The authors describe an infant with a severe spastic paraparesis caused by two codominant mutations of the spastin gene. This highlights the multiple molecular mechanisms that are likely to be involved in the molecular pathology of SPG4 and illustrates the importance of complete screening of the spastin gene in affected individuals, particularly if the index case has an unusual phenotype.
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From spastic paraplegia to infantile neurodegenerative disorder: Expanding the phenotypic spectrum associated with biallelic SPAST variants.
Eur J Neurol
January 2025
Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France.
Purpose: Heterozygous pathogenic variants in SPAST are known to cause Hereditary Spastic Paraplegia 4 (SPG4), the most common form of HSP, characterized by progressive bilateral lower limbs spasticity with frequent sphincter disorders. However, there are very few descriptions in the literature of patients carrying biallelic variants in SPAST.
Methods: Targeted Sanger sequencing, panel sequencing and exome sequencing were used to identify the genetic causes in 9 patients from 6 unrelated families with symptoms of HSP or infantile neurodegenerative disorder.
[Successful application of preimplantation genetic testing combined with thirdgeneration sequencing for blocking hereditary spastic paraplegia].
Nan Fang Yi Ke Da Xue Xue Bao
November 2024
Department of Reproductive Medicine, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjng 210002, China.
Article Synopsis
- A family with hereditary spastic paraplegia (HSP) due to mutations in the SPAST gene underwent third-generation sequencing (TGS) and preimplantation genetic testing (PGT) to prevent passing the condition to their children.
- They identified a specific mutation in the SPAST gene and used advanced genetic testing during in vitro fertilization to select embryos free of the mutation.
- The successful process resulted in the birth of a healthy baby girl, demonstrating that TGS and PGT-M are effective methods for managing hereditary diseases and ensuring the health of offspring.
Unraveling Isoform Complexity: The Roles of M1- and M87-Spastin in Spastic Paraplegia 4 (SPG4).
Mov Disord
November 2024
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
Article Synopsis
- Spastic Paraplegia 4 (SPG4) is a serious neurological disorder that causes increasing weakness and stiffness in the legs, affecting walking ability, and is linked to mutations in the SPAST gene which encodes the spastin protein.
- The review examines the two main forms of spastin (M1 and M87), their genetic structure, and their uncertain roles in SPG4, highlighting the need for more research on how these isoforms contribute to the disease's progression.
- The authors propose new theories on how M1- and M87-spastin interact, suggesting this could lead to new treatment approaches for SPG4 and emphasizing the importance of understanding the specific functions of each spastin
Spastin accumulation and motor neuron defects caused by a novel SPAST splice site mutation.
J Transl Med
September 2024
Department of Neurology, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China.
Article Synopsis
- Hereditary spastic paraplegia (HSP) is a rare disorder primarily caused by mutations in the SPAST gene, with a complex pathogenic mechanism that isn't fully understood.
- Researchers investigated a Chinese family to identify the causative gene of autosomal dominant HSP-SPAST and discovered a novel splice site variant that affects gene expression.
- Experiments showed that this mutation leads to a truncated protein causing cellular accumulation and resulting in significant developmental issues in zebrafish, including defects in motor neuron pathfinding and axon loss.
Spastin regulates ER-mitochondrial contact sites and mitochondrial homeostasis.
iScience
September 2024
Genethon, 91000 Evry, France.
Mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) emerged to play critical roles in numerous cellular processes, and their dysregulation has been associated to neurodegenerative disorders. Mutations in the SPG4 gene coding for spastin are among the main causes of hereditary spastic paraplegia (HSP). Spastin binds and severs microtubules, and the long isoform of this protein, namely M1, spans the outer leaflet of ER membrane where it interacts with other ER-HSP proteins.
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