1. Leukodystrophies in Adults August 12, 2004.

2. Objectives: To discuss the leukodystrophies which may present in adulthood, their etiologies, presentation, and management.

3. 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

4. The Leukodystrophies… Goetz: Textbook of Clinical Neurology, 2 nd ed. 2003.

5. …with adult presentation Metachromatic Leukodystrophy Krabbé globoid cell leukodystrophy Adrenoleukodystrophy / adrenomyeloneuropathy Refsum disease Pelizaeus-Merzbacher disease (Lowenberg-Hill type) Alexander disease

6. 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/

7. 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

8. 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 3 rd or 4 th decade of life Progressive corticobulbar, corticospinal, cerebellar changes

9. 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

10. 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/

11. 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

12. 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

13. 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

14. 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.

15. 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/

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

17. 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

18. 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.

19. Adult onset PMD Families described from American-Irish origin and Scottish-Irish origin. Begin in 4 th -5 th 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.

20. 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.

21. 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

22. 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.

23. 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, 2 nd edition. Rolak L. (2004). Differential Diagnosis of MS. American Academy of Neurology 56 th Annual Meeting Syllabi. Online Mendelian Inheritance of Man website http://www.ncbi.nlm.nih.gov/entrez/ United Leukodystrophy Foundation website http://www.ulf.org/