Mitochondrial DNA polymorphisms/haplogroups in hereditary spastic paraplegia

Abstract

Mitochondrial dysfunction could contribute to the development of spastic paraplegia. Among others, two of the genes implicated in hereditary spastic paraplegia encoded mitochondrial proteins and some of the clinical features frequently found in these patients resemble those observed in patients with mitochondrial DNA (mtDNA) mutations. We investigated the association between common mtDNA polymorphisms and spastic paraplegia. The ten mtDNA polymorphisms that defined the common European haplogroups were determined in 424 patients, 19% with a complicated phenotype. A rare haplogroup was associated with the disease in patients without a SPG3A, SPG4, or SPG7 mutation. Allele 10398G was more frequent among patients with a pure versus complicated phenotype. This mtDNA polymorphism was previously associated with the risk of developing other neurodegenerative diseases. In conclusion, some mtDNA polymorphisms could contribute to the development of spastic paraplegia or act as modifiers of the phenotype.

Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance

“…The same mutation has been connected to other diseases such as Leigh syndrome suggesting that modifying factors are likely playing a role in the variability of phenotypic expression of the disease [12]. There are also indications that mtDNA polymorphisms contribute to the development of SPGs [22].…”

“…Causative genes of 16 subtypes have been identified and 16,22) include CYP7B1 (SPG5), SPG7 (SPG7), KIAA1840 (SPG11), ZFYVE26 (SPG15), ERLIN2 (SPG18), SPG20 (SPG20), ACP33 (SPG21), KIF1A (SPG30), FA2H (SPG35), NTE (SPG39), GJA12/GJC2 (SPG44), KIAA0415 (SPG48), and 4 genes encoding for the AP4 complex (SPG47) ( Table 2). A subgroup of SPGs comprises those with thin corpus callosum (TCC) on imaging.…”

“…SPG3, SPG4, SPG7, SPG8, SPG10, SPG11, SPG31) [22] and a rational diagnostic scheme is used according to the clinical and genealogical criteria mentioned above (Fig. 1) [156].…”

Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms

“…Phenotypic similarity has been observed between patients carrying mitochondrial DNA (mtDNA) mutations and HSP patients. On the basis of these observations, a recent work evaluated the possible involvement of common mitochondrial polymorphisms/haplogroups on the risk of developing HSP (Sánchez-Ferrero et al, 2011).…”

The Ageing Brain, Mitochondria and Neurodegeneration

“…An mtDNA mutation in MTATP6 (m.9176T>C) was identifi ed in a large HSP pedigree [ 150 ] and a mutation in the mitochondrial 12 s rRNA (m.1432A>G) was identifi ed in an Amish family who demonstrated abnormal mRNA maturation [ 151 ]. A single study investigating the role of mtDNA haplogroups appears negative, but is largely inconclusive due to low sample size and genetic heterogeneity [ 152 ].…”