Spasticity and a thin corpus collosum are common in specific forms of hereditary spastic paraplegia 

Spasticity and a thin corpus collosum are common in specific forms of hereditary spastic paraplegia 

Published on 6 Oct. 2020, in Brain

Summarized by Niamh Mortimer 

Original article by D Ebrahimi-Fakhari, J Teinert, R Behne, M Wimmer, A D’Amore, K Eberhardt, B Brechmann, M Ziegler, DM Jensen, P Nagabhyrava, G Geisel, E Carmody, U Shamshad, KA Dies, CJ Yuskaitis, CL Salussolia, TS Pearson, A Saffari, A Ziegler, S Kölker, J Volkmann, A Wiesener, DR Bearden, S Lakhani, D Segal, A Udwadia-Hegde, A Martinuzzi, J Hirst, S Perlman, Y Takiyama, G Xiromerisiou, K Vill, WO Walker, A Shukla, RD Gupta, N Dahl, A Aksoy, H Verhelst, MR Delgado, RK Pourova, AA Sadek, NM Elkhateeb, L Blumkin, AJ Brea-Fernández, D Dacruz-Álvarez, T Smol, J Ghoumid, D Miguel, C Heine, J Schlump, H Langen, J Baets, S Bulk, H Darvish, S Bakhtiari, MC Kruer, E Lim-Melia, N Aydinli, Y Alanay, O El-Rashidy, S Nampoothiri, C Patel, C Beetz, P Bauer, G Yoon, M Guillot, SP Miller, T Bourinaris, H Houlden, L Robelin, M Anheim, AS Alamri, AAH Mahmoud, S Inaloo, P Habibzadeh, MA Faghihi, AC Jansen, S Brock, A Roubertie, BT Darras, PB Agrawal, FM Santorelli, J Gleeson, MS Zaki, SI Sheikh, JT Bennett, M Sahin 

Takeaway

• The spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia (AP-4-HSP) is characterized by developmental delays in children, alongside microcephaly, spasticity and a thin corpus callosum.

Why this matters

• Children with these characteristics should undergo testing for AP-4-HSP to quickly diagnose or rule out the condition before further progression.

Study design

• Objective: to identify the clinical, radiographic and molecular features of people with AP-4-HSP.
• 156 people from 110 families, with a confirmed diagnosis of AP-4-HSP and a mean age at diagnosis of 10.2±8.5 years (38% had the AP4M1-associated SPG50 subtype, 34% had AP4B1-associated SPG47, 15% had AP4S1-associated SPG51, and 13% had the AP4E1-associated SPG52 subtype).
• Whole exome sequencing was carried out and several scales were used to assess clinical features of AP-4-HSP including the Spastic Paraplegia Rating Scale (SPRS).
• The primary endpoints were the core clinical and radiographic features found across the cohort (defined as being present in more than 50% of individuals with AP-4-HSP). 

Key results

• The core clinical features of AP-4-HSP were identified as motor (100%) and speech delays (99%), spasticity (97%), infantile hypotonia (89%), postnatal microcephaly (83%), dysmorphic facial features (78%), foot deformities (69%), febrile seizures (62%), epilepsy (66%) and stereotypic laughter (56%).
• In terms of core radiographic features, 90% of individuals had a thin corpus callosum, 65% had ventriculomegaly, and 68% showed white matter loss/changes.
• Most individuals had early-onset global developmental delay, showing signs at an average age of 9.2±7.5 months.
• 54% of individuals required wheelchair use by age 9.0±5.3 years.
• The average SPRS score was 32.6±9.7 and the Four Stage Functional Mobility test identified that most individuals required assistance with ambulation (56%).
• The authors concluded that there is a common clinical phenotype across all subtypes of AP-4-HSP, labelled ‘AP-4-deficiency syndrome’, consisting primarily of developmental delays, microcephaly, spasticity and a thin corpus callosum.

Limitations

• None reported.

Ebrahimi-Fakhari D, et al. Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. Brain. 2020; doi:10.1093/brain/awz307.

Article posté le 25/11/2020