Leukodystrophy

1. Leukodystrophy Tyler Reimschisel, MD September 6, 2013

2. Clinical Presentations of IMD • Intoxication • Urea cycle defects • Energy Failure • Mitochondrial disease • Glycogen storage disease • Complex Molecule • Lysosomal storage disease • Glycogen storage disease • Peroxisomal storage disorders

3. Diseases that Cause Leukodystrophy Some examples • Adrenoleukodystrophy • Metachromatic leukodystrophy • Tay-Sachs • Krabbe • Canavan • Mitochondrial

4. Clinical Presentation of Leukodystrophy • Developmental delay: relentless regression • Seizures • UMN signs • Failure to thrive (less common) • +/- dysmorphisms

5. Testing for Leukodystrophy • Lysosomal enzyme profile • VLCFA (very long chain fatty acids) • Urine organic acids • Lactate • Pyruvate: not clinically useful lab due to timing; in equilibrium with alanine • Alanine (order via Plasma amino acids)

6. Pelizaeus-Merzbacher • Xq22 mutation in proteolipid protein 1 (PLP1) • Onset in first few months of life with rotary head movements, rotary nystagmus, & motor delay • Then ataxia, tremor, choreoathetosis, spasticity • Seizures • Optic atrophy and ocular impairments • MRI: Reversal of gray-white signal due to diffuse dymyelination

7. Pelizaeus-Merzbacher

8. Gal-GalNAc Nana-Gal-Glc-Cer GalNAc Nana-Gal-Glc-Cer GalNAc-Gal-Gal-Glc-Cer GM1 (- Galactosidase) Sandhoff (-Hexosaminidase A & B) Gal-Gal-Glc-Cer GM2 (-Hexosaminidase A) Nana-Gal-Glc-Cer Fabry (-Galactosidase) Neuraminidase Gal-Glc-Cer Niemann-Pick A/B (Sphingomyelinase) Glc-Cer Gaucher (-Glucosidase) Phosphorylcholine-Cer (Sphingomyelin) Ceramide SO3H-Gal-Cer Gal-Cer MLD (Arylsulfatase A) Krabbe (- Galactosidase) Farber (Ceraminidase) Sphingosine

9. Krabbe • AR defect of galactocerebroside-beta-galactosidase on chromosome 14 • Pure neurologic condition • Onset at 3-8 months of age • Irritability, intermittent fevers, heightened startle reflex, feeding problems • Develop seizures, opisthotonus • Deafness and blindness by 9 months • MRI:

10. KRABBE DISEASE

11. Metachromatic Leukodystrophy • AR defect of arylsulfatase-A • Leukodystrophy as well as disease of adrenal glands, kidneys, pancreas, liver

12. Metachromatic Leukodystrophy • 3 Presentations • Late infantile (18-24 months) • Gait disturbance, hypotonia to hypertonia, regression, involuntary movements, neuropathy, cherry red spot • Juvenile (4-10 years) • Bradykinesia, poor school performance, ataxia, movement disorder, neuropathy, slower progression • Adult • After puberty get personality and mental changes, cortical and cerebellar regression to frank dementia in third to fourth decade

13. Metachromatic Leukodystrophy

14. L.B. • 4-year-old girl with GDD, hypotonia, & worsening ataxia • Development at 12-18 month level • Hyperactivity, inattention and aggression (Tenex) • Family history • Maternal cousin with chromosome deletion • Paternal half-sister with B12 deficiency (?) • Labs • CMA, karyotype, FRX, purine/pyrimidines, biotinidase, MECP2, AS/PWS, EEG, brain MRI (9/2010)

15. First Visit • Labs: PAA, acylcarnitine profile, vitamin B12, homocysteine, MMA level, creatine metabolites • Repeat brain MRI consistent with MLD

16. Second Visit • Lysosomal enzyme panel, VLCFA, coenzyme Q10 level • Arylsulfatase A level 1.5 (low) • GM1, mannosidosis, fucosidosis, Krabbe, Tay-sachs normal

17. Follow Up Testing • No mutations in arylsulfatase A gene • Parental testing showed normal arylsulfatase A enzyme activity

18. Additional Testing • Arylsulfatase B enzyme activity at 4-5% normal • Huge peak of sulfatides in patient • Multiple sulfatase deficiency diagnosed • Molecular testing pending

19. Multiple Sulfatase Deficiency • AR, mutations in sulfatase-modifying factor-1 gene (SUMF1) on 3p26 • Austria: 1 in 1.4 million individuals • Affects 12 sulfatase enzymes • Post-translation modification defect in which cystein residue of enzyme is not activated • Defect in enzyme that causes oxidation of a thiol group in cysteine to generate an alpha-formylglycine residue • Alpha-formylglycine residue may accept the sulfate during sulfate ester cleavage by hydrolysis • Examples: arylsulfatase, steroid sulfatase, heparansulfatase, N-acetylglucosamine-6-sulfatase

20. Multiple Sulfatase Deficiency • 3 phenotypes • Neonatal MSD: severe mucopolysaccharidosis • Late infantile MSD: late-onset MLD • Juvenile MSD • Combined features of MLD, Hunter, Sanfilippo A, Morquio, Maroteaux-Lamy, X-linked ichthyosis

21. Canavan • AR deficiency of asparto-acylase • Macrocephaly, lack of head control, and developmental delays by the age of three to five months • Develop severe hypotonia and failure to achieve independent sitting, ambulation, or speech • Hypotonia eventually changes to spasticity • Life expectancy is usually into the teens • Diagnosis of Canavan disease relies upon demonstration of very high concentration of N-acetyl aspartic acid (NAA) in the urine

