Nasu-Hakola disease: The first case reported by Nasu and review

The 50th Anniversary of Japanese Society of Neuropathology

Authors


Minoru Kaneko, MD, PhD, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. Email: kane_min@shinshu-u.ac.jp

Abstract

Nasu-Hakola disease (NHD) was first reported separately by Nasu and Hakola around the same time in the 1970s. It is an autosomal recessive inherited disorder characterized by progressive dementia and repeated pathological fractures during adolescence. It has recently been demonstrated that NHD is caused by a mutation in the TREM2 or DAP12 gene. The present paper demonstrates the first patient reported by Nasu and reviews NHD. The patient was a man who died at the age 38 years. His family history was unremarkable. There was no abnormal developmental history. At the age of 26, the patient suffered a pathological fracture of the right tibia, and X-ray confirmed bone resorption in the right tibia. As for mental status, the patient tended to be euphoric. After that, bone resorption was also seen in other long bones. At the age of 33, the patient could not walk after suffering a right femoral neck fracture. He was apathetic and exhibited behavioral abnormalities. At the age of 38, he could not move or speak and subsequently died. General pathological examination showed yellow opaque gelatinous substances in the medullary cavities, matching translucent cystic lesions in the femur, tibia, and fibula on X-rays. Light microscopy showed numerous membranocystic changes in the substances. The brain weighed 1050 g. Symmetric systemic cerebral atrophy, in particular atrophy of the cerebral white matter in the occipital and temporal lobes, was confirmed. Histological examination showed white matter degeneration and diffuse sclerosis accompanied by astroglial proliferation. Severe demyelination was confirmed. Axonal degeneration and destruction were marked. In demyelinated areas, fat granule cells appeared, and lipid granule-positive cells aggregated around vessels. Cerebral cortical neurons were relatively maintained. In the brain, no membranocystic lesions could be recognized. In the DAP12 gene, the patient had a conversion of nucleotide at position 116 resulting in serine 38 to asparagine substitution.

INTRODUCTION

Nasu-Hakola disease (NHD) is very rare and was first reported separately by Nasu and Hakola around the same time in the 1970s. This autosomal recessive inherited disorder is characterized by progressive dementia and repeated pathological fractures during adolescence.1,2 In recent years, studies have demonstrated that NHD is caused by a mutation in the DAP12 gene (DNAX-activating protein 12) (TYROBP: TYRO protein tyrosine kinase binding protein, KARAP: killer-cell activating receptor associated protein) or the TREM2 gene (triggering receptor expressed on myeloid cells 2).3,4 The present paper demonstrates the first patient reported by Nasu and reviews NHD.

PATIENT (MALE, 38 YEARS OLD AT DEATH)5

Clinical history

There was no notable family history or consanguineous marriage, and the patient's developmental history was not abnormal. At the age of 26 years, the patient suffered a pathological fracture in the right tibia. Due to poor bone fusion, the patient visited the Department of Orthopedic Surgery, Shinshu University Hospital, and X-ray examination confirmed bone resorption in the right tibia. Psychologically, the patient was talking quickly, loquacious, cheerful and euphoric. The next year, bone resorption was also seen in the lower end of the right tibia and fibula. Then, bone resorption was seen in the contralateral tibia and fibula and the left and right hand and foot bones, and at around the age of 30 years, lesions spread to the femur and humerus, making walking difficult. At the age of 33 years, the patient suffered a pathological fracture in the right femoral neck and could no longer walk. As for psychological symptoms, the patient was apathetic and exhibited behavioral abnormalities. At the age of 34 years, the patient had an epileptiform seizure, and although the seizures gradually subsided, voluntary upper limb movements and speech became difficult. In response to external stimulation, the patient could move his eyeballs and swallow a liquid substance placed in the mouth. At the age of 38 years, he could not move or speak and subsequently died.

General pathological findings

Systemic emaciation and subcutaneous fat tissue degeneration were marked, the liver, spleen, and lymph nodes were severely atrophied, and abnormal lipid deposition was not seen at all. In long bones, such as the femur, tibia, fibula, and ribs, the medullary cavity at both ends was filled with yellow opaque gelatinous substances, matching the translucent cystic lesions seen on X-rays, the bone substance was highly resorbed, and the bone cortex was so thin that it could be damaged when pressed by a finger. In the substances, numerous membranocystic changes were widely distributed on light microscopy, and surrounding fat cells and other cell components were markedly reduced (Fig. 1).

