Given the scarce information available on BCS1L genetic variants and their outcomes for patients, researchers recommend genetic screening in patients with such diseases and priority studies in those identified with BCS1L variants.
The cases were described in the study, “Molecular genetic investigations identify new clinical phenotypes associated with BCS1L-related mitochondrial disease,” that was published recently in the journal Human Molecular Genetics.
Mutations at the BCS1L gene can lead to a spectrum of mitochondrial diseases including Complex III deficiency, characterized by kidney problems, liver failure and/or brain disease, GRACILE syndrome, and mild Björstand syndrome (characterized by abnormal hair and hearing problems).
This gene gives instructions for the production of a component of a group of proteins known as the Complex III, which is fundamental for the generation of energy inside cells. The complex belongs to a larger set of enzymes, known as the respiratory chain, that is found inside the cells’ “power plants” — the mitochondria.
Understanding how different BCS1L variants manifest clinically has been challenging. The poor correlations available between genetic variants and clinical outcomes make it difficult to establish a diagnosis.
U.K. and Italian researchers reported the clinical findings of two patients who carried novel BCS1L variants.
One of the patients was a 32-year old man who carried two variants — c.166C>T, p.(Arg56*) and the novel variant c.205C>T, p.(Arg69Cys) — one in each copy of the gene (one inherited from the mother and other from the father).
The second was a child, in the first months of life, who was carrying a novel variant in both copies — c.325C>T, p (Arg109Trp).
Each of the patients had different manifestations of illness. The man had aminoaciduria, which is characterized by abnormal amount of amino acids in urine and consistent with kidney disease. The man also was having seizures, sensorineural deafness (involving the inner hear), and learning difficulties. His kidney function slowly worsened over the years.
The infant showed classical manifestations of GRACILE syndrome, including poor fetal growth during pregnancy, reduced blood sugar levels, metabolic acidosis with high lactate and ammonia blood levels, which resulted in her death at four months of age.
Analysis of muscle biopsies and fibroblasts (a common type of cell found in the skin) collected from each patient revealed low levels of BCS1L protein, but indicated a normal activity of the respiratory chain. More detailed tests designed for mitochondrial studies also revealed defects in the formation of Complex III in the man, and a combination of impairments in the infant’s mitochondrial respiratory chain.
Additional studies strengthened the idea that the two novel BCS1L mutations identified could impair the process of energy production of cells.
“We have discovered and characterized new clinical phenotypes [manifestations] associated with BCS1L variants,” researchers wrote. “Detailed mitochondrial studies were able to reveal defects that were absent on muscle biopsy and confirm the pathogenicity [disease-causing potential] of the BCS1L variants.”
The findings suggest that BCS1L is a “candidate disease gene in patients presenting without an obvious mitochondrial defect in muscle,” the report stated.
In light of their findings, researchers recommend that patients with GRACILE syndrome or BCS1L-related mitochondrial disease “should be directly screened for the presence of BCS1L variants, or BCS1L variants identified by next-generation sequencing should be prioritized for further investigation.”