Psychosomatics 39:446-448, October 1998
© 1998 The Academy of Psychiatric Medicine
Recurrent Psychotic Depression Associated With GM2 Gangliosidosis
Mark B. Hamner, M.D.
Received May 24, 1996; revised October 7, 1996; accepted October 18, 1996. From the Psychiatry Service, Ralph H. Johnson Veterans Affairs (VA) Medical Center, Charleston, South Carolina. Address reprint requests to Dr. Hamner, Psychiatry Service (116A), Ralph H. Johnson VA Medical Center, 109 Bee Street, Charleston, SC 29401.
Key Words: Depression • Psychosis • Tay-Sachs • Gangliosidosis
The gangliosidoses are diseases secondary to abnormal accumulation of gangliosides in lysosomes due to deficiencies of ganglioside hydrolases. GM2 gangliosidoses are due to beta-hexosaminidase A deficiency. The inheritance is autosomal recessive with variable phenotypic expression. Relatively recently, an adult variant of Tay-Sachs disease has been described.1–7
There are several clinical subtypes of hexosaminidase A deficiency. Tay-Sachs disease (Type 1, Infantile) has an age at onset of 3 to 6 months and is characterized by motor weakness, doll-like facies, cherry-red spots in macular region, mental retardation, progressive blindness, deafness, convulsions, and age at death of less than 5 years. The pathology involves neuronal lipidosis, axonal degeneration, central demyelination, cortical gliosis, and cytoplasmic membranous bodies.
Sandoff's disease (Type 2) has clinical and pathologic aspects similar to Tay-Sachs. This disorder involves deficiency of both hexosaminidase A and B. The age at onset and clinical course are similar to infantile Tay-Sachs. Visceral histiocytosis may occur. Juvenile GM2 gangliosidosis (Type 3) has an age at onset of between 2 and 6 years and is characterized by progressive ataxia, dysarthria, spasticity, athetoid posturing of hands and extremities, seizures, and death between ages 5 and 15. Pathology involves neuronal lipidosis and cytoplasmic membranous bodies.
In adult or chronic GM2 gangliosidosis, the age at onset is from 5 to 25 years, but with slower progression of ataxia, dysarthria, weakness, and other neurological symptoms. Of particular relevance to mental health clinicians, psychiatric symptoms, including depression, psychosis, and dementia, have been reported in association with this variant. Clinically normal, healthy adults with partial hexosaminidase A deficiency have also been described. The following is a case of depression with psychotic features associated with the adult variant.
Case
A 45-year-old, left-handed man of Ashkenazi Jewish origin presented with a 3-year history of recurrent sad mood, anhedonia, decreased concentration, insomnia, severe anorexia, fatigue, psychomotor retardation, suicidal ideation, and auditory hallucinations. The sad mood was pervasive in that the patient was unable to recall when he had last felt "normal," experienced pleasure, or enjoyed activities. He had profound psychomotor retardation with minimal mobility, brief responses to questions, and virtually no verbal spontaneity.
He required much prompting by nursing staff to attend to activities of daily living or to eat or take fluids. His anorexia had resulted in about a 20-lb. weight loss at the time of admission. The treatment team was on the verge of initiating nasogastric tube feedings prior to the patient's subsequent clinical improvement. The insomnia was characterized by early morning awakening. The auditory hallucinations involved multiple voices that were mood-congruent, which were distressing to the patient, and at times involved commands to harm himself. These symptoms had not responded to previous trials with amitriptyline, chlorpromazine, or haloperidol. He had a 25-year history of progressive ataxia, uncoordination, tremor, dysarthria, weakness, muscle atrophy, fasciculation, and hyperreflexia. He was married, with two children in good health, and had been unemployed for over 20 years due to neurological disability. He had no known family history of mental illness or neurological disorder.
Lysosomal enzyme assay obtained prior to this admission revealed a beta-hexosaminidase A plus B activity of 525.2 nanomoles/·hr-1 · mg-1 (% A: 4.7). Normal activity was 716.8 ± 27.0 nanomoles/hr/mg with (% A: 55.8). This was consistent with severe hexosaminidase A deficiency. No other abnormalities of lysosomal enzyme activity were detected. Pathology prior to admission demonstrated that ganglion cells from rectal biopsy contained large numbers of typical membrane-bound cytoplasmic lamellar bodies.