Figure 1.

Arabesque membranocystic lesions are confirmed in the bone fatty marrow. HE staining. Scale bar = 50 µm.

Membranocystic lesions were also seen in the bone fatty marrow, subepicardium, mediastinum, mesentery, thymus, systemic adipose tissue around the kidney and lymph nodes, adrenal glands, testes, hepatic sinusoids, and pulmonary vascular lumina. Membranous structures were positive for Sudan III, stained blue with Nile blue, and most were positively stained by Luxol fast blue.

Neuropathological findings

The brain weighed 1050 g. As for macroscopic findings, symmetric systemic atrophy of the brain, in particular severe atrophy of the occipital and temporal white matters, was seen. The gyrus was narrow, the cerebral sulcus was somewhat broad and deep, and the meninx was smooth. On cross-sections, marked white matter atrophy was confirmed. The boundary between the white and gray matters was slightly unclear. The basal ganglia were mildly atrophied, and the ventricles were severely enlarged in a symmetrical manner. Bleeding or softening was not confirmed. No notable findings were seen in the cerebellum, pons or medulla oblongata. The spinal cord was not examined.

As for histological findings, the white matter was broadly degenerated, and diffuse sclerosis accompanied by astroglial proliferation was confirmed (Fig. 2). Gemistocytic astrocyte was the major component, and fibrillary gliosis was mild. Inflammatory cellular infiltration was absent. Myelin sheath staining confirmed severe demyelination, but U-fibers were relatively conserved. Axonal degeneration and destruction were marked, and the axons were bloated in a balloon fashion and ruptured (Fig. 3), and positively stained using Sudan III or PAS. In demyelinated areas and the adjacent myelin sheaths, fat granule cells and free fat granules appeared, and lipid granule-positive cells aggregated around vessels.

Figure 2.

Brain cross-sections. The white matter is broadly degenerated, and severe demyelination is confirmed. Diffuse sclerosis is accompanied by astroglial proliferation. a: HE staining and b: Holzer staining.

Figure 3.

Axons have degenerated and swollen, destruction is marked and spheroids are sporadic. Bodian staining. Scale bar = 50 µm.

The cerebral cortex was relatively maintained, and cortical atrophy and neuronal loss and atrophy were mild. Metachromatic substance deposition was not seen. Although slight small vessel proliferation was confirmed, there were no globoid cells in the vicinity. In the thalamus, loosening was confirmed. The hypothalamus was maintained, and in the hippocampus, marked neuronal loss was seen. Although the cerebellum was relatively maintained, mild degeneration was seen in the white matter. In the brain, no membranocystic lesion was observed.

Genetic mutation of DAP12

The patient had a conversion of nucleotide at position 116 resulting in serine 38 to asparagine substitution.

REVIEWS OF NHD

History

In the 1961 Convention of the Japanese Orthopedic Association, Terayama named the characteristic osseous lesions of the disease multiple membranocystoses.6 After performing an autopsy, Nasu and colleagues tentatively named the disease membrano-cystic lipodystrophy and presented it at the 1970 Tokyo Pathology Conference. Then, in the 1971 Convention of the Japanese Society of Pathology and the 1972 Convention of the Japanese Society of Neuropathology, the disease was referred to as membranous lipodystrophy.7

The disease was also reported in Finland and Sweden, and in 1964, Järvi and colleagues coined the term “cystic capillary-necrotic osteodysplasia”.8 In 1970, Hakola and colleagues documented “osteodysplasia polycystica hereditaria combined with sclerosing leucoencephalopathy”, and Hakola reported thorough studies in 1972.2,9 In 1973, when Yakumaru reported an autopsy case of membranous lipodystrophy, he pointed out similarities with Finnish and Swedish cases.10 In Japan, the disease was named Nasu disease, and in 1981, Hanawa and colleagues proposed that since Nasu disease, membranous lipodystrophy, and the Finnish cases were the same, the diseases should be referred to as NHD.11 In Finland, the disease was named “polycystic lipomembranous osteodysplasia with sclerosing leucoencephalopathy” (PLOSL) in 1980.12 So far, there have been approximately 200 cases, and while most patients have been Japanese and Finnish, cases have been reported in Sweden,13,14 the USA,15,16 Norway,17 Italy,18 South Africa,19 Austria,20 Turkey,21 Belgium,22 France,23 Brazil,4 Germany,24 Spain25 and Bolivia.26 The prevalence in Finland has been reported as 2/1000 000.27

