Genetics

Most of the lysosomal storage diseases have an autosomal recessive pattern of inheritance. Thus, inheritance of a mutant allele from the mother as well as father will lead to disease. In case of an identified patient, brothers and sisters have a baseline risk of 25% for also being affected.

However, three of the LSDs are X-linked. These include Fabry disease, Hunter disease (MPS II), and Danon disease. Whereas MPS II is considered X-linked recessive, and thus typically only affects male hemizygotes, Fabry and Danon often do cause clinical disease in female heterozygotes.. In general, female patients have a less severe phenotype (in terms of organ involvement and time course) than male patients, but can still suffer from severe morbidity and early mortality.

In X-linked diseases, the disease typically is familial in the sense that it affects multiple generations. The specific pattern of transmission can be of help in making or excluding the diagnosis in an index patient as well as in the timely identification of affected relatives in case of a known index patient.

father to son transmission excludes X-linked disease

index male will transmit disease to all daughters

index female patient might transmit disease to half of her children (regardless of sex)

index female can have inherited disease from father as well as mother

index male patient can only have inherited disease from mother

de novo mutations can occur

two affected siblings make de novo extremely unlikely

DNA analysis is important in all LSDs, regardless of pattern of inheritance. Often this is done after a diagnosis has been made, but sometimes it is the DNA analysis that will allow making or excluding the diagnosis. Post-diagnostic DNA analysis is important to study or use genotype-phenotype correlations, or to allow testing of siblings (in recessive disorders) and further relatives (in X-linked diseases).