Objective: We present a case of a patient who presented with limb dystonia and was found to have HSP associated with a previously unreported compound heterozygous SPG7 mutation.

Background: Spastic paraplegia gene 7 (SPG7) mutation is an autosomal recessive type of HSP (1). The SPG7 gene encodes for paraplegin, a protein found in mitochondria as a part of the mitochondrial permeability transition pore (2). Many patients present with ataxia, spasticity, and hyperreflexia, but a variety of other rarer findings have been reported.

Methods: A 40-year-old right-handed man presented to our center with difficulty writing. For three months, when writing, his thumb and index finger would extend. He also had difficulty using utensils to eat or stir. He endorsed mild imbalance while walking up stairs, but no falls. On examination, he was noted to have right thumb abduction and index finger extension while writing with either hand. He had right hand ulnar deviation with writing, dystonic posturing of the fingers more prominently on the left, and incoordination bilaterally particularly with heel tapping and heel-to-shin testing. Reflexes were brisk throughout with negative Hoffmann’s sign, bilateral ankle clonus, and positive left Babinski sign. Lower extremity tone was mildly spastic.

Results: MRI of the brain, cervical and thoracic spine was unremarkable. EMG revealed moderate right median neuropathy at the wrist. Thyroid studies, serum levels of vitamins B1, B12, and E, ceruloplasmin, serum copper, ESR, CRP, anti-GAD antibodies, and HTLV serology were all negative. Genetic studies for autosomal recessive HSP revealed compound heterozygous SPG7 mutations-c.2096dupT (p.Met699IlefsX4) and c.1529 C>T (p.Ala510Val), and a heterozygous AP4S1 mutation (c.289 C>T, p.Arg97Ter).

Conclusions: One of our patient’s mutations, p.Ala510Val, is widely reported in the literature, while the other, p.Met699IlefsX4, has never been reported to our knowledge. Dystonia is a rare presenting feature of HSP. We could not find other published cases of limb dystonia, although cervical dystonia, which our patient did not have, has been described in two patients (1). Although homozygous AP4S1 mutation has been associated with early-onset spastic paraparesis, intellectual disability, and seizures (3), heterozygous mutations have not been reported as pathogenic and so this mutation is likely incidental.

References: 1. van Gassen, K.L.I.; van der Heijden, C.D.C.C.; de Bot, S.T.; den Dunnen, W.F.A.; van den Berg, L.H.; Verschuuren-Bemelmans, C.C.; Kremer, H.P.H.; Veldink, J.H.; Kamsteeg, E.-J.; Scheffer, H., et al. Genotype-phenotype correlations in spastic paraplegia type 7: A study in a large dutch cohort. Brain 2012, 135, 2994-3004. 2. Shanmughapriya, S.; Rajan, S.; Hoffman, Nicholas E.; Higgins, Andrew M.; Tomar, D.; Nemani, N.; Hines, Kevin J.; Smith, Dylan J.; Eguchi, A.; Vallem, S., et al. Spg7 is an essential and conserved component of the mitochondrial permeability transition pore. Molecular Cell 2015, 60, 47-62. 3. Hardies, K.; May, P.; Djemie, T.; Tarta-Arsene, O.; Deconinck, T.; Craiu, D.; Helbig, I.; Suls, A.; Balling, R.; Weckhuysen, S., et al. Recessive loss-of-function mutations in ap4s1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of ap-4 complex assembly. Hum Mol Genet 2015, 24, 2218-2227.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hereditary-spastic-paraplegia-presenting-as-limb-dystonia-with-a-novel-spg7-mutation/