Clinical symptoms

A typical patient often has bone symptoms occurring during adolescence and slowly progressive dementia. Most patients first experience bone symptoms, and beginning with hand, foot and knee pains and with increased susceptibility, the patient suffers repeated pathological fractures. Dementia is mostly characterized by personality changes, and patients experience euphoria, indifference, slouchy lifestyle, apathy, disinhibition, and lack of insight into their disease. They also suffer progressive amnesia, memory disorder, apraxia, agnosia, acalculia, and disorientation, eventually resulting in akinetic mutism and apallic syndrome. Some patients exhibit urinary or stool incontinence, convulsive attacks and pyramidal signs, such as paraplegia, spastic gait, and positive bilateral Babinski signs. Some convulsive attacks occasionally result in status epilepticus.

Hakola divided the clinical course into the following four stages: (i) latent; (ii) osseous; (iii) early neuropsychiatric; and (iv) late neuropsychiatric phases.9,27,28 However, some patients begin with psychological symptoms, and some do not have any bone symptoms.11,29

One patient underwent bone transplantation and did not experience recurrent bone cysts or psychiatric symptoms for 16 years.30 One patient had epilepsy at the age of 11 years and euphoria, loquacity, and amnesia after adolescence, and although bone findings and symptoms, such as multilocular translucency and talar fracture, were confirmed at the age of 31 years, these lesions were localized in the carpal and tarsal bones, and the patient only experienced pain while walking 2 years after curettage and bone transplantation.31

Examination findings

Bone X-rays confirmed multiple translucent cystic lesions in the long bones, particularly the epiphyses. Head imaging findings confirmed ventricular enlargement and atrophy of the cerebral hemisphere, predominantly in the frontal and temporal lobes. Bilateral and symmetric calcification of the basal ganglia was also often seen. EEG showed generalized irregular slow waves and spikes. Single-photon emission computed tomography showed reduced blood flow in the bilateral frontal and temporal lobes, basal ganglia, and thalamus, and positron-emission tomography confirmed reduced glucose metabolism in the bilateral frontal lobe white matter, thalamus and basal ganglia.32–34

General pathological findings

Yellow opaque gelatinous substances filled the medullary cavity, matching bone cystic lesions on X-rays, and inside these substances, characteristic arabesque membranocystic lesions were observed.

Membranocystic lesions were broadly seen in not only bone fatty marrow, but also in systemic adipose tissues, subepicardium, mediastinum, mesentery, thymus, around the kidney and lymph nodes, adrenal glands, testes, hepatic sinusoids, and pulmonary vascular lumina. These lesions are characteristic of NHD, but not specific. They were seen in 36 of 1000 randomly selected autopsy cases. They are also seen in the subcutaneous adipose tissue of dermal disease patients, the bone marrow of acute leukemia patients, or the adipose tissue around the adrenal glands of patients with various malignancies.35,36

Neuropathological findings

Macroscopically, the brain was generally atrophied, in particular the white matter. Lateral ventricular enlargement was severe. While the thalamus and basal ganglia became generally smaller, they were better maintained when compared to the cortex or the white matter. The total volume of the cerebellum and brainstem tended to be low, but the degree of reduction was smaller when compared to the cerebrum.

The main lesions were located in the cerebral white matter, and both sides were affected in the same manner, particularly severely in the frontal and temporal lobes. In most cases, sclerosing leukoencephalopathy was seen, and mild demyelination and marked fibrillary gliosis were seen. In the present patient, sudanophilic leukodystrophy was seen, with broadly marked demyelination, and Sudan III-positive fat granule cells were observed around vessels and inside tissue, but fibrillary gliosis was slight.

Axonal changes and calcification were also often seen. The axons were swollen and deformed in spherical, rod-like, and spindle fashions to form spheroids. Calcification was particularly seen in the basal ganglia and cerebral white matter. In the spinal cord, neuronal loss and chromatolysis were seen in the anterior horn.28 Membranous structures were not seen in the brain or meninx.

Autopsy cases

Finnish and Swedish groups have repeatedly documented vascular lesions, such as angiofibrosis, small vessel medial defects, and intimal proliferation.2,9,12,13 While reports from Japan vary slightly, the majority of autopsy cases are from Japan (16 men and 17 women).1,10,11,29,37–64 Here, the Japanese reports are summarized (Table 1).

