Clinical description: Menkes disease, occipital horn syndrome (OHS), and ATP7A-related distal motor neuropathy (DMN) are disorders caused by pathogenic variants in the ATP7A, the X-linked gene that encodes a copper-transporting ATPase. Classic Menkes disease typically presents after a six- to 12-week period of good health following a normal pregnancy and birth. Feeding difficulties and/or a seizure event are the usual initial presenting features. In the absence of a known or suspected positive family history, these issues prompt a diagnostic evaluation that may consume months, by which time hypotonia and significant neurodevelopmental delays are evident. OHS is milder neurologically and is not recognized until late childhood or adolescence. Both phenotypes involve subnormal serum copper levels and other manifestations of perturbed copper metabolism, including connective tissue weakness. In contrast, ATP7A-related DMN typically presents in early adulthood with isolated muscle weakness and atrophy, in the absence of overt copper metabolism abnormalities.
While nonspecific temperature instability and hypoglycemia in the neonatal period may be noted retrospectively, infants with classic Menkes disease appear healthy until age 1.5 to three months, when loss of developmental milestones, hypotonia, seizures, and failure to thrive occur. The diagnosis is usually suspected when infants exhibit neurologic findings and concomitant characteristic changes of the hair (short, sparse, coarse, twisted, and often lightly pigmented). Without treatment, premature death is typical, often by age three years.
OHS is characterized by "occipital horns," distinctive wedge-shaped calcifications at the sites of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone. Occipital horns may be clinically palpable or observed on skull radiographs. Individuals with OHS also have lax skin and joints, bladder diverticula, inguinal hernias, and vascular tortuosity. Intellect is normal or slightly reduced.
ATP7A-related DMN, an adult-onset disorder resembling Charcot-Marie-Tooth disease, shares none of the clinical or biochemical abnormalities characteristic of Menkes disease or OHS.
Diagnosis/testing: Menkes disease and OHS are characterized by low concentrations of copper in some tissues as a result of impaired intestinal copper absorption, accumulation of copper in other tissues, and reduced activity of copper-dependent enzymes such as dopamine-beta-hydroxylase (DBH) and lysyl oxidase. While serum copper concentration and serum ceruloplasmin concentration are low in Menkes disease and OHS, they are normal in ATP7A-related DMN. Notably, serum copper and ceruloplasmin levels are low in healthy newborns for the first several months of life; thus, these are not reliable diagnostic biomarkers in infants younger than age two months.
The diagnosis of ATP7A-related copper transport disorders is most often confirmed in a proband by detection of either a hemizygous ATP7A pathogenic variant in a male or a heterozygous ATP7A pathogenic variant in a female with skewed X inactivation, or with a X-autosome translocation; the latter scenarios are quite rare.
Management: Prevention of primary manifestations (and treatment): Subcutaneous injections of copper histidinate beginning by age 28 days (corrected for prematurity/gestational age) enhances survival and improves neurodevelopmental outcomes.
Treatment of manifestations:
Classic Menkes disease. Seizure management per neurologist; early intervention and individualized education plan per developmental pediatrician, feeding therapy and gastrostomy tube placement to enhance caloric intake; antibiotic prophylaxis to prevent bladder infection and surgery for bladder diverticula; RSV, influenza and COVID vaccinations due to risk of recurrent pneumonia; social work support.
Occipital horn syndrome. Possible droxidopa treatment for dysautonomia; early academic support and individualized education plan as indicated per developmental pediatrician; surgical treatment of bladder diverticula and antibiotic prophylaxis as necessary; physical therapy; joint splints per orthopedist or rheumatologist for joint laxity.
ATP7A-related distal motor neuropathy. Special shoes with good ankle support; ankle-foot orthoses; physical therapy; occupational therapy; orthopedic surgery for severe pes cavus deformity; mobility devices; and exercise as tolerated.
Menkes disease. At each visit assess seizures, developmental progress, educational needs, growth and nutrition, therapy needs, mobility, self-help skills, frequency of pulmonary infections, and family needs.
Occipital horn syndrome. At each visit assess orthostatic blood pressures, development, and educational needs. Annual pelvic ultrasound for bladder diverticula.
ATP7A-related distal motor neuropathy. Annual neurologic exam, electroneurography of peripheral nerves, electromyography/electroneurography, physical therapy assessment, occupational therapy assessment, foot examination for pressure sores or poorly fitting footwear.
Genetic counseling: The ATP7A-related copper transport disorders are inherited in an X-linked manner. Approximately one third of affected males have no family history of Menkes disease/OHS/DMN. If the mother is a heterozygote, the risk of transmitting the ATP7A pathogenic variant is 50% in each pregnancy: a male who inherits the pathogenic variant will be affected with the disorder present in his brother; females who inherit the pathogenic variant will be heterozygotes and generally will not be affected. Male Menkes disease survivors and males with OHS or ATP7A-related DMN theoretically could pass the pathogenic variant to all of their daughters and none of their sons. When a pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.
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