Elsevier

Parkinsonism & Related Disorders

Volume 80, November 2020, Pages 28-31
Parkinsonism & Related Disorders

Short communication
Neurofilament light chain in serum is significantly increased in chorea-acanthocytosis

https://doi.org/10.1016/j.parkreldis.2020.09.004Get rights and content

Highlights

  • Neurofilament light chain in serum (sNfL) is increased in chorea-acanthocytosis.

  • sNfL reflects chronic, central and peripheral neuroaxonal injury in this condition.

  • We propose clinical and paraclinical parameters for biomarker validation in this condition.

Abstract

Introduction

Chorea-acanthocytosis (ChAc) is a rare hereditary neurodegenerative disease, characterized by hyper- and hypokinetic movement disorders, peripheral neuropathy and acanthocytosis. Biomarkers are not established; possible candidates include neurofilament reflecting neuroaxonal damage.

Methods

We studied serum neurofilament light chain (sNfL) of six ChAc patients compared to two healthy control cohorts (A, six age/sex matched and B, historical cohort of 59 healthy adult subjects) and in two patients with the very similar condition of McLeod syndrome (MLS), the second core syndrome of neuroacanthocytosis. sNfL was quantified using single-molecule array analysis.

Results

sNfL concentration was significantly higher in the ChAc cohort (18.73 pg/ml; IQR 15.65–27.70) compared to both healthy control cohorts (A, 7.37 pg/ml; IQR 5.60–9.05; B, 3.10 pg/ml; IQR 2.43–3.98). In MLS patients, a similar sNfL increase was observed.

Conclusions

sNfL is significantly increased in ChAc and MLS and seems to reflect neuroaxonal damage in the peripheral as well as the central nervous system.

Introduction

Chorea-acanthocytosis (ChAc) is a rare neurodegenerative disease of young adulthood which is one of the core neuroacanthocytosis syndromes, along with the X-linked McLeod syndrome (MLS) [1,2]. Autosomal-recessively inherited ChAc is caused by mutations in the VPS13A gene [3]. Subsequent loss of function of the encoded protein chorein affects various organ systems: The appearance of misshaped erythrocytes, referred to as acanthocytes, is characteristic and represents an important, yet not obligatory diagnostic feature [1,2]. Disease manifestation in the central and peripheral nervous system, however, has the major impact on morbidity and mortality. Central and peripheral nervous system involvement of ChAc was successfully reproduced in vitro using patient derived iPSC models [4,5].

The disease phenotype is quite variable, its course slowly progressive, frequently devastating, with a significantly reduced life span [1]. Clinical characteristics include various movement disorders (both hyper- and hypokinetic, e.g. chorea, parkinsonism and orofacial dyskinesia) as a consequence of the degeneration of the basal ganglia. Further, seizures, peripheral neuropathy as well as behavioral and affective disorders and cognitive decline are common. Pronounced hyper-CKemia is characteristic [1,2]. Taken together, ChAc represents an important differential diagnosis of Huntington's disease (HD) [2].

Treatment remains purely symptomatic [2]. However, recent studies have been successful in identifying promising drug targets, e.g. the tyrosine kinase Lyn, for a potentially disease modifying therapy [2,4]. Considering the rarity and the high variability of the natural history of the disease, there is an obvious and urgent need for robust biomarkers to achieve clinical trial readiness.

Promising biomarker candidates include the neurofilament light chain (NfL) protein. NfL concentration in cerebrospinal fluid (CSF) and serum reflecting neuroaxonal damage, both of the central and the peripheral nervous system, was evaluated for diagnosis and prognosis in several neurological conditions. Recent studies have revealed increased serum neurofilament light chain (sNfL) concentrations in both neurodegenerative and neuroinflammatory diseases, such as HD, Alzheimer's disease as well as multiple sclerosis (MS) and peripheral neuropathies [[6], [7], [8], [9], [10]]. Fourth-generation assays permit highly sensitive, longitudinal detection of NfL levels in the blood [6]. In this exploratory study, we therefore aimed to investigate sNfL in a ChAc cohort.

Section snippets

Study design and participants

We longitudinally studied six patients (27–52 years; mean age 42.50 years; SD = 10.63; 5 males) diagnosed with ChAc based on clinical phenotype and confirmation by absent erythrocyte membrane chorein in Western blot and/or detection of VPS13A mutations. Two genetically confirmed MLS cases (51 and 57 years, both males) were studied in addition as this disorder is very similar to ChAc, but has a later onset [1]. Two healthy control cohorts consisted of A) age and sex matched controls (n = 6;

Results

Age and sex distribution of the cohorts are summarized in Table S2. There were no significant differences between ChAc and control A) subjects, whereas control B) had a significantly younger mean age as well as more females than the ChAc cohort.

Median sNfL levels in the ChAc patients (18.73 pg/ml; IQR 15.65–27.70; range 14.90–28.90) were significantly higher than in both healthy control cohorts A) (7.37 pg/ml; IQR 5.60–9.05; range 4.09–10.50; p = 0.0022) and B) (3.10 pg/ml; IQR 2.43–3.98; range

Discussion

In this study, we revealed a moderate increase of serum levels of NfL in a cohort of ChAc and MLS patients (six, respectively two). Both neuroacanthocytosis syndromes are characterized by degeneration of central and peripheral nervous system structures. Even though comparisons across studies must be viewed with caution because of absente multicenter assay validation [6], the sNfL levels presented here are similar to early premanifest HD (caveat: plasma NfL) [9] or chronic peripheral neuropathy

Funding sources for study

This research was funded by the Advocacy for Neuroacanthocytosis Patients, UK (to AH), and by the Federal Ministry of Education and Research, Germany (BMBF FKZ: 01GM1303), under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases (EMINA2 consortium, to AH). AH is supported by the Hermann and Lilly Schilling-Stiftung für medizinische Forschung im Stifterverband, Germany. KP received funding from the Else Kröner Clinician Scientist Program (TU Dresden, Germany) and the Rostock

Authors' roles

1) Research project: A. Conception, B. Organization, C. Execution; D. Supervision.

2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique;

3) Manuscript: A. Writing of the first draft, B. Review and Critique.

KP: 1 A-C; 1 A-B; 3 A.

KA; CBe; TZ; CBu; AD: 2 C; 3 B.

AH: 1 A-D; 2 A + C; 3 B.

Financial disclosures

KP received funding from the Else Kröner Clinician Scientist Program (TU Dresden, Germany) and the Rostock Academy for Clinician Scientists (RACS, University of Rostock, Germany).

KA received honoraria for presentation and consulting service from Biogen Idec, Merck, Sanofi and Roche.

TZ received honoraria for presentation and consulting service from Biogen, Bayer, Celgene, Novartis, Roche, Sanofi, Teva. He received additional financial support for research activities from BAT, Biogen, Novartis,

Declaration of competing interest

None.

Acknowledgment

We thank the patients and healthy control subjects for participation in this study. Special thanks go to Glenn (✝) and Ginger Irvine who founded and run the Advocacy for Neuroacanthocytosis Patients (www.naadvocacy.org).

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