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. Ceramide Sphingosine Glc-Cer Gal-Glc-Cer Gal-CerSO 3 H-Gal-Cer Phosphorylcholine-Cer (Sphingomyelin) Gal-Gal-Glc-Cer GalNAc-Gal-Gal-Glc-Cer Nana-Gal-Glc-Cer GalNAc Nana-Gal-Glc-Cer Gal-GalNAc Nana-Gal-Glc-Cer Gaucher (  -Glucosidase) Farber (Ceraminidase) Niemann-Pick A/B (Sphingomyelinase) Fabry (  -Galactosidase) MLD (Arylsulfatase A) Krabbe (  - Galactosidase) Neuraminidase GM 2 (  -Hexosaminidase A) GM 1 (  - Galactosidase) Sandhoff (  -Hexosaminidase A & B)

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, heparan sulfatase, 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 Courtesy Dr. Ralph Lachman Canavan disease

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 pachypolymicrogyr ia 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

43. X-ALD