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Table of Contents    
Year : 2018  |  Volume : 66  |  Issue : 2  |  Page : 538-541

Nasu–Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy): First report from India

1 Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
2 Department of Neurology, National Institute of Mental Health and Neurological Sciences, Bengaluru, Karnataka, India

Date of Web Publication15-Mar-2018

Correspondence Address:
Dr. Afshan Jabeen Shaik
Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.227319

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How to cite this article:
Chepuru R, Shaik AJ, Tandra SR, Gaddamanugu P, Alladi S, Kaul S. Nasu–Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy): First report from India. Neurol India 2018;66:538-41

How to cite this URL:
Chepuru R, Shaik AJ, Tandra SR, Gaddamanugu P, Alladi S, Kaul S. Nasu–Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy): First report from India. Neurol India [serial online] 2018 [cited 2020 Nov 29];66:538-41. Available from:


Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as Nasu–Hakola disease, is an autosomal recessive disease characterized by a combination of progressive presenile dementia and polycystic bone lesions with pathological fractures.[1],[2] It is extremely rare and has never been reported in India. We report genetically proven Nasu–Hakola disease (NHD) in two brothers with different clinical presentations.

The two brothers were born of consanguineous parentage. Their birth and developmental milestones were normal. None of the other family members suffered with similar or other chronic illnesses. The detailed pedigree chart is shown in [Figure 1]. The clinical presentations of these two siblings are as detailed below.
Figure 1: Pedigree chart of the family showing the position of the 2 patients

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  Case 1 (Elder Brother) Top

A 38-year old male patient presented with a 3 year history of mood and behavioral disturbances in the form of excessive anger and disinhibited behavior followed by memory disturbances. One year ago, he sustained fracture at the lower end of femur after a minor trauma. Nine months later, another minor trauma resulted in right radial fracture. He had frequent hospital admissions with cluster of seizures (generalised tonic clonic seizures [GTCS]), including once for status epilepticus. On general examination, there was bilateral knee and ankle swelling and the long bones were tender. Neurological examination revealed impairment of all cognitive domains, brisk deep tendon reflexes, and bilateral extensor plantar. Frontal release signs were strongly positive. Plain MRI of the brain revealed diffuse cerebral atrophy, bilateral basal ganglionic hypointensities, with diffuse white matter hyperintensities, on a T2-weighted sequence. [Figure 2]a,[Figure 2]b,[Figure 2]c. The non-contrast computed tomographic (CT) scan of the brain showed bilateral basal ganglia calcification [Figure 1]d. His X-ray images of both hands including wrist demonstrated multiple bone cysts [Figure 2]e,[Figure 2]f.
Figure 2: (a and b) Non-contrast MRI of the brain, T2 flair images, showed basal ganglia hypointensities with diffuse cerebral atrophy. (c) Non-contrast MRI of the brain, T1-weighted image, showed basal ganglia hyperintensities with diffuse cerebral atrophy. (d) Non-contrast CT scan of the brain showing calcifications in bilateral basal ganglia. (e and f) X-ray images of the hand showing multiple cysts in the carpal as well as the metacarpal bones, and the digits

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  Case 2 (Younger Brother) Top

A 30-year old school teacher was noticed by his mother to have behavioral changes in the form of overfamiliarity and inappropriate smiling with intermittent withdrawn behavior for one year. Later, he had memory disturbances, stiffness in both lower limbs, and gait disturbances. However, he did not have any history of seizures. He had sustained fracture of the tibia with trivial injury. The general examination was unremarkable. Complete neurological and neuropsychological assessment was done that revealed executive dysfunction, constructional impairment, and acalculia. Language and praxis were normal. There was mild gait ataxia with frontal lobe release signs. MRI of the brain (plain images) revealed cerebral atrophy with enlarged sulci causing ex-vacuo hydrocephalus. CT scan of the brain (plain images) suggested diffuse cerebral atrophy with calcification in the left putaminal region. Plain X-ray of the wrist and fingers suggested the presence of multiple bone cysts [Figure 3].
Figure 3: (a) CT of the brain, plain images, showing a tiny calcification (white arrow) in the left basal ganglia. (b and c) MRI of the brain, plain T2-FLAIR images showed diffuse cerebral atrophy. (d) X-ray image of the left shoulder showing the cyst (black arrow) in the humeral head. (e and f) X-ray image of the right and left wrist showing multiple cysts (black arrow) in the carpal bones

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The genetic analysis was done in the younger brother that showed homozygous nonsense variation in exon 2 of the TYROBP gene (PGln28Ter) - DAP12, which confirmed our clinical diagnosis of Nasu–Hakola disease.

Dementia associated with bone cyst-like lesions was initially described in Finland and Japan during the 60s, and later named as Nasu–Hakola disease after the people who described it. Hakola suggested the name lipomembranous polycystic osteodysplasia in 1972.[1] It is an autosomal recessive disease that is characterized by pathologic bone fractures with multiple bone cysts, accompanied by progressive dementia. The total number of the cases in the literature is not exceeding 200, and so far, it has not been reported from India.

The clinical course of PLOSL can be divided into four different stages: (1) latent, (2) osseous, (3) early neurological, and (4) late neurological.[2] The typical radiographic findings in the early stages are a generalized reduction of the trabeculae in the epiphyses and metaphyses of the long bones. Subsequently, a total loss of bone occurs in the affected areas with the formation of cystic lesions, typically in the distal small bones of the extremities and the long tubular bones.[3],[11] Neuroimaging shows changes only several months or even years after the beginning of neuropsychiatric symptoms. In our patients, the neuroimaging was done 6 years after the onset of neuropsychiatric symptoms. The first changes are usually frontal and temporal polar atrophy, as was evident in our case [Figure 2] and [Figure 3]. In addition, T2-weighted imaging reveals nonspecific and diffuse changes in the white matter and hypointense signal in the basal ganglia that are possibly related to the calcium and non-hemin iron (ferritin) deposits observed in these regions.[4]

The differential diagnosis includes the established forms of familial and nonfamilial frontotemporal dementia (e.g., Pick's disease, nonspecific frontal lobe degeneration, the various entities of frontotemporal dementia, and Parkinsonism linked to chromosome 17). The typical combination of frontal-type dementia beginning in the fourth decade and radiologically demonstrable polycystic osseous lesions makes it easy to clinically distinguish PLOSL from the above entities.

