Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy Panel

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as Nasu-Hakola disease, is a progressive neurodegenerative disease characterized by multiple bone cysts and early frontal lobe dementia. Pain in the hands and feet, followed by recurrent fractures of the wrists and ankles are usually the first symptoms. They appear during the third decade of life. Frontal lobe symptoms appear later and include behavioral changes, memory loss, euphoria, inappropriate social conduct, disinhibition, and loss of verbal fluency. They are usually accompanied by upper motor neuron symptoms in the form of spasticity, generalized seizures and gait disturbance. Neuroimaging and neuropathological findings indicate cerebral and cerebellar atrophy, demyelination of the cerebral white matter, and calcification of the basal ganglia (Ohtani et al. 2014). The disease progresses relatively rapidly, and death occurs by the end of the fifth decade of life (Bird et al. 1983; Verloes et al. 1977; Paloneva et al. 2001).

PLOSL is clinically heterogeneous. Fractures and bone cysts have been identified in the majority of the reported cases. However, patients with no apparent bone involvement have been documented, prompting a recommendation for ankles and wrists radiography in patients with frontal lobe dementia of unknown etiology (Paloneva et al. 2001; Chouery et al. 2008; Yamazaki et al. 2015).

PLOSL is rare with less than 1/1,000,000 people affected. Although most cases have been reported in the Japanese, Finnish and Swedish populations, patients have been reported worldwide (Pekkarinen et al. 1998; Klunemann et al. 2005).

PLOSL is inherited in an autosomal recessive manner. It is caused by defects in one of two genes: TYROBP or TREM2. Pathogenic variants in TYROBP account for 79% of patients with a clinical diagnosis and MRI findings of PLOSL; and pathological variants in TREM2 account for about 21% of patients (Paloneva et al. 2002). They have been reported in patients from various ethnic and geographical populations.

To date, about 10 different pathogenic variants have been reported in TYROBP and TREM2 each. The majority is predicted to result in truncated proteins and includes nonsense, splicing, and small deletions or insertions (Paloneva et al. 2000; Kondo et al. 2002; Paloneva et al. 2002; Klünemann et al. 2005). Large pathogenic deletions appear to be rare. Only one such deletion has been reported in TYROBP (Paloneva et al. 2000); while none have been reported in TREM2 (Human Gene Mutation Database).

The TREM2 gene encodes Triggering Receptor Expressed on Myeloid cells 2. The TYROBP gene encodes Tyrosine Kinase Binding Adaptor Protein. The encoded proteins form two different subunits of a receptor-signaling complex. The TREM2-TYROBP complex is involved in the regulation of immune responses, the phagocytic activity of microglia, and the differentiation of dendritic cells and osteoclasts (Turnbull et al. 2006). In vitro studies revealed that pathogenic variants in either gene result in a reduction of bone resorption capacity in osteoclasts (Cella et al. 2003; Humphrey et al. 2006).

Pathogenic variants in the TREM2-TYROBP complex appear to account for the vast majority of patients with clinical and MRI findings suggestive of PLOSL. TYROBP variants were identified in 79% of patients, and TREM2 variants in 21% of patients. All patients presented with identical features (Paloneva et al. 2002).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).