Leukodystrophies in Adults

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Leukodystrophies in Adults
August 12, 2004.
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Objectives
To discuss the leukodystrophies which may present
in adulthood, their etiologies, presentation, and
management.
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Leukodystrophy

• Genetic diseases showing morphological changes in
  white matter.
• Myelin dysfunction due to enzymatic abnormality
• Demyelination destruction of normally formed
  myelin
• Dysmyelination loss of defective myelin
• Classically, affects white matter with sparing of
  subcortical U-fibers.
• Enzymatic defects can be in
• Peroxisomes
• Mitochondria
• Metabolism of sphingolipids

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The Leukodystrophies
Goetz Textbook of Clinical Neurology, 2nd ed.
2003.
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with adult presentation
Metachromatic Leukodystrophy Krabbé globoid cell
leukodystrophy Adrenoleukodystrophy /
adrenomyeloneuropathy Refsum disease Pelizaeus-M
erzbacher disease (Lowenberg-Hill
type) Alexander disease
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Metachromatic leukodystrophy

• Sulfatide lipidoses lysosomal storage disorders
• CNS microglia and neurons
• PNS Schwann cells
• Periphery kidneys, pancreas, adrenals, liver,
  gall bladder
• Mutations
• arylsulfatase A gene (ARSA) on chromosome 22q13
• sphingolipid activator protein saposin B on
  chromosome 10q21
• Autosomal recessive inheritance
• ARSA mutations type O and type R
• Type O infantile form
• Type R adult form
• O/R heterozygote juvenile form

OMIM (Online Mendelian Inheritance in Man)
http//www.ncbi.nlm.nih.gov/entrez/
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Metachromatic leukodystrophy

• Epidemiology
• Total prevalence (all forms) of 1 in 100,000 live
  births.
• Increased incidence in some ethnic groups
• Habbanite Jewish community has 1.3 frequency
  infantile form

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Metachromatic leukodystrophy (Adult form)

• Onset after puberty
• Presenting symptoms
• Personality and mental changes leading to
  dementia
• Seizures
• Behavioural changes
• Hypospontaneity and blunted affect
• Inattention and hyperactivity
• Often misdiagnosed as schizophrenia or bipolar
  disorder
• Later symptoms
• Movement/postural disorders
• Dementia by 3rd or 4th decade of life
• Progressive corticobulbar, corticospinal,
  cerebellar changes

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Metachromatic leukodystrophy (Adult form)

• Investigations
• Spinal fluid moderately elevated protein at 1.5
  3.0 g/L
• Urine
• Deficiency in arylsulfatase A activity (or in
  leukocytes)
• Metachromatic granules
• Cholecystogram/ultrasound decreased gall
  bladder function
• Evoked potentials abnormalities in ABR, VEP,
  SSEP
• Nerve conduction velocities decreased
• MRI symmetric diffuse signal abnormalities

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Krabbé (Globoid Cell) Leukodystrophy

• Another lysosomal disorder
• Decreased oligodendrocytes in areas of
  demyelination
• Globoid cells periodic acid-Schiff (PAS)
  staining cells in
• CNS white matter
• Genetics
• Galactocerebroside ß-galactosidase (GALC gene,
  chromosome 14)
• Saposin A deficiency
• Autosomal recessive
• Epidemiology
• 1 in 100,000 births
• More in Druze community in Northern Israel and
  two Arab villages near Jerusalem (carrier rate
  1/6)

OMIM (Online Mendelian Inheritance in Man)
http//www.ncbi.nlm.nih.gov/entrez/
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Krabbé (Globoid Cell) Leukodystrophy

• Forms
• Early onset in infancy
• Late onset extremely uncommon, in childhood to
  adulthood
• Late-onset presentation
• Progressive amaurosis in childhood
• Progressive gait impairment (spasticity /
  dystonia)
• Dementia
• Investigations
• CT periventricular hyperdensities
• MRI confluent periventricular signal
  abnormalities
• cerebral and cerebellar involvement
• Electrophysiology peripheral demyelination

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Adrenoleukodystrophy (ALD)

• Peroxisomal disorders include adrenoleukodystrophy
  (and Refsum disease)
• Accumulation of very long chain fatty acids
  (VLCFA)
• In adrenals Addisons disease
• In white matter leukodystrophy
• Genetics
• ALD protein (ABCD1 gene) mutation on X chromosome
• X-linked disorder
• Forms
• Childhood ALD
• Adrenomyeloneuropathy (AMN) adolescent and
  adult men

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Adrenomyeloneuropathy (AMN)

• Symptoms
• Adrenal impairment
• Difficulty walking (spasticity)
• Urinary disturbance / impotence
• Cognitive / emotional disturbance
• Progresses over decades.
• Female carriers may have progressive paraparesis,
• moderate sensory loss, peripheral neuropathy.
• Normal adrenal function.
• Blood tests
• For VLCFA
• Genetic testing
• MRI confluent posterior white matter changes

