Case Report
An in-frame deletion in BICD2 associated with a non-progressive form of SMALED

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Highlights

  • We report a new family with 3 members affected with a non-progressive form of SMALED2.

  • The patients harbor the first described inframe deletion in BICD2: p.Lys508del.

  • The variants p.Lys508del and p.Lys508Thr lead to different phenotypes.

Introduction

Spinal muscular atrophy (SMA) is a group of inherited disease characterized by degeneration of spinal cord motor neuron. The most common form is caused by biallelic loss-of-function variants in the SMN1 gene. Other forms of SMA are genetically heterogeneous. Among them, spinal muscular atrophy lower extremity-predominant autosomal dominant form (SMALED) is characterized by muscle weakness predominantly affecting the proximal muscles of the lower extremities. This entity is divided between SMALED1 (MIM #158600) and SMALED2 (MIM #615290), caused by heterozygous pathogenic variants in DYNC1H1 [1] (MIM #600112) and BICD2 [2] (MIM #609797) respectively.

BICD2 codes for an evolutionary conserved cargo adaptor protein. In the presence of dynactin, BICD2 converts dynein from a non‐processive to a highly processive motor. In addition to the dynein-dynactin complex, BICD2 interacts with kinesin-1, a plus end-directed microtubule motor, and could play a more complex role in the regulation of microtubule cargo transport. To date, patients in 18 families with SMALED2 have been reported, carrying 11 different BICD2 variants [2,3]. Other defects than SMA have also been associated with BICD2 variants, such as cerebellar hypoplasia, chronic myopathy, and a prenatal form with arthrogryposis multiplex congenita and polymicrogyria. All the reported variants are heterozygous missense variants. The variant c.320C>T seems to be a mutational hot spot, as it has been observed in 7 affected families [2,4]. In order to expand the clinical and mutational spectrum of BICD2 pathogenic variants, we describe here a new family with 3 affected members, harboring the first described BICD2 in-frame deletion.

Section snippets

Case report

The proband (Patient 1) is the first child of an unrelated couple. He walked alone at the age of 18 months. His parents noticed difficulties in running and climbing stairs. He was first seen at the age 5 years for a persistent waddling gait. Upon clinical examination, a mild lordosis and a scoliosis with a right dorsal hump were noted. The patient was able to stand on one leg only for a brief moment, and unable to jump on one leg. The Gower’s sign was negative. A very mild distal wasting of the

Discussion

We report 3 related patients for whom a BICD2 variant segregated with SMALED2. The long term follow-up of our patients showed that their symptoms did not worsen, arguing for a non-progressive form. Progression of muscle wasting, despite stable muscle weakness, has been reported [4]. On the contrary, decrease of increased reflexes is unusual; BICD2 patients have usually progression of pyramidal signs, when present. Furthermore, even if the Patient 2 is only very slighted affected, the muscle MRI

Conclusion

In conclusion, we report here a family with three members affected by SMALED2, caused by the first in-frame deletion of BICD2 ever described. However, in the absence of other clinical reports or functional study, the specific effect of this variant on microtubule-based transport remains unknown.

Acknowledgements

We are grateful to the DNA and cell biobank of the Pitié-Salpêtrière Hospital (S. Forlani) for its help in this study and to the IGenSeq facility (Y. Marie) of the ICM institute for sequencing. The authors received fundings from the Agence Nationale de la Recherche (“Spatax Quest”, to GS), the 7th European Framework programme (Neuromics, to AD), the IHU-Investissements d’avenir (to the ICM institute) and the Verum Foundation (to GS).

References (5)

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Cited by (6)

  • Long-term follow-up of a patient with autosomal dominant lower extremity-predominant spinal muscular atrophy-2 due to a BICD2 variant

    2022, Brain and Development
    Citation Excerpt :

    Other forms of SMA are genetically heterogeneous. Among them, autosomal-dominant lower extremity-predominant spinal muscular atrophy (SMA-LED) is characterized by muscle weakness that predominantly affects the proximal muscles of the lower extremities [1]. These include SMA-LED1 [MIM #158600] and SMA-LED2 [MIM #615290], caused by heterozygous variants in dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) [2] and bicaudal D homolog cargo adaptor 2 (BICD2) [3], respectively.

  • SMALED2 with BICD2 gene mutations: Report of two cases and portrayal of a classical phenotype

    2020, Neuromuscular Disorders
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    However, it is clinically difficult to distinguish from DYNC1H1 mutations except that seizures and brain malformations are more commonly described with DYNC1H1 mutations. . Approximately 70 cases of SMALED with a BICD2 gene mutation have been described in the literature [3–15] (Table 1). Most of the clinical phenotype data we have come from one case series with 32 affected individuals from 9 families [6].

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