Metachromatic Leukodystrophy

Metachromatic leukodystrophy is a rare inherited disorder that progressively destroys the protective covering around nerve cells in the brain and nervous system. This buildup of fatty substances leads to a gradual loss of physical abilities, mental function, and eventually results in severe disability.

Table of contents

• What is metachromatic leukodystrophy?
• Causes and inheritance
• Different forms of the disease
• Signs and symptoms
• How the disease is diagnosed
• Treatment options
• How common is the disease

What is metachromatic leukodystrophy?

Metachromatic leukodystrophy (MLD) is a rare hereditary disorder that causes fatty substances called sulfatides to build up in cells, particularly in the brain, spinal cord and peripheral nerves^[1]. These fatty materials accumulate because the body lacks enough of a crucial enzyme that normally breaks them down^[2].

The disease gets its name from the way affected cells appear under a microscope. When stained for examination, the accumulated sulfatides pick up color differently than surrounding cellular material—a property called metachromatic^[4]. The term “leukodystrophy” refers to the progressive destruction of white matter in the brain, where “leuko” means white and “dystrophy” means wasting away^[2].

MLD belongs to a group of conditions called lysosomal storage diseases. Lysosomes are cellular structures that work as recycling centers within cells. When they don’t function properly due to missing or insufficient enzymes, unprocessed molecules accumulate and become toxic to cells^[3].

The buildup of sulfatides particularly damages myelin—the protective covering around nerve fibers that allows messages to travel quickly between nerve cells. This damage affects both the central nervous system (brain and spinal cord) and the peripheral nervous system (nerves connecting the brain and spinal cord to muscles and sensory cells)^[4]. Without healthy myelin, messages from the brain travel slowly or stop altogether, leading to serious nerve problems^[6].

Causes and inheritance

Most individuals with metachromatic leukodystrophy have mutations in the ARSA gene, located on chromosome 22. This gene provides instructions for making an enzyme called arylsulfatase A, which is responsible for breaking down sulfatides^[4]. Two specific gene variants, called A and I alleles, account for approximately 50 percent of cases^[3].

In rare cases, MLD is caused by deficiency of a different protein called saposin B (also known as sphingolipid activator protein SAP-B). This protein helps arylsulfatase A work properly to break down sulfatides. This form results from mutations in the PSAP gene^[3]. Although the two genes are different, the symptoms and outcome are the same^[6].

MLD follows an autosomal recessive pattern of inheritance. This means that both parents must carry a copy of the faulty gene for their child to develop the disorder^[5]. Parents who are carriers are healthy themselves because they have one normal gene that can overcome the faulty one^[5].

When two carriers have a child, each pregnancy carries a 25% chance that the child will be affected with MLD, a 50% chance the child will be a carrier (but not affected), and a 25% chance the child will have two normal genes^[5].

Different forms of the disease

There are three distinct forms of metachromatic leukodystrophy, classified based on when symptoms first appear. Each form has different characteristics and rates of progression^[2].

Late infantile MLD is the most common form, affecting about 50 to 60 percent of all individuals with this disorder^[4]. Symptoms usually appear in the second year of life, typically between 12 and 20 months of age^[2]. Affected children initially develop normally, then begin having difficulty walking. As the disease progresses, they lose speech they have developed, become weak, and experience muscle stiffness. Most children with this form do not survive past childhood, typically dying by age 5^[2].

Juvenile MLD affects approximately 20 to 30 percent of people with the condition. This form begins between the ages of 3 and 10, though some experts distinguish between early-juvenile (ages 3-7) and late-juvenile forms^[8]. The first signs may be behavioral problems and increasing difficulty with schoolwork, representing intellectual decline^[4]. Affected children may also develop behavioral difficulties, personality changes, seizures, and lack of control over muscle movement^[2]. Progression is slower than in the late infantile form, and affected individuals may survive for about 10 to 20 years after diagnosis^[2].

Adult MLD affects approximately 15 to 20 percent of individuals with the disorder. This form typically begins after age 16, often with onset in the fourth or fifth decade of life^[8]. Behavioral problems such as alcohol or substance use disorder, or difficulties at school or work are often the first symptoms to appear^[4]. Adult MLD mainly causes psychiatric changes with minor or no motor symptoms^[2]. People with this form may survive for 20 to 30 years after diagnosis, with periods of relative stability alternating with periods of more rapid decline^[4].

Signs and symptoms

Damage to the protective myelin covering around nerves results in progressive worsening of brain and nervous system functions. All forms of MLD lead to a decline in mental and motor functions, though the specific symptoms vary based on the form of the disease^[1].

In babies and young children with late infantile MLD, early symptoms include difficulty walking, which eventually leads to an inability to walk. Children develop weak muscle tone (called hypotonia), developmental delays, and difficulty speaking (called dysarthria)^[2]. They experience progressive loss of vision that leads to blindness and difficulty swallowing (called dysphagia)^[2]. As the disease worsens, muscle tone generally first decreases, then increases to the point of rigidity^[4].