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Bone marrow transplantation
Bone marrow transplantation has been used to slow
the progression of metachromatic leukodystrophy,
Krabbé globoid cell leukodystrophy, and
adrenoleukodystrophy, with less impact on
infantile forms.
Krivit W, Peters C, Shapiro EG. (1999). Bone
marrow transplantation as effective treatment of
central nervous system disease in globoid cell
leukodystrophy, metachromatic leukodystrophy,
adrenoleukodystrophy, mannosidosis, fucosidosis,
aspartylglucosaminuria, Hurler, Maroteaux-Lamy,
and Sly syndromes, and Gaucher disease type III.
Curr Opin Neurol. 12167-176.
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Refsum disease

• Another peroxisomal disorder.
• Accumulation of phytanic acid in blood and
  tissues.
• Genetics
• Phytanoyl-CoA hydroxylase (PAHX, chromosome 10)
• Peroxin-7 (PEX7 gene, chromosome 6)
• Autosomal recessive

OMIM (Online Mendelian Inheritance in Man)
http//www.ncbi.nlm.nih.gov/entrez/
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Refsum disease

• Presents from childhood to age 50 (peak 20).
• Features
• Retinitis pigmentosa
• Peripheral neuropathy
• Ataxia
• Elevated CSF protein
• Nystagmus
• Anosmia
• Ichthyosis
• Epiphyseal dysplasia

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Refsum disease

• Treatment
• Most treatable lipid storage disorder.
• Control by diet restrictions against phytanic
  acid
• dairy
• tuna, cod, haddock
• lamb, stewed beef
• white bread, white rice, boiled potatoes
• egg yolk.
• Plasmapheresis as supplement initially

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Pelizaeus-Merzbacher disease (PMD)

• Sudanophilic leukodystrophy (dysmyelination)
• Classic disorder shows patchy loss of
  oligodendrocytes with accompanying loss of axons,
  but preservation of neurons.
• Classic histopathologic appearance of tigroid
  leukoencephalopathy on staining with Sudan black
• More common childhood form is X-linked, with
  defect in the proteolipid protein (PLP gene).
• Adult form (Lowenberg-Hill disease, or Autosomal
  Dominant Leukodystrophy) is very rare, autosomal
  dominant with unknown enzyme defect (ADLD gene at
  chromosome 5q31).

Coffeen C et al. (2000). Genetic localization of
an autosomal dominant leukodystrophy mimicking
chronic progressive multiple sclerosis to
chromosome 5q31. Hum Molec Genet 9 787-783.
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Adult onset PMD

• Families described from American-Irish origin and
  Scottish-Irish origin.
• Begin in 4th-5th decade of life.
• Autonomic dysfunction (bowel/bladder regulation,
  orthostatic hypotension) often first.
• Cerebellar, pyramidal findings also. Progressive
  spasticity.
• Episodic psychotic events characteristic of
  Lowenberg-Hill disease.
• Survival to 20 years.
• CT/MRI findings of symmetric atrophy of white
  matter (confluent lesions)
• Often misdiagnosed as primary progressive
  multiple sclerosis.

OMIM (Online Mendelian Inheritance in Man)
http//www.ncbi.nlm.nih.gov/entrez/ Eldridge R et
al. (1984). Hereditary adult-onset leukodystrophy
simulating chronic progressive multiple
sclerosis. New Eng J Med. 311 948-953. Laxova A,
Hogan K, Haun J. (1985). A new autosomal dominant
adult onset progressive leukodystrophy. Am J Hum
Genet. 37 A65.
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Alexander disease

• Disorder of astrocytes, of glial fibrillary
  acidic protein (GFAP).
• Rosenthal fibers cytoplasmic eosinophilic
  hyaline inclusions in astrocytes
• Genetics
• Dominant mutations
• GFAP gene on chromosome 17
• Forms
• Infantile, juvenile, and adult-onset forms exist.

Johnson, A. (2002). Alexander disease a review
and the gene. Int J Devl Neuroscience. 20
391-394. Stumpf, E et al. (2003). Adult Alexander
disease with autosomal dominant transmission a
distinct entity caused by mutation in the glial
fibrillary acid protein gene. Arch Neurol 60
1307-1312.
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Alexander disease

• Adult form characterized by
• Sleep disturbances and constipation from
  childhood
• Other features develop at 3rd-4th decade
• Bulbar signs, ataxia, and pyramidal signs
• Mild dysmorphic features
• progressive kyphosis
• arched palate
• short neck
• MRI - atrophy of the medulla without signal
  abnormalities
• Also can be confused with multiple sclerosis

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Summary

• Leukodystrophies are rare genetic disorders of
  white matter, mostly presenting in childhood, but
  sometimes in adulthood.
• Can be confused for other more common disorders
  such as schizophrenia and multiple sclerosis.
• Most are managed supportively, but bone marrow
  transplantation has been used for lysosomal and
  peroxisomal disorders. Refsum disease can be
  managed with diet control.

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Other references resources
Baumann N, Turpin J-C. (2000). Adult-onset
leukodystrophies. J Neurol. 247751-759. Goetz
C.G. (2003). Leukodystrophies. Textbook of
Clinical Neurology, 2nd edition. Rolak L.
(2004). Differential Diagnosis of MS. American
Academy of Neurology 56th Annual Meeting
Syllabi. Online Mendelian Inheritance of Man
website http//www.ncbi.nlm.nih.gov/entrez/ Unite
d Leukodystrophy Foundation website
http//www.ulf.org/