Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis

Cogan G(1), Zaki MS(2), Issa M(2), Keren B(1), Guillaud-Bataille M(1), Renaldo
F(3), Isapof A(3), Lallemant P(4)(5), Stevanin G(5)(6), Guillot-Noel L(5),
Courtin T(1), Buratti J(1), Freihuber C(3), Gleeson JG(7)(8), Howarth R(7)(8),
Durr A(5), de Sainte Agathe JM(1), Mignot C(9)(10).

Author information:
(1)APHP Sorbonne Université, Département de Génétique, Groupe Hospitalier
Pitié-Salpêtrière-Hôpital Trousseau, Centre de Référence Déficiences
Intellectuelles de Causes Rares, ERN-ITHACA, 47-83 Boulevard de l’hôpital,
75013, Paris, France.
(2)Clinical Genetics Department, Human Genetics and Genome Research Institute,
National Research Centre, Cairo, Egypt.
(3)APHP Sorbonne Université, Service de Neuropédiatrie, Centre de Référence
Neurogénétique, Hôpital Armand Trousseau, Paris, France.
(4)APHP Sorbonne Université, Service de Médecine Physique et de Réadaptation
Pédiatrique, Hôpital Armand Trousseau, Paris, France.
(5)Sorbonne Université, Institut du Cerveau, Paris Brain Institute ICM, Inserm,
CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France.
(6)Bordeaux University, INCIA, UMR5287, CNRS, EPHE, 33000, Bordeaux, France.
(7)Department of Neurosciences, University of California, San Diego, La Jolla,
CA, 92093, USA.
(8)Rady Children’s Institute for Genomic Medicine, San Diego, CA, 92130, USA.
(9)APHP Sorbonne Université, Département de Génétique, Groupe Hospitalier
Pitié-Salpêtrière-Hôpital Trousseau, Centre de Référence Déficiences
Intellectuelles de Causes Rares, ERN-ITHACA, 47-83 Boulevard de l’hôpital,
75013, Paris, France. .
(10)Sorbonne Université, Institut du Cerveau, Paris Brain Institute ICM, Inserm,
CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France.
.

Biallelic variants in the ERLIN1 gene were recently reported as the cause of two
motor neuron degeneration diseases, SPG62 and a recessive form of amyotrophic
lateral sclerosis. However, only 12 individuals from five pedigrees have been
identified so far. Thus, the description of the disease remains limited.
Following the discovery of a homozygous pathogenic variant in a girl with SPG62,
presenting with intellectual disability, and epilepsy, we gathered the largest
series of SPG62 cases reported so far (13 individuals) to better understand the
phenotype associated with ERLIN1. We collected molecular and clinical data for
13 individuals from six families with ERLIN1 biallelic variants. We performed
RNA-seq analyses to characterize intronic variants and used Alphafold and a
transcripts database to characterize the molecular consequences of the variants.
We identified three new variants suspected to alter the bell-shaped ring formed
by the ERLIN1/ERLIN2 complex. Affected individuals had childhood-onset
paraparesis with slow progression. Six individuals presented with gait ataxia
and three had superficial sensory loss. Aside from our proband, none had
intellectual disability or epilepsy. Biallelic pathogenic ERLIN1 variants induce
a rare, predominantly pure, spastic paraparesis, with possible cerebellar and
peripheral nerve involvement.

© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany,
part of Springer Nature.

DOI: 10.1007/s00439-024-02702-0
PMCID: PMC13108457
PMID: 39367212 [Indexed for MEDLINE]

Conflict of interest statement: Conflict of interest The authors have no
relevant financial or non-financial interests to disclose.

Auteurs Bordeaux Neurocampus