Mitochondrial dysfunction in hereditary spastic paraparesis with mutations in DDHD1/SPG28

Area of Science:

• Genetics
• Neuroscience
• Cell Biology

Background:

• Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders.
• SPG28, a subtype of HSP, is caused by mutations in the DDHD1 gene.
• Mitochondrial dysfunction has been implicated in SPG28 pathogenesis.

Observation:

• Two siblings with SPG28 presented with spastic paraparesis, gait issues, and motor axonal neuropathy.
• A novel homozygous nonsense mutation (c.1429C>T/p.R477*) in DDHD1 was identified using next-generation sequencing.
• Skeletal muscle and skin fibroblasts from patients showed significant mitochondrial abnormalities.

Findings:

• Histochemical analysis revealed mitochondrial alterations and multiple mitochondrial DNA (mtDNA) deletions in skeletal muscle.
• Respiratory chain enzyme activities were altered, and mitochondrial ATP levels were reduced in patient 1.
• Skin fibroblasts exhibited mitochondrial fragmentation, indicating impaired cellular energy production.

Implications:

• The identified DDHD1 mutation likely abolishes protein function, leading to altered oxidative metabolism.
• Qualitative changes in mtDNA may play a significant role in the disease's development.
• DDHD1 gene analysis is recommended for patients presenting with multiple mtDNA deletions.