22. Canavan disease Courtesy Dr Isabelle Desguerre, Paris Necker Hospital

23. NAA Canavan disease Courtesy Dr. Ralph Lachman

24. L-2-Hydroxyglutaric Aciduria • Underlying defect unknown • Clinical • Normal to mild delays in infancy and early childhood • Slowly progressive encephalopathy • Variable rate of progressive ataxia, seizures, pyramidal signs, movement disorder (dystonia, tremor, choreoathetosis), dementia • 50% with macrocephaly • Laboratory: no metabolic decompensation, increased plasma lysine, elevated 2-hydroxyglutaric acid in urine

25. Brain MRI

26. L-2-Hydroxyglutaric Aciduria • Neuroimaging • Severe cerebellar atrophy • Mildly swollen white matter with gyral effacement • Leukoencephalpathy more prominent closer to cerebral cortex • Increased signal intensity in dentate and striatum • Differential Diagnosis • D-2-hydroxyglutaric aciduria presents earlier • GAII causes elevations of D-2-hydroxyglutaric acid • Treatment - none

27. Alexander Disease • AD mutation in GFAP at 17q21.31 • Onset at around 6 months (birth – 2 yrs) • Psychomotor regression, spasticity and seizures • Juvenile patients have ataxia and spasticity • Adult patients have MS-like presentation • Diffuse demyelination, especially in frontal lobes

28. Alexander Disease

29. Brain MRI: Leigh Syndrome From Osborn. Neuroradiology, 2000

30. Brain MRI From Osborn. Neuroradiology, 2000

31. Peroxisome Function • Synthesis • Plasmologens (ether-phospholipids) • Bile acid from mevalonate • Catabolism • -oxidize very long chain fatty acids (esp C24:0 and C26:0), pristanic acid and bile acid intermediates • -oxidize phytanic acid (chlorophyll derivative) to pristanic acid • Lysine via pipecolic acid and glutaric acid • Glyoxylate to prevent conversion to oxalate

32. Peroxisomal Disorders • 16 disorders • 15 are autosomal recessive • 1 is X-linked (adrenoleukodystrophy) • Predominant features • Dysmorphisms • Neurologic dysfunction • Liver disease

33. Peroxisomal Disorders • Biosynthesis Defects • Zellweger spectrum disorders (ZD, IRD, NR) • Rhizomelia chondrodysplasia punctata • Single Peroxisomal Enzyme Deficiencies • Adrenoleukodystrophy (ABCD1 on Xq28) • RCDP type 2 (GNPAT on 1q42.1-42.3) • RCDP type 3 (AGPS on 2q33) • Refsum (PHYH/PAHX on 10p15-p14) • Glutaric aciduria type 3 (?) • Mulibrey nanism (TRIM on 17q22-23) • 9 others

34. Peroxisomal Biogenesis • Peroxisomes multiply by division • Proteins carried from free polyribosomes to peroxisomes by peroxisomal targeting signals (PTS) • PTS1 • Last 3 carboxy terminal amino acids • PTS1 receptor encoded by PEX5 • PTS2 • Stretch of 9 amino acids • PTS2 receptor encoded by PEX7

35. Peroxisomal Biogenesis • PTS receptors deliver proteins to peroxisomal protein import machinery • Import machinery transports proteins across membrane • Transporter complex has at least 15 peroxins (PEX1, 2, 3, 5, 6, 10, 12, 13, 14, 16, 19, 26)

36. Zellweger Spectrum Disorders • CZ, NALD, and IRD • Genetic heterogeneity • Dysmorphism (large fontanelle, high forehead, abn ears, micrognathia, low/broad nose, redundant skin folds) • Neuronal migration disorders and delayed myelination • Seizures • Hypotonia • Sensorineural deafness • Ocular abnormalities (retinopathy, cataracts, ON atrophy) • Liver disease (hepatomegaly, cholestasis, hyperbilirubinemia) • Failure to thrive • Death in first year of life

37. Zellweger Syndrome From Google Images

38. ZELLWEGER SYNDROME

39. Zellweger Spectrum Disorders • Classic Zellweger (CZ) • Neonatal adrenoleukodystrophy (NALD) • Somewhat less severe than CZ • May lack dysmorphisms altogether • Neonatal or infantile onset of seizures, hypotonia, and progressive leukodystrophy • May have pachypolymicrogyria • Infantile Refsum disease (IRD) • Least severe phenotype, regression over time • May be asymptomatic at birth • No progressive leukodystrophy • Variable expressivity of cognitive dysfunction • Deafness and vision changes (retinopathy) • May survive to adulthood

40. Adrenoleukodystrophy/Adrenomyeloneuropathy • Most common peroxisomal disorder (1/20,000) • Mutation in ABCD on Xq28 leads to defect in peroxisomal uptake of VLCFA • ALD: progressive neurologic disorder that begins at 5-12 years • Boys with new onset school difficulties & ADHD • Visuo-spatial deficits and hearing loss • Spasticity, ataxia, maybe seizures • Hypoglycemia, salt losing, hyperpigmentation • Rx: steroids, presymptomatic stem cell transplant, Lorenzo’s oil ineffective (oleic and erucic acids) • AMN: early adulthood progressive spastic paraparesis, cerebral demyelination (males)

41. CLASSIC X-ALD

42. CLASSIC X-ALD

43. X-ALD