Friedreich ataxia 1 is defined in the packet as any Friedreich ataxia in which the cause of the disease is a mutation in the FXN gene. GeneReviews characterizes Friedreich ataxia (FRDA) as progressive ataxia with onset from early childhood to early adulthood, a mean age at onset of 10 to 15 years, and a reported range from age two years to the eighth decade. The packet lists autosomal recessive inheritance, an OMIM identifier (OMIM:229300) and a MeSH identifier, and the packet's onset category list is empty. GeneReviews reports that about 75% of individuals with FRDA have typical Friedreich ataxia and about 25% of those with biallelic full-penetrance GAA repeat expansions have atypical forms, including late-onset, very late-onset and retained-reflexes presentations.

The packet contains two structured phenotype entries out of a total count of 26: reduced visual acuity and visual impairment, each with HPO frequency OCCASIONAL (5-29%). The remainder of this section draws on the GeneReviews clinical description.

GeneReviews states that gait ataxia is present in all individuals with FRDA, is the earliest manifestation in most, and results from spinocerebellar degeneration combined with loss of joint position sense. Poor balance is accentuated when visual input is eliminated (Romberg sign). Within five years of onset, most individuals are described as exhibiting scanning dysarthria, lower-extremity weakness, and diminished or absent distal joint position and vibration sense. Ankle and knee jerks are generally absent and plantar responses usually upgoing. Dysarthria is reported in 95% of individuals and dysphagia in 92%, with significant airway compromise observed in 34% and silent aspiration in 26% in one study. A mixed axonal peripheral neuropathy is described. Muscle weakness is often present, pes cavus is reported in 55%, restless leg syndrome in 32%-50% in two studies, and spasticity in 21%. Scoliosis is present in approximately two thirds of individuals when assessed clinically, and spastic bladder is reported in 41%. GeneReviews also lists, among suggestive findings, hypertrophic non-obstructive cardiomyopathy, glucose intolerance, diabetes mellitus, and optic atrophy or deafness.

The packet lists FXN (chromosome 9) as the associated gene, and the packet's gene validity record gives the symbol without a ClinGen validity classification, so the strength of the gene-disease evidence is not stated in this packet beyond the definition. The packet lists autosomal recessive inheritance. The packet does not supply a molecular mechanism field.

Per the GeneReviews chapter, FRDA is caused by biallelic pathogenic variants in FXN, of two classes: GAA repeat expansions and FXN sequence variants, including base substitutions, small indels or large deletions. GeneReviews reports that approximately 96% of individuals with FRDA have biallelic FXN GAA repeat expansions in intron 1, and approximately 4% are compound heterozygotes for a repeat expansion and either an intragenic variant or a large deletion. It describes repeat size classes of normal (5-33 repeats), intermediate (34-65), borderline (44-65) and pathogenic full-penetrance (66 to approximately 1,300). GeneReviews states that penetrance is complete for biallelic pathogenic repeat sizes or compound heterozygosity with a pathogenic sequence variant or deletion, while onset ranges from younger than age five to older than age 50 years. It reports carrier frequency of 1/60-1/100 and describes intergenerational instability of expanded repeats.

The packet's diagnostic method fields are not populated, so this section follows the GeneReviews diagnosis chapter. GeneReviews states that no consensus diagnostic criteria for FRDA have been published. It describes suspicion on the basis of neurologic features (progressive ataxia, dysarthria, decreased position or vibration sense in the lower limbs, pyramidal involvement), musculoskeletal features (weakness, scoliosis, pes cavus), cardiomyopathy, endocrine features and optic atrophy or deafness, typically but not always with onset before age 25 years. Brain MRI is described as often normal in early stages, with cervical spinal cord and cerebellar atrophy possible in advanced disease. Family history is described as consistent with autosomal recessive inheritance, and absence of a known family history does not preclude the diagnosis.

