Midbrain atrophy, commonly referred to as the hummingbird or penguin sign, can be a manifestation of fragile X-associated tremor/ataxia syndrome (FXTAS) and can mimic progressive supranuclear palsy, a case report suggests.
The case was described in the study “Late-onset hummingbird sign in a woman with fragile X permutation,” published in the Journal of the Neurological Sciences.
Similar to fragile X syndrome (FXS), FXTAS is also a genetic disorder caused by the expansion of CGG repeats within the sequence of the fragile X mental retardation 1 (FMR1) gene. These two disorders differ by the number of CGG repeats, with patients with fragile X commonly having more than 200 (full mutation) and those with FXTAS having 55 to 200 (premutation).
FXTAS affects mostly older male patients and is often associated with motor and cognitive impairments. But its presentation can vary significantly among patients, with a broad spectrum of symptoms.
Typically, FXTAS diagnosis can be confirmed by the presence of white matter lesions in the middle cerebellar peduncle (MCP) — a small bridge made of nerve fibers that connects the cerebellum to the spinal cord — that can be detected by magnetic resonance imaging (MRI).
Other neurological features, such as cerebellar and cortical atrophy, and abnormally higher MRI signal intensity of other brain regions, can also be detected in patients with FXTAS.
A team of Brazilian researchers reported an atypical case of a woman, 82, with FXTAS who did not have the typical MCP manifestations but instead showed the hummingbird sign.
The hummingbird sign refers to an atrophy of the midbrain that, together with the surrounding structures, appears in MRI scans in the form of the bird’s characteristic shape. This neurological feature is often seen in patients with progressive supranuclear palsy (PSP), but it has also been previously reported in a patient with FXTAS.
Progressive supranuclear palsy, the second-most common Parkinsonian syndrome after Parkinson’s disease, is characterized by gait, balance, speech, vision, behavioral, and cognitive impairments.
The woman had a two-year history of slowly progressive gait impairment and postural instability. She did not show any other signs of movement disorders, cognitive or psychiatric symptoms.
Her son, who was 60, also had similar symptoms for approximately six years.
A brain MRI revealed that he had the hummingbird sign as well as high-intensity signals in the corpus callosum — the bridge between the left and right sides of the brain. A genetic analysis revealed that he had a FMR1 premutation with 100 CGG repeats, which confirmed the diagnosis of FXTAS.
The woman’s genetic analysis confirmed that she also had the FMR1 premutation, but with 75 CGG repeats. In addition, some abnormalities in the substantia nigra — a brain area that controls movement and produces the important brain chemical messenger dopamine — were also detected.
Alterations in the substantia nigra and consequent impaired production of dopamine are hallmark features of PSP and Parkinson’s disease.
“Our report brings about important issues related to the association between FMR1 gene permutation and PSP,” the researchers said.
Women with FMR1 gene premutation may have very late onset of neurological symptoms and brain MRI abnormalities that could resemble PSP. In addition, these manifestations may be linked to a “non-responsive dopaminergic dysfunction,” they suggested.
The patient was followed up through three years with stability of symptoms and no additional signs of PSP.
To overcome the potential low levels of dopamine, and potential cause of her motor symptoms, the woman began treatment with 800 mg of levodopa daily — a gold-standard therapy for Parkinson’s disease. However, treatment resulted in no improvement.