Table 1.  Clinicopathological findings of the 33 Japanese autopsy cases
CaseSexAge (years)Onset age (years)Duration (years)Bone signsEpileptic seizuresBrain weight (g)Areas affectedType of lesion of cerebral white matterSpheroids of white matterSpheroids of cerebral cortexSenile plaque
  1. n.m. not mentioned; F, frontal; O, occipital; T, temporal; lt, left; rt, right.

 1M382612++1050T + OSudanophilic leukodystrophy++n.m.
 2M272161030F + TTransitional type++n.m.
 3F362511880TSclerosing leukoencephalopathy+n.m.
 4F422715++830F + TSclerosing leukoencephalopathy+
 5F333031040F + TSclerosing leukoencephalopathy+++
 6M442816++1150F + TTransitional type+n.m.
 7F37298+1010F + TSclerosing leukoencephalopathy++
 8F38308++920FSclerosing leukoencephalopathy+n.m.
 9M503515+1030FSclerosing leukoencephalopathy++n.m.
10F413516++860F + TSclerosing leukoencephalopathy++
11M401525+980n.m.Sclerosing leukoencephalopathyn.m.n.m.n.m.
12M354510++990DiffuseSclerosing leukoencephalopathy++n.m.n.m.
13M401624+980DiffuseSudanophilic leukodystrophyn.m.
14M431023++680F + TTransitional type++n.m.
15M563026++595lt > rtSudanophilic leukodystrophyn.m.n.m.n.m.
16F433310++940F + TLoosening±n.m.
17M402911+1040F + TSclerosing leukoencephalopathy++
18F541935+n.m.n.m.F + Tn.m.n.m.n.m.++
19F433310+940F + TSclerosing leukoencephalopathyn.m.
20M463412++1030FSclerosing leukoencephalopathy+n.m.
21F501733++740diffuseSudanophilic leukodystrophyn.m.n.m.++
22F413011+840FSclerosing leukoencephalopathy+n.m.
23F35278++910diffuseSclerosing leukoencephalopathyn.m.n.m.n.m.
24F332211++1033TSclerosing leukoencephalopathy+
25F503515+910F + Tn.m.+n.m.n.m.
26M473611+1180F + Tn.m.++n.m.n.m.
27M38326++1190Fn.m.+n.m.n.m.
28F482028++840diffusen.m.+n.m.
29M422418++1180n.m.Sclerosing leukoencephalopathy+n.m.
30M422317++910n.m.n.m.+n.m.n.m.
31M501733++920F + Tn.m.++n.m.n.m.
32F453312+935F + TSclerosing leukoencephalopathy+n.m.
33F553322+580F + TSclerosing leukoencephalopathy+n.m.+

The onset age ranged from 10 to 45 years, with an average of 27 years. The average disease duration was 16 years, the longest being 35 years. More than half of the patients had epileptic events. The weight of the brain was below 600 g in some patients. Lesions were generally strongest in the frontal lobe, and sclerosing leukoencephalopathy was the main lesion. Spheroids were seen in most cases. Numerous senile plaques were seen in the cortex of several patients, including a patient who had the disease for 35 years.

Etiology

Nasu considered that the cerebral white matter degeneration and the unique adipose tissue degeneration resulting in membranous material formation were based on a series of disturbances to lipid metabolism cells.1,5,7 Hakola also perceived the bone lesions as osteodysplasia and deduced that recessive inheritance was involved.2,9 More studies were performed, and in 2000, Paloneva reported an abnormality in the DAP12 gene located in chromosome 19.3 In 2002, an abnormality in the TREM2 gene was documented in a patient without any DAP12 gene abnormality,4 thus clarifying that NHD is caused by a defect in trem2/DAP12 signal transmission.

DAP12 is expressed in NK cells, myeloid cells, and oligodendrocytes, while TREM2 is expressed in myeloid cells. The level of intracellular Ca is elevated to activate microglia and is involved with osteoclast and dendritic cell differentiation and function.65 While various reports of DAP12 and TREM2 gene abnormalities have been documented, there has not been a report of TREM2 gene mutation in Japan.3,4,66,67

PATIENT SUMMARY

  • 1The cerebral white matter lesions were sudanophilic leukodystrophy.
  • 2The appearance and course of the bone and psychiatric symptoms, bone lesions and white matter degeneration were typical, but occipital lobe atrophy, mild fibrillary gliosis, and severe demyelination were atypical.
  • 3The patient had a conversion of nucleotide at position 116 resulting in serine 38 to asparagine substitution in DAP12.

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