Nasu–Hakola Disease: Crippling the Brain and Bones!

Nasu–Hakola disease, also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a rare autosomal recessive neurodegenerative disorder affecting young adults. It manifests with presenile dementia and repeated pathological fractures related to cystic bone lesions.[1] We report cystic bone lesions and diffuse cerebral atrophy with ventricular dilatation in a young male with PLOSL.

A 38-year-old male, born out of third-degree consanguineous parentage, presented with a 4.5-year history of recurrent pathological fractures, abnormal gait, and cognitive decline. Initially, he developed a progressive leftward truncal tilt while walking, along with slowness in activities of daily living. Subsequently, he developed urinary frequency, urgency, and urge incontinence. Two years into the illness, he lost interest in family matters, started misplacing objects, and made errors in monetary transactions. He started urinating in inappropriate places. Subsequently, he fractured his left tibia and left femur following separate, trivial falls a year apart. He suffered generalized seizures 2 weeks before presenting to us. There was no history of a similar illness in his family or of drug use, including antipsychotics and antidepressants. Neurological examination revealed impaired cognition, with a Montreal Cognitive Assessment score of 11/30. He had a poor attention span and comprehension. Frontal assessment revealed impaired digit span, judgement, fund of information, Stroop test, trail-making test, fluency, abstract thinking, and perseveration, with a positive applause sign. The patient had hypophonic speech and continuous jaw movements resembling jaw stereotypies [Video 1]. There was bradykinesia and rigidity, predominantly on the left side. He had apraxia and an abnormal gait with short steps, bent knees, and a truncal skew to the left [Video 1]. Routine laboratory evaluations were unremarkable. X-rays showed osteopenia in the metacarpals and metatarsals, along with bone cysts [Figure 1a–c]. Brain magnetic resonance imaging (MRI) revealed diffuse cerebral atrophy with predominant frontal involvement, ventricular dilatation, caudate atrophy, and T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities in the periventricular white matter (PVWM) [Figure 1d–f]. Whole-exome sequencing revealed a homozygous missense mutation in the triggering receptor expressed on myeloid cells 2 (TREM2)(-) gene (chr6:g.41163042C>T;Depth:134×), confirming the PLOSL diagnosis. Levetiracetam 500 mg orally twice a day controlled the seizures, but he remained caregiver dependent.

Figure 1.

(a and b) X-rays of hands and feet show hypodensities at the epiphyses (arrow) and carpal bones (arrowhead), suggestive of cysts. (c) Significant osteopenia (arrow) in the left tibia with an implant in situ and cysts in the tarsal bones (arrowhead). (d-f) Diffuse atrophy of the cerebrum with caudate atrophy [frontal horn width to inter-caudate distance ratio = 1.50 (normal range = 2.2–2.6)], periventricular white matter hyperintensity (arrow), and ex vacuo hydrocephalus (arrow)

PLOSL is caused by mutations in the tyrosine kinase binding protein (TYROBP) gene or TREM2 gene. The TREM2 gene encodes a receptor expressed on microglia, critical for maintaining brain homeostasis and immune responses. The TYROBP gene is expressed in natural killer cells, myeloid cells, microglia, and osteoclasts. TREM2 interacts with the TYROBP protein, forming a receptor-adaptor complex that regulates key processes such as phagocytosis, cytokine synthesis, and microglial proliferation and survival. In PLOSL, mutations in the TYROBP or TREM2 gene disrupt normal microglial activity, resulting in abnormal inflammatory responses and exacerbating neuronal damage.[2,3]

The disease has four clinical stages. The latent stage (normal development) is followed by the osseous stage (third decade), where patients experience foot and ankle discomfort and fractures in the extremities due to cystic bone lesions. The early neurological stage include frontal lobe dysfunction, gait abnormalities, upper motor neuron involvement, urinary incontinence, parkinsonism, and ataxia. Patient becomes immobile and demented in the late neurological stage, with death ensuing by age 50.[1] Our patient showed the majority of these features.

Trabecular bone loss and cystic lesions in the phalanges, metacarpals, and metatarsals are seen on X-rays. Brain computed tomography may show basal ganglia calcifications. Brain MRI reveals diffuse cerebral and caudate atrophy, ventricular dilatation, and PVWM T2/FLAIR-hyperintensities,[1] as was seen in our patient.

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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.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.