Challenges in genetic diagnosis of HSP

Improved genetic testing strategies the key

Purpose of review

The hereditary spastic paraplegias (HSPs) are a group of disorders characterised by progressive lower limb weakness and spasticity. We address the challenges and controversies involved in the genetic diagnosis of HSP.

Recent findings

There is a large and rapidly expanding list of genes implicated in HSP, making it difficult to keep gene testing panels updated. There is also a high degree of phenotypic overlap between HSP and other disorders, leading to problems in choosing the right panel to analyse.

Kishore Kumar

We discuss genetic testing strategies for overcoming these diagnostic hurdles, including the use of targeted sequencing gene panels, whole-exome sequencing and whole-genome sequencing. Personalised treatments for HSP are on the horizon, and a genetic diagnosis may hold the key to access these treatments. Developing strategies to overcome the challenges and controversies in HSP may hold the key to a rapid and accurate genetic diagnosis.

SOURCE:  Curr Neurol Neurosci Rep. 2021 Feb 28;21(4):15. doi: 10.1007/s11910-021-01099-x. PMID: 33646413

Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

Lydia Saputra  1 Kishore Raj Kumar  2   3   4   5

1. Northern Beaches Hospital, Frenchs Forest, New South Wales, Australia.

2. Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.

3. Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, Sydney, New South Wales, Australia.

4. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.

5. Institute of Precision Medicine & Bioinformatics, Sydney Local Health District, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.

Skill and knowledge needed

Modern gene testing more than mechanical

Even in this era of next-generation sequencing (NGS) for genetic testing, this study highlights the need for and value of experienced clinicians in the diagnostic assessment and clinical research of the HSPs and cerebellar ataxias (CA).


The molecular characterization of Hereditary Spastic Paraplegias (HSP) and inherited cerebellar ataxias (CA) is challenged by their clinical and molecular heterogeneity. The recent application of Next Generation Sequencing (NGS) technologies is increasing the diagnostic rate, which can be influenced by patients’ selection.

To assess if a clinical diagnosis of CA/HSP received in a third-level reference center might impact the molecular diagnostic yield, we retrospectively evaluated the molecular diagnostic rate reached in our center on 192 unrelated families (90 HSP and 102 CA) (i) before NGS and (ii) with the use of NGS gene panels.

Overall, 46.3% of families received a genetic diagnosis by first-tier individual gene screening: 43.3% HSP and 50% spinocerebellar ataxias (SCA). The diagnostic rate was 56.7% in AD-HSP, 55.5% in AR-HSP, and 21.2% in sporadic HSP. On the other hand, 75% AD-, 52% AR- and 33% sporadic CA were diagnosed. So far, 32 patients (24 CA and 8 HSP) were further assessed by NGS gene panels, and 34.4% were diagnosed, including 29.2% CA and 50% HSP patients. Eleven novel gene variants classified as (likely) pathogenic were identified. Our results support the role of experienced clinicians in the diagnostic assessment and the clinical research of CA and HSP even in the next generation era.

SOURCE:  Brain Sci. 2021 Feb 16;11(2):246. doi: 10.3390/brainsci11020246. PMID: 33669240

Application of a Clinical Workflow May Lead to Increased Diagnostic Precision in Hereditary Spastic Paraplegias and Cerebellar Ataxias: A Single Center Experience

Vittorio Riso  1   2 Salvatore Rossi  1   2 Tommaso F Nicoletti  1   2 Alessandra Tessa  3 Lorena Travaglini  4   5 Ginevra Zanni  4   5 Chiara Aiello  4   5 Alessia Perna  1   2 Melissa Barghigiani  3 Maria Grazia Pomponi  6 Filippo M Santorelli  3 Gabriella Silvestri  1   2

1. UOC Neurologia, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, 00168 Rome, Italy.

2. Department of Neurosciences, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

3. Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56018 Pisa, Italy.

4. Unit of Muscular and Neurodegenerative Diseases, Department of Neurosciences, Bambino Gesù Children’s Hospital, 00165 Rome, Italy.

5. Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, 00165 Rome, Italy.

6. UOC Genetica Medica, Fondazione Policlinico Universitario “A.Gemelli” IRCCS, 00168 Rome, Italy.

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