Objective: To describe a patient with spinocerebellar ataxia type 28 (SCA28) presenting with isolated spastic paraparesis.

Background: Autosomal dominant (AD) mutations in the ATPase family gene 3-like 2 (AFG3L2) gene are reported to cause SCA28, which manifests as a cerebellar syndrome with pyramidal signs and oculomotor abnormalities [1, 2]. We report a unique patient who presented with spastic paraparesis and eventually found to have a heterozygous missense mutation in the AFG3L2 gene.

Method: We review the atypical clinical course of a patient with SCA28.

Results: A 23-year-old man presented with 3 years of progressive gait unsteadiness. The examination showed spastic paraparesis with exaggerated deep tendon reflexes and bilateral sustained ankle clonus. He had no other neurological signs. The patient is a product of non-consanguinous marriage and has 1 unaffected sister. MRI of the brain and cervicothoracic spine were normal. Upon further questioning, his father reported gait instability from the 6^thdecade of life, with 5 of 6 siblings having similar symptoms. Examination of his father revealed cerebellar ataxia, restricted extraocular movements and mild parkinsonism. Two years after the patient’s initial presentation, he developed gaze-evoked nystagmus, slow saccades and broken pursuit, bilaterally limited eye abduction, mild dysarthria and bilateral dysmetria. Genetic testing for trinucleotide repeat expansions causing SCA types 1, 2, 3, 6, 7 and dentatorubral-pallidoluysian atrophy was negative. In view of strong suspicion for an autosomal dominant spastic ataxia, whole exome sequencing was performed, identifying a pathogenic heterozygous missense mutation in the exon region of AFG3L2 gene (variant c.1996A>G p.Met666Val). SCA28 with initial spastic paraparesis and a significant delay in development of cerebellar dysfunction (5 years from disease onset) has not been previously reported. The cerebellar ataxia with oculomotor abnormalities, including progressive external ophthalmoplegia-like features, inherited in an AD pattern, is eventually consistent with SCA28 [3].

Conclusion: This case highlights the wide phenotypic variability of SCA28 which may reflect the underlying disturbance in mtDNA maintenance. SCA28 should be a differential diagnosis in a patient presenting with spastic paraplegia. Deep and repeated phenotyping throughout the disease course, as well as examination of affected family members, can help elucidate genetic etiologies.

References: [1] Mariotti C, Di Bella D, Di Donato S, Taroni F. “Chapter 39 – Spinocerebellar ataxia type 28.” Handbook of Clinical Neurology, edited by Sankara H. Subramony and Alexandra Dürr, Elsevier, Volume 103, 2012, pp 575-579.
[2] Cagnoli C, Stevanin G, Brussino A, Barberis M, Mancini C, Margolis RL, Holmes SE, Nobili M, Forlani S, Padovan S, Pappi P, Zaros C, Leber I, Ribai P, Pugliese L, Assalto C, Brice A, Migone N, Dürr A, Brusco A. Missense mutations in the AFG3L2 proteolytic domain account for ∼1.5% of European autosomal dominant cerebellar ataxias. Hum Mutat. 2010 Oct;31(10):1117-24.
[3] Gorman GS, Pfeffer G, Griffin H, et al. Clonal Expansion of Secondary Mitochondrial DNA Deletions Associated With Spinocerebellar Ataxia Type 28. JAMA Neurol. 2015;72(1):106–111.

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