Two gene mutations have been detected in genetic studies. The genes are DAP12 (TYRO protein tyrosine kinase-binding protein, TYROBP) and TREM2 (triggering receptor expressed on myeloid cells) genes.[5],[6] Pathogenic variants in TREM2 have been reported to cause dementiaand frontal lobe syndrome typical of PLOSL without osseous manifestations.[7] The pathogenesis of this unusual combination of dementia and bone lesions is still unexplained. Initially, it was thought to be a lipid storage disease.[1] Later, the pathological studies lead to postulation of vascular damage.[8] As the insights into the molecular aspects followed in the year 2000, a new pathogenesis was proposed. The mutations in TYROBP and TREM2 that are expressed in microglia and osteoclasts (both derived from monocyte–macrophage lineage). This causes an inefficient and delayed differentiation of osteoclasts and microgliosis, resulting in an imbalance of the bone-remodeling capability. As a consequence, bony cysts develop, and inflammatory and immunological imbalance in the brain result in brain atrophy and dementia.[9] Therefore, PLOSL should be considered in all cases of early onset dementia of unknown origin.[10] [Table 1] summarizes the important literature regarding this disease. The treatment is only symptomatic. PLOSL is inherited in an autosomal recessive manner. Carrier testing for at-risk relatives, and prenatal testing for pregnancies at increased risk, are possible if the pathogenic variants in the family have been identified, as was observed in our case.[12],[13],[14]
Table 1: Few important case reports that provided insights into the characteristics of the PLOSL disease

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Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Hakola HP. Neuropsychiatric and genetic aspects of a new hereditary disease characterized by progressive dementia and lipomembranous polycystic steodysplasia. Acta Psychiatr Scand Suppl 1972;232:1-173.  Back to cited text no. 1
Paloneva J, Autti T, Raininko R, Partanen J, Salonen O, Puranen M, et al. CNS manifestations of Nasu-Hakola disease: A frontal dementia with bone cysts. Neurology 2001;56:1552-8.  Back to cited text no. 2
Bianchin, MM, Capella HM, Chaves DL, Steindel M, Grisard EC, et al. Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy-PLOSL): A dementia associated with bone cystic lesions. From clinical to genetic and molecular aspects. Cell Mol Neurobiol 2004;24:1-24.  Back to cited text no. 3
Araki T, Ohba H, Monzawa S, Sakuyama K, Hachiya J, Seki T, et al. Membranous lipodystrophy: MR imaging appearance of the brain. Radiology 1991;180:793-7.  Back to cited text no. 4
Nakamagoe K, Shioya A, Yamaguchi T, Takahashi H, Koide R, Monzen T, et al. A Japanese case with Nasu-Hakola disease of DAP12 gene mutation exhibiting precuneus hypoperfusion. Intern Med 2011;50:2839-44.  Back to cited text no. 5
Numasawa Y, Yamaura C, Ishihara S, Shintani S, Yamazaki M, Tabunoki H, et al. Nasu-Hakola disease with a splicing mutation of TREM2 in a Japanese family. Eur J Neurol 2011;18:1179-83.  Back to cited text no. 6
Le Ber I, De Septenville A, Guerreiro R, Bras J, Camuzat A, Caroppo P, et al. Homozygous TREM2 mutation in a family with atypical frontotemporal dementia. Neurobiol Aging 2014;35:2419.  Back to cited text no. 7
Kalimo H, Sourander P, Jarvi O, Hakola P. Vascular changes and blood-brain barrier damage in the pathogenesis of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (membranous lipodystrophy). Acta Neurol Scand1994;89:353-61.  Back to cited text no. 8
Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet2002;71:656-62.  Back to cited text no. 9
Verloes A, Maquet P, Sadzot B, Vivario M, Thiry A, Franck G. Nasu-Hakola syndrome: Polycystic lipomembranous osteodysplasia with sclerosing leucoencephalopathy and presenile dementia. J Med Genet1997;34:753-7.  Back to cited text no. 10
Akai M, Tateishi A, Cheng CH, Morii K, Abe M, Ohno T, Ben M. Membranous lipodystrophy: A clinicopathological study of six cases. J Bone Joint Surg Am 1977;59:802-9.  Back to cited text no. 11
Nasu T, Tsukahara Y, Terayama K. A lipid metabolic disease- “membranous lipodystrophy”-an autopsy case demonstrating numerous peculiar membrane-structures composed of compound lipid in bone and bone marrow and various adipose tissues. Acta Pathol Jpn 1973;23:539-58.  Back to cited text no. 12
Kocer N, Dervisoglu S, Ersavasti G, Altug A, Cokyuksel O. Case report 867. Membranous lipodystrophy (polycystic lipomembranous osteodysplasia). Skeletal Radiol 1994;23:577-9.  Back to cited text no. 13
Motohashi N, Shinohara M, Shioe K, Fukuzawa H, Akiyama Y, Kariya T. A case of membranous lipodystrophy (Nasu–Hakola disease) with unique MRI findings. Neuroradiology 1995;37:549-50.  Back to cited text no. 14


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]


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