Thursday, February 11, 2021

Juvenile Huntington's disease

Cepeda C, Oikonomou KD, Cummings D, Barry J, Yazon VW, Chen DT, Asai J, Williams CK, Vinters HV. Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations. J Neurosci Res. 2019 Dec;97(12):1624-1635. doi: 10.1002/jnr.24503. Epub 2019 Jul 28. PMID: 31353533; PMCID: PMC6801077.


Huntington's disease (HD), an inherited neurodegenerative disorder that principally affects striatum and cerebral cortex, is generally thought to have an adult onset. However, a small percentage of cases develop symptoms before 20 years of age. This juvenile variant suggests that brain development may be altered in HD. Indeed, recent evidence supports an important role of normal huntingtin during embryonic brain development and mutations in this protein cause cortical abnormalities. Functional studies also demonstrated that the cerebral cortex becomes hyperexcitable with disease progression. In this review, we examine clinical and experimental evidence that cortical development is altered in HD. We also provide preliminary evidence that cortical pyramidal neurons from R6/2 mice, a model of juvenile HD, are hyperexcitable and display dysmorphic processes as early as postnatal day 7. Further, some symptomatic mice present with anatomical abnormalities reminiscent of human focal cortical dysplasia, which could explain the occurrence of epileptic seizures in this genetic mouse model and in children with juvenile HD. Finally, we discuss recent treatments aimed at correcting abnormal brain development.

From the article

HD is generally conceived as an adult-onset neurodegenerative disorder. However, another less common (5–10%) juvenile form (JHD, known as rigid or Westphal variant) of the disease also exists, typically when the CAG triplet repeat expansion is >65. Studies have shown that the sex of the transmitting parent, usually the father, exerts a major influence on CAG repeat expansion leading to earlier symptom onset. The symptoms of JHD differ from those typically seen in adult-onset HD. Children with HD display mental retardation, hyperactivity, and aggressive behavior. Some of these children also have microcephaly, suggesting that this form of HD may represent a developmental rather than a neurodegenerative disorder. With disease progression, dystonia, rigidity, and chorea also occur. A fundamental difference between JHD and adult-onset HD is the high prevalence of epileptic seizures in the juvenile form. The cause of epileptic seizures remains unknown. However, we have hypothesized that seizures could be the result of faulty development of cortical circuits, similar to those observed in malformations of cortical development (MCD), specifically focal cortical dysplasia (FCD) of Taylor.  This was based on evidence that in some animal models of HD, and presumably also in human cases, the cerebral cortex progressively becomes hyperexcitable.

Kendrick LM, Hudgell D, Hellman A, Weaver MS. Attending to Total Pain in Juvenile Huntington Disease: A Case Report Informed by Narrative Review of the Literature. J Palliat Care. 2019 Jul;34(3):205-207. doi: 10.1177/0825859719835560. Epub 2019 Apr 5. PMID: 30950323.


Objectives: To consider the impact of juvenile Huntington disease (JHD) from a biomedical, symptom burden, and total pain palliative care perspective. 

Methods: This case report was informed by a narrative review of the literature with inclusion of expert opinion from pediatric palliative care, an adult and pediatric neurologist, and a child psychiatrist. Audio-recorded qualitative interview and coauthorship with the pediatric patient's primary caregiver (his mother). 

Results: The JHD impacts all domains of child and family function. 

Significance of results: Application of the concept of total pain to JHD informs and guides care for this complex, challenging condition.

Cui SS, Ren RJ, Wang Y, Wang G, Chen SD. Tics as an initial manifestation of juvenile Huntington's disease: case report and literature review. BMC Neurol. 2017 Aug 8;17(1):152. doi: 10.1186/s12883-017-0923-1. PMID: 28789621; PMCID: PMC5549341.


Background: Huntington's disease (HD) is an autosomal dominant disorder, typically characterized by chorea due to a trinucleotide repeat expansion in the HTT gene, although the clinical manifestations of patients with juvenile HD (JHD) are atypical. 

Case presentation: A 17-year-old boy with initial presentation of tics attended our clinic and his DNA analysis demonstrated mutation in the HTT gene (49 CAG repeats). After treatment, his symptoms improved. Furthermore, we performed literature review through searching the databases and summarized clinical features in 33 JHD patients. 

Conclusion: The most prevalent symptoms are ataxia, and two cases reported that tics as initial and prominent manifestation in JHD. Among them, 88% patients carried CAG repeats beyond 60 and most of them have family history. This case here illustrates the variable range of clinical symptoms of JHD and the necessity of testing for the HD mutation in young patients with tics with symptoms unable to be explained by Tourette's syndrome (TS).

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