Metachromatic Leukodystrophy

What is Metachromatic Leukodystrophy?

Lysosomal storage diseases (LSDs) are a set of inherited diseases that interfere with specific enzymes, which play a key role in various cell functions. These enzymes help break down and recycle different parts of cells, which is a highly intricate process. When these enzymes don’t work properly, it leads to the build-up of substances that the enzymes were supposed to break down. These residual substances can be harmful to the cell. Cases of LSDs more commonly begin in early infancy or childhood, but some may not start until adulthood. As the disorder progresses, it could damage the nerves, lead to multiple organ failures, and in severe cases, result in death.

Leukodystrophies are another set of genetic disorders that mainly impact the white matter, a part of the brain and spinal cord that contains nerve fibers. Components of these nerve fibers can be affected, such as glial cells that support and protect neurons, the myelin sheath that insulates nerve fibers, and the axon which conducts electrical impulses. These disorders often involve complications related to metabolism, DNA processing, protein production, and the structural integrity of neurons.

An example of these diseases is Metachromatic leukodystrophy, a genetic disorder that causes the breakdown of a crucial part of the brain’s white matter, due to a defect in an enzyme stored in cells called arylsulfatase A. The lack of this enzyme leads to the build-up of substances called sulfatides, causing the destruction of the protective layer around nerve fibers called myelin sheaths not only in the brain and spinal cord but also in other organs like the kidneys, testes, and gallbladder. The disease, which varies based on when it starts and how it presents, leads to a gradual decline in neurodevelopment and cognitive function.

What Causes Metachromatic Leukodystrophy?

Metachromatic leukodystrophy is a condition that occurs when the body doesn’t produce enough of an enzyme called arylsulfatase A. This deficiency is usually caused by genetic mutations in a specific gene (ARSA gene), located on chromosome 22q13.3-qter.

Research has found that two variants of this gene known as A and I are found in about half of the cases and lead to different ways the disease shows up in individuals.

In some instances, the condition isn’t due to a lack of arylsulfatase A but another enzyme called saposin B (SAP-B). This enzyme helps breaking down certain fats called sulfatides. This particular form of the disease is caused due to mutations in a different gene, known as the prosaposin gene (PSAP gene).

Risk Factors and Frequency for Metachromatic Leukodystrophy

Metachromatic leukodystrophy is a disease that occurs in about 1 in every 40,000 to 1 in 100,000 people within the northern European and North American populations. In the United States, it’s estimated to occur in about 1 in every 40,000 births. The disease affects all genders and races equally and can start at different ages.

• For some, it begins in infancy, specifically 6 months to 4 years old. This is known as the late infantile form.
• For others, the disease starts in childhood. People who get it at this age are divided into two groups:
• Early juvenile: This affects kids aged 4 to 6 years.
• Late juvenile: This impacts those aged 6 to 16 years.
• Finally, some people don’t experience symptoms until they’re adults, which is any age beyond 16 years. This is known as the adult form.

Signs and Symptoms of Metachromatic Leukodystrophy

Leukodystrophies are conditions that often affect children and can cause developmental delays. These conditions can affect the nervous system, and the first symptoms may involve problems with nerves outside of the brain and spinal cord, that affect movement and sensation. As the diseases progress, a child might lose motor skills they once possessed. Symptoms vary depending on the age at which the disease begins.

• Before 30 months: These young children meet early developmental milestones, but then, demonstrate a loss of motor skills, issues with coordination and speech (ataxia, dysarthria), muscles that are too tight or too loose (spasticity, hypotonia), decreased reflexes (hyporeflexia), abnormal limb posture (extensor plantar posturing), and vision deterioration (optic atrophy). Psychiatric testing can reveal these problems. Approximately half of leukodystrophies start before 30 months.
• Between 30 months and puberty: Children in this group also reach early developmental milestones before losing motor and intellectual skills. They might struggle with school, behave differently, and undergo personality changes. Additionally, they may experience ataxia, upper motor neuron signs, and nerve damage outside the brain and spinal cord (peripheral neuropathy). Some might also have seizures. Tests might reveal dementia, memory loss, lack of restraint, impulsiveness, decreased motor function, and vision impairment.
• From adolescence onwards: Leukodystrophy in teenagers and adults is primarily associated with cognitive and psychiatric issues. They may experience altered sensation (dysesthesias), mental disorders like psychosis or schizophrenia, and seizures. These conditions are often misdiagnosed as bipolar disorder or dementia. Unlike with younger patients, motor skills are not usually affected, and their cognitive test results could resemble those of the juvenile group.

