said.
Comparing the disease course in two of the newly described patients also suggested that the more aggressive cardiovascular treatment in one of them could explain his longer survival. “Accordingly, we would recommend frequent and vigorous cardiovascular evaluations for GD3c patients,” researchers said.
Patient 1b also developed a behavioral disorder, consisting of temper tantrums. This was the first case of a type 3c Gaucher patient described as developing a psychiatric disorder over time.
“While this may have been a comorbidity not strictly related to GD3c, it may also be a true rare disease feature not previously described due to the small sample size of GD3c patients and the paucity of published long-term patient follow-ups,” they noted.
Further evaluations revealed that patient 1b also had interstitial lung disease (ILD). To date, such a manifestation affecting the lungs had only been described in another patient who had pulmonary fibrosis.
One 4-year-old girl (patient 3) was also found to show an atypical presentation of the disease, as she lacked heart disease and oculomotor apraxia — two hallmarks of type 3c Gaucher disease.
Only three patients (7.5% of reported cases) have been described without a heart problem, while neurological findings of GD3c consist mainly of oculomotor apraxia in 80% of cases.
Other rare and uncommon findings that have been previously described in GD3c patients include skeletal defects (including pes cavus, hallux valgus, pectus excavatum, and spine deformities), connective tissue disease, gallstones, and varicose disease (swollen, twisted veins).
“In view of these unique features, we recommend a revised surveillance protocol,” researchers said. They propose that “coronary arteries and pulmonary evaluations should be added to the standard follow-up routine of GD3c patients, especially since these contribute to patient morbidity and mortality.”
The team also stressed that heart evaluations “should begin in late childhood with periodic echocardiograms,” and that heart and pulmonary evaluations should be emphasized before invasive procedures.
“We also recommend psychological and/or psychiatric evaluation and follow-up for GD3c patients to enable early diagnosis and treatment in those developing behavioral changes,” they said.
More studies are needed to better understand disease course and provide more detailed information on the best management approach for these patients.