Objective: To perform a clinical and a genetic study in an Italian family with a complicated form of hereditary spastic paraplegia (HSP) and Alzheimer’s disease (AD).

Background: Mutations in the SPG4/SPAST gene are the major cause of HSPs, a group of genetic disorders leading to progressive spasticity and weakness of the lower limbs. AD is a degenerative disorder of the central nervous system. Early-onset familial AD (EOFAD) accounts for 3-5% of all AD cases and denotes families in which onset is reliably before age 60 to 65 years and sometimes before age 55 years. Two HSP-SPAST Italian families with pure HSP and AD and one Japanese family with complicated HSP and AD were previously described by our research team.

Methods: Whole exome sequencing (WES), Sanger sequencing, Multiplex Ligation dependent Probe Amplification (MLPA) analysis, bioinformatics, neurological evaluation, diagnostic imaging, and pathological assessment.

Results: One Italian man was diagnosed as certainly affected by slowly progressive autosomal dominant HSP, according to the Harding criteria. The age at onset of the first motor symptoms was 32 years. At 57 years, the phenotype was complicated by cognitive impairment; a diagnosis of EOFAD based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria was formulated. The case was definite Alzheimer’s disease (autopsy proven): the brain pathology showed plaques with a congophilic core and neuritic pathology. Additional four affected subjects revealed the same initial symptoms of dementia and HSP was diagnosed. Additional clinical signs, such as hearing impairment, seizures, and pes cavus, were present in the affected individuals. WES revealed in all patients a new heterozygous change in SPG4/SPAST. MLPA analysis excluded the presence of deletions/duplications in SPG4/SPAST. Bioinformatic analyses and population study confirm a pathogenetic role of such mutation. Screening of PS1, PS2, and βAPP genes did not reveal any coding mutation. No affected subject carried out APOE genotype ε4/ε3 or ε4/ε4.

Conclusions: To our knowledge, this work describes the first Italian family with a new SPG4/SPAST mutation and association of a complicated form of HSP and EOFAD.

References: 1. Kawarai T, Montecchiani C, Miyamoto R, Gaudiello F, Caltagirone C, Izumi Y, Kaji R, Orlacchio A: Spastic paraplegia type 4: a novel SPAST splice site donor mutation and expansion of the phenotype variability. Journal of the Neurological Sciences 2017, 380: 92-97. 2. Lo Giudice T, Lombardi F, Santorelli FM, Kawarai T, Orlacchio A: Hereditary spastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms. Experimental Neurology 2014, 261C: 518-539.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-new-spg4-spast-mutation-in-an-italian-family-with-hereditary-spastic-paraplegia-and-alzheimers-disease/