Dysmyelination syndromes

1. Dysmylelination syndromes Amr Hasan, M.D. Associate Professor of Neurology Cairo University

2. Stage 4 Myelination :  Inferior to superior; posterior to anterior.  5 - 15 months; matures by 3 years. Failure: developmental delay dysmyelinating disease

3. “demyelination”, used when there is loss of myelin. “hypomyelination”, which means that too little myelin is formed and this deficiency is permanent. “dysmyelination”, used when the process of myelination is disturbed, leading to abnormal, patchy, or irregular myelination. “delayed myelination”, used when the process of myelination is retarded but progressing.

4.  Stage IV: Failures of Myelination Dysmyelinating Disorders Metachromatic leukodystrophy. Krabbe's disease Adrenoleukodystrophy Zelweger disease. Canavan's disease. Alexander's disease. Others.

6. Clinical Presentation of Leukodystrophy  Developmental delay: relentless regression  Seizures  UMN signs  Failure to thrive (less common)  +/- Dysmorphisms

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

8. Metachromatic Leukodystrophy Mutations: • arylsulfatase A gene (ARSA) on chromosome 22q13 • 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/

9. Metachromatic Leukodystrophy

10. Metachromatic Leukodystrophy Late infantile (18-24 months) The infantile form includes the following: Gait disturbances Memory deficits Seizures (may be present) Loss of motor developmental milestones Decreased attention span Speech disturbances Decline in school performance        

11. Metachromatic Leukodystrophy Early juvenile form The early juvenile form includes the following: Gait disturbances Tremors Clumsiness Loss of previously achieved skills Intellectual decline Behavioral changes Seizures (possible)        

12. Metachromatic Leukodystrophy 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

13. Metachromatic Leukodystrophy 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

14. Metachromatic Leukodystrophy

15. Metachromatic Leukodystrophy SPARING SUBCORTICAL U SHAPED FIBRES

16. Metachromatic Leukodystrophy (cont.)

17. Metachromatic Leukodystrophy

18. Metachromatic Leukodystrophy

19. Metachromatic Leukodystrophy (cont.)

20. Krabbé (Globoid Cell) Leukodystrophy 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) • 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)

21. Krabbé (Globoid Cell) Leukodystrophy

22. Krabbé (Globoid Cell) Leukodystrophy  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

23. 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

24. Krabbé (Globoid Cell) Leukodystrophy

25. Krabbé (Globoid Cell) Leukodystrophy

26. Krabbé (Globoid Cell) Leukodystrophy

27. Krabbé (Globoid Cell) Leukodystrophy hypointense basal ganglia and THALAMI .

28. Krabbé (Globoid Cell) Leukodystrophy

29. Peroxisomes Peroxisomes (microbodies) are simple, membrane- bound vesicle with a diameter of 0.1 to 1.0 um. Peroxisomes are multifunctional organelles, containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens. These organelles were named “peroxisomes” because they are the site of synthesis and degradation of hydrogen peroxide (H2O2), a highly reactive and toxic oxidizing agent.

30. 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

31. Enzymatic pathways in peroxisomes  Fatty acid oxidation (VLCFA, PA)  H2O2 detoxification (catalase)  Docohexanoic acid (DHA) synthesis  Bile acid synthesis  Plasmalogen (ether phospholipid) synthesis  Cholesterol synthesis  Glyoxylate detoxification  Lysine catabolism (pipecolic acid)

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. Zellweger Spectrum Disorders  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

35. Craniofacial dysmorphism (ZS)  Widely patent fontanels and sutures  Prominent high forehead  Shallow orbital ridges  Low broad nasal bridge  Anteverted nares  Hypertelorism  Epicanthal folds  High arched palate  Micrognathia  Redundant skin folds of neck

36. Zellweger Syndrome From Google Images

37. Zellweger syndrome

38. Zellweger syndrome

39. Zellweger syndrome MRI Features include:  ventricular enlargement  abnormal gyration patterns – pachygyria: especialy medial gyri around peri-rolandic regions – polymicrogyria: laterally

40. Zellweger spectrum disorder (ZSD), a clinical continuum Zellweger Syndrome Infantile Refsum Disease

41. 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

42. 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

43. Adrenoleukodystrophy (ALD) 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

44. Multiple phenotypes of X-ALD  Childhood cerebral form – Onset - ~6-12 yrs (survival: several years) – 90% with adrenal insufficiency  Adrenomyeloneuropathy (AMN) – Spastic paraparesis and sphincter dysfunction – Onset - ~2nd-5th decade (survival: decades) – 2/3 with adrenal insufficiency  Other phenotypes – Addison disease only – Adult-onset cerebral involvement - dementia  Female heterozygotes- 50% with mild AMN-like Sx ~35% ~50% ~15%

45. CLASSIC X-ALD

46. CLASSIC X-ALD

47. X-ALD

48. Adrenoleukodystrophy. bilateral symmetrical pareitooccipital WM involvement ,progression form posteior to anterior ,progressive atrophy

49. Adrenoleukodystrophy

50. Adrenoleukodystrophy (cont.)