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

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; Huntington’s disease; huntingtin protein; immunohistochemistry; juvenile Huntington’s disease; literature review; neuropathology.

Figure 1

Brain MRI in juvenile Huntington’s disease (case 1). Neuroimaging demonstrates diffuse volume loss involving the caudate nucleus with associated ventriculomegaly (T2) as well as mild cerebellar volume loss, particularly of the vermis (T1).

Figure 2

Four-generation pedigree. Case 1 (IV-1) is the affected son of case 2 (III-2). Family history indicates that members of earlier generations also had Huntington’s disease, including the father and paternal grandmother of case 2.

Figure 3

Gross pathology. The juvenile (A) and the adult onset (D) case both demonstrate moderate atrophy of the caudate nucleus and putamen (Vonsattel grade 3). Sagittal sections of the cerebellum in the juvenile case also highlight the mild medial, predominantly vermian, atrophy (B) with thinning of the folia (C). In contrast, the cerebellum in the late onset case lacks significant cerebellar atrophy (E, F).

Figure 4

Histopathology of the cortex and neostriatum (caudate nucleus). There is no significant loss of neocortical neurons in the juvenile case (A) compared to mild to focally moderate neuron loss in the adult onset case (D) (H&E) associated with increased astrogliosis in both cases (B, E) (GFAP). Huntingtin-positive intranuclear and cytoplasmic neuronal inclusions are present in the cerebral cortex of both cases (C, F). There is significant neostriatal neuron loss (G, J) (H&E) and associated astrogliosis (H, K) (GFAP). Striatal Huntingtin-positive neuronal intranuclear and cytoplasmic inclusions are present in both cases (I, L).

Figure 5

Histopathology of the cerebellum. Marked atrophy of cerebellar cortex with associated severe gliosis is evident in H&E, Bielschowsky, and GFAP-stained sections in JHD (A-E) but not in the adult onset case (G-K). Rare huntingtin-positive intranuclear inclusions are identified in the cerebellum of the JHD brain (F) that are not identified in the AOHD case (L).