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Leukodystrophies in Adults
August 12, 2004.
Objectives:
To discuss the leukodystrophies which may present in adulthood, their
etiologies, presentation, and management.
Leukodystrophy
Genetic diseases showing morphological changes in white matter.
1. Myelin dysfunction due to enzymatic abnormality
2. Demyelination – destruction of normally formed myelin
3. 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
The Leukodystrophies…
Goetz: Textbook
of Clinical
Neurology, 2nd
ed. 2003.
…with adult presentation
Metachromatic Leukodystrophy
Krabbé globoid cell leukodystrophy
Adrenoleukodystrophy / adrenomyeloneuropathy
Refsum disease
Pelizaeus-Merzbacher disease (Lowenberg-Hill type)
Alexander disease
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/
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
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
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
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/
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
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
• In adrenals – Addison’s 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
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
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.
12:167-176.
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/
Refsum disease
Presents from childhood to age 50 (peak 20).
Features:
• Retinitis pigmentosa
• Peripheral neuropathy
• Ataxia
• Elevated CSF protein
• Nystagmus
• Anosmia
• Ichthyosis
• Epiphyseal dysplasia
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
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.
Adult onset PMD
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•
•
•
•
•
•
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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.
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.
Alexander disease
Adult form characterized by:
•
•
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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
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.
Other references & resources
Baumann N, Turpin J-C. (2000). Adult-onset leukodystrophies. J Neurol. 247:751-759.
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/
United Leukodystrophy Foundation website http://www.ulf.org/