Polycystic Lipomembranous Osteodysplasia With Sclerosing Leukoencephalopathy 1

A number sign (#) is used with this entry because of evidence that polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy-1 (PLOSL1), also known as Nasu-Hakola disease, is caused by homozygous mutation in the DAP12 gene (TYROBP; 604142) on chromosome 19q13.

Description

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy is characterized by presenile dementia along with large-scale destruction of cancellous bones. Initial symptoms, starting in the twenties, are pain and swelling resulting from cysts in the wrists and ankles. Extremity bone fractures could occur with minor trauma. At around 30 years of age, patients gradually develop neuropsychiatric symptoms, including epileptic seizures, agnosia, apraxia, speech disorder, memory disturbance, euphoria, and loss of social inhibitions. The disorder usuallly leads to death in the fifth decade of life (summary by Kondo et al., 2002).

Genetic Heterogeneity of Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy

Also see PLOSL2 (618193), cause by mutation in the TREM2 gene (605086) on chromosome 6p21.

Clinical Features

Hakola (1972) reported a disorder in Finland in which affected patients had onset in the third decade of pain and swelling following strain of the wrist or ankle; fractures occurred after minor accidents. Radiographs showed cystic rarefactions in the epiphyseal regions of bones. The cysts contained jelly-like material and microscopically showed membranous and lamellar structures between fatty and collagenous connective tissue. In the fourth decade, patients developed neuropsychiatric symptoms, including memory impairment, euphoria, loss of social inhibitions, and impotency or frigidity. Neurologic examination showed exaggerated deep tendon reflexes, pathologic reflexes, and dysplasia. The EEG was typical: synchronous, episodic, and diffuse 6 to 8 cycle per second activity and replacement of the alpha rhythm by amorphous theta and delta activity. Pneumoencephalography showed dilated ventricles consequent to cortical atrophy. The disorder occurred in multiple sibs with consanguineous parents, and most of the affected persons originated from 1 Finnish province, suggesting autosomal recessive inheritance. The same disorder was observed in Japan (Nasu et al., 1973; Harada, 1975) and in Sweden (Adolfsson et al., 1978). Patients usually die between ages 35 and 45, and the later features of the disorder resemble those of Alzheimer disease. Adolfsson et al. (1978) observed 7 affected persons in 2 families in northern Sweden.

According to Jarvi et al. (1980), 13 cases in 9 sibships were identified in Finland, 25 in 23 sibships in Japan, 11 in 3 sibships in Sweden, and a single case in the United States. Onset occurred at about age 20 years with pain and swelling in the wrists and ankles after stress or injury. Neuropsychiatric symptoms began after age 30 years: progressive dementia with an accentuated prefrontal syndrome, signs of upper motor neuron involvement, agnostic-apractic-aphasic symptoms, myoclonic twitches, and epileptic seizures. Cysts, filled with partly necrotic fatty tissue, occurred in the phalanges, metacarpals, carpals, metatarsals, tarsals, patella, and ends of long bones. Small vessels were narrowed and damaged in bone and brain. Jarvi et al. (1980) postulated a primary defective development of the vascular system.

Kalimo et al. (1994) described the histopathologic, immunohistochemical, and electron microscopic findings in 8 patients with polycystic lipomembranous osteodysplasia and sclerosing leukoencephalopathy. The disorder was first manifested by multiple bone cysts, with development of a severe neuropsychiatric disorder around the age of 30 years. The typical macroscopic features were marked hydrocephalus ex vacuo due to severe destruction of the white matter, with extensive secondary astrocytic gliosis and relatively better preserved gray matter. Kalimo et al. (1994) showed that the basement membranes of blood vessels with 'plump' endothelium were thickened and often multiplied, most prominently in the white matter. Extravasation of plasma constituents was demonstrated immunohistochemically. On the basis of the vascular changes, also present in bone lesions, Kalimo et al. (1994) proposed that severe chronic vasogenic brain edema is the main pathogenetic mechanism of the severe leukoencephalopathy.

Verloes et al. (1997) reported a further case and reviewed the epidemiology of clinical features--radiology, pathology, pathophysiology, biochemistry, and differential diagnosis.

Mapping

Pekkarinen et al. (1997, 1998) stated that approximately 160 cases of this disorder had been identified since the 1960s, mainly in Finland and Japan. By a modification of the haplotype-sharing method, Pekkarinen et al. (1997, 1998) carried out a random genome screen for the disease locus, called PLOSL by them, in affected individuals from Finland. Markers in genomic regions with extensive haplotype sharing were genotyped in 12 PLOSL families from Finland, 3 from Sweden, and 1 from Norway. Significant evidence of linkage to chromosome 19q13.1 was found in the Finnish families. Haplotype analysis of 1 of the Swedish families and the Norwegian family indicated that the disorder was not linked to 19q13.1, suggesting genetic heterogeneity. The critical region in the Finnish families was bordered by obligatory recombinations in D19S191 and D19S420, which are separated by 9 cM. By linkage-disequilibrium analysis, Pekkarinen et al. (1997, 1998) further restricted the critical region to approximately 1.8 Mb. By the same method in a later study, Pekkarinen et al. (1998) narrowed the critical region for PLOSL to 153 kb. Pekkarinen et al. (1998) noted that the amyloid precursor-like protein-1 (APLP1; 104775) is located in the same region of chromosome 19; no mutations were detected in the coding region of the APLP1 gene.

Molecular Genetics

In Finnish patients with PLOSL, Paloneva et al. (2000) identified a large deletion in the TYROBP gene (604142.0001). In a Japanese patient, they identified a frameshift mutation in TYROBP (604142.0002).

In 5 of 6 Japanese patients with Nasu-Hakola disease, Kondo et al. (2002) identified mutations in the DAP12 gene. One patient had no such mutation and normally expressed DAP12.

Population Genetics

Although PLOSL has a global distribution, most of the patients have been diagnosed in Finland and Japan, with an estimated population prevalence of 2.0 x 10(-6) in Finns (Hakola, 1990).

Nomenclature

Paloneva et al. (2000) referred to the disorder by the simplified designation 'presenile dementia with bone cysts.' The condition is also known as Nasu-Hakola disease for the persons who described the condition in Japan and Finland, respectively.