Abnormal Red Blood Cells Found in 4 Chinese Huntington’s Patients
Findings undermine scientists' attempts to distinguish 2 genetic diseases
Abnormal red blood cells, known as acanthocytosis, were identified in four unrelated Chinese adults with Huntington’s disease — undermining researchers’ attempts to differentiate the neurodegenerative disorder from another similar genetic disease.
Researchers had expected that the presence or absence of such abnormally shaped red blood cells would help to discriminate between Huntington’s and a similar condition called neuroacanthocytosis, characterized by these misshapen, spiny red blood cells, and neurological abnormalities.
However, “in this study, we demonstrate four patients who present with [Huntington’s] and acanthocytosis,” the scientists wrote, noting that these cases indicate that Huntington’s disease can co-exist with abnormal red blood cells.
“Our study highlights the complexity and diversity of [Huntington’s disease],” the team wrote.
The study, “Acanthocytes Identified in Huntington’s Disease,” was published in the journal Frontiers in Neuroscience.
Finding abnormal red blood cells in Huntington’s patients
Huntington’s disease is a genetic disorder caused by excessive repeats of a portion of DNA, called CAG triplets, within the HTT gene. Healthy people normally have between 10 and 35 CAG repeats, but those with Huntington’s may have 36 to 120 repeats. Longer repeats are tied to early disease onset.
Excessive CAG repeats lead to the production of a longer-than-normal huntingtin protein that accumulates to toxic levels inside nerve cells in the brain, causing progressive neurodegeneration.
With a wide spectrum of signs and symptoms, the disease is mainly characterized by motor problems, with chorea — involuntary, abrupt, and irregular movements — manifesting in the majority of patients. Other symptoms, including cognitive, behavioral, and psychiatric issues, often are present before the onset of motor impairments.
A key problem for clinicians in making a diagnosis is that the hallmark symptom of chorea also is present in other diseases. One example is neuroacanthocytosis, an umbrella term for a group of rare genetic disorders whose hallmark is acanthocytosis and other abnormalities, especially movement disorders. Chorea also is the most common movement disorder associated with neuroacanthocytosis.
The abnormal or misshaped spiny red blood cells form clumps that cause the degeneration of a brain area called the basal ganglia, which is responsible for the control of voluntary movements.
Huntington’s disease and neuroacanthocytosis “are two of the genetic causes of chorea,” the researchers wrote, adding that “it is sometimes difficult to distinguish them clinically because they have similar clinical symptoms and imaging findings.”
The presence of acanthocytes was believed to help distinguish both disorders, as it is one of the main features of neuroacanthocytosis. But now, a team of researchers in China described four cases of unrelated Huntington’s patients with acanthocytosis.
This combination “has not been previously reported,” the team wrote.
Looking for data in red blood cells
The researchers analyzed red blood cell data from 40 adults with Huntington’s who were followed at the Xuanwu Hospital, in Beijing, from 2014 to 2022. They found that four (10%) — all Han Chinese, unrelated, with ages between 45 and 61, and a disease duration of 4–10 years — had acanthocytosis.
Chorea was found in all four patients, psychiatric symptoms were seen in three, and dementia in two.
The first patient, a 61-year-old man, had experienced fast involuntary movements of the head and shoulders, progressing to the limbs, for the previous four years.
His family reported irritability, persecutory delusions, and cognitive problems. In neuropsychiatric questionnaires, he showed decreased cognitive function. Both his sister and his father’s sister experienced symptoms suggestive of Huntington’s from the age of 60.
The second patient, a man, 55, had a 10-year history of chorea, which first affected his head and shoulders, and later spread to the limbs, face, and tongue. In the prior two years, he developed personality changes and slurred speech. His mother and three siblings also showed involuntary movements.
A woman, 45, was the third patient, and had a 10-year history of cognitive decline. At age 40, she developed involuntary repetitive movements of the mouth and face, slurred speech, and rapid involuntary movements in the limbs. The jerky movements happened during waking hours and were absent during sleep.
Neurological examination showed speech impairment, chorea, lack of coordination in the limbs and trunk, decreased muscle tone, and overactive reflexes. Further tests showed signs of moderate dementia. Family history showed a three-generation movement disorder, affecting her mother, as well as her maternal uncle and grandmother.
The last patient, a 56-year-old woman, had a four-year history of rapid jerky movements affecting the trunk and limbs. According to her relatives, for the prior two years she experienced low mood, problems sleeping, suicidal ideation, and slurred speech. These psychiatric symptoms manifested ahead of the motor symptoms.
On physical examination, she presented with chorea-like movements of the trunk and limbs. She had no family history of movement or psychiatric disorders.
Blood work for all patients was, in general, unremarkable, but brain MRI scans showed signs of shrinkage in the caudate nucleus, a key part of the basal ganglia, and of the outer layer of the brain.
The patients’ red blood cells were examined using a specialized microscope called a scanning electron microscope. The first patient had a mild proportion, between 6–10%, of acanthocytes among his red blood bloods; this proportion was high, above 20%, in the remaining patients. Normal ranges are below 3% of total red blood cells.
Genetic analysis showed all four patients carried a mutation in the HTT gene, consistent with Huntington’s disease. The first patient carried 42 CAG repeats, the second 37 CAG repeats, the third 47, and the fourth 41. No other potential disease-causing mutations were detected.
Based on the absence of both other typical symptoms and mutations in genes linked to neuroacanthocytosis, this condition “was ruled out,” the researchers wrote.
Overall, these findings show that Huntington’s disease can co-exist with acanthocytosis, and that this may lead to an expansion of clinical symptoms, the team noted.
“Even though the primary gene defect appears to be predominately directed at the brain, a peripheral defect can be seen in HD [Huntington’s disease],” the researchers wrote.
“A meticulous clinical evaluation, laboratory tests, and genetic study are essential to make the final diagnosis,” they concluded.
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