Revisiting genotype-phenotype overlap in neurogenetics: Triplet-repeat expansions mimicking spastic paraplegias

Abstract

ABSTRACT:Hereditary spastic paraplegias (HSPs) constitute a heterogeneous group of neurological disorders, characterized primarily by progressive spasticity and weakness of the lower limbs. HSPs are caused by mutations in multiple genes (at least 48 loci and 28 causative genes). The clinical spectrum of HSPs is wide and important differences have been reported between patients with distinct mutations in the same gene, or even between different family members bearing the same mutation. Many patients with HSP present clinical deficits related to the involvement of neuronal systems other than corticospinal tracts, namely, peripheral nerves, sensory, or cerebellar pathways. These cases may be difficult to differentiate from other neurological diseases (e.g., hereditary ataxias), also genetically and clinically heterogeneous. As an illustration of how overlapping this genotype-phenotype relationship is, and the difficulties that it brings upon the development of neurogenetic algorithms and databases, we review the main clinical and genetic features of HSPs, and summarize reports on cases of triplet-repeat spinocerebellar ataxias that can mimic HSP phenotypes. This complex scenario makes the necessity of high-quality, curated mutation databases even more urgent, in order to develop adequate diagnostic guidelines, correct interpretation of genetic testing, and appropriate genetic counseling.

Exome sequencing is a useful diagnostic tool for complicated forms of hereditary spastic paraplegia

“…Similar to what has been previously described (3,(17)(18)(19), clinical heterogeneity within a given HSP kindred was evident in our patients, making their diagnosis more difficult. We described two siblings harboring the same mutation, but with distinct clinical presentations, from which we can highlight the mental impairment in the proband ( Fig.…”

Exome sequencing reveals novel SPG11 mutation in hereditary spastic paraplegia with complicated phenotypes

“…Molecular diagnoses by conventional techniques are usually impractical as they employ expensive and time consuming gene-by-gene screenings that are sometimes unavailable in small laboratories [25]. It is even more complex in situations where the pathogenesis of a disease has not been revealed or there is an abundance of candidate genes present in the mapped region.…”

PMCA4 (ATP2B4) Mutation in Familial Spastic Paraplegia

“…We also carefully screened our patients for non-synonymous mutations among 61 FSP candidate genes [including 47 genes causing various types of Familial Spastic Paraplegias (AFG3L2, ALS2, AP4B1, AP4E1, AP4M1, AP4S1, AP5Z1, ATL1, BSCL2, C12orf65, CCT5, CYP2U1, CYP7B1, DDHD1, ELOVL4, ERLIN2, FA2H, GAD1, GJA1, GJC2, HSPD1, KANK1, KIAA0196, KIF1A, KIF5A, L1CAM, NIPA1, PLP1, PNPLA6, REEP1, RTN2, SLC16A2, SLC33A1, SPAST, SPG11, SPG20, SPG21, SPG7, TECPR2, VCP, VPS37A, ZFYVE26, B4GALNT1, C19orf12, GBA2, NT5C2 and ZFYVE27) [3], [8] and 14 newly proposed genes (ARL6IP1, ERLIN1, KIF1C, USP8, WDR48, AMPD2, ENTPD1, ARSI, DDHD2, PGAP1, FLRT1, RAB3GAP2, MARS and ZFR) by Novarino et al [3]. Finally, we replicated the short list of sequence variants by conventional Sanger sequencing in all available family members to exclude false positives of the high-throughput sequencing.…”