Testing for Metachromatic Leukodystrophy

In simple terms, you might need to take some laboratory tests to check for a disease called Metachromatic Leukodystrophy. This disease affects an enzyme (a type of protein that facilitates chemical reactions in our body) called Arylsulfatase A. It is usually found in white blood cells or skin cells. Normal levels of this enzyme can decrease to almost undetectable levels or less than 10% of normal in patients with the disease.

However, some people, who make up about one percent of the population, naturally have low levels of Arylsulfatase A but don’t have Metachromatic Leukodystrophy. This condition is called Arylsulfatase A pseudo deficiency, which isn’t harmful and doesn’t cause any symptoms or diseases. For these people, the Arylsulfatase A levels can be between 5% to 20% of normal values. The doctor will use the following tests to tell the difference between the two:

* Measuring the levels of sulfatide (a type of fat) in your urine
* Radiolabeled sulfatide fibroblast loading, a test that studies the metabolism of sulfatide in your skin cells.
* DNA mutation analysis or next-generation sequencing. This will help identify mutations in the ARSA gene which causes Metachromatic Leukodystrophy.

Apart from laboratory tests, Imaging Studies like Brain MRI might be used. This shows images of the brain and can reveal certain patterns that might suggest Metachromatic Leukodystrophy, even though these patterns could be seen in other diseases too. This disease damages the protective sheath called myelin, which covers the nerve fibers in your brain, causing the MRI to show dark spots. However, a normal MRI doesn’t necessarily mean you don’t have Metachromatic Leukodystrophy.

Ultrasounds or CT scans of the abdomen can detect polyps (abnormal growths) on the gallbladder, which could put you at risk for gallbladder cancer.

Additional tests can include:

* Nerve conduction and ENG studies: measures how fast the nerves transmit signals
* EMG: shows a pattern where your nerve cells responsible for muscle movement and feeling are affected.
* Neurocognitive and neuropsychological testing: measures your mental abilities, like memory and attention.

There are also a few procedures that might help in diagnosing the disease.

* Lumbar Puncture: measures the protein levels in the cerebrospinal fluid. Cerebrospinal fluid surrounds your brain and spinal cord, protecting it from injury.
* Peripheral nerve biopsy: a rare procedure where a tiny piece of nerve outside the brain and spinal cord is removed for examination. It can show metachromatic lipid deposits, a marker of the disease.

Lastly, there is a screening test for newborns which is still being developed. It uses a technique called mass spectrometry to measure the molecules in a sample. However, it can’t differentiate between those with Metachromatic Leukodystrophy and pseudo deficiency.

Treatment Options for Metachromatic Leukodystrophy

At present, there isn’t a specific cure for this disease, so the main goal is to better the quality of life by dealing primarily with symptoms. This involves treatment plans designed to deal with cognitive and psychological issues, seizures, muscle stiffness and involuntary movements (dystonias), difficulty swallowing and constipation.

Here is a brief explanation of the treatments aimed at alleviating specific symptoms:

• Seizures – managed with broad-spectrum drugs called anti-epileptics, like levetiracetam, zonisamide, lacosamide, and valproic acid.
• Muscle Stiffness (Spasticity) – can be eased through the use of drugs such as baclofen, cyclobenzaprine, or botox toxin A.
• Involuntary muscle contractions (Dystonias) – botox toxin A can provide relief.
• Drooling, sudden falls due to nerve malfunction (dysautonomia) – can be controlled with anticholinergeic therapy and oral medications like midodrine or fludrocortisone.
• Pain – medication like NSAIDs (Nonsteroidal anti-inflammatory drugs), gabapentin, pregabalin, and serotonin-norepinephrine reuptake inhibitors can help.
• Digestive issues and problems with nutrition – feeding tubes can help, along with medication like famotidine or pantoprazole and laxatives like docusate, senna.
• Sleep/Mood issues – SNRIs like mirtazapine, tricyclic antidepressants (TCAs), and serotonin reuptake inhibitors (SSRIs) can help.
• Issues with mobility and performing daily tasks – physical, occupational, cognitive and gait therapy can provide assistance.

Since this disease is inherited in a recessive manner, genetic counselling can help families understand their risk. Each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being a symptom-free carrier, and a 25% chance of neither being affected nor a carrier. When both of the disease-causing genetic changes (variants) are known in a family, carrier testing and prenatal testing can be done.

New and experimental therapies include a combination of gene therapy and a procedure called hematopoietic stem cell transplantation (HSCT), where blood-forming cells are transplanted. This seems to show promise, particularly in cases caught early. Yet, while this treatment can help stabilize cognitive function, a progressive loss of motor function can still be seen. Also, transplantation may slow the disease’s progress in the late juvenile and adult-onset forms.

Further therapy options under exploration include gene therapy, enzyme replacement, and small molecule therapy. Early studies suggest these emerging treatments could provide promising results. However, more extensive clinical trials are needed before they can be declared effective or safe for general use.

