Neuropathological Comparison of Adult Onset and Juvenile Huntington’s Disease with Cerebellar Atrophy: A Report of a Father and Son

Article type: Research Article

Authors: Latimer, Caitlin S.^a | Flanagan, Margaret E.^{a; 1} | Cimino, Patrick J.^a | Jayadev, Suman^{b; c} | Davis, Marie^{b; d} | Hoffer, Zachary S.^{a; 3} | Montine, Thomas J.^{a; 2} | Gonzalez-Cuyar, Luis F.^a | Bird, Thomas D.^{b; c; d} | Keene, C. Dirk^{a; *}

Affiliations: [a] Department of Pathology, Division of Neuropathology, University of Washington School of Medicine, Seattle, WA, USA | [b] Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA | [c] HDSA Center of Excellence at the University of Washington Medical Center, Seattle, WA, USA | [d] GRECC, VA Puget Sound Health Care System, Seattle, WA, USA

Correspondence: [*] Correspondence to: C. Dirk Keene, MD, PhD, Nancy and Buster Alvord Endowed Chair in Neuropathology, Associate Professor of Pathology, Division of Neuropathology, Harborview Medical Center, 325 Ninth Ave, MS 359791, Seattle, WA 98104, USA. Tel.: +1 206 744 8273; Fax: +1 206 897 4688; E-mail: cdkeene@uw.edu.

Note: [1] Present Address: University of Minnesota, Minneapolis, MN, USA.

Note: [2] Present Address: Stanford University, Department of Pathology, Stanford, CA, USA.

Note: [3] Present Address: Madigan Healthcare System, Joint Base Lewis McChord, WA, USA.

Abstract: Background:Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by a trinucleotide (CAG) repeat expansion in huntingtin (HTT) on chromosome 4. Anticipation can cause longer repeat expansions in children of HD patients. Juvenile Huntington’s disease (JHD), defined as HD arising before age 20, accounts for 5–10% of HD cases, with cases arising in the first decade accounting for approximately 1%. Clinically, JHD differs from the predominately choreiform adult onset Huntington’s disease (AOHD) with variable presentations, including symptoms such as myoclonus, seizures, Parkinsonism, and cognitive decline. Objective:The neuropathologic changes of AOHD are well characterized, but there are fewer reports that describe the neuropathology of JHD. Here we report a case of a six-year-old boy with paternally-inherited JHD caused by 169 CAG trinucleotide repeats who presented at age four with developmental delay, dysarthria, and seizures before dying at age 6. The boy’s clinical presentation and neuropathological findings are directly compared to those of his father, who presented with AOHD and 54 repeats. Methods:A full autopsy was performed for the JHD case and a brain-only autopsy was performed for the AOHD case. Histochemically- and immunohistochemically-stained slides were prepared from formalin-fixed, paraffin-embedded tissue sections. Results:Both cases had neuropathology corresponding to Vonsattel grade 3. The boy also had cerebellar atrophy with huntingtin-positive inclusions in the cerebellum, findings not present in the father. Conclusions:Autopsies of father and son provide a unique opportunity to compare and contrast the neuropathologic findings of juvenile and adult onset HD while also providing the first immunohistochemical evidence of cerebellar involvement in JHD. Additionally this is the first known report to include findings from peripheral tissue in a case of JHD.

Keywords: Autopsy, huntingtin protein, Huntington’s disease, immunohistochemistry, juvenile Huntington’s disease, literature review, neuropathology

DOI: 10.3233/JHD-170261

Journal: Journal of Huntington's Disease, vol. 6, no. 4, pp. 337-348, 2017