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Congenital cerebral hypomyelination; network for Pelizaeus-Merzbacher disease and related disorders

  • Inherited white matter disorders
  • Congenital cerebral hypomyelination

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Guidelines on Hereditary Leukodystrophies

What are cerebral leukodystrophies?

Cerebral leukodystrophies are inherited forms of dysmyelination disorders that affect around 1 in 100,000 people. Affected patients have poor muscle tone in early childhood and later develop spasticity. Complications include intellectual disability, cerebellar and basal ganglia impairments, and epilepsy. The use of magnetic resonance imaging is important for the diagnosis.

1. Overview

Definition

A group of diseases characterized by the inherited dysmyelination of the central nerves. The peripheral nerves may or may not be affected (1-3).

Epidemiology

A Japanese epidemiological study found that the incidence in Japan was 0.78 per 100,000 births, of which 0.26 were Pelizaeus-Merzbacher disease (4). Similar incidences have been reported in the United States and Germany (4, 5) (6).

Etiology and pathophysiology

Cerebral leukodystrophy may be caused by a defect in one of the proteins required for the formation of myelin around the central nerves (proteolipid protein or myelin base protein), the transcription factor necessary to regulate the expression of these proteins (SOX10), or one of the other factors necessary for myelination (e.g., polymerase III, SLC16A2, and impaired thyroid hormone transport) (Table 1).

Clinical symptoms

Signs seen in all cases of congenital cerebral leukodystrophy consist of those due to motor pathway impairment, including spastic palsy of the legs of varying degrees of severity, nystagmus, and intellectual disability; those due to cerebellar impairment, including trunk and limb ataxia, intention tremor, and dysmetria, conversion disorders, and slurred speech during childhood; and those due to basal ganglia impairment, including rigidity, dystonia, and epilepsy (5, 7). Poor muscle tone is common in early childhood, but the tendon reflexes of the arms and legs increase, with the persistence of the Babinski reflex and other pathologic reflexes, and spastic palsy of the legs gradually develops. Some mild cases are known to exhibit the phenotypes of complex or pure spastic paraplegia in which leg spasticity is the first apparent symptom. Delayed psychomotor development is seen in almost all patients. Motor disabilities are generally more severe than intellectual disabilities, while language comprehension abilities exceed language expression skills. Cerebellar disorders occur via the efferent and afferent pathways. Trunk and limb ataxia, intention tremors, dysmetria, conversion disorders, and slurred speech during childhood may be present. Rigidity, dystonia, and other basal ganglia symptoms often appear over time. Depending on the white matter abnormality, epilepsy may also be present as a cortical symptom (8-10).

Imaging and other investigations

To evaluate myelination, magnetic resonance imaging is useful for reaching a definitive diagnosis (11, 12). The signal intensity in the affected areas of the cerebral white matter are compared on T1- and T2-weighted images. Compared with the healthy cerebral cortex, affected areas of white matter are hyperintense on T2-weighted imaging but exhibit a variety of signal intensities on T1-weighted imaging ranging from hyperintense (normal pattern) to isointense and mildly hypointense with similar signal intensity from the subcortical white matter to the deep periventricular white matter seen in many cases. In demyelination, the white matter in the affected areas is strongly hyperintense on T1-weighted imaging and strongly hypointense on T1-weighted imaging; the subcortical white matter (U fibers) is generally spared in the early disease stages. Hypodense areas of white matter may appear on computed tomography, but this finding is of low diagnostic value. In physiological tests, impaired central transmission is evident in the auditory brainstem response, somatosensory evoked potentials, and visual evoked potentials. Cerebral leukodystrophy can also be classified according to the presence or absence of peripheral neuropathy measured by peripheral nerve transmission velocity or electromyography (12). With the exception of Allan-Herndon-Dudley syndrome, serum and physiological test results are non-specific.

References

(Unless otherwise noted at the end, all are evidence level 6.)

  1. Boespflug-Tanguy O. Inborn errors of brain myelin formation. Handbook Clin Neurol 2013; 113: 1581-1592.
  2. Pouwels PJ, Vanderver A, Bernard G, Wolf NI, Dreha-Kulczewksi SF, Deoni SC, et al. Hypomyelinating leukodystrophies: translational research progress and prospects. Ann Neurol. 2014;76(1):5-19.
  3. Charzewska A, Wierzba J, Izycka-Swieszewska E, Bekiesinska-Figatowska M, Jurek M, Gintowt A, et al. Hypomyelinating leukodystrophies - a molecular insight into the white matter pathology. Clin Genet 2016; 90(4): 293-304.
  4. Numata Y, Gotoh L, Iwaki A, Kurosawa K, Takanashi J, Deguchi K, et al. Epidemiological, clinical, and genetic landscapes of hypomyelinating leukodystrophies. J Neurol 2014; 261(4): 752-758.
  5. Hobson GM, Kamholz J. PLP1-Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, et al., editors. GeneReviews(R). Seattle WA: University of Washington, Seattle; 1993.
  6. Heim P, Claussen M, Hoffmann B, Conzelmann E, Gartner J, Harzer K, et al. Leukodystrophy incidence in Germany. Am J Med Genet 1997; 71(4): 475-478.
  7. Vanderver A, Tonduti D, Schiffmann R, Schmidt J, van der Knaap MS. Leukodystrophy Overview. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle WA: University of Washington, Seattle; 1993.
  8. Osaka H, Inoue K. Pathophysiology and emerging therapeutic strategies in Pelizaeus–Merzbacher disease. Exp Opin Orphan Drugs 2015; 3(12): 1447-1459.
  9. Inoue K. PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 2005; 6(1): 1-16.
  10. Hobson GM, Garbern JY. Pelizaeus-Merzbacher disease, Pelizaeus-Merzbacher-like disease 1, and related hypomyelinating disorders. Semin Neurol 2012; 32(1): 62-7.
  11. Barkovich AJ, Deon S. Hypomyelinating disorders: An MRI approach. Neurobiol Dis 2016; 87: 50-58.
  12. Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 2009; 72(8): 750-759.
Literature search

PubMed

  • "leukodystrophy[All Fields] AND definition[All Fields] 9 results, hypomyelination[All Fields] AND ("disease"[MeSH Terms] OR "disease"[All Fields]) 514 results, hypomyelination[All Fields] AND ("syndrome"[MeSH Terms] OR "syndrome"[All Fields])　205 results

Igaku Chūō Zasshi

  • 大脳白質形成不全症/AL 42 results
  • 髄鞘形成不全/AL 67 results