Clinical, pathological, imaging, and genetic findings in a family with multiple allelic mutations of metachromatic leukodystrophy (MLD) are reported from McGill University, Montreal, and McMaster University, Hamilton, Canada. The propositus, a 23-year-old man, presented at age 18 with a 3-year history of clumsiness and stiffness of gait. Two maternal uncles, ages 48 and 56, were also neurologically impaired. Two siblings, a brother aged 30 and sister aged 25, the mother, and father were clinically normal and had normal electrical studies and MRIs, but their arylsulfatase activity was reduced. Allele-specific amplification confirmed the pseudodeficiency (PD) allele, with no clinical dysfunction, in the mother and her 2 unaffected children. The mother was a PD/MLD compound heterozygote since she was an obligate MLD carrier. The father was a normal (N/MLD) heterozygote. The family was unique in the unusual occurrence of MLD in consecutive generations in the absence of consanguinity. [1]

COMMENT. Three phenotypes of MLD are recognized based on age of onset: late infantile (0-2 years), juvenile (3-16 years), and adult. The time of onset is determined by the amount of residual arylsulfatase A activity, those retaining some activity having a delayed onset of the disease. A variety of allelic mutations has been identified, including a pseudodeficiency allele with no clinical dysfunction. Cloning of the enzyme gene and genotype identification at the molecular level for the PD and MLD mutations allow appropriate genetic counselling for the families. With these advances in diagnosis, the authors conclude that unnecessary testing of spouses and prenatal screening of pregnancies can be avoided.