A study published in Movement Disorders Clinical Practice reports on the unusual case of a family with 2 generations of pseudodominant Friedreich ataxia (FA). The report notes that the high frequency of carriers and variety of expressions in FA should alert clinicians to the possibility of pseudodominance in this condition.
“FA is highly challenging at a genetic level as, (1) in a minority of patients it may be due to a compound heterozygous GAA repeat expansion with a point mutation; (2) the range of pathogenic expanded alleles is wide, with expansions ranging from 44 to 66 being unstable and conferring high risk for disease; and (3) the frequency of heterozygotes in the general population is estimated at 1/100,” the authors wrote. “Here, we describe a FA family, genetically confirmed, exhibiting phenotypic variability and pseudodominant inheritance.”
Read more about FA etiology
The family described is Portuguese and includes 5 members with FA in 2 consecutive generations. They have been followed for 30 years at a movement disorders clinic, and the fact that all 4 siblings had FA, which is atypical for an autosomal recessive condition, led the researchers to assess both parents.
The parents were asymptomatic, but the mother carried 1 expanded allele and the father had 1 short and 1 larger expanded allele. The pattern of pseudodominance seen in this family has rarely been reported, and in all 7 cases in the literature, the parents had late- or very late-onset FA. In this family, the father was only diagnosed with FA after all of his children were diagnosed with the disease.
The authors note that due to the family’s origin in a very small village, as well as living in a region where the prevalence of FA is triple the national average, they could not be certain whether the pseudodominant pattern was due to “hidden consanguinity” or the high frequency of carriers in the region.
They aim to increase clinician awareness of the potential for this pattern to avoid delays in genetic and clinical analyses, diagnoses, and counseling.
Reference
Malaquias MJ, Oliveira J, Santos M, et al. Pseudodominance in Friedreich ataxia – impact of high prevalence of carriers and intrafamilial clinical variation. Mov Disord Clin Pract. Published online February 9, 2023. doi.10.1002/mdc3.13694
