Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.

Nasu-Hakola disease (NHD), also referred to as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a rare inherited leukodystrophy characterized by progressive presenile dementia associated with recurrent bone fractures due to polycystic osseous lesions of the lower and upper extremities.

Over 200 cases have been reported worldwide in the literature, the majority of them being in the Japanese and Finnish population. The prevalence in Finland is estimated between 1/500,000 and 1/1,000,000.

The disease course is generally divided into four stages: latent, osseous, early neurologic, and late neurologic. After a normal development during childhood (latent stage), the disease starts manifesting during adolescence or young adulthood (typical age of onset 20-30 years) with pain in the hands, wrists, ankles, and feet. Patients then start suffering from recurrent bone fractures due to polycystic osseous and osteoporotic lesions in the limb bones (osseous stage). During the third or fourth decade of life (early neurologic stage), patients present with pronounced personality changes (e.g. euphoria, lack of concentration, loss of judgment and social inhibitions) characteristic of a frontal lobe syndrome. Patients also typically suffer from initially mild, but progressive, memory disturbances. Epileptic seizures are frequently observed. Finally (late neurologic stage), patients progress to a profound dementia, are unable to speak and move, and usually die by the age of 50 years. Occasionally, the disease presents a different course with the neurologic symptoms preceding the osseous ones.

NHD is due to mutations in either the TYROBP or TREM2 genes encoding the tyrosine kinase binding adaptor protein and the triggering receptor expressed on myeloid cells 2 respectively. These genes encode components of a signaling complex involved in the regulation of immune responses, the differentiation of dendritic cells and osteoclasts, and in the phagocytic activity of microglia. The exact pathogenic mechanism is unknown.

Diagnosis is based on clinical and radiologic examination. X-ray imaging shows multifocal cystic lesions on the bones of hands, wrists, feet and ankles. Brain computed tomography (CT) or magnetic resonance imaging (MRI) shows frontally accentuated atrophy of the cerebral white matter. Bilateral calcifications of the basal ganglia are typical. EEG is normal in the early stages but shows diffuse slowing and irritative activity in late stages. Histopathologically, loss of axons and myelin as well as fibrillary gliosis are observed. Molecular genetic testing confirms the diagnosis in ambiguous cases.

The combination of frontal-type dementia starting in the fourth decade and radiologically demonstrable polycystic osseous lesions is unique and facilitates the differentiation of NHD from other forms of familial and non-familial frontotemporal dementia such as frontotemporal dementia and parkinsonism linked to chromosome 17 (see this term).

Due to the low carrier frequency of the mutation in the general population, prenatal diagnostic procedures are usually not reasonable, except in genetic isolates.

Transmission is autosomal recessive. Children of an NHD patient are healthy carriers of the mutation unless they have also inherited a disease-causing mutation in the TYROBP or TREM2 genes from the other parent. Presymptomatic testing is commercially available.

There is no curative treatment for the disease. Management is supportive. Antiepileptic drugs are prescribed to prevent seizures. A regular orthopedic and neurologic surveillance is recommended.

NHD is a progressive disease that is fatal usually during the fifth decade of life.

Visit the Orphanet disease page for more resources.

Last updated: 9/1/2012

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