Menkes disease

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: ATP7A (HGNC:869)
• Literature Search: 01/17/2019
• Curation Status: Released (1.1.3)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
ATP7A	Menkes disease (0010651)	309400	Moderate Actionability

Actionability Assertion Rationale

• Most experts agreed with the assertion computed according to the rubric. There were some concerns of limited actionability due to low quality evidence of the effectiveness of the intervention.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Death / Subcutaneous copper-histidine (initiated before 30 days of life)	2	3C	2B	2	9CB
Neurodegeneration / Subcutaneous copper-histidine (initiated before 30 days of life)	2	3C	2A	2	9CA

Severity of Outcome

Prevalence of the Genetic Condition

Population prevalence data for Menkes disease (MD) are not available. The incidence of MD at birth is estimated to be 1/300,000 in Europe and 1/360,000 in Japan. In Australia, the birth incidence of MD is reported to be much higher (1/40,000-100,000), which may be due to a founder effect.

Clinical Features (Signs / symptoms)

The clinical spectrum of ATP7A-related copper transport disorders ranges from classic MD at the severe end to occipital horn syndrome to distal motor neuropathy. This report focuses only on MD. MD is a rare neurodegenerative disorder. Clinical findings include neurologic changes (hypotonia, seizures, loss of milestones, and intellectual disability) and characteristic changes of hair (pili torti, short, sparse, coarse, often lightly pigmented). Autonomic dysfunction, including temperature instability and hypoglycemia may be present in the neonatal period. Skin laxity, jowly appearance with sagging cheeks, pectus excavatum, umbilical or inguinal hernias, frontal bossing, vascular tortuosity, bladder diverticula that can result in bladder outlet obstruction, and gastric polyps are common features. Additional symptoms include failure to thrive, poor eating, vomiting, syncope, and diarrhea. Imaging studies can show defective myelination, atrophy with ventriculomegaly, vascular tortuosity, "corkscrew" appearance of cerebral vessels, Wormian bones, metaphyseal spurring, and rib fractures. Muscular tone is often decreased in early life, but is later replaced by spasticity and weakness of the extremities.

Natural History (Important subgroups & survival / recovery)

Infants with MD often appear healthy at birth until age 2 to 3 months when loss of developmental milestones, hypotonia, seizures, and failure to thrive occur. However, cephalohematomas and spontaneous fractures are occasionally observed at birth. The age at diagnosis is usually about 8 months. Without early treatment with parenteral copper, and sometimes even with such treatment, MD progresses to severe neurodegeneration and death between ages seven months and 3.5 years. Subdural hematomas and cerebrovascular accidents are common. Respiratory failure, often precipitated by pneumonia, is a common cause of death.Mildly affected individuals have been described. Individuals with this milder form of MD may walk independently and talk. Weakness, ataxia, tremor, and head bobbing are characteristic neurologic findings. Seizures, if present, commence in mid to late childhood; intellectual disability is mild. Connective tissue problems may be more prominent in this milder form of MD. Pili torti are present. Females heterozygous for an ATP7A pathogenic variant are typically asymptomatic, in some instances because of favorably skewed X-chromosome inactivation. In theory, unfavorably skewed X-chromosome inactivation in some heterozygous females could be associated with neurologic or other clinical findings related to the disorders. There are a small number of reported cases of MD in females, and they have an attenuated form of the disease.

Likelihood of Outcome

Prevalence of Genetic Variants

Pathogenic variants in ATP7A account for all cases of MD.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

MD is fully penetrant in males.

Tier 4

About 50% of females who are obligate heterozygotes for MD demonstrate regions of pili torti.

Tier 3

Expressivity

Intrafamilial phenotypic variability is occasionally observed in MD.

Tier 3

Intervention Effectiveness

Patient Management

There is no definitive cure for symptomatic MD and management is mainly based on symptoms.

Tier 4

To establish the extent of disease and needs in a male diagnosed with MD, the following evaluations are recommended:

• Developmental assessment

• Evaluation of feeding and nutrition

• Assessment of bladder function.

Tier 4

Neonatal treatment with subcutaneous copper-histidine (initiated before 30 days of life) is recommended for asymptomatic males with a diagnosis of MD, but is not recommended for symptomatic boys or after 30 days of life. Treatment should be continued indefinitely. In an open-label clinical trial, 12 patients with MD treated with copper-histidine within 22 days of life had 92% survival after a mean follow-up of 4.6 years compared to 13% in a historical control group of 15 patients treated after a late diagnosis (mean age at diagnosis: 163 ± 113 days, range: 42 to 390). Two of the 12 patients with earlier treatment had normal neurological development. A second open-label trial of 35 presymptomatic patients receiving copper-histidine at less than a month of age reported significant improvement of four major neurodevelopmental (gross motor, fine motor/adaptive, personal/social, and language) domains and a non-significant lower mortality (28.5% vs 50%) at age of 3 years (or age of death) compared to 22 patients treated later and after onset of symptoms.

Tier 1

Antibiotic prophylaxis may be necessary to prevent bladder infection.

Tier 4

Surveillance

No surveillance recommendations were identified.

Circumstances to Avoid

No circumstances to avoid were identified.

Nature of Intervention

Nature of Intervention

Copper-histidine is administered subcutaneously twice-daily for the first year of life and then daily after the first year of life. Treatment is life-long.

Context: Pediatric

Chance to Escape Clinical Detection

Neurodegeneration and failure to thrive commence at age two to three months, and the age at diagnosis of MD is usually about eight months of age, which is after the 30-day window where treatment with copper-histidine is shown to have a beneficial effect.

Context: Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			ATP7A			309400	0010651

References List

MENKES DISEASE. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 309400, (2016) World Wide Web URL: http://omim.org/

Menkes disease. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=565

SG Kaler. ATP7A-Related Copper Transport Disorders. (2003) [Updated Aug 18 2016]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1413/

Tumer Z, Klomp L. (2011) Clinical utility gene card for: Menkes disease. European journal of human genetics : EJHG. 19(10).

Vairo FPE, Chwal BC, Perini S, Ferreira MAP, de Freitas Lopes AC, Saute JAM. (2019) A systematic review and evidence-based guideline for diagnosis and treatment of Menkes disease. Molecular genetics and metabolism. 126(1):6-13.