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Reduced penetrance of an eastern French mutation in ATL1 autosomal-dominant inheritance (SPG3A): extended phenotypic spectrum coupled with brain 18F-FDG PET

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Abstract

ATL1-related spastic paraplegia SPG3A is a pure form of hereditary spastic paraplegia. Rare complex phenotypes have been described, but few data concerning cognitive evaluation or molecular imaging of these patients are available. We relate a retrospective collection of patients with SPG3A from the Neurology Department of Nancy University Hospital, France. For each patient were carried out a 18F-FDG PET (positron emission tomography), a electromyography (EMG), a sudoscan®, a cerebral and spinal cord MRI (magnetic resonance imaging) with measurement of cervical and thoracic surfaces, a neuropsychological assessment. The present report outlines standardised clinical and paraclinical data of five patients from two east-France families carrying the same missense pathogenic variation, NM_015915.4(ATL1): c.1483C > T p.(Arg495Trp) in ATL1. Mean age at onset was 14 ± 15.01 years. Semi-quantitatively and in comparison to healthy age-matched subjects, PET scans showed a significant cerebellar and upper or mild temporal hypometabolism in all four adult patients and hypometabolism of the prefrontal cortex or precuneus in three of them. Sudoscan® showed signs of small fibre neuropathy in three patients. Cervical and thoracic patients’ spinal cords were significantly thinner than matched-control, respectively 71 ± 6.59mm2 (p = 0.01) and 35.64 ± 4.35mm2 (p = 0.015). Two patients presented with a dysexecutive syndrome. While adding new clinical and paraclinical signs associated with ATL1 pathogenic variations, we insist here on the variable penetrance and expressivity. We report small fibre neuropathy, cerebellar hypometabolism and dysexecutive syndromes associated with SPG3A. These cognitive impairments and PET findings may be related to a cortico-cerebellar bundle axonopathy described in the cerebellar cognitive affective syndrome (CCAS).

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Authors and Affiliations

  1. Service de Neurologie, CHRU Nancy, Nancy, France

    Armand Hocquel, Lucie Hopes, Mylène Meyer, Céline Dillier, Maud Michaud, Arnaud Lardin, Anne-Laure Kaminsky & Mathilde Renaud

  2. Laboratoire de Génétique Médicale, CHRU Nancy, Nancy, France

    Jean-Marie Ravel, Céline Bonnet & Bronner Myriam

  3. Université de Lorraine, NGERE, Inserm U1256, 54000, Nancy, France

    Jean-Marie Ravel, Laetitia Lambert, Céline Bonnet, Carine Bossenmeyer-Pourié & Mathilde Renaud

  4. Service de Génétique Médicale, CHRU de Nancy, Nancy, France

    Laetitia Lambert & Mathilde Renaud

  5. Sorbonne Université, AP-HP, GH Pitié-Salpêtrière, Département de génétique, Paris, France

    Guillaume Banneau, Bophara Kol & Laurène Tissier

  6. Service de Neuroradiologie, CHRU Nancy, Nancy, France

    Emmanuelle Schmitt, Liang Liao & François Zhu

  7. Service de Médecine Nucléaire, CHRU Nancy, Nancy, France

    Antoine Verger

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Corresponding author

Correspondence to Mathilde Renaud.

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The study was approved by the local ethics committee.

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Written informed consent was obtained from all individuals contributing a blood sample for molecular investigations and the local ethics committees approved the study. A distinct consent form was also signed if videos were recorded.

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Appendix

Appendix

Table 3 Nerve conduction studies
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Table 4 Individual patient areas compared to group control
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Fig. 6
figure 6

ATL1 Gene expression. Data obtained from the NIH Genotype-Tissue Expression (GTEx) project. Data Source: GTEx Analysis Release V8 (dbGaP Accession phs000424.v8.p2)

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Fig. 7
figure 7

Pes cavus (patient 3)

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Hocquel, A., Ravel, JM., Lambert, L. et al. Reduced penetrance of an eastern French mutation in ATL1 autosomal-dominant inheritance (SPG3A): extended phenotypic spectrum coupled with brain 18F-FDG PET. Neurogenetics 23, 241–255 (2022). https://doi.org/10.1007/s10048-022-00695-4

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