eMedicine Specialties > Neurology > Pediatric Neurology

Menkes Disease: Differential Diagnoses & Workup

Author: Celia H Chang, MD, Associate Health Sciences Clinical Professor, Department of Neurology, University of California at Davis
Contributor Information and Disclosures

Updated: Nov 24, 2009

Differential Diagnoses

Other Problems to Be Considered

Leigh disease
Phenylketonuria (PKU)

Differential diagnosis for specific hair findings is as follows:

Trichorrhexis nodosa (ie, beaded, fractured hair shafts)

  • Biotin deficiency
  • Argininosuccinic aciduria - A urea cycle defect with elevated ammonia and argininosuccinic acids
  • Pollitt syndrome - Nonprogressive autosomal recessive disease with mental retardation, spasticity, and seizures

Pili torti (twisted hair shafts)
  • Isolated finding
  • Pollitt syndrome
  • A syndrome associated with dental abnormalities, corneal opacities, deafness, and ichthyosis
  • Autosomal dominant mental retardation and postpubertal pili torti
  • Citrullinemia - A urea cycle defect
  • Trichothiodystrophy - A defect of DNA repair with photosensitivity, ichthyosis, and mental retardation
  • In heterozygotes, possibly areas of hair with 30-50% pili torti or skin depigmentation

Workup

Laboratory Studies

  • Serum copper level less than 70 mg/dL (reference 80-160)
  • Serum ceruloplasmin level less than 20 mg/dL (reference 20-60)
  • Copper and ceruloplasmin levels may be normal in the milder variants and in the neonatal period. The total body copper content can be normal in the infant until 2 weeks after birth or later. Ceruloplasmin levels are 6-12 mg/dL initially and only later are considered pathologically low. Normal term newborns also have lower serum copper (32 mcg +/- 21 mcg/dL) with even lower levels in preterm infants. The fetal hair also may be normal.
  • Plasma catecholamines
    • Decreased norepinephrine level
    • Elevated hydroxyphenylalanine (DOPA) and dihydroxyphenylglycol (DHPG) ratio due to decreased activity of dopamine beta-hydroxylase (higher values may reflect more severe disease)
      • Greater than 5 in serum (normal 1.7-3.3)
      • Greater than 1 in cerebrospinal fluid (normal 0.3-0.7)
    • Kaler et al found that asymptomatic infants at risk for Menkes disease could be separated into affected and unaffected based on plasma neurochemical profiles. Although there was potential overlap for the absolute levels of dopamine, dihydroxyphenylacetic acid, norepinephrine, and DHPG, 2 ratios clearly separated affected from unaffected infants. The differences were more distinct for older infants but were present in infants younger than 1 month.8
      • Ratio of dihydroxyphenylacetic acid to DHPG
        • 13.0 +/- 6.6 for affected infants
        • 1.5 +/- .4 for unaffected infants
      • Ratio of dopamine to norepinephrine
        • .83 +/- .71 for affected infants
        • .04 +/- .03 for unaffected infants
    • Urine homovanillic acid/vanillylmandelic acid (HVA/VMA) ratios above 4. (In once study, only 0.18% of controls had an HVA/VMA ratio greater than 4.9 )
  • Increased intestinal and kidney copper
  • Decreased hepatic copper
  • Hypoglycemia
  • Deoxypyridinoline (D-Pyr) is synthesized by lysyl oxidase, which is defective in Menkes disease. D-Pyr levels in urine may remain low despite treatment.

Imaging Studies

  • Computerized tomography (CT) and magnetic resonance imaging (MRI)
    • White matter dysmyelination
    • Other white matter lesions may be symmetrical and involve the corpus callosum.10
    • Tortuous blood vessels
    • Atrophy: This was reported by Geller et al in a 5-week-old who was flaccid, without pupillary responses or Moro reflex when born at term. Cranial ultrasound and CT prior to that had demonstrated prominent fluid spaces.11
    • Subdural hematomas and effusions (see following image)

    • Magnetic resonance imaging of the brain of a pati...

      Magnetic resonance imaging of the brain of a patient with Menkes disease. Subdural effusion is evident in the left frontal lesion. Brain atrophy is also evident.

