Autosomal Recessive Cerebellar Ataxias With Elevated Alpha‐Fetoprotein: Uncommon Diseases, Common Biomarker

Renaud, Mathilde; Tranchant, Christine; Kœnig, M.; Anheim, Mathieu

doi:10.1002/mds.28307

Cited by 25 publications

(9 citation statements)

References 78 publications

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“…Together, our findings identify an immunosuppressive mechanism that could account for why some groups of patients with mitochondrial dysfunction are vulnerable to infections. It may also explain why patients with elevated circulating AFP levels owing to ataxia telangiectasia or other cerebellar ataxias with suspected mitochondrial involvement are also prone to recurrent infection ( 48 , 49 ). However, considering the tremendous clinical heterogeneity of mitochondrial diseases it is likely that additional mechanisms contribute to immunosuppression in a context-dependent manner that have yet to be identified.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction reactivates α-fetoprotein expression that drives copper-dependent immunosuppression in mitochondrial disease models

Jett¹,

Baker²,

Hossain³

et al. 2023

Journal of Clinical Investigation

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Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders.Here, we identified a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that resulted in atrophy of the spleen and thymus and caused a peripheral white blood cell deficiency. We demonstrated that the leukopenia was caused by afetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death. We further showed that a-fetoprotein expression was upregulated in several cell types upon inhibition of oxidative phosphorylation. Collectively, our data argue that a-fetoprotein may be secreted by bioenergetically stressed tissue to suppress the immune system, an effect which may explain the recurrent or chronic infections that are observed in a subset of mitochondrial diseases or in other disorders with secondary mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction reactivates α-fetoprotein expression that drives copper-dependent immunosuppression in mitochondrial disease models

Jett¹,

Baker²,

Hossain³

et al. 2023

Journal of Clinical Investigation

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“…In the present study, we report a rst AOA2 Chinese case presented with head tremor, cervical dystonia and signi cantly elevated AFP. At rst, a characteristic AFP elevation which is very suggestive of a limited number of autosomal recessive cerebellar ataxias was detected [15], then we performed the NGS and identi ed a novel homozygous missense mutation c.3455T > G (p.Phe1152Cys) in the SETX gene. Hence, in patients with ataxia phenotype, more extensive serum AFP screening followed by molecular genetic analysis should be performed.…”

Section: Discussionmentioning

confidence: 99%

Clinical features of ataxia with oculoapraxia type 2 in China

Tian

Yang

Gao

2023

Preprint

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Background: Ataxia with oculomotor apraxia type 2 (AOA2) is very rare in China. This study aims to report on a Chinese girl with AOA2, and summarize the characteristics of Chinese AOA2 patients previously reported. Methods: We compiled a series of seven previously reported and one novel ataxic patients who underwent senataxin gene (SETX) sequencing because of suspected AOA2. The clinical and molecular features of a series of Chinese AOA2 patients with proven SETX mutations were summarized. Results: A novel homozygous missense mutation c.3455T>G (p.Phe1152Cys) in SETX was identified in a 17-year-old girl with ataxia, tremor, cervical dystonia and significantly elevated level of AFP (346 ng/mL). We reviewed a series of eight Chinese AOA2 patients from five families, including two males and six females. Onset of the disease occurred at an average age of 15.1 years, ranging from 10 to 20 years. The disease duration ranged from 3 to 24 years. The initial symptom was cerebellar ataxia in all cases (100%). Slurred speech and gaze nystagmus were present in six subjects (75%). None of the patients had OMA (0). One patient showed mild mental decline (12.5%). Cerebellar atrophy, pes cavus and polyneuropathy were found in 7 out of 8 cases (87.5%). Raised serum AFP levels were detected in five patients (62.5%). Extrapyramidal symptoms were found in three subjects (37.5%). Early-onset menopause was reported in one patient (12.5%). Five new mutations in the SETX were identified by molecular analyses. Among the variants, 10 homozygous or compound heterozygous variants in SETX were exonic, comprising 6 missense mutations, 2 nonsense mutations, 2 frameshift mutations. Conclusions: This is the first reported AOA2 case in China, exhibiting tremor, cervical dystonia and high AFP, which broadens the spectrum of Chinese AOA2. The phenotype of Chinese AOA2 shows a higher frequency of pes cavus, lower percentage of AFP elevation and the absence of OMA in comparison with AOA2 patients worldwide. Future studies in a larger cohort are needed to validate these findings.

