In a small percentage of patients with Friedreich ataxia (FA), the pathogenic mutation is compound heterozygous, consisting of a guanine–adenine–adenine (GAA) trinucleotide repeat expansion in one allele, and a deletion, point mutation, or insertion in the other. In 2 cases of compound heterozygous FA, the GAA expansion was inherited from the mother, and deletions from the father. Compound heterozygous FA patient 1, an 11-year-old boy (GAA, 896/c.11_12TCdel), had ataxia, chorea, cardiomyopathy, and diabetes mellitus. Compound heterozygous FA patient 2, a 28-year-old man (GAA, 744/exon 5 del), had ataxia, cardiomyopathy, and diabetes mellitus. Microscopy showed cardiomyocyte hypertrophy, iron-positive inclusions, and disrupted intercalated discs. The cardiac lesions were similar to those in age-matched homozygous FA patients with cardiomyopathy and diabetes mellitus (boy, 10, GAA 1016/1016; woman, 25, GAA 800/1100). The neuropathology was also similar and included hypoplasia of spinal cord and dorsal root ganglia, loss of large axons in dorsal roots, and atrophy of the dentate nucleus (DN). Frataxin levels in heart and DN of all 4 FA cases were at or below the detection limits of the enzyme-linked immunosorbent assay (≤10 ng/g wet weight) (normal DN: 126 ± 43 ng/g; normal heart: 266 ± 92 ng/g). The pathologic phenotype in homozygous and compound heterozygous FA is determined by residual frataxin levels rather than unique mutations.
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机译：在少数腓特烈共济失调（FA）患者中，致病突变是复合杂合的，由一个等位基因中的鸟嘌呤-腺嘌呤-腺嘌呤（GAA）三核苷酸重复扩增组成，在另一个等位基因中缺失，点突变或插入。在2例复合杂合FA中，GAA扩增是从母亲继承而来的，而从父亲继承而来。复合杂合FA患者1（11岁男孩，GAA，896 / c.11_12TCdel）患有共济失调，舞蹈症，心肌病和糖尿病。复合杂合FA患者2，一名28岁的男性（GAA，744 / exon 5 del），有共济失调，心肌病和糖尿病。显微镜检查显示心肌细胞肥大，铁阳性内含物和插入的椎间盘破裂。心脏病变与年龄匹配的患有心肌病和糖尿病的纯合FA患者相似（男孩，10岁，GAA 1016/1016；女性，25岁，GAA 800/1100）。神经病理学也相似，包括脊髓和背根神经节发育不全，背根大轴突缺失和齿状核（DN）萎缩。所有4 FA病例的心脏和DN中的frataxin水平均达到或低于酶联免疫吸附测定的检测极限（≤10ng / g湿重）（正常DN：126±43 ng / g；正常心脏：266± 92 ng / g）。纯合和复合杂合FA中的病理表型是由残留的frataxin水平而不是独特的突变决定的。
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