Huntington's very rarely occurs spontaneously; it is almost always the result of inheriting the defective gene from an affected parent. However, sporadic cases of Huntington's in individuals who have no history of the disease in their families do occur. Among these sporadic cases, there is a higher frequency of individuals with a parent who already has a significant number of CAG repeats in their HTT gene, especially those whose repeats approach the number (36) required for the disease to manifest. Each successive generation in a Huntington's-affected family may add additional CAG repeats, and the higher the number of repeats, the more severe the disease and the earlier its onset. As a result, families that have had Huntington's for many generations show an earlier age of disease onset and faster disease progression. Non-trinucleotide expansions The majority of diseases caused by expansions of simple DNA repeats involve trinucleotide repeats, but tetra-, penta- and dodecanucleotide repeat expansions are also known that cause disease. For any specific hereditary disorder, only one repeat expands in a particular gene. Mechanism Triplet expansion is caused by slippage during DNA replication or during DNA repair synthesis. Because the tandem repeats have identical sequence to one another, base pairing between two DNA strands can take place at multiple points along the sequence. This may lead to the formation of 'loop out' structures during DNA replication or DNA repair synthesis. This may lead to repeated copying of the repeated sequence, expanding the number of repeats. Additional mechanisms involving hybrid RNA:DNA intermediates have been proposed. Diagnosis See also C9orf72 RAN translation References External links GeneReviews/NCBI/NIH/UW entry on DRPLA National Institute of Neurological Disorders and Stroke Genetics Home Reference Genetic disorders by mechanism Huntington's disease