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Ovid: Fifty Neurologic Cases from Mayo Clinic

Editors: Noseworthy, John H. Title: Fifty Neurologic Cases from Mayo Clinic, 1st Edition Copyright ©2004 Oxford Unversity Press (Copyright 2004 by Mayo Foundation for Medical Education and Research) > Table of Contents > Case 2: Episodic psychosis, progressive ataxia, and spasticity Case 2: Episodic psychosis, progressive ataxia, and spasticity CASE 2 History A 30-year-old man first developed trouble arising from the floor and climbing stairs during puberty. Through adolescence, he had a progressive decrease in academic and athletic performance. At age 20, he had a manic episode with paranoia. Over the next 10 years, he had multiple psychiatric hospitalizations for episodes of psychosis, mania, and depression that were relatively refractory to medication. Also, he developed progressive slurred speech, trouble swallowing, and a gait disorder resulting in frequent falls. Recently, he has become increasingly withdrawn, anxious, depressed, and distractible, and occasionally he appeared unresponsive. There was no past medical history of meningitis, substance abuse, or toxin exposure. The paternal family was of northern European descent and the maternal family was of non-Jewish Russian and Yugoslavian ancestry. One brother was said to have ataxia and a bipolar mood disorder. Examination He was withdrawn and slow to respond to tests of cognitive function. He made errors on tests of attention, calculation, and recall. He had a mixed spastic-ataxic dysarthria. There was moderate, asymmetric dysdiadochokinesia and dysmetria of the upper and lower limbs, and gait was ataxic. Appendicular spasticity, hyperreflexia, and a right Babinski response were present. Cranial nerve function, sensory examination findings, and strength were normal. There were no Kayser-Fleischer rings. Investigations Magnetic resonance imaging studies showed marked cerebellar and brainstem atrophy and a posterior fossa cyst (Figure). Studies for spinocerebellar ataxia types 1, 2, 3, 6, and 8 and Friedreich’s ataxia were negative. Test results for vitamin B12 metabolism, VDRL, ceruloplasmin, thyroid-stimulating hormone, human immunodeficiency virus, and vitamin E deficiency were normal, as were results of cerebrospinal fluid analysis and electroencephalography. Anti-gliadin antibodies were weakly positive. P.6

FIGURE. Sagittal magnetic resonance imaging scan demonstrating marked cerebellar and moderate brainstem atrophy.

DIAGNOSIS CASE 2 GM2 gangliosidosis (adult-onset Tay-Sachs disease)
Commentary by Dr. James H. Bower The patient’s total leukocyte hexosaminidase activity was slightly reduced at 14.5 U/g protein (normal, 16.4-36.2 U/g protein), but percent A was only 5% (normal, 63%-75%). This finding confirmed the diagnosis of GM2 gangliosidosis (adult-onset Tay-Sachs disease). The diagnosis was suspected because the disorder was slowly progressive, spanning more than two decades, with features of cognitive, behavioral, extrapyramidal, pyramidal, and cerebellar dysfunction, and demonstrated cerebellar and brainstem atrophy. GM2 gangliosidoses are a group of autosomal recessive disorders that result from the accumulation of GM2 ganglioside in neuronal lysosomes. The β-hexosaminidase enzyme cleaves the N-acetylgalactosamine moiety from the GM2 ganglioside. Deficiency of this enzyme or its cofactor, the GM2 activator protein, leads to the accumulation of GM2 ganglioside. β-Hexosaminidase A consists of α and β subunits, whereas β-hexosaminidase B consists of β subunits only. The α subunit is encoded on chromosome 15. More than 75 identified mutations of this gene result in the deficiency of β-hexosaminidase A. The β subunit is encoded on chromosome 5, and 14 identified mutations of this gene result in the deficiency of β-hexosaminidase A and β-hexosaminidase B. Other mutations have been identified in the GM2 activator protein, leading to more than 100 mutations that can cause the accumulation of GM2 ganglioside in lysosomes. Tay-Sachs disease is an infantile encephalopathy that usually affects the Ashkenazi Jewish population. It is caused by the absence of β-hexosaminidase A. A clinically similar disease, Sandhoff’s disease, is caused by the absence of β-hexosaminidase A and β-hexosaminidase B. Since the identification of Tays-Sachs disease and Sandhoff’s disease, however, it has been recognized that late juvenile and adult-onset GM2 gangliosidoses also exist and result from only partial enzyme deficiencies. Adult-onset GM2 gangliosidoses usually present in the first through third decades of life with a varied phenotypic spectrum. Atypical spinocerebellar ataxia, atypical motor neuron disease, and atypical psychosis are the three most common presentations. P.8
Atypical spinocerebellar ataxia with spasticity, dysarthria, and muscle atrophy has been reported in some families. Upper and lower motor neuron findings, dementia, and psychosis may also be present. Patients may present with motor neuron disease—weakness, cramps, proximal muscle wasting, hyperreflexia, and extensor plantar responses. Ataxia or psychosis may appear later. Psychosis has been reported in up to one-half of all patients with adult-onset GM2 gangliosidosis. A mood disorder (either depression or mania or both) has been reported in up to 40% of patients. Phenothiazines and tricyclic antidepressants may worsen the condition because they may inhibit the activity of lysosomal enzymes and thus increase lipidosis. Other reported clinical features include dystonia, dementia, choreoathetosis, and peripheral neuropathy. Computed tomographic and magnetic resonance imaging scans show cerebellar atrophy and sometimes cerebral atrophy. Rectal biopsy specimens can show the typical membranous cytoplasmic bodies in swollen ganglion cells. The measurement of β-hexosaminidase A activity is a relatively easy laboratory test to perform to help make the diagnosis. Although only three mutations account for 98% of the mutations that lead to Tay-Sachs disease in the Ashkenazi Jewish population, the numerous mutations that cause the disease in other populations make routine genetic testing in these populations impractical. Treatment has been unsuccessful. Attempts at enzyme infusion, substrate depletion, bone marrow transplantation, and gene therapy are continuing. REFERENCE Federico A, Palmeri S, Malandrini A, et al. The clinical aspects of adult hexosaminidase deficiencies. Dev Neurosci 1991;13:280-7.

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