Metachromatic Leukodystrophy - Causes, Symptoms, Diagnosis, and Treatment

Introduction:

Metachromatic leukodystrophy (MLD) affects one in 40,000 to one in 160,000 individuals.

The condition got its name by:

• Leukodystrophy: The build-up of fatty substances in myelin cells destroys the white matter of the brain, spinal cord, and peripheral nerves.

• Metachromatic: When viewed under a microscope, the fatty deposits appear in varying colors to that of other cells.

• It is otherwise known as Greenfield disease, diffuse brain sclerosis, and metachromatic leukoencephalopathy.

What Is Metachromatic Leukodystrophy?

It is a rare inherited disorder characterized by the accumulation of fatty substances (sulfatides) chiefly in the cells of the brain, spinal cord, and peripheral nerves. The sulfatides deposit in the myelin cells and thus destroy the protective coverings (myelin sheath) of the central nervous system and the nerves that connect muscles and sensory cells to the brain and spinal cord. It also accumulates in the testes, gallbladder, and kidneys.

What Causes Metachromatic Leukodystrophy?

• The leading cause of metachromatic leukodystrophy is the genetic alterations (mutations) in the ARSA gene. The ARSA gene is responsible for giving the arylsulfatase A enzyme instructions to break down the sulfatides. Thus the defective ARSA gene causes the accumulation of sulfatides in body cells.

• Another cause is the mutation in the PSAP gene that leads to the deficiency of a specific protein called saposin B; it leads to a lack of breakdown of sulfatides, and it gets deposited especially in myelin cells.

• It is an autosomal recessive disorder, meaning a child acquires two copies of the defective gene from both parents. The parent may remain carriers (asymptomatic) of the disease with one copy of the normal gene and another mutated copy. But there is a 25 % chance of the child acquiring the mutated gene from both mother and father.

How Is Metachromatic Leukodystrophy Classified?

According to the age of onset, metachromatic leukodystrophy is classified as follows:

• Late Infantile MLD: The symptoms appear in the first three years of life. It is the most common form, and 50 % to 60 % of infants are affected. The symptoms mainly occur due to the destruction of myelin sheath in the peripheral nerves.

• Juvenile MLD occurs in children between 3 years to 16 years of age. It affects 20 to 30 % of children. It is subdivided into the early (4 years to 6 years) and late juvenile (6 years to 16 years) forms of MLD.

• Adult MLD: The symptoms develop after 16 years of age, and it is the least common form affecting 15 to 20 % of the population.

What Are the Signs and Symptoms?

Late Infantile Form: The children suffer from speech difficulties, weakness, loss of muscle function, and walking problems. Decreased muscle tone, repeated muscle contractions (dystonia), and optic atrophy (a condition that worsens vision) also occurs. Infants affected usually do not survive after childhood.

Juvenile Form: The characteristic features include behavioral problems, personality changes, and difficulty in schoolwork. The progression of symptoms is a little slower, and the children may survive for 20 years after the symptoms appear. The children may present with or without seizures in the late juvenile form of MLD.

Adult Form: Behavioral and psychological issues such as difficulty in school and the workplace, alcohol and drug abuse, schizophrenia, hallucination, and delusion also occur. The symptoms remain stable for some period, and worsening of functions occurs during a specific period. The adults may survive for more years.

The other common symptoms are as follows:

• Difficulty in walking, speaking, and swallowing.

• Loss of muscle function.

• Emotional disturbances.

• Seizures.

• Unresponsiveness.

• Vision and hearing loss.

How Is Metachromatic Leukodystrophy Diagnosed?

• A blood examination is ordered to detect the deficiency of arylsulfatase A enzyme due to mutation in the ARSA gene.

• A urine test helps detect abnormal levels of certain substances excreted in the urine. In metachromatic leukodystrophy, levels of sulfatides are checked in the urine samples.

• Magnetic resonance imaging (MRI) detects any lesion, cyst, or tumor in the brain and spinal cord. The MRI of metachromatic leukodystrophy shows the classical striped pattern of white matter in the brain and the destruction of the myelin sheath.

• A lumbar puncture involves the removal of a sample of cerebrospinal fluid (CSF) from the lower back region surrounding the brain and spinal cord to diagnose various neurological conditions. The CSF shows elevated proteins in metachromatic leukodystrophy.

• Nerve conduction study (NCS): In this study, two electrodes are attached to the skin; one stimulates the nerves, and the other measures the response from the nerve. It helps measure the movement of impulses within the nerve and evaluate any nerve damage.

• Molecular genetic testing is a confirmatory test. It helps in determining the mutation in genes that causes metachromatic leukodystrophy.

• A neurocognitive test determines memory loss, decreased motor function, and impulsiveness in juvenile and adult forms of MLD.

What Are the Related Disorders?

The disorders that possess similar characteristics to metachromatic leukodystrophy are listed below:

• Krabbe disease develops in infants less than six months of age, and it affects the protective coverings of the brain and spinal cord. It causes muscle weakness, feeding difficulties, irritability, vision loss, and seizures.

• X-lined adrenoleukodystrophy is also characterized by damage to the adrenal glands and myelin sheath. As a result, the individuals develop behavioral disturbances, lack of coordination, and muscle weakness during childhood, adolescence, or adulthood.

• Childhood-onset schizophrenia is a rare but severe mental disorder. It affects children below 13 years of age. The clinical features include thinking and behavioral disturbances, hallucinations, and delusions.

Can Metachromatic Leukodystrophy Be Cured?

No specific treatment cures metachromatic leukodystrophy. However, the following management is practiced to alleviate the symptoms and provide support.

• Anti-epileptics like Lacosamide and Valproic acid are suggested in case of seizures.

• Botox A (Botulinum toxin A) is provided to get relief from severe muscle contractions and twitching.

• Serotonin–noradrenaline reuptake inhibitors such as Mirtazapine are given to treat depression, mood, or sleeping issues.

• Specialists provide physical therapies to improve the range of muscle movement and flexibility.

• Occupational therapy is also given to children to improve their school performance.

• Nutritional support is given as the child may have feeding difficulties. It includes the placement of feeding tubes and administering medications.

• Gene, stem cell, and enzyme replacement therapies are still under study to treat metachromatic leukodystrophy.

Conclusion:

Metachromatic leukodystrophy is a progressive disorder. Education of the patient and their families is essential in understanding the disease and providing support. In addition, having a regular follow-up with the specialist plays a significant role in improving the quality of life. Even though it seems problematic, several medications aid in relieving the symptoms; you can consult doctors on icliniq.com for further information.