Leukodystrophies

Leukodystrophies are rare, metabolic, progressive and mainly hereditary diseases. They are named by the “white” substance – myelin, which insulates by protecting structures of the nervous system, ensuring the high velocity of the propagation of the nervous signals. In leukodystrophies the growth or maintenance of myelin is disrupted, which is caused by a multitude of mutations in several genes. Depending on the gene and its mutation, many classes of leukodystrophins are distinguished and a variety of symptoms are present. They may be inherited either autosomally in a recessive or dominant or X-linked pattern. But they may also be due to random mutations. They resemble multiple sclerosis (MS), since myelin is also lost in this disease, but the cause is autoimmune in that case.

Namely, leukodystrophies are distinguished in:

  1. 18q Syndrome with Deficiency of Myelin Basic Protein
  2. Acute Disseminated Encephalomyeolitis (ADEM)
  3. Acute Disseminated Leukoencephalitis
  4. Acute Hemorrhagic Leukoencephalopathy
  5. Adrenoleukodystrophy (ALD)
  6. Adrenomyeloneuropathy (AMN)
  7. Adult Onset Autosomal Dominant Leukodystrophy (ADLD)
  8. Adult Polyglucosan Body Disease
  9. Aicardi-Goutieres Syndrome
  10. Alexander Disease
  11. Autosomal Dominant Diffuse Leukoencephalopathy with Neuroaxonal Spheroids (HDLS)
  12. Autosomal Dominant Late-Onset Leukoencephalopathy
  13. Canavan Disease
  14. Childhood Ataxia with Diffuse CNS Hypomyelination (CACH or Vanishing White Matter Disease)
  15. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
  16. Cerebroretinal Micro-Angiography with Calcifications and Cysts
  17. Cerebrotendinous Xanthomatosis (CTX)
  18. Craniometaphysical Dysplasia with Leukoencephalopathy
  19. Cystic Leukoencephalopathy (RNASET2 related)
  20. Elongation of Very Long-Chain Fatty Acids-4 (ELOVL4; Pseudo-Sjogren-Larsson)
  21. Extensive Cerebral White Matter Abnormality without Clinical Symptoms
  22. Familial Adult-Onset Leukodystrophy Manifesting as Cerebellar Ataxia and Dementia
  23. Familial Leukodystrophy with Adult Onset Dementia and Abnormal Glycolipid Storage
  24. Fatty Acid 2-Hydroxylase Deficiency
  25. Fucosidosis
  26. Fukuyama Congenital Muscular Dystrophy
  27. Galactosialidosis
  28. Globoid Cell Leukodystrophy (Krabbe Disease)
  29. GM1 Gangliosidosis
  30. GM2 Gangliosidosis (Tay-Sachs Disease)
  31. Hereditary Adult Onset Leukodystrophy Simulating Chronic Progressive Multiple Sclerosis
  32. Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC)
  33. Hypomyelination, Hypogonadotropic, Hypogonadism and Hypodontia (4H Syndrome)
  34. Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation (LBSL)
  35. Lipomembranous Osteodysplasia with Leukodystrophy (Nasu Disease)
  36. Metachromatic Leukodystrophy (MLD)
  37. Megalencephalic Leukodystrophy with subcortical Cysts (MLC)
  38. Neonatal Adrenoleukodystrophy (NALD)
  39. Oculodetatoldigital Dysplasia with Cerebral White Matter Abnormalities
  40. Orthochromatic Leukodystrophy with Pigmented Glia
  41. Ovarioleukodystrophy Syndrome
  42. Pelizaeus Merzbacher Disease (X-linked spastic paraplegia)
  43. Refsum Disease
  44. Sjogren-Larsson Syndrome
  45. X-linked Adrenoleukodystrophy (X-ALD)
  46. Zellweger Spectrum: Zellweger Syndrome, Neonatal Adrenoleukodystrophy, and Infantile Refsum Disease

Symptoms

Their symptoms may begin to appear from birth or during childhood or during adulthood, depending on the type of mutation. Each type of leukodystrophy affects different sites of the myelin site resulting in a different spectrum of symptoms. Motion, growth, vision (even progressive blindness), memory (dementia in some cases), thought, balance can be affected. Muscular contractions, nystagmus and even strokes, macrocephaly, hypotonia, speech problems, cardiac problems, paralysis, hepatosplenomegaly, migraines, and nausea (dry and lax skin) may develop.

Diagnosis

  • Personal and family history.
  • Clinical examination.
  • Lumbar puncture.
  • Genetic tests.
  • Blood tests.
  • Magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (H-MRS).

Management

It is symptomatic as each case may be. Generally, scoliosis with contractures can be treated with orthopaedics and other symptoms with medications. Physiotherapy and appropriate exercises, as well as assistive devices (e.g., orthotics and trolleys), nutritional support, pharmaceutical administration of enzymes, which may be missing in any case, are recommended. In some cases, plasmapheresis, stem cell or bone marrow transplantation occurs and gene therapy is applied lately.

Information about clinical trials conducted globally: https://www.centerwatch.com/clinical-trials/listings/condition/350/muscular-dystrophy/?page=1

https://www.centerwatch.com/clinical-trials/listings/condition/690/progressive-multifocal-leukoencephalopathy-pml/ and

https://clinicaltrials.gov/ct2/home

References

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