Titel: Two sisters with a novel homozygous pathogenic variant in PSAP causing metachromatic leukodystrophy
ID: P-ClinG-060
Art: Postertalk
Redezeit: 2 min
Session: Poster Session
ClinG 2

Referent: Britta Hanker (Lübeck/DE)

Abstract - Text


Metachromatic leukodystrophy (MLD) is a neurodegenerative disorder with progressive demyelination and dysfunction of the central and peripheral nervous system. Most of the cases are caused by variants in the ARSA gene. Less frequently pathogenic variants in the PSAP gene, which affect the function of saposin B, are known to be responsible for MLD. PSAP encodes prosaposin which is cleaved to four glycoproteins which play a role  for the function of specific lysosomal hydrolases.


We report on two girls of a consanguineous family with three years and 11 months of age. The older sister was born at term. The pregnancy was uneventful. Body measurements were in normal range. The first months of life were normal. At the age of 18 months regression was noticed, especially gait disturbances. A brain MRI showed signs of leukodystrophy. The younger girl was born at term. Body measurements were within the normal range. She showed normal development to first presentation.


After normal karyotyping and array-CGH in the older girl exome sequencing was performed showing a homozygous in frame deletion in PSAP. The two sisters showing the same homozygous variant c.679_681delAAG; p.(Lys227del). The parents were both heterozygous carriers for this variant.

Here we report on two sisters with this pathogenic variant in PSAP, the first time described in homozygous condition. The younger sister is still in a pre-symptomatic stage of the disease. Our findings expand the list of patients with MLD due to pathogenic variants in PSAP.

A review of the literature showed only 12 pathogenic variants in PSAP in saposin B. Most of the patients with pathogenic variants show regression of acquired skills. Most of them show gait disturbances, hypotonia, abnormal movements, dysarthria, speech regression and loss of fine motor skills. Ataxia is mentioned too. In contrast to MLD caused by pathogenic variants in ARSA a genetic therapeutic approach is not available.