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What is 4H leukodystrophy?

4H leukodystrophy is short for hypomyelination, hypogonadotropic hypogonadism and hypodontia. Hypomyelination means that there is lack of myelin in the central nervous system. In hypogonadotropic hypogonadism, normal puberty development is absent or delayed because the central nervous system is not able to initiate it properly. Hypodontia means that not all teeth are present.

What causes 4H leukodystrophy?

4H leukodystrophy is caused by mutations in one of four genes: POLR3A, POLR3B, POLR1C, and POLR3K. 4H leukodystrophy is inherited in an autosomal recessive manner. This means that parents are healthy but each carry one defective copy of the responsible gene. If a child inherits two defective copies of this gene, they will be affected.

How is 4H leukodystrophy diagnosed?

4H leukodystrophy is diagnosed based on the clinical symptoms, the results of an MRI, and genetic testing.

What are the symptoms of 4H leukodystrophy?

A child with 4H leukodystrophy develops normally at first. Signs and symptoms usually appear before six years of age, but later onset has been described.

Neurological symptoms include:

  • Ataxia (problems with balance and walking)
  • Tremor
  • Dysarthria (speech is difficult to understand)
  • Dystonia (uncontrolled muscle contractions)
  • Spasticity (abnormally stiff muscles and restricted movements)
  • Seizures (these are rare)

Other symptoms:

  • Abnormal tooth development
  • Atypical puberty
  • Short stature
  • Myopia (near sightedness)
  • Difficulty swallowing

What is the treatment for 4H leukodystrophy?

There is no cure for 4H leukodystrophy; treatment is supportive.

Is prenatal diagnosis possible?

When two carriers of 4H leukodystrophy have children together, for each pregnancy, there is a 25% (1 in 4) chance their child will be affected. Families may consider meeting with a genetic counselor to discuss this risk and reproductive options available to them.

How is scientific research on 4H leukodystrophy progressing towards improved treatment or diagnosis?

Researchers are still uncovering how mutations in the POLR3 genes cause 4H leukodystrophy. Further discovery and collection of data from patients and their families are essential to developing targeted treatments and therapies.

Other names for 4H leukodystrophy:

  • POLR3-Related Leukodystrophy
  • 4H syndrome

Helpful Resources:

Thank you to the Yaya Foundation for keeping this page updated! (8/18/2021)