Common symptoms across all forms include loss of the ability to detect sensations such as touch, pain, heat and sound, as well as loss of intellectual, thinking and memory skills^[1]. Affected individuals lose motor skills such as walking, moving, speaking and swallowing, and develop stiff, rigid muscles with poor muscle function and paralysis^[1].

Additional symptoms include loss of bladder and bowel control, seizures, emotional and behavioral problems including unstable emotions, and damage to nerves outside the brain and spinal cord (called peripheral neuropathy)^[1]. Eventually, affected individuals lose awareness of their surroundings and become unresponsive^[4].

While neurological problems are the primary feature, effects of sulfatide accumulation on other organs have been reported, most often involving the gallbladder^[4].

How the disease is diagnosed

Doctors perform a physical examination, including a neurological exam, and review symptoms and medical history to check for signs of metachromatic leukodystrophy^[9]. Several tests help diagnose the disorder and determine its severity.

Blood tests look for deficiency of the arylsulfatase A enzyme that causes metachromatic leukodystrophy. These tests show an absence or reduced levels of the enzyme^[5].

Urine tests can check for elevated levels of sulfatides, the fatty substances that accumulate in the disease^[5][9].

Genetic tests identify mutations in the genes associated with metachromatic leukodystrophy. Doctors may also recommend testing family members, particularly women who are pregnant (prenatal testing), for mutations in the gene^[9].

An MRI scan (magnetic resonance imaging) uses powerful magnets and radio waves to produce detailed pictures of the brain. These images can identify a characteristic striped pattern (called tigroid pattern) of abnormal white matter in the brain^[9].

A nerve conduction study measures electrical nerve impulses and function in muscles and nerves by passing a small current through electrodes on the skin. This test looks for nerve damage (peripheral neuropathy), which is common in people with metachromatic leukodystrophy^[9].

Doctors may also assess psychological and thinking abilities and evaluate behavior through psychological and cognitive tests. These tests help determine how the condition affects brain function. Psychiatric and behavioral problems may be the first signs in juvenile and adult forms of metachromatic leukodystrophy^[9].

Treatment options

There is no cure for metachromatic leukodystrophy yet. Treatment focuses on managing symptoms and improving quality of life^[1]. However, several treatment approaches show promise, and early identification and treatment may help manage some signs and symptoms and delay progression of the disorder^[1].

Supportive care plays a big role in managing MLD and includes a wide range of treatments and services. Important elements include medications for behavioral disturbances, feeding difficulties through tube feeding if needed, treatment for muscle stiffness including intrathecal Baclofen, anti-epileptic drugs for seizures, and social and psychological support^[13][10]. Physical therapy and occupational therapy can help improve muscle strength, flexibility, and mobility^[2].

Hematopoietic stem cell transplantation (HSCT), also called bone marrow transplant, is currently the standard treatment for certain patients with MLD. After conditioning treatment, the patient receives a transfusion with stem cells from bone marrow, peripheral blood, or umbilical cord blood of a healthy donor^[13]. This treatment provides clinical and survival benefits for pre-symptomatic and early-symptomatic patients with juvenile and adult MLD^[13]. However, the replacement of deficient cells in the central nervous system is relatively slow, with a delay estimated at 12-24 months until the disease stabilizes^[13]. This makes HSCT unsuitable for patients with rapid disease progression, including those with late-infantile MLD^[13].

Gene therapy is an approved treatment in Europe that shows good outcomes for pre-symptomatic and early-symptomatic patients with late-infantile MLD. In this treatment, the patient’s own stem cells are modified with a healthy copy of the ARSA gene using a virus-based delivery system. In December 2020, a gene therapy product called Libmeldy received marketing authorization from the European Medicines Agency^[13]. Clinical trials showed robust evidence of safe, stable gene expression and improved clinical outcomes in both late-infantile and juvenile MLD patients younger than age 7^[13]. In 2024, the FDA approved LENMELDY (atidarsagene autotemcel) as a one-time gene therapy^[7].

Intrathecal enzyme replacement therapy is being investigated in clinical trials. This approach involves administering recombinant human arylsulfatase A directly into the fluid surrounding the brain and spinal cord. Early results from phase 1/2 trials showed that this treatment is safe in the short-term, but treatment effects still need to be demonstrated^[13].

Other therapies being researched include substrate reduction therapy, which aims to reduce the production of sulfatides rather than increasing the enzyme that breaks them down^[14].

How common is the disease

Metachromatic leukodystrophy is rare. Researchers estimate that it affects 1 in every 40,000 to 160,000 people worldwide^[4]. The prevalence ranges from 1 in 40,000 to 1 in 100,000 in northern European and North American populations^[3].

MLD may be more common in certain isolated populations. For example, the Navajo have a higher prevalence rate of 1 in every 2,500 people^[2]. Among a small group of Jews who immigrated to Israel from southern Arabia (Habbanites), the condition occurs in 1 in 75 individuals. Among Arab groups in Israel, the rate is approximately 1 in 8,000^[4].