Center of Applied Human Genetics, Kennedy Center, Gl, Landevej 7, Glostrup, Denmark.
Orphanet J Rare Dis. 2012 Jan 22;7:6. doi: 10.1186/1750-1172-7-6.
Menkes Disease (MD) is a rare X-linked recessive fatal neurodegenerative disorder caused by mutations in the ATP7A gene, and most patients are males. Female carriers are mosaics of wild-type and mutant cells due to the random X inactivation, and they are rarely affected. In the largest cohort of MD patients reported so far which consists of 517 families we identified 9 neurologically affected carriers with normal karyotypes.
We investigated at-risk females for mutations in the ATP7A gene by sequencing or by multiplex ligation-dependent probe amplification (MLPA). We analyzed the X-inactivation pattern in affected female carriers, unaffected female carriers and non-carrier females as controls, using the human androgen-receptor gene methylation assay (HUMAR).
The clinical symptoms of affected females are generally milder than those of affected boys with the same mutations. While a skewed inactivation of the X-chromosome which harbours the mutation was observed in 94% of 49 investigated unaffected carriers, a more varied pattern was observed in the affected carriers. Of 9 investigated affected females, preferential silencing of the normal X-chromosome was observed in 4, preferential X-inactivation of the mutant X chromosome in 2, an even X-inactivation pattern in 1, and an inconclusive pattern in 2. The X-inactivation pattern correlates with the degree of mental retardation in the affected females. Eighty-one percent of 32 investigated females in the control group had moderately skewed or an even X-inactivation pattern.
The X- inactivation pattern alone cannot be used to predict the phenotypic outcome in female carriers, as even those with skewed X-inactivation of the X-chromosome harbouring the mutation might have neurological symptoms.
Menkes 病（MD）是一种罕见的 X 连锁隐性致死性神经退行性疾病，由 ATP7A 基因突变引起，大多数患者为男性。由于随机 X 染色体失活，女性携带者是野生型和突变型细胞的嵌合体，她们很少受到影响。在迄今为止报道的最大的 MD 患者队列中，我们共发现了 517 个家族中有 9 名神经受累的携带者具有正常核型。
我们通过测序或多重连接依赖性探针扩增（MLPA）来检测 ATP7A 基因突变的风险女性。我们使用人雄激素受体基因甲基化检测（HUMAR）分析了受影响的女性携带者、未受影响的女性携带者和非携带者女性的 X 染色体失活模式，作为对照。
受影响女性的临床症状通常比具有相同突变的受影响男孩轻。虽然在 49 名受影响的未受影响携带者中观察到 94%的突变 X 染色体存在偏性失活，但在受影响的携带者中观察到了更为多样化的模式。在 9 名受影响的女性中，有 4 名表现出对正常 X 染色体的优先沉默，2 名表现出对突变 X 染色体的优先失活，1 名表现出均匀的 X 染色体失活模式，2 名表现出不确定的模式。X 染色体失活模式与受影响女性的智力障碍程度相关。在对照组的 32 名女性中，81%的女性具有中度偏性或均匀的 X 染色体失活模式。
X 染色体失活模式本身不能用于预测女性携带者的表型结果，因为即使那些具有携带突变的 X 染色体偏性失活的女性也可能有神经症状。
