Adult onset leukodystrophy

Gene: TPP2

Comment on list classification: Promoting from grey to amber. 2 cases (4 individuals) with homozygous variants in this gene reported with an MS-like phenotype, but some doubt over the pathogenicity of the variant in 1 case.

Created: 29 Sep 2022, 3:08 p.m. | Last Modified: 29 Sep 2022, 3:08 p.m.

Panel Version: 1.44

Associated with Immunodeficiency 78 with autoimmunity and developmental delay, #619220 in OMIM.

2 cases reported of homozygous missense variants in TPP2 and a MS-type phenotype. However, 1 of the variants is also found in some MS patients in the heterozygous state.

PMID: 33586135 - Atallah et al 2021- (not PMID: 25414442) summarises 14 patients with TPP2 pathogenic variants reported in their study and other publications. They report that 'the adult form, described in four patients, manifests as a chronic non-infectious brain inflammation with demyelinating brain disease and calcifications somewhat similar to multiple sclerosis.'. These 4 patients are reported in PMID: 30533531 (Reinthaler et al 2018) who describe a Syrian family with milder symptoms of sterile brain inflammation mimicking MS and no developmental delay. A missense variant, c.82T>G, p.Cys28Gly, in TPP2 was identified in all 3 affected siblings of the family. A Jordian patient with MS was also identified to have a homozygous missense variant (c.2027C>T, p.Thr676Ile) in TPP2. This variant also occurs in heterozygous form in other MS cases and in 6 ExAC control individuals so the authors acknowledge that it may not be pathogenic. Age of diagnosis for these patients was 35 year plus.

Other cases with variants in this gene are reported in PMIDS: 25414442; 25525876; 30533531, however these present in childhood with a recurrent respiratory infections, autoimmune cytopenias, developmental delay and progressive combined immunodeficiency.

Created: 29 Sep 2022, 3:06 p.m. | Last Modified: 29 Sep 2022, 3:12 p.m.

Panel Version: 1.46

Publications

• 33586135
• 25414442
• 25525876
• 30533531

Green List (high evidence)

14 individuals with "TRIANGLE" (TPPII-related immunodeficiency,
autoimmunity, and neurodevelopmental delay with impaired glycolysis
and lysosomal expansion) syndrome are summarized in 25414442, where 4/14 presented in adulthood with white matter leasions mimicking multiple sclerosis.
Should be rated green.
Sources: Literature

Created: 24 Dec 2021, 10:48 a.m. | Last Modified: 24 Dec 2021, 10:48 a.m.

Panel Version: 1.36

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
White matter abnormalities; autoimmunity; immunodefficiency; developmental delay

Publications

• PMID:25414442