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      Magnetic resonance imaging of the brain of a pati...

      Magnetic resonance imaging of the brain of a patient with Menkes disease. Subdural effusion is evident in the left frontal lesion. Brain atrophy is also evident.

    • Cerebrovascular accidents
  • Angiography and magnetic resonance angiography - Elongated and tortuous vessels, both intracranially and extracranially
  • Proton magnetic resonance spectroscopy shows elevated lactate and reduced N -acetyl aspartate (NAA)– total creatine (tCr) ratio with a z score of -3.0. After 120 days of treatment, the lactate signal disappeared, and the NAA signal increased to a z score of -1.5. The choline/Cr ratio also markedly decreased during treatment. Although, neuronal metabolism appeared improved, the neurologic symptoms and imaging abnormalities on MRI did not change.

Other Tests

  • Cultured fibroblasts and lymphoblasts: These exhibit impaired copper metabolism, increased copper accumulation, and decreased copper release. Heterozygotic carriers also have abnormalities of fibroblast copper metabolism.
  • Increased placental copper
  • EEG
    • Early stage
      • Ictal EEG - Runs of slow spike waves and slow waves in the posterior regions
      • Interictal EEG - Multifocal and polymorphic slow waves or mixed slow spike-waves and slow waves
    • Intermediate stage: Interictal EEG - Modified hypsarrhythmia or diffuse irregular slow waves and spike-waves
    • Late stage: Interictal EEG - Multifocal high amplitude activity mixed with irregular slow waves
  • Visual-evoked potential - Low amplitude or absent
  • Electroretinogram - Reduced amplitude; scotopic responses (rod isolated) more severely affected than photopic responses (cone isolated)

Histologic Findings

Light microscopy of the hair shaft

  • Pili torti - 180° twisting
  • Trichoclasis - Transverse fracture
  • Trichoptilosis - Longitudinal splitting
  • Trichorrhexis nodosa - Small, beaded swelling with fractures at regular intervals
  • Monilethrix elliptica - Swelling with intervening tapered constrictions

Autopsy of brain

  • Diffuse atrophy
  • Focal degeneration of neurons
  • Prominent neuronal loss in the cerebellum affecting the Purkinje cells
  • Abnormal dendritic arborization (so called "weeping willow") and perisomatic processes
  • Focal axonal swelling ("torpedoes")
  • Increased number and size of mitochondria on electron microscopy with electron-dense inclusions
  • Marked reduction of internal granule cells
  • Eosinophilic spheroid bodies (probably proliferated smooth endoplasmic reticulum) in the molecular layer

Skin

  • Thin strand of amorphous elastin associated with numerous microfibrils

Cerebral and systemic arteries

  • Tortuous with irregular lumens
  • Frayed and split intimal linings
  • Disrupted elastin fibers on electron microscopy

Muscle

  • Accumulation of glycogen
  • Predominance of type 2 fibers

More on Menkes Disease

Overview: Menkes Disease
Differential Diagnoses & Workup: Menkes Disease
Treatment & Medication: Menkes Disease
Follow-up: Menkes Disease
Multimedia: Menkes Disease
References
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References

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Further Reading

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Keywords

Menkes disease, neurodegenerative disease, impaired copper transport, abnormal copper metabolism, kinky hair disease, dietary copper, occipital horn syndrome, X-linked cutis laxa, Ehlers-Danlos type 9, Xq13.3 gene

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Contributor Information and Disclosures

Author

Celia H Chang, MD, Associate Health Sciences Clinical Professor, Department of Neurology, University of California at Davis
Celia H Chang, MD is a member of the following medical societies: American Academy of Neurology and Child Neurology Society
Disclosure: Nothing to disclose.

Medical Editor

Beth A Pletcher, MD, Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey
Beth A Pletcher, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Kenneth J Mack, MD, PhD, Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic
Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, and Society for Neuroscience
Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD, Assistant Professor, Department of Pediatrics, Division of Pediatric Neurology, Department of Neurology, Oregon Health and Science University; Consulting Staff, Shriners Hospital for Children
Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society
Disclosure: Nothing to disclose.

 
 
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