Neurologic involvement in patients with atypical Chediak-Higashi disease

Abstract

Objective: To delineate the developmental and progressive neurodegenerative features in 9 young adults with the atypical form of Chediak-Higashi disease (CHD) enrolled in a natural history study.

Methods: Patients with atypical clinical features, but diagnostically confirmed CHD by standard evaluation of blood smears and molecular genotyping, underwent complete neurologic evaluation, MRI of the brain, electrophysiologic examination, and neuropsychological testing. Fibroblasts were collected to investigate the cellular phenotype and correlation with the clinical presentation.

Results: In 9 mildly affected patients with CHD, we documented learning and behavioral difficulties along with developmental structural abnormalities of the cerebellum and posterior fossa, which are apparent early in childhood. A range of progressive neurologic problems emerge in early adulthood, including cerebellar deficits, polyneuropathies, spasticity, cognitive decline, and parkinsonism.

Conclusions: Patients with undiagnosed atypical CHD manifesting some of these wide-ranging yet nonspecific neurologic complaints may reside in general and specialty neurology clinics. The absence of the typical bleeding or infectious diathesis in mildly affected patients with CHD renders them difficult to diagnose. Identification of these individuals is important not only for close surveillance of potential CHD-related systemic complications but also for a full understanding of the natural history of CHD and the potential role of the disease-causing protein, LYST, to the pathophysiology of other neurodevelopmental and neurodegenerative disorders.

Figure 1. Hair and skin pigmentation, blood smears, and hair microscopy of representative patients with atypical Chediak-Higashi disease (CHD)

(A) Hair and skin pigmentation. (B) Characteristic giant inclusions (arrows) within neutrophils are numerous and variable in size. (C) A solitary giant inclusion is typically seen within lymphocytes. (D) Light microscopy reveals atypical pigment clumping within hair shafts. Note uniform distribution of pigment in normal hair (CHD-5 inset).

Figure 2. LYST protein expression and lysosome size and distribution in Chediak-Higashi disease (CHD) fibroblasts

(A) High-molecular-weight immunoblots of protein extracts from normal control fibroblasts (lane 1), negative control fibroblasts CHD-4 (lane 2), and 7 different CHD patients' fibroblast cultures. β-Actin was used as a loading control. Values given are percentage expression of LYST normalized to β-actin and relative to control. (B) Fibroblasts are stained with LAMP-1 antibodies (green) to visualize lysosomal membranes and with an F-actin marker (phalloidin, red) to visualize the cell boundaries. Control fibroblasts show a typical distribution of lysosomes throughout the cell. Classic CHD-4 fibroblasts show enlarged lysosomes restricted to the perinuclear area. CHD-5 fibroblasts show enlarged lysosomes in the perinuclear area and normal-sized lysosomes in the periphery. CHD-6 fibroblasts show slightly enlarged lysosomes. CHD-17 and CHD-18 fibroblasts have slightly enlarged lysosomes with a typical distribution of lysosomes throughout the cell. Marked white dotted squares in left panels are zoomed out in right panels. Scale bar 20 μm.

Figure 3. Brain MRIs of patients with atypical Chediak-Higashi disease (CHD)

Midline MRI sagittal images for 6 patients with atypical CHD obtained at the time of their initial evaluation. (A–F) Patients CHD-6, 19, 24, 17, 23, and 20. The tentorial angle (in degrees) and lines converging on the tentorial angle are represented for each image. (G) Similarly processed image in one representative age-matched control. (H, I) Coronal MRI views at the level of the cerebellar hemispheres for mild (case CHD-23) and advanced (case CHD-20) neurologic impairment demonstrate cerebral and cerebellar atrophy in the more severely affected patient.