Adult-Onset Sandhoff Disease in a Filipino Patient: Asymmetric Weakness, Whole HEXB Gene Deletion, and Coexisting MYH7 Pathogenic Variant

Discussion

Adult-onset SD appears to be rare in the Filipino population. The atypical asymmetric pattern of weakness from LMN disease and the whole HEXB gene deletion occurring in compound heterozygosity with an established pathogenic missense variant are novel clinical and genetic findings, respectively. Coexistence of an independent MYH7 pathogenic variant is not reported in SD. Thus, our patient harbors pathogenic variants in 2 genes causative of rare disorders (double trouble), both potentially involving the neuromuscular system.

Hereditary adult-onset LMN disorders encompass various disorders, including SD, Tay-Sachs disease, 5q- and non–5q-SMA, Kennedy disease, and familial ALS. Adult-onset SD is uncommon. Retrospective review of clinically and biochemically characterized adult-onset SD cases combined from a French cohort and the literature identified only 17 patients carrying 14 unique HEXB variants (frequently p.Arg505Glu in homozygosity).¹ Among LMN presentations, weakness is classically symmetric, beginning in quadriceps and psoas muscles and later involving the upper limbs, predominantly triceps. Our patient had clearly asymmetric LMN disease, although predominantly involved muscles typically affected in SD. Most patients with SD display generalized cerebellar atrophy, often with minimal to no cerebellar symptoms or signs associated, as in our patient (Figure 1).

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Figure 1 Cerebellar Atrophy in Adult-Onset Sandhoff Disease

Sagittal (A) and axial (B) T2 fluid-attenuated inversion recovery images demonstrate generalized cerebellar atrophy.

Pathogenic variants in MYH7 causative of cardiomyopathy cluster in the head and neck domain of the protein.⁵ Those causative of skeletal myopathy with or without cardiomyopathy localize to the distal rod domain, although exceptions occur.⁵ The patient's MYH7 pathogenic variant (p.Arg1045His) in the distal neck domain could explain hypertrophic cardiomyopathy and congestive heart failure in the brother and mother, respectively. However, this variant had no cardiac correlate in the proband and her sister, suggesting low- or age-related penetrance, well described in MYH7-related cardiomyopathies.⁶ MYH7 pathogenic variants can cause skeletal myopathy; however, this specific variant is not reported with skeletal myopathy, and no definite myopathic features were demonstrated on muscle biopsy (Figure 2). Nevertheless, we cannot exclude that the MYH7 variant could contribute to the patient's weakness. Indeed, the MYH7 myopathologic spectrum comprises varied findings (congenital fiber-type disproportion, hyaline bodies staining for slow heavy chain myosin, and cores/minicores) including nonspecific features.⁷

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Figure 2 Muscle Biopsy Findings in Adult-Onset Sandhoff Disease

Hematoxylin and eosin–stained section (A) demonstrates a group of atrophic muscle fibers (arrow). The atrophic fibers overreact for nonspecific esterase (B) and in ATPase-reacted section at pH 4.3 (C) are of both histochemical type (type 1 fibers are dark), indicating denervation atrophy. ATPase-reacted section at pH 4.6 (D) demonstrates grouping of both type 1 (dark) and type 2A (light) muscle fibers, consistent with reinnervated skeletal muscle (magnification: ×20, A–C; ×5, D). There was no evidence of muscle lysosomal dysfunction by acid phosphatase or LAMP2 staining (not shown).