MENKES (KINKY HAIR) DISEASE
 
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MENKES (KINKY HAIR) DISEASE

 

DEFINITION:

A progressive neurodegenerative disorder characterized by degeneration of the CNS grey matter with distinctive facies and hair and progressive neurological deterioration.

EPIDEMIOLOGY:

  • incidence: 1/35-50,000 male live births
  • age of onset:
    • first months of life
  • risk factors:
    • familial - X-linked recessive
      • chrom. #: Xq13.3
      • gene: Copper-binding P-type ATPase

PATHOGENESIS:

1. Background

  • there are 3 inherited disorders known to be caused by genetic defects in copper metabolism:
    • Wilson Disease
    • Menkes Disease
    • Occipital Horn Syndrome
  • isolation of the Menkes disease gene (Cu-binding P-type ATPase) was first reported in 1993 by three groups (Vulpe et. al, Chelly et al., Mercier et al., Nature Genetics 3:7-25, 1993) and is a member of a cation-transporting P-type ATPase subfamily
  • expression of the Cu-binding P-type ATPase occurs in all tissues except the liver and thus on biopsy there is increased copper deposition in intestinal and kidney samples but decreased copper deposition in liver samples taken from patients with Menkes Disease (Chelly and Monaco, Nature Genetics 5:317-318, 1993)
  • the function of cuproenzymes is dependent on copper:

1. Oxidases

  • ascorbate oxidase, cytochrome c oxidase, lysyl oxidase, monamide oxidase

2. Others

  • dopamine-beta-hydroxylase, superoxide dismutase, tyrosinase

2. Genetic Defect

  • genetic defect -> decreased copper transport across cellular compartments (particularly in the gut) -> decreased availability of copper for cuproenzymes -> dysfunction of numerous copper-dependent enzyme systems:
    • ascorbate oxidase - skeletal deformities
    • cytochrome c oxidase - hypothermia
    • lysyl oxidase - intimal cleavage
    • monamide oxidase - kinky hair
    • tyrosinase - depigmentation of hair, skin pallor
  • because the defective gene is expressed in all other tissues except the liver, there is an intracellular non-toxic accumulation of copper throughout the body except in the liver
  • the main difference in pathogenesis between Menkes Disease and Wilson Disease is that in the former there is not a toxic accumulation of copper throughout the body but dysfunction of numerous copper-dependent enzyme systems

PATHOLOGY:

  • extensive focal degeneration of grey matter with axonal degeneration in the white matter
  • loss of internal granule cell layer and necrosis of Purkinje cells within the cerebellum
  • tortuous cerebral vessels

CLINICAL FEATURES:

1. Neurological Manifestations

1. Initial

  • presents in the neonatal period with:
    • generalized seizures
      • myoclonic (occasionally tonic-clonic)
      • most common initial symptom
      • peak incidence at 3 months of age
    • hypotonia with prolonged head lag
    • hypothermia

2. Later

  • motor developmental delay
  • severe mental retardation
  • progressive neurologic deterioration with death usually by 2 years of age (although some as old as 13 years)

2. Other Manifestations

1. Secondary Hair

  • kinky, colourless, friable
  • includes scalp, eyebrow, and eyelash hair

2. Distinctive Facies

  • chubby, rosy cheeks
  • depressed nasal bridge
  • expressionless face

3. Ocular

  • pale optic discs
  • optic atrophy -> blindness

4. Others

  • arterial rupture/thrombosis
  • cutis laxa
  • feeding difficulties with failure to thrive
  • hematuria
  • hypothermia

INVESTIGATIONS:

1. Serum

  • low copper and ceruloplasmin levels (initially low in the neo-natal period so may need serial assessment)

2. Hair

  • microscopic examination of hair shaft
    • monilethrix (periodic narrowing)
    • pili torti (twisted)
    • trichorrhexis nodosa (fractures)

3. Imaging Studies

1. MRI/CT

  • cortical areas of encephalomalacia (low density areas)
  • progressive degeneration of grey matter
  • cerebral atrophy
  • subdural hematomas

2. Cerebral Angiogram

  • tortuous winding vessels

3. Skeletal X-Rays

  • flaring of anterior ribs
  • long bones
    • metaphyseal spurring
    • diphyseal periosteal reaction

4. Renal Ultrasound

  • bladder diverticulate
  • hydronephrosis
  • hydroureter

4. Electrodiagnostic

  • EEG - hypsarrhythmia after 5 months of age
  • Evoked Potentials - low amplitude or absent

5. Diagnostic

  • reduced activity of cuproenzymes particularly cytochrome c oxidase and superoxide dismutase
  • intrauterine - increased copper content of fibroblasts or chorionic villi
  • in vitro - increased copper accumulation with decreased copper release

MANAGEMENT:

1. Copper

1. Parenteral

  • cupric acetate 550-800 ug/kg/day till copper and ceruloplasmin levels are normal then 190-220 ug/kg IV twice per week
  • normalizes serum copper and ceruloplasmin levels but not CNS copper levels and while improving seizure control will not interrupt the progression of neurologic manifestations

2. Intramuscular

  • copper histidinate 250-600 ug/d
  • may be able to cross the blood-brain barrier and thus interrupt the progression of neurological manifestations

 

 

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