Three possible new mutations in patients with Gaucher disease type 2 were identified by researchers in Turkey, who also found a higher-than-usual incidence of this rare subtype in the group studied, a case study reports.
These findings of likely new mutations highlight the variability of this severe lysosomal storage disorder. And, based on one infant’s case, they also call attention to the need for careful and regular evaluation of brain damage in babies to avoid delays in diagnosis or a misdiagnosis.
The study, “Four Gaucher disease type II patients with three novel mutations: a single centre experience from Turkey,” appeared in the journal Metabolic Brain Disease.
Gaucher disease (GD) is caused by mutations in the GBA gene, which causes insufficient production of glucocerebrosidase, an enzyme that breaks down a lipid molecule called glucocerebroside.
This deficiency leads to the buildup of glucocerebroside in the liver, spleen, bone marrow, and possibly the central nervous system, affecting how well they function. While Gaucher type 1 does not impact the nervous system, type 2 and type 3 do and these patients have neurologic symptoms and damage.
Type 2 Gaucher — also known as acute neuronopathic disease — is its most severe and lethal form, and considered a rare subtype that accounts for less than 1% of all patients. It manifests either before birth or in the first months of life, with patients showing spleen and liver enlargement, specific skin abnormalities, and extensive and progressive brain damage.
Current treatments, such as enzyme replacement therapy or substrate inhibition therapy, are of limited effectiveness in type 2 patients, especially as they show no benefit in easing neurologic problems.
An analysis of 81 Gaucher patients at a clinical center in Turkey found a higher-than-expected incidence of GD type 2: four type 2 infants, or 4.9 percent, of this patient group. Three of these infants — two of Turkish origin and two of Arab origin — had likely new disease-causing mutations in the GBA gene.
The first case described a newborn boy with “collodion baby” features — a term given to infants enveloped at birth in a tight and shiny membrane that resembles a film of dried glue — and generalized dry, thickened, and scaly skin. Genetic tests revealed a new mutation — p.H326P — thought to be a disease-causing mutation.
A 9-month-old boy in the second case had, among other symptoms, skin abnormalities. Genetic tests again identified an unknown mutation — p.R398L — but the potential implications of this type of mutation are still unknown.
A 2-month-old boy in the third case described had two GBA mutations: p.D409H, a known disease-causing mutation, and p.F147SfsX14, a newly identified one. Further analysis showed this new mutation is likely disease-causing, as it leads to a shorter and less efficient glucocerebrosidase protein.
Due to the absence of skin or brain abnormalities when he was admitted to a hospital, the baby was diagnosed with GD type 1. At age 8 months and after a single neurological problem, doctors changed the diagnosis to type 3. But further brain problems were evident when he was 1 year old, and the boy was then correctly diagnosed with atypical Gaucher type 2.
These cases support the idea that heterogeneity exists not only among GD’s three subtypes, but also within the same subtype. It also suggests, the researchers said, that doctors must be extra careful in making a subtype diagnosis, and regularly check for new evidence of brain damage in babies with Gaucher disease.
Three of four type 2 infants were born of consanguineous couples — meaning the couple are biological relatives with at least one shared ancestor — as can be common in their home countries.
Parental consanguinity can relatively often be found in autosomal recessively genetic diseases like GD — those in which two mutated copies of a disease-causing gene, one from each parent, must be inherited for a child to manifest that disease. The researchers believe this may explain the higher rate of GD type 2 seen in the patient population studied.
But “more studies should be done … to describe the real distribution of Gaucher prevalence between different subtypes,” they concluded.