metachromatic leukodystrophy

Reduced leukocyte arylsulfatase A activity

MLD is caused by too little of the enzyme arylsulfatase A (ARSA). Measuring low ARSA activity in white blood cells is a central part of diagnosing the disease, because without the enzyme a fatty substance called sulfatide builds up and destroys the protective myelin around nerves.

Gait disturbance

Trouble with walking is one of the most common early signs of metachromatic leukodystrophy in the late-infantile form, often appearing along with delays in motor development.

Progressive peripheral neuropathy

Metachromatic leukodystrophy can damage the nerves outside the brain and spinal cord, affecting both feeling and movement. In one group, nerve-conduction testing showed this kind of nerve damage in most patients.

Abnormal cerebral white matter morphology

Brain MRI characteristically shows symmetric abnormal signal in the cerebral white matter, reflecting the progressive loss of myelin. It is a central diagnostic clue.

Peripheral demyelination

Metachromatic leukodystrophy damages the protective coating (myelin) around the nerves outside the brain and spinal cord. In one study, nerve testing showed this damage in every patient, affecting both sensation and movement.

Hyporeflexia

In metachromatic leukodystrophy, reflexes can be reduced or absent. In one group of patients, many had weak or missing reflexes even when muscle stiffness was also present.

Ataxia

Unsteady, uncoordinated movement and walking (ataxia) is a common neurological sign of metachromatic leukodystrophy as the disease affects the brain and nerves.

Decreased nerve conduction velocity

In metachromatic leukodystrophy, the signals that travel along the nerves can slow down. Nerve testing has shown nerve-signal speed well below what is typical for a child of the same age.

Seizure

Seizures can occur in metachromatic leukodystrophy. In one group of children with the late-infantile form, seizures were reported alongside loss of developmental milestones and walking difficulties.

Loss of speech

Loss of previously acquired speech is part of the progressive decline in metachromatic leukodystrophy, often appearing alongside other regression.

Mental deterioration

In the juvenile form of metachromatic leukodystrophy, a decline in thinking and learning skills is one of the most common reasons families seek help, often together with trouble walking.

Autosomal recessive inheritance

Metachromatic leukodystrophy is inherited in an autosomal recessive pattern: a child is affected only when both inherited copies of ARSA carry disease-causing variants, while carriers with a single variant are typically unaffected.

Hypotonia

The late-infantile form of metachromatic leukodystrophy is the most severe. It can begin with low muscle tone (floppiness), weakness, and difficulty walking, and then progresses to decline in both mental and physical abilities.

Spastic tetraplegia

As MLD progresses, the loss of myelin in the brain and spinal cord leads to stiff, weak limbs and eventually spastic paralysis of all four limbs (spastic quadriparesis), leaving the person unable to move or sit unsupported.

Gallbladder dysfunction

Beyond the nervous system, metachromatic leukodystrophy can affect the gallbladder. One study found that gallbladder problems are common in people with the condition.

Developmental regression

In the late-infantile form of metachromatic leukodystrophy, children often lose or fall behind on motor skills they were developing, alongside trouble with walking, and these are commonly among the first signs.

Peripheral neuropathy

Beyond the brain, the peripheral nerves are affected too, producing a polyneuropathy with weakness and altered sensation; nerve conduction is typically slowed.

Psychosis

Because sulfatide builds up in the brain, MLD produces neurological and psychiatric symptoms. In the adult-onset form these can include psychosis, with disordered thinking and perceptions, sometimes before the movement problems appear.

Personality changes

In adult-onset metachromatic leukodystrophy, changes in behavior can be among the first signs, with problems affecting the nervous system developing in later stages.

Metachromatic leukodystrophy

Diagnosed using: arylsulfatase A enzyme activity in leukocytes.

Metachromatic leukodystrophy

Diagnosed using: urinary sulfatide measurement.

Metachromatic leukodystrophy

Diagnosed using: ARSA gene molecular analysis.

Metachromatic leukodystrophy

Diagnosed using: two-tiered newborn screening (dried-blood-spot sulfatides then ARSA activity).

atidarsagene autotemcel

Atidarsagene autotemcel (Libmeldy) is an ex vivo gene therapy in which a patient's own blood stem cells are modified to carry a working ARSA gene and returned to the body; it is used for pre-symptomatic or early-symptomatic early-onset disease and works best when given before symptoms appear.

Used to help with: Metachromatic leukodystrophy.

hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation is a treatment option for the juvenile and adult forms of metachromatic leukodystrophy, used in people who have no symptoms yet or only early symptoms.

Used to help with: Metachromatic leukodystrophy.

atidarsagene autotemcel (Libmeldy) gene therapy

In the late-infantile form of metachromatic leukodystrophy, the nerve damage outside the brain and spinal cord was significantly improved in children treated with the gene therapy arsa-cel compared with untreated children of similar age.

Used to help with: Metachromatic leukodystrophy.

ARSA

In metachromatic leukodystrophy, the specific change in the ARSA gene can shape how the condition shows up. Certain ARSA variants are linked to later (late-juvenile or adult) onset with a decline in thinking but relatively preserved movement.

Described as modulating: Metachromatic leukodystrophy.