Long-read sequencing revealing intragenic deletions in exome-negative spastic paraplegias.

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness in the lower extremities. To date, a total of 88 types of SPG are known. To diagnose HSP, multiple technologies, including microarray, direct sequencing, multiplex ligation-dependent probe amplification, and short-read next-generation sequencing, are often chosen based on the frequency of HSP subtypes. Exome sequencing (ES) is commonly used. We used ES to analyze ten cases of HSP from eight families. We identified pathogenic variants in three cases (from three different families); however, we were unable to determine the cause of the other seven cases using ES. We therefore applied long-read sequencing to the seven undetermined HSP cases (from five families). We detected intragenic deletions within the SPAST gene in four families, and a deletion within PSEN1 in the remaining family. The size of the deletion ranged from 4.7 to 12.5 kb and involved 1-7 exons. All deletions were entirely included in one long read. We retrospectively performed an ES-based copy number variation analysis focusing on pathogenic deletions, but were not able to accurately detect these deletions. This study demonstrated the efficiency of long-read sequencing in detecting intragenic pathogenic deletions in ES-negative HSP patients.

[A case of primary central nervous system lymphoma with marked cauda equina enlargement].

An 80-year-old woman presented with subacute right lower limb pain and bilateral lower limb weakness. MRI of the spine showed marked cauda equina enlargement with contrast enhancement. Cerebrospinal fluid (CSF) examination showed elevated cell count, decreased glucose, and elevated protein. Cytology of the CSF showed class V, which together with B-cell clonality by flow cytometry, led to the diagnosis of primary central nervous system lymphoma (PCNSL). The patient was treated with steroid, radiation, and chemotherapy. Despite the reduction in lesion size, her neurological symptoms revealed no improvement. PCNSL with cauda equina lesions are rare and often require highly invasive cauda equina biopsy for diagnosis. In recent years, some studies reported useful CSF biomarkers, but they may have some problems. Therefore, as in this case, the combination of cytology, flow cytometry and, CSF biomarkers could be a substitute method for invasive biopsies, and contribute to the early treatment of PCNSL.