Clinical Guidance

The amount of residual ATPase enzyme activity correlates with the phenotype in Menkes disease, OHS, and ATP7A-related distal motor neuropathy (DMN) and, in part, with response to early copper treatment in Menkes disease . Milder variants of Menkes disease and OHS are often associated with splice junction pathogenic variants that alter but do not eliminate proper RNA splicing (i.e., "leaky" splice junction defects). The pathogenic variants associated with ATP7A-related DMN involve unique missense variants within or near the luminal surface of the protein, which may be relevant to the abnormal intracellular trafficking shown for these defects and to the mechanism of this form of motor neuron disease .

Source: GeneReviews — "ATP7A-Related Copper Transport Disorders"

Diagnostic Criteria

Suggestive Findings

An ATP7A-related copper transport disorder (Menkes disease, occipital horn syndrome, or ATP7A-related distal motor neuropathy) should be suspected in individuals with the following clinical and laboratory findings.

Clinical Findings

Classic Menkes disease is suspected in males who develop hypotonia, failure to thrive, and seizures between age six and twelve weeks. Shortly thereafter, hair changes become manifest: the scalp and (usually) eyebrow hair is short, sparse, coarse, twisted, and often lightly pigmented (white, silver, or gray). The hair is shorter and thinner on the sides and back of the head. The hair can be reminiscent of steel wool cleaning pads.

Source: GeneReviews — "ATP7A-Related Copper Transport Disorders"

Differential Diagnosis

Menkes disease. While classic Menkes disease often presents with a highly distinctive clinical and biochemical phenotype, a differential diagnosis may include other infantile-onset neurodevelopmental syndromes, including:

• Biotinidase deficiency

• Organic acidurias

• Aminoacidurias

• Mitochondrial myopathies (See Mitochondrial Disorders Overview.)

Occipital horn syndrome. The differential diagnosis includes any conditions that involve skin and/or joint laxity, including:

• FBLN5-related cutis laxa, inherited in an autosomal recessive or (less commonly) autosomal dominant manner and caused by pathogenic variants in FBLN5;

• ELN-related cutis laxa, inherited in an autosomal dominant manner and caused by pathogenic variants in ELN;

• EFEMP2-related cutis laxa.

Source: GeneReviews — "ATP7A-Related Copper Transport Disorders"

Management Guidelines

No formal clinical practice guidelines for ATP7A-related copper transport disorders have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in a male diagnosed with an ATP7A-related copper transport disorder, the evaluations summarized in , , and (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3a.

Recommended Evaluations Following Initial Diagnosis in Individuals with Classic Menkes Disease Phenotype

System/Concern | Evaluation | Comment

Neurologic

| Neurologic eval | • Incl brain imaging (MRI/MRA) to assess degree of cerebral/cerebellar atrophy.

• Consider EEG if seizures present.

• Assess for signs/symptoms of autonomic dysfunction (dizziness, syncope, chronic diarrhea).

Development

| Developmental assessment | • To incl gross motor, fine motor, personal-social, language development

• Eval for early intervention/ special education /or PT, OT, speech therapy

Gastrointestinal/

Feeding

| Gastroenterology/ nutrition/ feeding team eval | • To incl eval of aspiration risk nutritional status

Therapies Under Investigation

CuHis received FDA FastTrack (2018) and Breakthrough (2020) designations from the US Food and Drug Administration and the European Medicines Agency Committee for Orphan Medicinal Products issued a positive opinion for Orphan Drug Designation in 2020. An expanded access clinical trial that provides CuHis for individuals with Menkes disease in the US (NCT04074512) is currently in progress. For updated preliminary results on subcutaneous CuHis treatment for Menkes disease, click here. Adeno-associated viral (AAV) gene therapy in combination with copper has also been investigated in Menkes disease mouse models, with promising results .

Source: GeneReviews — "ATP7A-Related Copper Transport Disorders"

Surveillance Guidelines

For infants being treated with CuHis (or temporarily with CuCl2), monitor serum copper and ceruloplasmin levels to avoid supranormal levels. Table 5a. Recommended Surveillance for a Male with Menkes Disease

Source: GeneReviews — "ATP7A-Related Copper Transport Disorders"