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Background and aims: We report on a 58-year-old female
patient suffering from slowly progressive gait disturbances
since 10 years with a positive family history of walking
difficulties. Genetic testing revealed hitherto novel mutations
of the genes spastin and epsilon sarcoglycan (SGCE), whereas
the clinical findings led to the diagnosis of hereditary spastic
paraplegia type 4 (HSP4). This report intends to contribute to
the discussion concerning the translation of genetical findings
into clinical practice and associated factors such as epigenetics.
Methods: Clinical and electrophysiological examinations, lab
work-up and genetic testing.
Results: The leading clinical signs were a spastic ataxic gait
with brisk tendon reflexes of both lower extremities and
bilateral extensor plantar responses. No dystonic or myoclonic
features could be detected. The diagnostic work-up revealed a
history of migraine, multiple microvascular cerebral lesions, a
primary antiphospholipid syndrome and unremarkable
electrophysiological results. Genetic testing showed hitherto
unknown mutations of the spastin and SGCE gene. Concerning
both mutations 5 out of 6 in-silico models foretold
pathogenicity.
Conclusion: This case highlights that the clinical picture is still
the eventually defining element despite the ever growing
importance and knowledge concerning underlying genetical
alterations in some diseases. Combining clinical and genetic
information a novel mutation of the spastin gene causing HSP4
could be diagnosed. There could be a couple of explanations
for the missing pathogenicity of the SGCE mutation, i.e.
incomplete penetrance, epigenetic modifiers which for
example consist of DNA methylation and chromatin
remodelling or the actual non-pathogenicity of the mutation
itself. The responsible mechanism has yet to be identified.