Per GeneReviews, the diagnosis is established in a proband with biallelic pathogenic or likely pathogenic variants in FXN identified by molecular genetic testing. It states that identification of a heterozygous FXN variant of uncertain significance neither establishes nor rules out the diagnosis. Genetic confirmation details in the chapter include characterization of GAA repeat size in intron 1.

The packet has no approved_treatments or foundational_therapies fields and no verified FDA records, so this section reflects the GeneReviews management chapter and the orphan drug list. GeneReviews states that there is no cure for FRDA. Under targeted therapy, it states that omaveloxolone is approved in the United States and Europe for individuals aged 16 years and older, has been shown to slow progression, and is generally well tolerated, with noted effects on liver function and serum lipids. This approval statement comes from GeneReviews rather than a certified FDA field in the packet.

GeneReviews describes supportive care directed at quality of life, function and complications, typically involving multidisciplinary specialists including neurologists, ophthalmologists, physical and occupational therapists, cardiologists, endocrinologists, speech-language therapists and psychologists. Manifestation-specific approaches described include physical and occupational therapy and adaptive devices for ataxia, speech-language therapy for dysarthria, dietary modification and in late stages feeding tubes for dysphagia, orthopedic interventions for scoliosis and foot deformities, treatment of cardiac disease, and treatment of bladder dysfunction. GeneReviews also lists evaluations following diagnosis across neurologic, musculoskeletal, cardiac, endocrine, ophthalmologic, audiologic and psychiatric domains.

The orphan drug list records designations, which are not approvals. Elamipretide (Stealth Biotherapeutics, Inc.) and trans-resveratrol (Jupiter Orphan Therapeutics) are DESIGNATED. A D-amino acid oxidase inhibitor (Takeda Development Center Americas, Inc.) and an AAV9 frataxin gene vector construct (Novartis Institute for BioMedical Research, Inc.) have WITHDRAWN status.

The packet has no natural_history field, so prognosis is not certified as a structured element. GeneReviews describes FRDA as characterized by progressive ataxia, with neurologic manifestations resulting from progressive degeneration of the dorsal root ganglia, posterior columns, corticospinal tracts, dorsal spinocerebellar tracts and cerebellum. Gait ataxia is described as the earliest manifestation in most affected individuals, and dysphagia severity is described as correlating with disease duration and severity. GeneReviews notes that onset age varies widely, including among siblings, and that the size of the cervical spinal cord correlates with disease severity as measured by the Friedreich Ataxia Rating Scale. No life expectancy figure is supplied in the packet.

The packet lists 28 clinical trial records, 10 of which are detailed. These include NCT07778836 (subcutaneous nomlabofusp, phase 3, Larimar Therapeutics, recruiting), NCT06447025 (open-label study of CTI-1601, phase 2, Larimar Therapeutics, recruiting), NCT06953583 (omaveloxolone in children and teens, phase 3, Biogen, active not recruiting), NCT06054893 (omaveloxolone pharmacokinetics and safety in ages 2 to 15, phase 1, Biogen, active not recruiting), NCT05302271 (AAVrh.10hFXN gene therapy for the cardiomyopathy of FRDA, phase 1, Weill Medical College of Cornell University, recruiting), NCT07721025 (LX2006 gene therapy in FRDA cardiomyopathy, phase 2, Lexeo Therapeutics, recruiting), NCT07869654 (ATI-105 in healthy adults, phase 1, Adjuvia Therapeutics, not yet recruiting), NCT06865482 (clinical course in participants with FA-CM, Lexeo Therapeutics, recruiting), NCT06016946 (UNIFIED natural history study, Friedreich's Ataxia Research Alliance, recruiting) and NCT07731971 (digital outcome assessment using AI active gaming, University of Exeter, not yet recruiting). GeneReviews lists therapies under investigation including nomlabofusp, DT-216P, vatiquinone, nicotinamide riboside, elamipretide, LX2006, leriglitazone and dimethyl fumarate.

The research landscape digest classifies 297 publications, with basic science and preclinical work dominant, and 13 case reports and 74 reviews. The packet lists no patient organizations.