Docosahexaenoic acid in ARSACS: observations in two patients

Background Spastic ataxia of Charlevoix-Saguenay is a neurodegenerative condition due to mutations in the SACS gene and without a cure. Attempts to treatments are scarce and limited to symptomatic drugs. Case presentation Two siblings harboring biallelic variants in SACS underwent oral supplementation (600 mg/die) with docosahexaenoic acid (DHA), a well-tolerated dietary supplement currently used in SCA38 patients. We assessed over a 20 month-period clinical progression using disease-specific rating scales. Conclusions DHA was safe over a long period and well-tolerated by the two patients; both showed a stabilization of clinical symptoms, rather than the expected deterioration, warranting additional investigations in patients with mutations in SACS.


Background
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a relatively common early-onset inherited disorder characterized by the combination of cerebellar ataxia, pyramidal signs, peripheral neuropathy and retinal involvement [1]. ARSACS is due to mutations in SACS, which encodes sacsin, a molecular chaperone involved in protein quality control, mitochondrial network dynamics and neurofilament homeostasis. The pathological mechanisms underlying neurodegeneration in sacsin-mutated neurons are not fully understood. A recent study in neuronal models of sacsin depletion suggests that loss of the protein could selectively impair mitophagy, leading to accumulation of damaged mitochondria and subsequent bioenergetic dysfunction, increased levels of oxidative stress products, and peroxidation of membrane phospholipids [2]. The hypothesis of bioenergetic and autophagy dysfunction in ARSACS pathogenesis suggests a potential therapeutic role for agents targeting these pathways.
Docosahexaenoic acid (DHA) is a well-tolerated dietary supplement able to cross the blood-brain barrier. It is the main component of brain phospholipids and is essential for normal central nervous system development. DHA derives mainly from diet and liver metabolism, while production within the brain itself is limited [3]. DHA has several neurobiological effects. It has neuroprotective properties, promoting neuronal survival and repair through neurotrophic, antiapoptotic and antiinflammatory signaling [4]. By blocking mTOR signaling, DHA also stimulates the autophagic pathway [5]. It is used in other neurodegenerative disorders characterized by cerebellar and pyramidal tract involvement, such as in patients with spinocerebellar ataxia 38 [6,7] and in mouse models of Friedreich's ataxia [8]. DHA is usually safe and well-tolerated, though adverse effects include gastrointestinal discomfort and diarrhea.

Case presentation
We here report clinical observations in two siblings with ARSACS who underwent DHA oral supplementation, 600 mg per day, for 20 months. Their full clinical and molecular data have been described elsewhere [9].
Briefly, P1 is a 41-year-old woman affected by ataxicspastic signs, evident from the age of 15 years. Her clinical evaluation before starting DHA supplementation (T0, 39 years) showed moderate spastic-ataxic gait, mild dysarthria, mild diffuse leg weakness and dysmetria, bilateral Babinski sign, pes cavus and hammertoes. She scored 16/52 and 7/40 on the Spastic Paraplegia Rating Scale (SPRS) [10] and the Scale for the Assessment and Rating of Ataxia (SARA) [11], respectively. Her diseasespecific severity index (DSI-ARSACS) [12] score was 11/ 32. She completed the 10-m walking test (10MWT) [13] in 15.8 s and covered a distance of 252 m on the 6-min walking test (6MWT) [13]. Electroneurography showed severe sensorimotor axonal and demyelinating polyneuropathy. Brain MRI documented mild cerebellar atrophy, prominent in the cerebellar vermis, and hypointense stripes in the pons. Spine MRI was normal. Her 40-year-old brother (case P2) displayed a similar neurological phenotype, present from the age of 16. Before starting DHA, his SPRS, SARA and DSI-ARSACS scores were 12/52, 9/40 and 9/32, respectively. He performed the 10MWT in 9.9 s and walked 400 m on the 6MWT. MRI showed slight atrophy of the superior cerebellar vermis, corpus callosum thinning, and cervical spinal cord atrophy. Neurophysiological examinations were consistent with sensorimotor axonal polyneuropathy.
Over the 20-month period, DHA was safe and welltolerated by the two patients; both showed an overall stabilization of clinical symptoms, as measured by SARA, SPRS, DSI-ARSACS, 6MWT and 10MWT (Table 1; Fig. 1), rather than the expected deterioration [14,15].

Discussion and conclusion
Description of pharmacological management in rare neurodegenerative conditions is useful to advice patients in case of self-administration and use of over-the-counter drugs, especially when no cures are seen over the horizon [17]. The reported data suggest that DHA supplementation in ARSACS patients seems to be safe and well tolerated and a promising add-on therapy in the complex treatment of this condition. Nevertheless, our anecdotal report should be read in view of future investigations in larger groups of subjects also to confirm long-term safety. DHA supplementation is associated with modifications in lipids profile and some studies suggest that DHA down-regulates expression of LDL receptors and LDLcholesterol clearance [18]. Therefore during DHA administration, lipoprotein pools in plasma should be monitored, especially in subjects with FH.

Acknowledgments
We thank Catherine J. Wrenn for expert editorial assistance and useful discussion.
Authors' contributions IR designed the study, served as study investigator, enrolled patients, and collected and assembled the data. AT, RT, GMB, and FMS analyzed and interpreted the data. IR and FMS prepared, revised, and reviewed the manuscript; and approved the final manuscript for publication. All authors read and approved the final manuscript.

Funding
This study was partially supported by the Italian Ministry of Health-Ricerca Finalizzata RF-2016-02361610 (to FMS), and the E-RARE-3 Joint Transnational Call grant "Preparing therapies for autosomal recessive ataxias" (PREPARE) (MoH; project 3398 to FMS). The funding body did not have roles in the design of the study and data collection, analysis, and interpretation and did not play any role in writing the manuscript.
Availability of data and materials All data generated or analyzed during this study are included in this published article.

Ethics approval and consent to participate
The study was approved by the Institutional Ethic Committee. Written consent was obtained from all study participants patients for this study.

Consent for publication
Written consent was obtained from study participants for publication of the data.

Competing interests
The authors declare that they have no competing interests.