Menkes Disease Workup

Updated: Oct 29, 2014
  • Author: Celia H Chang, MD; Chief Editor: Amy Kao, MD  more...
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Workup

Copper and Ceruloplasmin Levels

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.

Diagnostic findings are as follows:

  • Serum copper level less than 70 mg/dL (reference 80-160)

  • Serum ceruloplasmin level less than 20 mg/dL (reference 20-60)

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Plasma Catecholamines

Decreased norepinephrine level may be noted. Elevated hydroxyphenylalanine (DOPA) and dihydroxyphenylglycol (DHPG) ratio due to decreased activity of dopamine beta-hydroxylase may be observed, with higher values reflecting more severe disease. Diagnostic findings are as follows:

  • 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. [10]

Diagnostic ratios

The ratio of dihydroxyphenylacetic acid to DHPG is as follows:

  • 13 +/- 6.6 for affected infants

  • 1.5 +/- .4 for unaffected infants

Ratio of dopamine to norepinephrine is as follows:

  • .83 +/- .71 for affected infants

  • .04 +/- .03 for unaffected infants

Urine homovanillic acid/vanillylmandelic acid (HVA/VMA) ratios above 4 may be noted. In once study, only 0.18% of controls had an HVA/VMA ratio greater than 4. [11]

Other findings

Other findings may include the following:

  • Increased intestinal and kidney copper

  • Decreased hepatic copper

  • Hypoglycemia

  • Deoxypyridinoline (D-Pyr): D-Pyr is synthesized by lysyl oxidase, which is defective in Menkes disease. D-Pyr levels in urine may remain low despite treatment.

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CT and MRI

The following may be noted:

  • White matter dysmyelination

  • Other white matter lesions may be symmetrical and involve the corpus callosum [12]

  • 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. [13]

  • Subdural hematomas and effusions (see following image)

    Magnetic resonance imaging of the brain of a patie 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

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Proton Magnetic Rresonance Spectroscopy

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.

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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 may be noted.

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EEG

Early stage findings include the following:

  • 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 findings may include the following:

  • Interictal EEG - Modified hypsarrhythmia or diffuse irregular slow waves and spike-waves

Late stage findings may include the following:

  • Interictal EEG - Multifocal high amplitude activity mixed with irregular slow waves

Electroretinogram

Reduced amplitude and scotopic responses (rod isolated) may be noted in more severely affected than photopic responses (cone isolated).

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Histologic Findings

Light microscopy of the hair shaft

See the list below:

  • 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

See the list below:

  • 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

See the list below:

  • Thin strand of amorphous elastin associated with numerous microfibrils

Cerebral and systemic arteries

See the list below:

  • Tortuous with irregular lumens

  • Frayed and split intimal linings

  • Disrupted elastin fibers on electron microscopy

Muscle

See the list below:

  • Accumulation of glycogen

  • Predominance of type 2 fibers

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