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“…The presence of elevated AFP is suggestive of AOA1, AOA2, AT (AOA3), and AOA4. Apart from specific signs seen in each disease category, AFP thresholds may also provide us guidance in distinguishing among the differentials [ 12 , 13 ]. AFP levels are significantly elevated in most of AT and AOA2 patients, whereas they may also be slightly higher in AOA1 and AOA4 than in normal individuals.…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that we did not check the patient’s IgA or IgG levels; however, they may be of diagnostic value in AT [ 15 ]. Other clues that favor the diagnosis of AOA2 in comparison to the other differentials include no ocular telangiectasis or immunodeficiency (to exclude AT and ATLD), teenage onset (AOA1, AOA4, and AT typically have an onset < 10 years), normal albumin (more commonly decreased in AOA1), and cholesterol levels (more commonly increased in AOA1) [ 13 , 16 , 17 ]. Despite the name, oculomotor apraxia (OMA) is not a cardinal trait in AOA2, and OMA was observed in approximately 50% or less in most reported series of AOA2 ( Table 3 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel SETX Mutation in a Taiwanese Patient with Autosomal Recessive Cerebellar Ataxia Detected by Targeted Next-Generation Sequencing, and a Literature Review

2022

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Ataxia with oculomotor apraxia type 2 (AOA2), also known as autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2) (OMIM #606002), is a neurodegenerative disorder characterized by early-onset progressive cerebellar ataxia, polyneuropathy, and elevated levels of alpha-fetoprotein. It is caused by mutations in the SETX (OMIM #608465) gene. The prevalence of this disease is widely varied, from non-existent up to 1/150,000, depending on the region. Until now, no cases of AOA2/SCAN2 have been reported in Taiwan. Methods: Next-generation sequencing was used to detect disease-causing mutations of SETX in a Taiwanese patient presenting with autosomal recessive cerebellar ataxia, polyneuropathy, and elevated alpha-fetoprotein. The candidate mutations were further confirmed by polymerase chain reaction (PCR) and Sanger sequencing. Results: A compound heterozygous mutation of SETX c.6859C > T (p.R2287X) and c.7034-7036del was identified. The c.6859C > T (p.R2287X) has been previously found in a Saudi Arabia family, whereas c.7034-7036del is a novel mutation. Both mutations were predicted by bioinformatics programs to be likely pathogenic (having a damaging effect). We also reviewed the literature to address the reported clinical features of AOA2 from different populations. Conclusions: To our knowledge, we are the first to report a Taiwanese patient with AOA2/SCAN2, a result obtained by utilizing next-generation sequencing. The literature review shows that ataxia, polyneuropathy, and elevated AFP are common features and ocular motor apraxia (OMA) is a variable sign of AOA2 from different populations. OMA is rare and saccadic ocular pursuit and nystagmus are common in East Asian AOA2.

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Autosomal Recessive Cerebellar Ataxias With Elevated Alpha‐Fetoprotein: Uncommon Diseases, Common Biomarker

Cited by 25 publications

References 78 publications

Mitochondrial dysfunction reactivates α-fetoprotein expression that drives copper-dependent immunosuppression in mitochondrial disease models

Mitochondrial dysfunction reactivates α-fetoprotein expression that drives copper-dependent immunosuppression in mitochondrial disease models

Clinical features of ataxia with oculoapraxia type 2 in China

A Novel SETX Mutation in a Taiwanese Patient with Autosomal Recessive Cerebellar Ataxia Detected by Targeted Next-Generation Sequencing, and a Literature Review

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