What else can Metachromatic Leukodystrophy be?

Metachromatic leukodystrophy is a type of condition that needs to be differentiated from other similar conditions, such as arylsulfatase A pseudodeficiency. The latter can be distinguished using gene mutation analysis or by evaluating how fibroblasts (a type of cell) take up and accumulate a substance called radiolabeled sulfatide. When diagnosing metachromatic leukodystrophy, consideration should also be given to the following conditions:

• Krabbe diseases: This is a condition caused by deficient activity of an enzyme known as beta-galactosidase. Symptoms typically include irritability, muscle stiffness, an increased sensitivity to physical stimuli, and a halt in psychological and motor development.
• X-linked adrenoleukodystrophy: This primarily affects boys and results in adrenal insufficiency, cognitive issues (like a low IQ), behavior issues similar to ADHD, speech and writing difficulties, and deficits in vision and hearing. Features include abnormal white matter disease visible on MRI, elevated very-long-chain fatty acids (VLCFA), and a variant of the ABCD1 gene.
• Canavan disease: This condition primarily affects the Ashkenazi Jewish population and is characterized by intellectual disability, irritability, an abnormally large head (macrocephaly), swallowing difficulties, low muscle tone in early stages, spasticity and seizures in later stages, and optic atrophy. Typical findings include elevated levels of N-acetyl aspartate (NAA) in urine, abnormal white matter disease visible on MRI, and variants in the ASPA gene.
• Peroxisomal biogenesis disorders (including Zellweger disease): These conditions are caused by mutations in any of 13 different PEX genes, leading to dysfunctional peroxisomes (an organelle in cells). Symptoms can range from intellectual delay to sensorineural deafness and vision loss, among others. MRI can show abnormal brain structure, atrophy of the white matter, and enlarged ventricles with cysts. Abnormal liver enzymes and jaundice are common.
• Polyglucosan body disease: This is a condition that usually starts in adulthood and results in a progressive loss of bladder control, gait difficulties from mixed upper and lower motor neuron involvement, sensory loss mainly in the lower extremities, and some cognitive difficulties. MRI of the brain and spinal cord, and sural nerve biopsy shows clusters of polyglucosan deposition. The activity of the glycogen brancher enzyme (GBE) in skin fibroblasts is abnormal, and a mutation in GBE1 gene is typically observed.
• Fucosidosis: This very rare condition is caused by a mutation in the FUCA1 gene and is characterized by coarse facial features, recurrent infections, stiffness and muscular rigidity, bone abnormalities, angiokeratoma (small, dark spots on the skin), and organomegaly (enlarged organs).
• Childhood-onset schizophrenia: This severe form of psychosis begins at age 12 years or younger and has some neurological features similar to metachromatic leukodystrophy. It typically presents with delusions, hallucinations, disorganized speech and behavior, catatonic behavior, and negative symptoms.

What to expect with Metachromatic Leukodystrophy

Metachromatic leukodystrophy is a condition that gradually worsens over time. This disease leads to a complete loss of muscle and mental functions. The expected lifespan can heavily rely on when the individual first gets a diagnosis.

The disease has three forms, with each having different progression rates:

– Late infantile form: Unfortunately, this form of the disease often has the worst outlook. The disease progresses quickly and typically results in death within five to six years.
– Juvenile form: This form progresses more slowly and patients might live until early adulthood.
– Adult form: In this form, the disease might progress very slowly or even may hold steady and not get worse.

Possible Complications When Diagnosed with Metachromatic Leukodystrophy

Treatments are designed to improve the quality of life, and everyday functional activities can help in various areas, such as moving around, thinking, communicating, and eating. Measures should be taken to prevent falls at home. The disease often has several complications, including:

• Loss of mental functions (dementia)
• Loss of vision (for example, damage to the optic nerve)
• Not getting enough nutrients (malnutrition)
• Pneumonia caused by food or liquid entering the lungs (aspiration pneumonia)
• Death (typically 5 to 6 years into the late infantile form of the disease)

Preventing Metachromatic Leukodystrophy

As the illness gets worse, patients often find doing everyday tasks like eating, bathing, or walking to be more difficult. It’s important for patients and their families to be properly informed about how the illness progresses and what the long-term outcome might be. The illness can also come with other related health issues, like acid reflux, constipation, tooth decay, and vision problems, among other things.

There are various ways to manage the illness and its symptoms, like medications, physical therapies, and getting support from family. These can all help prevent the patient’s condition from getting worse and improve their quality of life.

Metachromatic leukodystrophy is a genetic disorder that’s passed down in families. If there’s a history of the condition in the family, parents should be counseled about how the condition is inherited. This can help them understand the risks and make informed decisions about future family planning.