Metachromatic Leukodystrophy (MLD): Enzyme, Signs & Lenmeldy

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency: sulfatides (cerebroside sulfate) build up in oligodendrocytes and Schwann cells, so myelin breaks down in both the brain and the peripheral nerves. The classic patient is a toddler who loses motor milestones with hypotonia, frequent falls and depressed reflexes; juvenile and adult forms often begin with school, behavior or psychiatric problems. Diagnosis needs low leukocyte ARSA activity plus raised urinary sulfatides or two disease-causing ARSA variants, because a common pseudodeficiency allele also lowers enzyme activity. Treatment is a race against symptoms: the gene therapy atidarsagene autotemcel (Lenmeldy, FDA 2024) is for presymptomatic late-infantile and presymptomatic or early-symptomatic early-juvenile MLD, and early-onset MLD joined the US Recommended Uniform Screening Panel (RUSP) for newborns in December 2025.

MLD at a glance

Pathophysiology: why sulfatides strip myelin

• Sulfatides are a normal myelin lipid, and ARSA breaks them down inside lysosomes. Without ARSA, sulfatides accumulate to toxic levels in the cells that make myelin, and the white matter is progressively destroyed.
• The result is progressive demyelination in both the CNS (leukodystrophy) and the PNS (neuropathy with slowed nerve conduction). That double hit is what sets MLD apart on exams.
• Saposin B deficiency (PSAP variants) causes an MLD-like disease with normal ARSA activity, so a normal enzyme result does not end the workup when the picture is classic.
• Multiple sulfatase deficiency (SUMF1) looks like MLD plus ichthyosis and mucopolysaccharidosis-like features, with low activity of ARSA and most other sulfatases.
• "Metachromatic" names the staining shift: on nerve or brain biopsy, sulfatide-rich deposits turn golden brown with acidified cresyl violet (the Hirsch-Peiffer stain) instead of the dye's usual color.

Clinical forms by age of onset

Treatment rules split the juvenile group: early juvenile means onset after 30 months but before 7 years. Late infantile plus early juvenile disease is early-onset MLD, the group that newborn screening and gene therapy target.

Diagnosis and the pseudodeficiency trap

1. Leukocyte ARSA activity below 10% of normal controls supports MLD.
2. The trap: ARSA pseudodeficiency. A common, harmless allele lowers ARSA activity to about 5-20% of normal in healthy people. Its key variant (p.Asn352Ser) appears in every population studied, and enzyme testing alone cannot reliably separate pseudodeficiency from disease.
3. Confirm with substrate and genes. Urinary sulfatides are raised in all forms of MLD, usually more than 10 times normal; a person with one pseudodeficiency allele and one MLD allele may excrete somewhat more sulfatide than normal, but not at MLD levels. ARSA sequencing should find two pathogenic variants (deletion/duplication testing if one or none is found).
4. MRI brain: symmetric periventricular white matter T2 hyperintensity, often with a tigroid (radial stripe) pattern; subcortical U-fibers and cerebellar white matter are spared early, and atrophy follows. Early scans can be normal.
5. Nerve conduction studies: slowed velocities from demyelinating neuropathy, common in late-infantile disease. A raised CSF protein can support the diagnosis.
6. Newborn screen: raised sulfatides (C16:0 and C16:1-OH) in the dried blood spot plus low ARSA activity, with or without ARSA variants, followed by confirmatory testing.

Treatment: the window closes fast

What the Lenmeldy label shows: 39 children were treated in clinical trials and an expanded-access program, 20 of them presymptomatic late infantile. In that group, 100% remained free of severe motor impairment or death at age 5, compared with 0% of untreated late-infantile children in the natural-history group; every treated child followed to age 6 was alive, while 42% of the natural-history children had died by then. Label warnings include thrombosis and thromboembolic events, encephalitis, serious infection, veno-occlusive disease, delayed platelet engraftment, neutrophil engraftment failure, insertional oncogenesis and hypersensitivity reactions.

Both disease-modifying options work best before symptoms, because in fast forms the disease outruns the time donor or corrected cells need to engraft.

Newborn screening: what changed in 2025

• RUSP: in December 2025, the HHS Secretary added early-onset MLD, along with Duchenne muscular dystrophy, to the Recommended Uniform Screening Panel as a core condition. Each state still decides whether to adopt it.
• States: New York became the first state to screen every newborn for MLD, starting on 12 September 2025 with a one-year pilot (planned to run through September 2026 and cover about 200,000 babies).
• Why it matters: babies with MLD look normal at birth, and HHS notes that most children with MLD are diagnosed at about 4-5 years, after major functional decline; New York's health department notes that most children diagnosed later will not be eligible for Lenmeldy. HRSA estimates that more than 30 US babies are born with MLD each year.
• Other leukodystrophies on the panel: infantile Krabbe disease and X-linked adrenoleukodystrophy (X-ALD) are also RUSP core conditions.

