trinucleotide repeats ataxia

the hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. frequently, atrophy of the cerebellum occurs. the hereditary ataxias are categorized by mode of inheritance and causative gene or chromosomal locus. genetic forms of ataxia must be distinguished from the many acquired (non-genetic) causes of ataxia. the genetic forms of ataxia are diagnosed by family history, physical examination, and neuroimaging. molecular genetic tests are available for the diagnosis of sca1, sca2, sca3, sca6, sca7, sca8, sca10, sca12, sca17, drpla, friedreich ataxia (frda), in iran. trinucleotide repeat disorders are a set of genetic disorders caused by trinucleotide repeats in certain genes exceeding the normal stable threshold which differs per gene. the mutation is a subset of unstable microsatellite repeats that occurs throughout all genomic sequences. if the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. trinucleotide repeat disorders are the result of extensive duplication of a single codon. in fact, the cause is trinucleotide expansion up to a repeat number above a certain threshold level. trinucleotide repeat disorders generally show genetic anticipation, where their severity increases with each successive generation that inherits them. in over half of these disorders, the repeated codon is cag and codes for glutamine (q) resulting in a polyglutamine tract. these diseases are commonly referred to as polyglutamine (or polyq) diseases. in the remaining disorders, repeated codons do not code for glutamine and are classified as non-polyglutamine diseases. friedreichs ataxia (frda) is characterized by slowly progressive ataxia with a mean age of onset between ten and 15 years and usually before 25 years of age. frda is typically associated with dysarthria, muscle weakness, spasticity in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, and loss of position and vibration sense. approximately two-thirds of individuals with frda have cardiomyopathy, up to 30% have diabetes mellitus, and approximately 25% have an atypical presentation as a later onset or retained tendon reflexes. individuals with frda have identifiable mutations in the fxn gene. the most common type of mutation, which is observed on both alleles in more than 98% of individuals with frda, is a gaa triplet-repeat expansion in intron 1 of fxn. approximately 2% of individuals with frda are compound heterozygotes for a gaa expansion in a disease-causing range in one fxn allele and another inactivating fxn mutation in the other allele. frda is inherited in an autosomal recessive manner. we studied 137 iranian patients (50 females and 87 males) from 110 unrelated families. dna from each patient was extracted and frequency and length of (gaa)n repeat was analyzed using a long-range polymerase chain reaction (pcr) test. also, we investigated the impact of gaa size on neurological findings, age of onset and disease development. homozygous gaa expansion was found in 101 (73%) cases. in four cases (27%), no expansion was observed, ruling out the diagnosis of friedreich’s ataxia. we also found that a biochemical defect in complex i activity and atp production, which may be due to iron accumulation in mitochondria, can be involved in age of onset of frda. we also showed the possibility of mutations in nd genes which could constitute a predisposing factor which affects age of onset and disease progression in combination with environmental risk factors. mitochondrial d-loop sequencing results showed that the rate of d-loop variations was higher in fa patients than controls (p<0.05). mtdna deletions were present in 76% of our patients representing mtdna damage which may be due to iron accumulation in mitochondria. synonyms for adca (autosomal dominant cerebellar ataxias) which were used prior to the identification of the molecular genetic basis of these disorders were maries ataxia, inherited olivopontocerebellar atrophy, cerebello-olivary atrophy, or the more generic term, spinocerebellar degeneration. the spinocerebellar ataxias (sca) comprise a heterogeneous group of severe late-onset neurodegenerative diseases that are promoted by the expansion of a tandem-arrayed dna sequence that modifies the primary structure of the protein. analysis of sca in 20 patients showed high levels of mtdna variations in lymphocytes. it can be proposed that the sca gene proteins (ataxins) are involved in the complicated intracellular mechanisms that affect cellular organelles and their components, such as the mitochondrial genome. the instability of cag repeats in polyglutamine diseases such as scas and huntingtons disease might be a causative factor in mtdna variation or possible damage.