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

Objective: To describe a Filipino patient with adult-onset Sandhoff disease manifesting with an atypical asymmetric lower motor neuron syndrome due to a novel whole HEXB deletion in trans with a pathogenic missense variant and with a coexisting MYH7 pathogenic variant.
Methods: We performed clinical, laboratory, myopathologic, and genetic evaluation with next-generation sequencing in the proband and targeted mutational analysis in an asymptomatic sibling.
Results: A 59-year-old Filipino woman presented with 15 years of slowly progressive, asymmetric, proximal-predominant, lower greater than upper extremity weakness, mildly elevated creatine kinase, and generalized cerebellar atrophy. Serum total β-hexosaminidase was significantly reduced, and hexosaminidase A percentage was increased. We identified a novel HEXB whole gene deletion in compound heterozygosity with a pathogenic missense variant (c.1513C>T, p.Arg505Trp) previously described in 1 patient with adult-onset Sandhoff disease. The patient, with a family history of cardiomyopathy, has a coexisting MYH7 pathogenic variant (c.3134G>A, p.Arg1045His), causative of cardiomyopathy but without cardiac involvement, likely due to variable penetrance. Myopathic features were absent from skeletal muscle biopsy. Discussion: This patient expands the genotypic, phenotypic, and ethnic spectrum of Sandhoff disease and highlights challenges generated by low-penetrant pathogenic variants, especially when considering a potentially polygenic phenotype.

Sandhoff disease (SD) is a rare autosomal recessive GM2 gangliosidosis due to pathogenic variants in HEXB, encoding the β subunit of β-hexosaminidase.[1] Clinically, GM2 gangliosidoses are indistinguishable and classified based on onset age: infantile (most common, featuring hypotonia, exaggerated startle, spasticity, seizures, blindness, and death before age 4), late infantile/juvenile (onset between 2 and 10 years with psychomotor regression, ataxia, spasticity, and seizures), and adult (least common, presenting with symmetric lower motor neuron (LMN) syndrome, ataxia, tremor, dystonia, and/or psychiatric features). Slow skeletal muscle/β-cardiac myosin heavy chain (MYH7)-related disorders are similarly varied, including autosomal dominant hypertrophic,[2] dilated,[3] and arrhythmogenic cardiomyopathy[4] and skeletal myopathies with or without cardiomyopathy.[5] Herein, we describe a Filipino patient with a family history of cardiomyopathy presenting with progressive, asymmetric LMN syndrome due to adult-onset SD with compound heterozygous HEXB pathogenic variants, including a novel whole HEXB deletion, in addition to a coexisting MYH7 pathogenic variant.

Case Presentation

The proband is a 59-year-old woman born to nonconsanguineous Filipino parents. At age 44 years, she developed slowly progressive, proximal lower limb weakness and within 10 years proximal upper limb weakness and muscle cramps. Her mother had congestive heart failure (onset in seventies), and a 55-year-old brother had hypertrophic cardiomyopathy (onset age 45 years) without reported muscle weakness. Four additional brothers and 2 sisters were asymptomatic.

Neurologic examination revealed asymmetric, proximal-predominant weakness (Table 1). Laboratory, imaging, electrodiagnostic, and myopathologic findings were as listed (Table 1). Serum hexosaminidase profile suggested SD. Next-generation sequencing panels of genes causative of lysosomal storage disorders, common myopathies, and peripheral neuropathies, including motor axonopathies (eTable 1, links.lww.com/NXG/A521; performed at Invitae, San Francisco, CA, in April 2021), identified a novel deletion of the full coding sequence of HEXB and a missense variant (c.1513C>T, p.Arg505Trp). The deletion, as other loss-of-function variants in HEXB, is expected to be pathogenic. The missense variant affects a highly conserved amino acid and was reported in compound heterozygosity in 1 patient with adult-onset SD.[1] In silico model predictions for this variant effect on protein structure and function were conflicting (SIFT 0.00, PolyPhen-2 probably damaging, and Align-GVGD Class C0). The patient also carried an MYH7 pathogenic variant (c.3134G>A, p.Arg1045His), segregating in families with cardiomyopathy,[2-4] but without abnormal cardiac findings. Targeted mutational analysis in an asymptomatic sister with normal neurologic examination demonstrated only the whole HEXB gene deletion, supporting the trans status of the patient's HEXB variants. This sister also carried the MYH7 variant without clinical correlate and normal ECG and echocardiogram. The remaining relatives in the Philippines were unavailable for evaluation.

Table 1

Neurologic Examination, Laboratory, Electrophysiologic, and Myopathologic Features

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).

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]

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).