Pseudodominance in Friedreich Ataxia—Impact of High Prevalence of Carriers and Intrafamilial Clinical Variation

Abstract

BackgroundBackground: Friedreich ataxia (FA) is the most common form of autosomal recessive (AR) ataxia. It is a rare disease, but carriers are frequent (1/100). Pseudodominance in FA has seldomly been reported; it may pose additional challenges for diagnosis. Cases Cases: A family with two consecutive generations affected by FA is described. The proband and two younger siblings had typical FA, characterized by infantile-onset ataxia, hyporeflexia, Babinski sign, cardiomyopathy, and loss of ambulation in the second decade of life. Another female sibling had delayed-onset (>25 years old), with mild cerebellar and sensitive ataxia since her mid-30s. Their father presented very late-onset FA (>40 years old), with sensitive axonal neuropathy. All five patients had biallelic (GAA) n expansion in FXN. The first three had larger expansions (>800 repeats), while the latter two had one shorter expanded allele ($90 repeats). Literature Review Literature Review: Pseudodominant inheritance has been described in 13 neurological disorders. Seven are movement disorders, of which three were associated with high frequency of carriers (FA, Wilson's disease and PRKN-related parkinsonism). Conclusions Conclusions: Clinicians should be aware of the possibility of pseudodominance when facing an apparent autosomal dominant pedigree, particularly in disorders with high frequency of carriers and variable expression. Otherwise, genetic diagnoses may be delayed.Friedreich ataxia (FA) (OMIM# 229300) is the commonest autosomal recessive (AR) ataxia in Caucasians, with an estimated prevalence of 0.5-1:100,000. 1,2 Most frequently, it is caused by a biallelic intronic (GAA) n expansion in FXN (OMIM Â 606829), resulting in decreased expression of frataxin, a protein involved in mitochondrial iron metabolism. 1 Typical FA starts before age 25, and involves the peripheral nervous system, posterior columns, cerebellum and pyramidal tracts. It is characterized by dysarthria, square wave jerks, muscle weakness, impaired proprioception and vibration, abolished deep tendon reflexes (DTR), Babinski sign and progressive gait and limb ataxia. 1 Non-neurological features include skeletal anomalies (scoliosis, pes cavus), neurosensorial deafness, hypertrophic cardiomyopathy, optic atrophy and diabetes. 1 Atypical FA is rare (about 15% of patients) and comprises late-onset FA (LOFA) and very LOFA (vLOFA), when starting after 25 and 40 years of age, respectively. These atypical forms are characterized by milder symptoms, slower progression and paucity of extra-neurological involvement. 3 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; 1 (2) the range of pathogenic expanded alleles is wide (66-1700 GAAs), with expansions ranging from 44 to 66 being unstable and conferring high risk for disease; 4 and (3) the frequency of heterozygotes in the general population is estimated at 1/100. 1,2,5 Two main clinical consequences emerge from this genotypic ...

RFC1regulates the expansion of neural progenitors in the developing zebrafish cerebellum

“…Although it is a rare syndrome, recent findings suggest that RFC1 expansions are a major cause of a broader phenotypic spectrum of late-onset progressive ataxias. Moreover, the pathogenic scope of these expansions has been expanded to other movement syndromes, now collectively referred to as RFC1related disorders, which include specific forms of parkinsonism and multiple systems atrophy (MSA) [16][17][18][19] . Although the pathogenicity of RFC1 repeat expansions is now well established, the underlying mechanisms remain unknown.…”