How is Menkes disease diagnosed?

Diagnosis of Menkes disease in newborns is challenging due to the nonspecific nature of clinical symptoms and overlap of biochemical biomarkers with healthy neonates1

Diagnosis of Menkes disease requires a high index of clinical suspicion followed by definitive biochemical and genetic testing2

Differential diagnosis of Menkes disease based on clinical signs and symptoms may include3:

  • Ehler-Danlos syndrome
  • Marfan syndrome
  • Cutis laxa
  • Osteogenesis imperfecta
  • Child abuse (battered child syndrome)
  • Mitochondrial disorders
Woman holding infant with Menkes kinky hair syndrome

“Menkes disease [is] an X-linked recessive disorder of brain copper metabolism…for which early diagnosis is crucial for any prospect of meaningful long-term outcome.” — Kaler 2014

Recognition of neonatal signs and symptoms is crucial for making an early diagnosis

The diagnostic goal is to identify Menkes disease as early as possible, but signs or symptoms may not be evident at birth.1 The healthcare team of any child with low birth weight and additional symptoms commonly seen in neonates with Menkes disease, such as jaundice, abnormal hair, or feeding difficulties, should be vigilant and proactive trying to identify or rule out the possibility of Menkes disease.4,5

Diagnostic opportunities for Menkes disease2,6,7

Ideal diagnosis frame

Test

Considering pregnancy

Test
  • ATP7A parental genetic testing based on family history*

Prenatal

Test
  • Prenatal genetic testing or DNA analysis of amniocytes

Postnatal: neonates and infants

Clinical Evaluation
  • Evaluation of signs and symptoms
  • Family history
Laboratory tests
  • Ceruloplasmin
  • Copper
  • Catecholamines (DOPAC/DHPG; DOPA/NE)
ATP7A Mutation Analysis
  • Single gene testing
  • Multigene panels†
  • Whole genome sequencing

DHPG; (S)-3,5-Dihydroxyphenylglycine. DOPA; dopamine. DOPAC; 3,4-Dihydroxyphenylacetic acid. NE; norepinephrine.
*Family history of severe cognitive disorders, metabolic disorders, Menkes disease, or maternally related male relatives with symptoms suggestive of Menkes disease and/or who died during childhood of unknown causes.
†May be included in but not limited to epilepsy and neurometabolic disorder panels.

Every patient has a different journey to diagnosis

Depending on the presentation of signs and symptoms and evidence of family history, your patient may enter the diagnostic path at different points. Consider genetic counseling and testing for parents who are considering pregnancy or are expecting who have a family history of Menkes disease or its symptoms. Postnatally, clinical suspicion of Menkes disease followed by one or more biochemical tests may be used for initial diagnosis.1,2

Laboratory tests should be considered for any patient with a clinical evaluation suggestive of Menkes disease2

Biochemical analyses for copper, ceruloplasmin, or catecholamines may be available at your institution but are also accessible through nationwide laboratory testing facilities, such as Quest Diagnostics or LabCorp.

Identification of mutations in ATP7A is the definitive diagnostic proof of Menkes disease8

ATP7A genetic testing is available on some panels, including epilepsy, neurometabolic disorder, and copper metabolism genetic testing panels. More information on genetic testing accessibility is available at the NIH Genetic Testing Registry.

Learn more about advocacy efforts for ATP7A to be included in standard neonatal screening.

Starting your patients on the pathway to diagnosis as soon as possible may lead to better quality of life and treatment outcomes1

There is no known cure for Menkes disease, and disease management is focused on decreasing symptom severity and enhancing quality of life.1 There are currently no approved treatments for patients with Menkes disease. For information on clinical trials, please visit clinicaltrials.gov.

Menkes disease doctor and care team

It takes a team to care for a patient with Menkes disease1,9

  • Neonatologist/Pediatrician
  • Neurologist
  • Geneticist
  • Gastroenterologist
  • Pulmonologist
  • Urologist
  • Dietitian
  • Occupational therapist
  • Speech pathologist
  • Social worker

Explore additional resources for more information and advocacy opportunities

  • References:
    1. Ojha R, Prasad AN. Menkes disease: what a multidisciplinary approach can do. J Multidiscip Healthc. 2016;9:371-385.
    2. Tümer Z, Møller LB. Menkes disease. Eur J Hum Genet. 2010;18(5):511-518.
    3. Horn N, Tümer Z. Menkes disease and the occipital horn syndrome. In: Royce PM, Steinmann B, eds. Connective Tissue and Its Heritable Disorders. 2nd ed. Wiley-Liss; 2002:651-685.
    4. Kaler SG. Neurodevelopment and brain growth in classic Menkes disease is influenced by age and symptomatology at initiation of copper treatment. J Trace Elem Med Biol. 2014;28(4):427-430.
    5. Fujisawa C, Kodama H, Sato Y, et al. Early clinical signs and treatment of Menkes disease. Mol Genet Metab Rep. 2022;31:100849.
    6. Kaler SG, DiStasio AT. ATP7A-related copper transport disorders. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews® [Internet]. University of Washington, Seattle; 2003. Updated April 15, 2021. https://www.ncbi.nlm.nih.gov/books/NBK1413/.
    7. Kim JH, Lee BH, Kim YM, et al. Novel mutations and clinical outcomes of copper-histidine therapy in Menkes disease patients. Metab Brain Dis. 2015;30(1):75-81.
    8. Tümer Z, Klomp L. Clinical utility gene card for: Menkes disease. Eur J Hum Genet. 2011;19(10).
    9. Kaler SG. Inherited disorders of human copper metabolism. In: Pyeritz RE, Korf BR, Grody WW, eds. Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics. 7th ed. Academic Press; 2021:413-443.