The Invitae ATP7A-Related Disorders Test analyzes ATP7A, the only known gene associated with Menkes disease and occipital horn syndrome. Some pathogenic variants can also cause ATP7A-related distal motor neuropathy.
Biochemical testing is unreliable in females and cannot be used to determine carrier status. Molecular studies are the only reliable way to determine carrier status.
Menkes disease is a multi-systemic disorder of copper metabolism that leads to deficient activity of several copper-dependent enzymes. It results in progressive neurodegeneration, connective tissue abnormalities, and kinky hair. There is a phenotypic spectrum with occipital horn syndrome at the mildest end and classical Menkes syndrome (which causes death by three years of age) at the severe end.
Severe, “classically” affected males usually present by six to ten weeks of life with hypotonia, failure to thrive, and seizures. Hair abnormalities, including sparse, lusterless, twisted, hypopigmented hair that resembles steel wool, is evident soon afterwards; examination by light microscopy identifies pili torti among other abnormalities. Developmental regression becomes apparent by five to six months of age, and other clinical findings can include a jowly facial appearance, pectus excavatum, skin laxity, umbilical or inguinal hernias, vascular tortuosity, and bladder diverticulae. Autonomic dysfunction is also common and includes temperature instability, hypoglycemia, syncope, and diarrhea. Individuals suffer from progressive neurodegeneration and death generally occurs between seven months and 3.5 years of age due to respiratory failure or vascular complications such as cerebral vascular rupture.
Occipital horn syndrome (OHS) is a much milder form and presents in early to middle childhood. It is primarily characterized by connective tissue abnormalities, including occipital horns—wedge-shaped calcifications protruding downward from the occipital bone that are visible by radiography and may also be palpable. Other observable clinical findings can include loose skin and joints, bladder diverticulae, inguinal hernias, dysautonomia, and cognitive deficits, but intelligence is generally considered normal. Lifespan is reduced and most affected individuals live until mid-adulthood.
Individuals with Menkes or occipital horn syndrome have reduced levels of both serum copper and ceruloplasmin. Additionally, plasma and CSF catecholamine levels are abnormal due to partial deficiency of DBH (dopamine-beta-hydroxylase)—a copper-dependent enzyme necessary for catecholamine biosynthesis.
ATP7A-related distal motor neuropathy is an adult-onset motor neuropathy whose features are similar to those of Charcot-Marie-Tooth disease. Although ATP7A-related distal motor neuropathy is caused by variants in the same gene, clinical and biochemical abnormalities are distinct from Menkes and occipital horn syndromes. It features progressive distal motor neuropathy without significant sensory problems, as well as foot drop, distal muscle weakness, extremity atrophy, and nerve conduction abnormalities.
Some cases of Menkes have been reported to be responsive to subcutaneous copper injections, provided treatment is started by ten days of age.
95%–100% of cases with a diagnosis of Menkes disease will possess a pathogenic variant in the protein-coding regions of ATP7A.
Pathogenic variants in ATP7A are inherited in an X-linked recessive manner. One-third of cases are due to spontaneous de novo variants. ATP7A-related disorders are fully penetrant in males. Affected female patients have been reported, the majority of whom have chromosome rearrangements affecting the X chromosome and preferential inactivation of the normal X chromosome, although missense variants with skewed X-inactivation have also been reported. Female carriers are clinically asymptomatic, but approximately half of female carriers show regions of pili torti.
Incidence is believed to be 1 in 300,000. In Australia, incidence is 1 in 50,000–100,000, possibly due to a founder effect.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|