Very Late-onset Friedreich’s Ataxia (VLOFA) Presenting as Spastic Ataxia in Later Life
Aditi Varma-Doyle1, Jeremy Schmahmann2
1Massachusetts General Hospital, 2Ataxia Center, Cognitive Behavioral Neurology Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School
Objective:

To highlight VLOFA as a cause of the late life phenotype of hereditary spastic paraplegia.

Background:

Friedreich’s Ataxia (FA) is an autosomal recessive hereditary ataxia due to GAA trinucleotide repeat expansion, or rarely point mutation, in intron 1 of X25 gene on chromosome 9q13-21.1. Clinical presentations of Late-onset FA (LOFA; onset 25-39 years) and VLOFA (onset ≥ 40 years) are distinct from young onset FA, which can hamper prompt and accurate diagnosis.

Design/Methods:

Two sisters, S-1 age 63y and S-2 age 67y presented with worsening gait, incoordination, and speech changes, S-1 over 1 year, S-2 over 8 years. There was no parental consanguinity. Neurological examination revealed bilateral lower extremity spasticity with diffuse hyper-reflexia, spastic dysarthria, distal vibratory deficits, and saccadic oculomotor pursuit. Cerebellar motor examination demonstrated end-point dysmetria in the upper extremities and jerking-in-plane with superimposed lateral movements on heel-to-shin testing. Gait was spastic with irregular cadence and widened stance, tandem gait was impossible, and Romberg test was positive. Plantar responses were normal in S-1, equivocal in S-2.

Results:

Normal studies included MRI brain and spinal cord, sensory-motor nerve conduction studies in arms and legs, and evaluation for peripheral neuropathies. Hereditary spastic paraplegia gene panel in S-2 was normal. Hypothesis-driven targeted genetic testing in S-1 demonstrated homoallelic pathogenic expanded allele (> 75 GAA trinucleotide repeats) in the frataxin gene, confirming the diagnosis of VLOFA. Subsequent testing in S-2 revealed GAA allelic expansions of 1066 and 99.

Conclusions:

VLOFA may present with the phenotype of hereditary spastic paraplegia with superimposed features of cerebellar ataxia.  Shorter numbers of trinucleotide repeats (< 400 in LOFA vs > 600-1000s in FA) inversely correlate with disease onset, progression and severity. Detailed neurological examination and high degree of suspicion for LOFA / VLOFA are important when evaluating adult patients with evolving spasticity with or without ataxia.

10.1212/WNL.0000000000205107