HYPOMYELINATION WITH BRAIN STEM AND SPINAL CORD INVOLVEMENT AND LEG SPASTICITY (HBSL)
WHAT IS HBSL?
HBSL is a progressive neurodegenerative disorder that affects the tracts in the brain and spinal cord which is called the Central Nervous System (CNS). It is caused by the defective formation of myelin in these areas which is known as hypomyelination and it is one of the Leukodystrophies. In the central nervous system, the neurons are organised in bundles called tracts. Ascending tracts carry impulses along the spinal cord toward the brain, and descending tracts carry them from the brain or higher regions in the spinal cord to lower regions. The tracts that are mainly affected with HBSL are the pyramidal and the dorsal column. The pyramidal tracts refer to the upper motor neurons that originate in the cerebral cortex and terminate in the spinal cord (corticospinal) or brainstem (corticobulbar). The Dorsal column refers to the rear or posterior spinal cord, which contains ascending sensory pathways that carry information about tactile sensations and bodily awareness or proprioception.
WHAT CAUSES HBSL?
HBSL is caused by mutations on the DARS1 gene which is situated on Chromosome 2. This gene provides instructions for the making of an enzyme called aspartyl-tRNA synthetase. This enzyme is found in all cell types and plays a vital role in the production of proteins. These mutations reduce the ability to form myelin (hypomyelination) particularly in the areas where the brain connects to the spinal cord. Myelin is a spongy substance which is white in appearance and those sending arms of the neuron, called axons, are myelinated and referred to as “the white matter” of the brain. The major purpose of the myelin is to increase the speed of transmission of an impulse (message) to the next neuron and also to prevent the electrical current from escaping.
Most of the mutations also cause changes with the amino acids in the aspartyl-tRNA synthetase enzyme. These changes happen in the active site where the aspartate and the tRNA come together and are meant to be transferred. The mutation obstructs this process and the adding of aspartate to proteins. It is not clearly understood why this reduced activity causes hypomyelination or why it particularly affects part of the brainstem and spinal cord.
FORMS OF HBSL
There are at least 16 mutations in the ARS1 gene which cause HBSL. The age of onset can be neonatal, infancy or adolescence. Symptoms are very variable and often do not appear until about 6 months old however from then onwards problems can occur. Those symptoms can include the following;
Symptoms:
- Problems with motor skills such as rolling over, crawling and sitting up
- Lack of muscle tone (hypotonia) floppy limbs and inability to hold the head
- Muscle stiffness (spasticity) an increase in muscle tone making them feel tight and rigid
- Inability to walk independently
- Involuntary rolling of the eyes side to side (nystagmus)
- Lack of muscle coordination which may affect the eye movement, speech, swallowing, walking, picking up objects and other voluntary movements (ataxia)
- Epilepsy
- Speech difficulty often slurred, slow and hard to understand (dysarthria)
- Deterioration in mental functioning
- Overactive reflexes (hyperreflexia)
- Underdevelopment of the corpus callosum (hypoplasia) which is that part of the brain that connects the left and right sides
- A Babinski response in a child over 2 or adult is abnormal and could be a sign of a problem in the CNS and most likely the pyramidal tract. The Babinski response is present if when the sole is stimulated the big toe bends up and back to the top of the foot and the other toes fan out. This must be interpreted by a neurologist or experienced clinician.
HOW DO WE DIAGNOSE HBSL?
As we know the mutation and where to find it we can very readily determine a diagnosis through genetic testing. We can use other imaging such as an MRI to confirm our diagnosis and the use of blood assays can be very helpful.
INCIDENCE
It is unknown but an incidence of 1:1,000,000 worldwide has been suggested.
INHERITANCE
It is inherited in an autosomal recessive pattern which means that the parents of a child each carry one copy of the mutated gene however they are unaffected by the condition.
If you are born to parents who carry the same autosomal recessive change (mutation), you have a 1 in 4 chance of inheriting the abnormal gene from both parents and developing the disease. You have a 50% (1 in 2) chance of inheriting one abnormal gene. This would make you a carrier. In other words, for a child born to a couple who both carry the gene (but do not have signs of disease), the expected outcome for each pregnancy is:
- A 25% chance that the child is born with two normal genes (normal)
- A 50% chance that the child is born with one normal and one abnormal gene (carrier, without disease)
- A 25% chance that the child is born with two abnormal genes (at risk for the disease)
TREATMENTS FOR MLD
There is no proven therapy therefore treatment is symptomatic and supportive. It is believed that there could well be some benefit in anti-inflammatory treatment so the use of steroid pulse therapy could be useful in HBSL.