Nasu–Hakola disease also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy is a rare disease characterised by early-onset dementia and multifocal bone cysts. It is caused by

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

loss of function mutations in either the ''

TREM2 Triggering receptor expressed on myeloid cells 2 (TREM2) is a protein that in humans is encoded by the ''TREM2'' gene. TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, which are immune cells ...

'' or ''

TYROBP TYRO protein tyrosine kinase-binding protein is an adapter protein that in humans is encoded by the ''TYROBP'' gene. Function This gene encodes a transmembrane signaling polypeptide which contains an immunoreceptor tyrosine-based activation mo ...

'' gene that are found most frequently in the Finnish and Japanese populations.

Signs and symptoms

Four stages are recognised in this condition. The first (latent stage) show no symptoms or signs. This stage typically lasts up to the early 20s. This is followed by the osseous stage. This is characterised by recurrent bone pain usually affecting the long bones of the limbs. This is usually followed by

pathological fracture A pathologic fracture is a bone fracture caused by weakness of the bone structure that leads to decrease mechanical resistance to normal mechanical loads. This process is most commonly due to osteoporosis, but may also be due to other pathologie ...

s of these bones. The third stage (early neurological) is marked by the onset of symptoms typical of a

frontal lobe syndrome Frontal lobe disorder, also frontal lobe syndrome, is an impairment of the frontal lobe that occurs due to disease or frontal lobe injury. The frontal lobe of the brain plays a key role in executive functions such as motivation, planning, social ...

(

euphoria Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...

, lack of concentration, loss of judgment and social inhibitions) with memory loss.

Epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

may occur. This stage usually has its onset in the late 20s and early 30s. The final stage is characterised by severe dementia and paralysis. Death usually occurs in the late 40s or early 50s.

Genetics

This condition has been associated with mutations in the TYRO protein tyrosine kinase binding protein (''

'') gene and in the triggering receptor expressed on myeloid cells 2 (''

'') gene. ''TYROBP'' is located on the long arm of

chromosome 19 Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 58.6 million base pairs, the building material of DNA. It is considered the most gene-rich chromosome ...

(19q13.12) and ''TREM2'' is located on short arm of

chromosome 6 Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total ...

(6p21.1).

Pathopysiology

This is not understood but appears to involve the

microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...

Diagnosis

This syndrome may be suspected on clinical grounds. The diagnosis is established by sequencing the ''TYROBP'' and ''TREM2'' genes.

Differential diagnosis

Frontotemporal dementia Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as ...

Investigations

X rays show the presence of bone cysts and

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...

. CT or

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

of the brain show loss of tissue in the frontotemporal lobes of the brain. Calcification of the

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...

is common.

EEG Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The biosignals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neocortex ...

is typically normal initially but diffuse slowing and irritative activity later.

Treatment

There is no specific treatment for this condition. Management is supportive.

Epidemiology

This condition is considered to be rare, with ~200 cases described in the literature. The estimated population prevalence is 2.0 x 10⁻⁶ in Finns.

History

This condition was first described in 1973.

References

{{Reflist Genetic diseases and disorders Rare syndromes