Clinical and Laboratory ObservationVariable clinical expression of an identical mutation in the ATP7A gene for Menkes disease/Occipital horn syndrome in three affected males in a single family☆
Section snippets
Clinical description
Two maternal half-brothers (patients 1 and 2) were born with skin laxity and large cephalhematoma, which was fatal in patient 1 after disseminated intravascular coagulation. Autopsy demonstrated ruptured vessels with a complete lack of elastic fibers.
In patient 2, skin histology similarly demonstrated many large fibroblasts and rarefaction of elastic fibers. Electron microscopy showed rare fragmented and small elastic fibers located between dense bundles of collagen fibers. Elastin deposits
Mutation analysis
Mutation screening was performed on genomic DNA from cultured skin fibroblasts of patient 2. In exon 20 a single base pair mutation c.3974C>T was identified, leading to the amino acid substitution Ala1325Val. Genomic DNA sequencing of exon 20 from patient 1 (paraffin-embedded tissue) and from patient 3 (fibroblasts) confirmed the presence of the same mutation. Sequencing of the whole coding region excluded a second mutation in both patient 2 and 3. Mosaicism was excluded in the uncle by
Discussion
Classic MD and OHS are two extremes of the same intracellular copper transport and metabolism disorder. Instead of categorizing patients into subgroups, Horn and Tümer3 proposed a disease continuum from the “neurological end” of the spectrum—classic MD—to its connective tissue end—OHS.
To date, about 225 mutations in the ATP7A gene have been identified,3., 4., 5. (unpublished, N. Horn, personal communication 2003). There is, however, poor genotype/phenotype correlation. Even similar splice site
Acknowledgements
We thank the family for participation in the study and Dr Sarioglu and Prof Vogel (Department of Pathology, Charité, Berlin) for the histological findings in patient 1.
References (12)
- et al.
Similar splice-site mutations of the atp7a gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome
Am J Hum Genet
(2000) - et al.
Functional consequences of alterations to amino acids located in the hinge domain of the ca(2+)-atpase of sarcoplasmic reticulum
J Biol Chem
(1991) - et al.
Importance of conserved alpha-subunit segment 709gdgvnd for mg2+ binding, phosphorylation, and energy transduction in na, k-atpase
J Biol Chem
(2000) - et al.
Successful early copper therapy in menkes disease associated with a mutant transcript containing a small in-frame deletion
Biochem Mol Med
(1996) - et al.
Localization of the translocation breakpoint in a female with menkes syndrome to xq13.2-q13.3 proximal to pgk-1
Am J Hum Genet
(1991) - et al.
Mapping of the menkes locus to xq13.3 distal to the x-inactivation center by an intrachromosomal insertion of the segment xq13.3-q21.2
Hum Genet
(1992)
Cited by (29)
Degenerative Disorders of the Newborn
2018, Volpe's Neurology of the NewbornA novel nonsense ATP7A pathogenic variant in a family exhibiting a variable occipital horn syndrome phenotype
2017, Molecular Genetics and Metabolism ReportsCitation Excerpt :The limit of truncating variants with residual enzymatic activity can therefore be shifted from exon 23 (codon 1451) to exon 22 (codon 1408). Moreover, the patient's possibly affected male relatives further support the idea that the intrafamilial phenotypic variability might be very wide when the variant has a residual enzymatic activity [4,21–23], and may be due to different expression of the mutant ATP7A, as previously demonstrated [23]. As a consequence of OHS phenotypic variability, males with ID and connective tissue abnormalities should be evaluated for biochemical evidence of defective copper transport.
Cutis laxa: A review
2012, Journal of the American Academy of DermatologyCitation Excerpt :Patients with Menkes disease may also demonstrate occipital horns. Occipital horns become more prominent with age and can be palpated or found on radiographs.79-81 Although patients with XLCL mainly have connective tissue problems, patients with Menkes disease have more severe neurologic defects, typically presenting at 2 to 3 months of age with developmental delay, hypotonia, seizures, and failure to thrive (Fig 7, A).77
Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B
2012, Journal of Biological ChemistryCitation Excerpt :It has been suggested that the clinical outcome depends on the type of mutation (8, 11, 48). Individuals with identical mutations, including twins (65) and also between family members, can have vastly different clinical phenotypes (66, 67), which suggests that other factors are involved in determining the clinical outcome of Menkes and Wilson diseases. Such factors may include allelic dominance, copper levels, the environment, and other interacting proteins that may serve to modify the phenotypes (68).
Clusterin (Apolipoprotein J), a molecular chaperone that facilitates degradation of the copper-ATPases ATP7A and ATP7B
2011, Journal of Biological ChemistryCitation Excerpt :Although genotype/phenotype correlations have been difficult, it is generally accepted that the clinical expression of these diseases and patient response to treatment depends on the type of mutation in ATP7A/ATP7B, which in turn can affect the levels and activity of ATP7A/ATP7B, their post-translational modifications, protein-protein interactions, cellular localization, and/or ability to traffic in response to copper (7–9). For both MD and WD, there are reports of identical mutations, even among siblings, conferring variable clinical expression (10, 11), thus implicating other factors in determining the clinical phenotype. Environmental factors and allelic variants of modifying genes may contribute to the diversity of patient symptoms and onset of disease.
Molecular diagnosis of Menkes disease: Genotype-phenotype correlation
2009, BiochimieCitation Excerpt :The p.R844H mutation has been identified in one family with mild symptoms [28], and in another family with classical Menkes disease [29]. Both the p. A1325V and the p.A1362D mutations have been identified in families with varying phenotypes, leading in one family member to OHS (Table 1) and in another to mild Menkes (Table 2) [14,17]. Both inter- and intra-familial variabilities have been observed for the p.S637L mutation.
- ☆
The molecular studies were supported by The Novo Nordisk Foundation, The Danish Medical Council, and the Foundation of 1870.