How USMLE tests it: MLD vs look-alikes

• Arylsulfatase A vs B: A is MLD, a leukodystrophy; B is MPS VI, a mucopolysaccharidosis with normal intellect. One letter, two disease families. The classic MPS pair is in Hurler vs Hunter syndrome.
• Peripheral neuropathy is not unique to MLD: Krabbe has it too. Separate them by enzyme, stored lipid, age (Krabbe usually starts before 1 year with extreme irritability and unexplained fevers) and pathology (globoid cells vs metachromatic deposits). Full details: Krabbe disease.
• A cherry-red spot points to Tay-Sachs or Niemann-Pick, not MLD.
• Adult MLD can pass for primary psychiatric illness: psychosis or personality change plus symmetric, confluent white matter disease is the adult MLD stem.
• Every enzyme-substrate pair is in the sphingolipidoses table.

Practice question

A 22-month-old girl has become clumsy over the past 6 months. She walked at 13 months, but she now falls often, walks on her toes and needs a hand to stand, and her speech has become slurred. She is afebrile and alert, with no hepatosplenomegaly, and funduscopy is normal. Examination shows hypotonia, distal weakness and absent ankle reflexes. Nerve conduction velocities are markedly slowed. Brain MRI shows symmetric periventricular white matter T2 hyperintensity with a radial-stripe pattern that spares the subcortical U-fibers. Deficiency of which enzyme best explains these findings?

A. Galactocerebrosidase B. Arylsulfatase A C. Arylsulfatase B D. Hexosaminidase A E. Sphingomyelinase

Answer: B. Arylsulfatase A. A late-infantile child with motor regression, hypotonia, lost reflexes, slow nerve conduction and a symmetric tigroid leukodystrophy has demyelination of both the CNS and PNS: MLD. Confirm with leukocyte ARSA activity plus urinary sulfatides and ARSA sequencing, so pseudodeficiency is not mistaken for disease.

• A. Galactocerebrosidase (Krabbe): also demyelinates brain and nerves, but infantile Krabbe usually starts before 1 year with extreme irritability, unexplained fevers and stiffness, and its pathology shows globoid cells.
• C. Arylsulfatase B (MPS VI): a mucopolysaccharidosis with skeletal dysplasia, corneal clouding and normal intelligence, not a leukodystrophy.
• D. Hexosaminidase A (Tay-Sachs): neurodegeneration with a cherry-red macula; her fundi are normal.
• E. Sphingomyelinase (Niemann-Pick A/B): hepatosplenomegaly and foam cells, with a cherry-red macula in type A; she has neither.

Follow-up: her 5-month-old brother carries the same two ARSA variants and has no symptoms. He fits presymptomatic late-infantile MLD, the core Lenmeldy indication; allogeneic HSCT is not recommended for late-infantile disease.

Key takeaways

• MLD = arylsulfatase A deficiency → sulfatide storage → CNS + PNS demyelination, autosomal recessive.
• Late infantile (before 30 months, 50-60%): hypotonia, falls, toe walking and lost reflexes, then spasticity and seizures; juvenile and adult forms start with school, behavior or psychiatric change.
• Pseudodeficiency trap: low ARSA activity alone is not diagnostic; confirm with urinary sulfatides and ARSA sequencing.
• MRI: symmetric periventricular tigroid leukodystrophy that spares U-fibers early; slow nerve conduction marks the neuropathy.
• Lenmeldy (one-time autologous lentiviral gene therapy, FDA 2024) is for presymptomatic late-infantile and presymptomatic or early-symptomatic early-juvenile MLD; allogeneic HSCT is for pre- or early-symptomatic juvenile and adult disease, not late infantile.
• Early-onset MLD has been on the RUSP since December 2025; states choose whether to screen, and New York started in September 2025.
• Arylsulfatase A = MLD; arylsulfatase B = MPS VI.

Sources

• Arylsulfatase A Deficiency — GeneReviews, NCBI Bookshelf (2024)
• Metachromatic leukodystrophy — MedlinePlus Genetics (2021)
• Metachromatic Leukodystrophy — StatPearls, NCBI Bookshelf (2023)
• LENMELDY (atidarsagene autotemcel) prescribing information — DailyMed (2026)
• Secretary Kennedy Adds Duchenne Muscular Dystrophy, Metachromatic Leukodystrophy to Newborn Screenings — HHS (2025)
• Recommended Uniform Screening Panel: Core Conditions — HRSA (2025)
• Metachromatic Leukodystrophy (MLD) — HRSA Newborn Screening Information Center (2026)
• New York Becomes First in the Nation to Implement Universal Newborn Screening for MLD — New York State Department of Health (2025)
• Krabbe disease — MedlinePlus Genetics (2018)
• X-linked adrenoleukodystrophy — MedlinePlus Genetics (2022)
• Niemann-Pick disease — MedlinePlus Genetics (2015)
• Mucopolysaccharidosis type VI — MedlinePlus Genetics (2021)