Menkes disease in affected females: The clinical disease spectrum

Abstract

Menkes disease (MIM 309400) is an X-linked, neurodegenerative disorder resulting from deficient activity of copper-dependent enzymes and caused by alterations in the APT7A gene. In its classic form, it manifests in boys with hypotonia, seizures, skin and joint laxity, hair twisting (pili torti), cerebrovascular tortuosity, and bladder diverticulae. Menkes disease phenotypes have been reported in females with X; autosome translocations- disrupting ATP7A gene function- or ATP7A gene alterations. Those females manifest variable clinical findings, some of which, such as pili torti, seizure presence and/or age of onset, cerebrovascular tortuosity, degree of intellectual disability, bladder divericulae are largely under-reported and under-studied. Here, we report three females with Menkes disease and variant phenotypes, sharing characteristic features; one with classic Menkes disease and two with Menkes disease variants. We conclude that Menkes disease in females manifests with a variable spectrum of clinical findings but a few are uniformly present such as neurodevelopmental disability, hypotonia, and connective tissue findings. Others, such as seizures, cerebral atrophy, and cerebrovascular tortuosity may be present but are under-reported and under-studied. We propose that the diagnosis of Menkes disease or variants in females with suspicious clinical findings is an important one to consider as early treatment with parenteral copper may be considered. The effect of this treatment on the disease course in females with MD is unknown and remains to be seen.

West syndrome: a comprehensive review

“…ISs have been also reported in children with neurodegenerative disorders including globoid cell leukodystrophy-Krabbe disease (caused by the GALC gene) and Menkes disease (caused by the ATP7A gene) [58][59][60]. Rare disorders associated with ISs also include cerebrotendineous xantomatosis (caused by the CYP27A1 gene) [61]; glucose transport 1 deficiency (caused by mutations in exon 9 of the SLC2A1 gene) [62]; disorders of glycosylation [63] (caused by the ALG1,6,11 genes: subtypes CDG and CDG 1x).…”

ATP7A Clinical Genetics Resource – A comprehensive clinically annotated database and resource for genetic variants in ATP7A gene

“…The compendium of curated variants encompasses a total of 602 variant entries in the ATP7A gene. These variants were derived from a total of 64 publications [6] , [8] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] , [78] , [79] , [80] , [81] , [82] and encompassed variants reported from 17 countries. Of the total compendium of variants, a total of 404 variants were unique and a large majority of variants mapped to exons 18,18% (328/404), while a small number were intronic 12% (49/404), splicing 6.18% (25/404) and UTR 0...…”

Breakpoint Mapping of Symptomatic Balanced Translocations Links the EPHA6, KLF13 and UBR3 Genes to Novel Disease Phenotype

“…Typically, XLR diseases are present only in male patients, while the our proband is female. However, there have been five reports of Menkes disease affecting female patients with translocations that damaged ATP7A [43]. The disease in these cases is probably caused by inactivation of the X chromosome skewed towards leaving the derived chromosome X functional (the opposite scenario leads to partial monosomy of the autosome involved in the BCTs which induces cell death [44]).…”