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AP4B1-associated hereditary spastic paraplegia: Expansion of clinico-genetic phenotype and geographic range

Salayev, Kamran; Rocca, Clarissa; Kaiyrzhanov, Rauan; Guliyeva, Ulviyya; Guliyeva, Sughra; Mursalova, Aytan; Rahman, Fatima; ... Houlden, Henry; + view all (2022) AP4B1-associated hereditary spastic paraplegia: Expansion of clinico-genetic phenotype and geographic range. European Journal of Medical Genetics , 65 (11) , Article 104620. 10.1016/j.ejmg.2022.104620. Green open access

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Abstract

BACKGROUND: Hereditary spastic paraplegias (HSP) are a group of neurodegenerative diseases that present with weakness and stiffness in the lower limb muscles and lead to progressive neurological decline. Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to complex HSP. This study aimed to identify causative genetic variants in consanguineous families with HSP from Azerbaijan and Pakistan. METHODS: We performed a thorough clinical and neuroradiological characterization followed by exome sequencing in 7 patients from 3 unrelated families. Segregation analysis was subsequently performed by Sanger sequencing. RESULTS: We describe 7 patients (4 males, 2-31 years of age) with developmental delay and spasticity. Similar to the previously reported cases with AP4B1-associated HSP, cases in the present report besides spasticity in the lower limbs had additional features including microcephaly, facial dysmorphism, infantile hypotonia, and epilepsy. The imaging findings included thin corpus callosum, white matter loss, and ventriculomegaly. CONCLUSION: In this study, we report 7 novel cases of HSP caused by bi-allelic variants in AP4B1 in Azerbaijani and Pakistani families. Our observations will help clinicians observe and compare common and unique clinical features of AP4B1-associated HSP patients, further improving our current understanding of HSP.

Type: Article
Title: AP4B1-associated hereditary spastic paraplegia: Expansion of clinico-genetic phenotype and geographic range
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ejmg.2022.104620
Publisher version: https://doi.org/10.1016/j.ejmg.2022.104620
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: AP4B1, Epilepsy, Genetics, Spastic paraplegia
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10160597
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