The point mutations I154F and W155R in frataxin cause FRDA and are clustered to one surface of the protein, and these mutations decrease the interaction of frataxin with ISD11.
To reinvestigate the mutation spectrum, we searched for mutations including exon deletions in six patients heterozygous for the GAA repeat expansion and found two unknown missense mutations, p.Asn146Lys and p.Leu186Arg, in trans to the expanded FRDA allele.
The genotypic and phenotypic spectrum of FRDA was similar to other populations, with one patient compound heterozygote for a known point mutation in FXN (Asn146Lys).
Here, we report three Turkish siblings from consanguineous parents presenting with a CMT-like phenotype who carry a homozygous c.493C>T, p.Arg165Cys mutation in the FXN gene that is the only known causative gene for Friedreich's ataxia (FRDA).
The point mutations I154F and W155R in frataxin cause FRDA and are clustered to one surface of the protein, and these mutations decrease the interaction of frataxin with ISD11.
In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function.
Compound heterozygous patients with FA who have a GAA expansion and a G130V mutation have been reported to have an atypical phenotype with a slow disease progression, minimal or no ataxia, or gait spasticity.
We describe here a 41-year-old man with profound vision deficit and episodic complete blindness associated with marked optic atrophy, spastic paraparesis, and sensory neuropathy without ataxia whose diagnostic evaluation revealed compound heterozygosity for two frataxin mutations, a 994 GAA repeat intronic expansion and c.389G > T (p.G130V) missense mutation.
Compound heterozygous patients with FA who have a GAA expansion and a G130V mutation have been reported to have an atypical phenotype with a slow disease progression, minimal or no ataxia, or gait spasticity.
We describe here a 41-year-old man with profound vision deficit and episodic complete blindness associated with marked optic atrophy, spastic paraparesis, and sensory neuropathy without ataxia whose diagnostic evaluation revealed compound heterozygosity for two frataxin mutations, a 994 GAA repeat intronic expansion and c.389G > T (p.G130V) missense mutation.
This report confirms that compound heterozygous patients with FA who have a GAA expansion and a G130V mutation may present with an ataxic phenotype and that intrafamilial phenotypic variability in these pedigrees can occur.
In agreement, the iron metallochaperone activity of the Friedreich's ataxia mutants was affected: some mutants precipitate upon iron binding (I154F and W155R) and others have a lower binding stoichiometry (G130V and D122Y).
Molecular testing for Friedreich ataxia showed significantly expanded GAA repeats at 799 (abnormal >67 GAA repeats) on one allele and a heterozygous disease causing mutation, c.317T>C (p.Leu106Ser) on the other allele, confirming the diagnosis.
In agreement, the iron metallochaperone activity of the Friedreich's ataxia mutants was affected: some mutants precipitate upon iron binding (I154F and W155R) and others have a lower binding stoichiometry (G130V and D122Y).
Compound heterozygous patients with FA who have a GAA expansion and a G130V mutation have been reported to have an atypical phenotype with a slow disease progression, minimal or no ataxia, or gait spasticity.
In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function.
Molecular testing for Friedreich ataxia showed significantly expanded GAA repeats at 799 (abnormal >67 GAA repeats) on one allele and a heterozygous disease causing mutation, c.317T>C (p.Leu106Ser) on the other allele, confirming the diagnosis.
Here, we report three Turkish siblings from consanguineous parents presenting with a CMT-like phenotype who carry a homozygous c.493C>T, p.Arg165Cys mutation in the FXN gene that is the only known causative gene for Friedreich's ataxia (FRDA).
In agreement, the iron metallochaperone activity of the Friedreich's ataxia mutants was affected: some mutants precipitate upon iron binding (I154F and W155R) and others have a lower binding stoichiometry (G130V and D122Y).
In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function.
In agreement, the iron metallochaperone activity of the Friedreich's ataxia mutants was affected: some mutants precipitate upon iron binding (I154F and W155R) and others have a lower binding stoichiometry (G130V and D122Y).
In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function.