Sensory neuronopathy in spinocerebellar ataxia type 25 due to the heterozygous PNPT1 variant

Dear Sir,

We report a rare and relevant case of a patient diagnosed with spinocerebellar ataxia type 25 (SCA25), associated with sensory ganglionopathy, illustrating the phenotypic variability of this condition and its diagnostic implications.

The patient, a 35-year-old man, presented with a history of progressive imbalance, distal paresthesias in the upper and lower limbs, and episodes of falls. Neurological examination shows mild gait ataxia, especially when walking in tandem, without motor deficit.

Sensory nerve conduction was performed in the median, ulnar, radial, sural, and superficial peroneal nerves bilaterally, using the antidromic technique. A motor nerve study was carried out in the median, ulnar, tibial, and peroneal nerves bilaterally, using an orthodromic technique. The sural/radial amplitude ratio (SRAR) was used aiming to differentiate axonopathy from neuronopathy.

Genetic investigation revealed a heterozygous variant c.2068del;p.(Arg690Glufs*5) in the PNPT1 gene (NM_033109.5), confirming the diagnosis of SCA25. The result of the genetic study of the only daughter was similar to that of the patient.

This finding was corroborated by neurophysiological studies, which demonstrated reduced amplitudes of sensory nerve action potentials (SNAPs) in the median, ulnar, sural, and superficial peroneal nerves, indicating a marked sensory ganglionopathy. The sensory nerve-to-compound muscle action potential ratio for the ulnar nerve (<0.71) (Garcia et al., 2013) as well as SRAR (>0.3) further supported this diagnosis.^[1]

SCA25, although characterized by a broad clinical spectrum and variable age of onset, stands out for the coexistence of cerebellar ataxia with prominent sensory neuronopathy (Stevanin and Dürr, 2012, Ferrera et al., 2024).^[2,3] Initial studies, such as the genetic mapping in a French family in 2004 (Stevanin et al., 2004) and subsequent analyses in Australian families, identified the PNPT1 gene as a primary contributor to SCA25 (Barbier et al., 2022).^[4,5] The observed mutation results in premature stop codons affecting the S1 domain of the PNPase protein (Barbier et al., 2022).^[5]

Electrophysiological findings in sensory ganglionopathies help differentiate them from other sensory neuropathies. The main feature is the generalized reduction in SNAP amplitudes, affecting both upper and lower limb nerves, even in patients with asymmetrical or irregular clinical presentations. This pattern reflects peripheral axonal degeneration that does not depend on nerve length, which is considered a hallmark of ganglionopathies.

Given the rarity of this condition, comparative neurophysiological studies are limited. In the study by Stevanin et al., SNAP assessments were performed exclusively in the median and sural nerves, confirming significant sensory neuropathy (Stevanin et al., 2004).^[4]

This case report reinforces the characteristic phenotype of SCA25, emphasizing the prominent presence of sensory neuronopathy, differentiating it from other spinocerebellar ataxias. With our report, we want to draw attention to the association of sensory neuronopathy in SCA25. In the real world, we relied on the pattern of symptoms and signs, with a predominance in the lower limbs, with ataxia, in a multisegmental pattern rather than a radicular or peripheral nerve pattern, to implicate the dorsal root ganglion. Electrophysiological changes show normal motor neuroconduction and small or absent SNAPs.

The identification of a mutation in the PNPT1 gene and the neurophysiological confirmation of sensory neuropathy highlight the importance of genetic and electrophysiological investigation in the precise diagnosis of these rare conditions. Additional studies are needed to expand the knowledge of the phenotypic and electrophysiological variations of SCA25 as well as to elucidate the underlying mechanisms of the observed neurological dysfunction.