Objective: We herein report two Austrian families harbouring mutations in the SPG21-gene.

Background: SPG21 is a complicated, autosomal recessive hereditary spastic paraplegia. It presents with dementia, cerebellar and extrapyramidal signs as well as a thin corpus callosum. The affected SPG21-gene was localized on chromosome 15 and encodes for the protein maspardin, which is thought to play a role in the trans-Golgi and endosomal networks. SPG21 has previously been reported in Old Order Amish and three families from Germany, Italy and Japan.

Method: Three subjects from two unrelated families were identified. Workup consisted of neurophysiological and neuropsychological testing, MRI, neurological examination and genetic testing (Centogene, Rostock).

Results: Patient I-1 has always had an unsteady gait. At the age of 35, she started exhibiting a spastic tetraparesis, dementia and a cerebellar syndrome. She was wheelchair-bound at the age of 44. Subject II-1 started noticing a gait disturbance at age 30 and later developed a cerebellar syndrome, dementia and spastic paraparesis. At age 40 she started using a wheelchair. Subject II-2 experienced impaired dexterity and an unsteady gait at age 10. He then developed cognitive impairment, spastic paraparesis and ataxia.
Motor and sensory evoked potentials showed decreased central conduction velocity to the lower extremities. EEG and nerve conduction studies were unremarkable. MRI revealed a thin corpus callosum (TCC), cerebral and cerebellar atrophy. In addition, family II exhibited iron accumulation in the globus pallidum bilaterally. Neuropsychological evaluations revealed globally reduced cognitive functions. Genetic analysis in subject I-1 found a novel homozygous c.487delA mutation in exon 6 of the SPG21-gene. In family II, analysis revealed a compound heterozygous mutation in exon 3. One mutation (c.118C>T, p.R40X) has previously been described in a patient from Germany while the other is a novel frameshift mutation (c.153delT, p.Val52fs). All mutations cause a premature stop codon.

Conclusion: Herein we describe the first three Austrian cases exhibiting SPG21. Main symptoms were spasticity, extrapyramidal signs, ataxia and cognitive impairment. MRI revealed iron accumulation, TCC, cortical and cerebellar atrophy. Given this clinical presentation and a recessive mode of inheritance, SPG21, although rare, should be considered outside the Amish community.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/spg21-in-europe-mutations-outside-the-amish-community/