Substance Abuse May Accelerate Onset of Motor Symptoms in Huntington's Disease

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Increased dopaminergic activity may be associated with an earlier age of motor symptom onset in Huntington’s disease.
Increased dopaminergic activity may be associated with an earlier age of motor symptom onset in Huntington’s disease.

Research published in Neurology provides further evidence that substance abuse has a strong effect on the age of onset of motor symptoms in Huntington's disease.

Patients who abused tobacco, alcohol, and drugs experienced the onset of motor symptoms several years earlier than patients who did not. The effect was particularly strong in women.

Jordan L. Schultz, PharmD, from the University of Iowa in Iowa City, and colleagues conducted a retrospective observational study of the Enroll-HD database.

Out of 4146 participants with Huntington's disease, 2314 had motor-manifesting Huntington's disease. After eliminating patients with an unreported age of onset of motor symptoms, patients with onset at 21 or younger, patients who didn't fit into any substance abuse category, and patients with a diagnostic confidence of zero, 1849 participants were evaluated.

Of the 1849 participants included in the analysis, 566 abused tobacco, 374 abused alcohol, and 217 abused drugs; 692 did not abuse substances and acted as the control group.

Patients who abused tobacco had an average age of motor symptom onset 2.3 years younger than the control group (F1, 1258 = 33.8, P <.0001); patients who abused alcohol had an average age of motor symptom onset 1 year younger than the control group (F1, 1066 = 4.2, P <.04); and patients who abused drugs had an average age of motor symptom onset 3.3 years younger than the control group (F1, 909 = 29.7, P <.0001).

In all of the substance abuse groups, the average age of motor symptom onset was younger in women than in men.

“The age at motor [symptom] onset of Huntington's disease is primarily determined by the number of CAG repeats within the HTT gene. However, environmental factors also contribute up to one-third of the variance of this age,” the researchers wrote.2

A previous study found that in mouse models the concentration of dopamine in the accumbens and caudate was highest from amphetamine and cocaine, followed by nicotine and alcohol.

“By extrapolating this information to the results of the current study — which showed that drug abuse is associated with the earliest age at motor [symptom] onset, followed by tobacco and alcohol abuse — increased dopaminergic activity may be associated with an earlier age at motor onset.”

“Further studies are needed to more definitively link monoamines and age at motor [symptom] onset in patients with Huntington's disease,” the investigators concluded.

Clinical Applicability

These findings may provide a simple, risk-free intervention that could add years of living without motor symptoms to the lives of patients with Huntington's disease.

“Identifying other environmental factors associated with the AMO [age at motor onset] is necessary to continue to provide the highest level of care to patients with HD [Huntington's disease],” the researchers said.

Limitations

  • It is possible that participants with pre-manifest Huntington's disease are more likely to abuse substances when motor symptoms are initially perceived
  • Limitations of the Enroll-HD database prevented the researchers from controlling for downstream single nucleotide polymorphisms (SNPs), which may affect the age of motor symptom onset, according to previous studies3
  • The study was retrospective
  • The classification of participants into abuse categories was based on reports from participants and family members
  • It is possible that participants in one category of abuse also used substances from other categories
  • A longitudinal prospective study would be needed to more definitively estimate the true effect of substances on the age of motor symptom onset

References

  1. Schultz JL, Kamholz JA, Moser DJ, Feely SME, Paulsen JS, Nopoulos PC. Substance abuse may hasten motor onset of Huntington disease: evaluating the Enroll-HD database [published online February 1, 2017]. Neurology. doi:10.1212/WNL.0000000000003661
  2. Wexler NS, Lorimer J, Porter J, et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc Natl Acad Sci USA. 2004;101:3498-3503.
  3. Jones L; on behalf of the CHDI GeM Consortium. A03 genetic modifiers affecting the age at motor onset in Huntington's disease. J Neurol Neurosurg Psychiatry. 2014;85:A1-A2.
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