Dysarthria and Stutter as Presenting Symptoms of Late‐Onset Tay‐Sachs Disease in Three Siblings

Abstract

Late-onset Tay-Sachs disease (LOTS) is a rare autosomal-recessive genetic disorder caused by insufficient activity of the lysosomal enzyme, beta-hexosaminidase A, resulting in intracellular accumulation of gangliosides in the central nervous system. Clinical manifestations can include unsteadiness in gait, muscle weakness, cognitive dysfunction, psychiatric disturbance, and dysarthric speech. The variable presentation of these symptoms, combined with the late onset of the disease, often results in misdiagnosis. We present video of 3 sibling cases of LOTS in which a dysarthric stutter was the sole presenting symptom in order to better characterize the phenotype of this disease.Late-onset Tay-Sachs disease (LOTS) is a rare autosomal-recessive genetic disorder caused by insufficient activity of the lysosomal enzyme, beta-hexosaminidase A, resulting in intracellular accumulation of gangliosides in the central nervous system. Clinical manifestations reported in the literature include ataxia, unsteadiness of gait, poor coordination, muscle weakness, difficulty climbing stairs, tremor, extrapyramidal signs (parkinsonism), pyramidal tract signs, dystonia, dysphagia, achalasia, dysarthria, stutter, saccades, ocular motor disturbances, motor neuron disease, cognitive dysfunction, intellectual impairment, psychiatric disturbance, psychosis, bipolar disorder, depression, and anxiety, all in the absence of a fundoscopic cherry-red spot (observed in infantile Tay-Sachs). [1][2][3][4][5][6][7][8] Imaging findings reported in the literature include cerebellar atrophy, cerebral atrophy, and hypodensity in the thalamus. 2,3,[5][6][7] The variable presentation of LOTS patients, combined with onset of symptoms in adolescence or adulthood, often contributes to misdiagnosis. In addition, video of the clinical presentation of a LOTS patient has never been presented in a medical journal. We present video of 3 sibling cases of LOTS in which a dysarthric stutter was the sole presenting symptom in order to better characterize the phenotype of this disease. Cases Case 1This 42-year-old female, born to nonconsanguineous parents of non-Jewish European background, first developed a stutter at approximately age 10. She participated in speech therapy at that time with no improvement. At age 22, the patient was evaluated for recurrent paroxysms of encephalopathy after an episode of psychosis. On exam, she exhibited symptoms of mild cognitive impairment, but had no cortical findings of aphasia, apraxia, agnosia, or neglect. The remainder of her neurological exam revealed bilateral Babinski signs, mild ataxia, and staccato dysarthria. Subsequent diagnostic testing revealed significantly decreased hexosaminidase A levels with normal total hexosaminidase, consistent with a diagnosis of LOTS. Brain MRI brain revealed mild cerebellar atrophy. Case 2This 45-year-old female, the older sister of the patient described in case 1, developed a stutter at age 8. In her early twenties, she was diagnosed with bipolar affective disorder and was hospital...

Oromandibular Dystonia – A Systematic Review

“…Jaw opening dystonia and facial dystonia have been described in type III GM1 gangliosidosis, observed in >80% of patients. [ 72 73 74 ] These are also seen in Niemann-Pick disease type C,[ 75 ] GM2 gangliosidosis,[ 76 ] Cerebrotendinous xanthomatosis,[ 77 ] Tay-Sachs disease[ 78 ] and Ataxia telangiectasia. [ 79 80 ]…”

Quantitative oculomotor and nonmotor assessments in late-onset GM2 gangliosidosis

“…Patients tend to have a slightly nasal dysarthria, sometimes with a stuttering quality, and stuttering can be an initial manifestation. 36,37 There is also a frequent, jerky, highfrequency postural tremor. It was notable that in our cohort, all patients with Sandhoff disease had normal speech and did not have postural tremor, in comparison to their LOTS counterparts.…”

The landscape of functional brain network impairments in late-onset GM2 gangliosidosis

“…Although cerebellar impairment has been the central observation in prior non-fMRI LOGG studies, extra-cerebellar abnormalities have also been described. These include cerebral white-matter hypo-density [21] and atrophy [31], reduced glucose metabolism in bilateral temporal and occipital lobes [22], and impaired occipital neuronal health [23]. With this background, we set out to discuss findings from each fMRI measure.…”

“…), hinting that deeper mechanistic insights beyond cerebellar atrophy are needed to better understand this disease. Other infrequent imaging findings in LOGG have included cerebral atrophy [31], thalamic hypodensities [31], mild midbrain and brainstem atrophy [32], and white matter lesions [33].…”