Revealing big picture overview
This analytical review (meta-analysis) was aimed at establishing connections and patterns between HSP type (genotype) and phenotype, comprising frequency of occurrence, age of disease onset, gender distribution and symptom profiles. Establishing evidence for such connections in the past has proved largely fruitless, so this review looked at the data from about 150 studies comprising 14,000 people with HSP.
AIMS: The hereditary spastic paraplegias (HSPs) are a heterogeneous group of inherited neurodegenerative disorders. Although, several genotype-phenotype studies have carried out on HSPs, the association between genotypes and clinical phenotypes remain incomplete since most studies are small in size or restricted to a few genes. Accordingly, this study provides the systematic meta-analysis of genotype-phenotype associations in HSP.
METHODS AND RESULTS: We retrieved literature on genotype-phenotype associations in patients with HSP and mutated SPAST, REEP1, ATL1, SPG11, SPG15, SPG7, SPG35, SPG54, SPG5. In total, 147 studies with 13,570 HSP patients were included in our meta-analysis.
The frequency of mutations in SPAST (25%) was higher than REEP1 (3%), as well as ATL1 (5%) in AD-HSP patients. As for AR-HSP patients, the rates of mutations in SPG11 (18%), SPG15 (7%) and SPG7 (13%) were higher than SPG5 (5%), as well as SPG35 (8%) and SPG54 (7%).
The mean age of AD-HSP onset for ATL1 mutation-positive patients was earlier than patients with SPAST, REEP1 mutations. Also, the tendency toward younger age at AR-HSP onset for SPG35 was higher than other mutated genes. It is noteworthy that the mean age at HSP onset ranged from infancy to adulthood.
As for the gender distribution, the male proportion in SPG7-HSP (90%) and REEP1-HSP (78%) was markedly high. The frequency of symptoms was varied among patients with different mutated genes. The rates of LL weakness, superficial sensory abnormalities, neuropathy, and deep sensory impairment were noticeably high in REEP1 mutations carriers. Also, in AR-HSP patients with SPG11 mutations, the presentation of symptoms including pes cavus, Neuropathy, and UL spasticity was higher.
CONCLUSION: Our comprehensive genotype-phenotype assessment of available data displays that the mean age at disease onset and particular sub-phenotypes are associated with specific mutated genes which might be beneficial for a diagnostic procedure and differentiation of the specific mutated genes phenotype among diverse forms of HSP.
SOURCE: J Neurol. 2019 Nov 19. doi: 10.1007/s00415-019-09633-1. [Epub ahead of print] PMID: 31745725
Genotype-phenotype associations in hereditary spastic paraplegia: a systematic review and meta-analysis on 13,570 patients.
1 Department of Medical Laboratory Technology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
2 Department of Medical Genetics and Immunology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
3 Department of Neurology, Imam Khomeini Hospital, Urmia University of Medical Sciences, Urmia, Iran.
4 Department of Laboratory Sciences, Faculty of Parmedicine, Yasuj University of Medical Sciences, Yasuj, Iran.
5 Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Velenjak St., Shahid Chamran Highway, Tehran, IR, Iran.
6 Department of Medical Genetics, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
7 Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Velenjak St., Shahid Chamran Highway, Tehran, IR, Iran. [email protected]