Clinical description:

Metachromatic leukodystrophy (MLD) is a neurodegenerative lipid storage disorder that results in progressive demyelination of the central nervous system and peripheral nerves. The majority of cases are caused by dysfunction of the lysosomal enzyme arylsulfatase A. Arylsulfatase A catabolizes sulfatides, which are the most abundant sphingolipid in myelin and function to maintain myelin. A deficiency of arylsulfatase A results in chronic progressive accumulation of sphingolipids within the lysosome, leading to myelin breakdown (leukodystrophy). A very small number of individuals with MLD have a deficiency of the activator protein saposin B, instead of arylsulfatase A. Saposins are cofactors for the lysosomal enzymes involved in degrading sphingolipids so defects in saposins can also lead to sulfatide accumulation and cause demyelination. Both forms present with similar clinical and neuroradiologic features, but individuals with PSAP variants have normal arylsulfatase A activity and abnormal urine sulfatide excretion. Pathogenic variants in SUMF1 lead to multiple sulfatase deficiency. Since arylsulfatase A is a sulfatase, individuals with multiple sulfatase deficiency have the combined features of MLD as well as mucopolysaccharidosis II, IIIA, IIID, IVA and VI, X-linked ichthyosis, and the X-linked recessive form of chondrodysplasia punctata.

Three primary clinical presentations, based on the age of symptom onset, are generally recognized: late infantile, juvenile, and adult.

The late-infantile presentation, representing 50%–60% of MLD cases, is the most commonly observed. It is due to a complete lack of arylsulfatase A activity and leads to the most severe form of the disease. The late-infantile form typically manifests between one and two years of age with a loss of motor milestones—typically a gait disorder after independent walking has already been achieved. Over the next several years, patients experience a rapid deterioration with muscle wasting, rigidity, strabismus, progressive vision loss, possible seizures, swallowing difficulties, and dementia. Death usually occurs by ten years of age.

The juvenile form represents 20%–30% of cases and is frequently subdivided into early and late-juvenile forms. The early juvenile form manifests between four and six years of age with gait and postural abnormalities, behavioral and emotional problems, vision loss, seizures, and progressive spastic tetraparesis. The late-juvenile form appears from six to sixteen years of age with an insidious progression. Impaired school performance, behavioral problems, and language regression are initially evident, followed by motor difficulties progressing to spastic tetraparesis. Premature death usually occurs between 10 and 20 years of age.

The adult form represents 15%–20% of cases and generally presents after 16 years of age with two main forms, motor and psychiatric, though affected individuals may express both categories of symptoms. The motor form presents with neurologic symptoms such as weakness, incontinence, and loss of coordination progressing to spasticity. Individuals are often misdiagnosed with multiple sclerosis or other neurodegenerative diseases. The psychiatric form presents with behavioral abnormalities such as emotional instability, unusual social interactions, poor decision making, and a progressive mental deterioration. Many patients are often misdiagnosed with schizophrenia or depression. Death usually occurs six to fourteen years after symptom onset and is most commonly due to pneumonia or other infection.

Clinical sensitivity:

The vast majority of cases of MLD are due to biallelic variants in ARSA. A very small percentage are due to pathogenic variants in PSAP, which encodes the Saposin-B (Sap-B) sphingolipid activator protein or Sulfatase-modifying factor-1 (SUMF1). Variants in SUMF1 cause multiple sulfatase deficiency.