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 abnormality2. Demyelination – destruction of normally formed myelin3. 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 disorderDecreased oligodendrocytes in areas of demyelinationGloboid 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

• 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:

• 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/