Metachromatic Leukodystrophy

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disorder, most often caused by deficiency of arylsulfatase A (ARSA, 22q13.33) and rarely by saposin B (PSAP) deficiency, resulting in accumulation of sulfatides in oligodendrocytes, Schwann cells and other tissues, with central and peripheral demyelination. Incidence is about 1 in 40,000 to 160,000.

Forms by age at onset: late infantile (before 30 months; about 50 to 60%), juvenile (3 to 16 years; early juvenile 30 months to 6 years; late juvenile 7 to 16 years) and adult (over 16 years). Genotype predicts phenotype (null alleles 0 and residual activity alleles R).

• Late infantile: after normal early development, gait disturbance, hypotonia and loss of walking, progressive spasticity, ataxia, speech loss, peripheral neuropathy (diminished reflexes), optic atrophy, seizures, and progressive loss of motor and cognitive function, leading to a vegetative state and death within 5 to 6 years of onset
• Juvenile: behavioural and school problems, cognitive decline, gait difficulty, spasticity and ataxia, seizures, and slower progression
• Adult: psychiatric presentation (psychosis, personality change, dementia), with later motor involvement, and survival over many years
• Gallbladder papillomatosis and cholecystitis, and hearing loss
• MRI shows symmetrical periventricular white matter changes with a tigroid (leopard) pattern sparing the subcortical U fibres early; MRI severity is scored (Eichler score)

1. Arylsulfatase A activity in leucocytes (low or absent; beware pseudodeficiency alleles that give low enzyme activity in about 1 to 2% of people with no disease).
2. Urinary sulfatides (elevated), and ARSA and PSAP genotyping (to differentiate pseudodeficiency and to predict phenotype).
3. MRI brain, nerve conduction studies (demyelinating neuropathy), CSF protein, and gallbladder ultrasound.
4. Newborn screening in some programmes (sulfatide and enzyme measurement).

• Atidarsagene autotemcel (Libmeldy/Lenmeldy; autologous haematopoietic stem cell gene therapy with lentiviral vector encoding ARSA): approved for pre-symptomatic late infantile and early juvenile MLD, and early symptomatic early juvenile with preserved walking; prevents or markedly slows disease progression, but requires myeloablative conditioning (busulfan) with associated risks (infertility, infections, veno occlusive disease); treatment must be carried out before significant motor decline.
• Haematopoietic stem cell transplantation (allogeneic): considered for pre-symptomatic or mildly affected juvenile and adult patients; benefits are modest in late infantile disease.
• Symptomatic management: antiepileptics, antispasticity therapy (baclofen, botulinum toxin), nutrition (gastrostomy), pain and irritability control, physiotherapy, psychiatric treatment for adult onset disease, and palliative care.
• Experimental: enzyme replacement therapy (intrathecal and intravenous recombinant ARSA, such as intrathecal ARSA), and AAV gene therapy.
• Genetic counselling: 25% recurrence risk, carrier testing, and prenatal diagnosis; interpret pseudodeficiency carefully.