Spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1) is a debilitating neurological disease that is caused by the mutation the Tyrosyl-DNA phosphodiesterase 1 (TDP1) DNA repair enzyme.
A homozygous mutation of human tyrosyl-DNA phosphodiesterase 1 (TDP1) causes the neurodegenerative syndrome, spinocerebellar ataxia with axonal neuropathy (SCAN1).
We found a novel MFN2 mutation - c.283A>G (p.Arg95Gly) - that results in an axonal neuropathy with variable clinical severity in a multigenerational family.
In contrast, UCHL3 is downregulated in spinocerebellar ataxia with axonal neuropathy (SCAN1), causing elevated levels of TDP1 ubiquitylation and faster turnover rate.
Mutations in TDP1 and APTX have been linked to Spinocerebellar ataxia with axonal neuropathy (SCAN1) and Ataxia-ocular motor apraxia 1 (AOA1), respectively, while mutations in PNKP are considered to be responsible for Microcephaly with seizures (MCSZ) and Ataxia-ocular motor apraxia 4 (AOA4).
MFN2 mutations cause axonal neuropathy, with associated lipodystrophy only occasionally noted, however homozygosity for the p.Arg707Trp mutation was recently associated with upper body adipose overgrowth.
We report on a 7-month-old white female with hypotonia, motor delay, distal weakness, and motor/sensory axonal neuropathy in which next-generation sequencing analysis identified compound heterozygous pathogenic variants (c.2054_2069_1170del and c.392A>G) in MFN2.
Exome sequencing and linkage analysis were utilized to investigate a large Taiwanese family with a dominantly inherited adult-onset motor and sensory axonal neuropathy in which mutations in common CMT2-implicated genes had been previously excluded.
A cohort of 139 unrelated Czech patients with axonal neuropathy was selected for sequencing and multiplex ligation-dependent probe amplification analysis (MLPA) testing of the MFN2 gene.
In small kindreds, specific MFN2 mutations have been reported to associate with severity of axonal neuropathy, optic atrophy, and involvement of the central nervous system.
Spinocerebellar ataxia with axonal neuropathy (SCAN 1) is an autosomal recessive disorder caused by a specific point mutation (c.1478A>G, p.H493R) in the tyrosyl-DNA phosphodiesterase (TDP1) gene.
Molecular analysis aimed at detecting mutations of MFN2 could be extremely useful in mild axonal neuropathies with slow evolution and indispensable in cases of dominant inheritance or optic atrophy.
The aim of this study was to investigate the mode of inheritance in three individuals with severe early-onset axonal neuropathy and homozygous or compound heterozygous MFN2 mutations.
Our results suggest that the sharply reduced efficacy of oxidative phosphorylation in MFN2-related CMT2A may contribute to the pathophysiology of the axonal neuropathy.
Our results suggest that the sharply reduced efficacy of oxidative phosphorylation in MFN2-related CMT2A may contribute to the pathophysiology of the axonal neuropathy.
In particular, spinocerebellar ataxia with axonal neuropathy (SCAN1) is a human disease that is associated with mutation of TDP1 (tyrosyl DNA phosphodiesterase 1) protein and with a defect in repairing certain types of SSBs.
Hereditary spinocerebellar ataxia with axonal neuropathy (SCAN1) is caused by an inactivating mutation (H493R) in the enzyme tyrosyl-DNA phosphodiesterase (Tdp1), which removes blocked 3'-termini at DNA strand breaks.