Objective: We present the clinical and genetic results of a SPG17 family with a vast intrafamilial phenotype from subclinical signs to a severe and rapidly progressing amyotrophic lateral sclerosis (ALS)-like phenotype.

Background: Mutations in the BSCL2 gene are responsible for autosomal dominant hereditary motor neuropathy type V (dHMN-V), Silver syndrome/SPG17, and Charcot-Marie-Tooth disease type 2 (CMT2). The predominant phenotype is weakness and atrophy of hand muscles early in the disease course. Other common signs include pyramidal tract involvement and peroneal muscle weakness.

Methods: Five members of a two-generation family of German origin were examined clinically and electrophysiologically. DNA of three patients was sequenced using the TruSight Exome sequencing panel (Illumina) consisting of 2761 genes. Data analysis was performed by GensearchNGS (PhenoSystems) and pathogenicity predictions were made by Alamut (Interactive Biosoftware). We filtered for variants common to all three family members and for exclusive variants in the index patient to find possible modifier mutations.

Results: The 49 year old male index patient suffered of rapidly progressive atrophic tetraparesis and bulbar palsy fulfilling the revised “El Escorial” criteria for clinically probable ALS. His sister showed at age 51 a unilateral atrophy of the IOD I and an axonal neuropathy of the peroneal motor nerve. Another 45 year old sister did not have any clinical symptoms or signs, but electrophysiology displayed a pure motor axonal neuropathy. Their mother was diagnosed with a multifocal motor neuropathy (MMN) at the age of 62 years due to a unilateral atrophy of the IOD I and a motor neuropathy with conduction blocks. Her 74 year old sister was clinically and electrophysiologically inconspicuous. We found a known heterozygous missense mutation in the BSCL2 gene (c.263A>G; p.N88S) which was confirmed by Sanger sequencing in all four affected family members. C9ORF72 has been ruled out by PCR and Southern blot in the ALS-like patient. No additional pathogenic mutation was found in the ALS-like patient in all 2761 genes, including 19 known ALS genes.

Conclusions: Our results confirm the vast phenotypical heterogeneity of BSCL2 mutations and broaden the spectrum to an ALS-like and MMN phenotype. Further research is needed to better understand the genetic modifiers causing the intrafamilial variability in this disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/familial-spg17distal-hereditary-motor-neuropathy-type-v-complicated-hereditary-spastic-paraplegia-with-many-faces/