Neuropsychological testing was consistent with impairment in attention and concentration, conceptual flexibility, and visual-spatial performance. Magnetic resonance imaging and computed tomography scan of the head were both consistent with advanced cerebellar atrophy. Electrodiagnostic studies, including electromyography testing, were consistent with motor neuron disease. The psychiatric diagnosis was major depressive disorder with psychotic and melancholic features secondary to adult GM2 gangliosidosis. The patient had a marked response to combined desipramine (100 mg po qhs) and lithium (300 mg po bid): complete resolution of both depressive and psychotic symptoms. An antipsychotic was not required and was not initiated due to concerns about affecting his neurologic status. No exacerbation in neurological symptoms was noted with psychotropic medication. Lithium was later discontinued, and remission was maintained with desipramine. At the time of last follow-up, 1 year later, the patient remained free of major depressive or psychotic features and did not appear to have adverse neurologic effects from the antidepressant.
Discussion
Adult GM2 gangliosidosis should be considered in the differential diagnosis of psychiatric patients with recurrent psychosis, mood disorders, or dementia who also show evidence for characteristic neurologic symptoms or who have certain risk factors such as Ashkenazi Jewish origin or a family history of Tay-Sachs disease. The neurologic symptoms that are referable to spinocerebellar degeneration or motor neuron disease may include ataxia, incoordination, dysanthia, tremor, and weakness. Neurologic examination may also demonstrate muscle atrophy, fasciculations, and hyperreflexia. Diagnostic strategies include lysosomal enzyme assays for hexosaminidase A activity, structural neuroimaging, peripheral mucosal biopsy for neuronal cell histology, and nerve conduction velocity testing with appropriate neurological consultations. These tests may reveal decreased hexosaminidase A activity, cortical or cerebellar atrophy, delayed nerve conduction, and neuronal cell membrane–bound lamellar inclusion bodies. Psychotropic medication may be indicated with careful monitoring for exacerbation of neurologic symptoms. Genetic counseling may be indicated.
This case adds to the literature suggesting that mood disorder and psychosis may be prominent features in the clinical presentation of adult Tay-Sachs. An interesting question is whether hexosaminidase A deficiency becomes manifest as depression or other psychiatric disturbances without neurologic findings. The adult variant of GM2 gangliosidosis is an example of a well-defined metabolic disorder with a genetic predisposition that produces delayed onset of neuropsychiatric symptoms. Understanding the pathophysiology of these disorders may conceivably yield clues to understanding primary psychiatric syndromes. In a review of 33 patients with adult GM2 gangliosidosis, Navon et al.5 noted psychosis in 10 (30%), dementia or memory disturbance in 6 (18%), depression in 3 (9%), and mania in 1 (3%). Streifler et al.8 reported three cases of adult GM2 gangliosidosis with various neuropsychiatric features, including psychosis, depression, and delirium. Hurowitz et al.9 reported two cases of psychiatric disorder associated with GM2 gangliosidosis. Neither case involved psychotic features. One patient had recurrent depression, and the other experienced a bipolar type II syndrome.
Neurologic symptoms may be more severe in psychotic vs. nonpsychotic patients with adult GM2 gangliosidosis.4 This may reflect a more severe or diffuse neuronal cell damage in the central nervous system. Alternatively, psychotropic medications may worsen neurologic symptoms either via side effects, for example, extrapyramidal side effects of neuroleptics or, theoretically, by contributing directly to ganglioside accumulation. Regarding the latter, antidepressants or other psychotropics may induce lipidosis. In one study, imipramine induced secretion of hexosaminidase from normal human skin fibroblasts in vitro, and this effect was prevented by preincubation with dexamethasone.5 The in vivo effects and clinical implications of this are unclear. If antidepressants or other psychotropics are given, there should be close observation for exaggerated side effects, for example, drug-induced parkinsonism or dystonic reactions from antipsychotics or worsening of neurologic symptoms, for example, incoordination, tremor, ataxia. Hurowitz et al.9 noted that exposure to phenothiazines and heterocyclic antidepressants may have worsened the course of illness in one patient. Since, theoretically, heterocyclic compounds may affect ganglioside accumulation, it is reasonable to choose a nonheterocyclic compound.
There are several possible mechanisms underlying psychiatric disturbance in adult GM2 gangliosidosis. Organic mental disorders may be due to neuronal involvement in the brain regions implicated in emotions, cognition, and perception. There may be involvement of critical neurotransmitter systems, including norepinephrine, dopamine, or acetylcholine, which have been implicated in psychoses, mood disorders, and dementia. In this patient, the improvement in psychotic depression with desipramine, a relatively selective norepinephrine reuptake inhibitor, may implicate noradrenergic dysfunction. Also, given the evidence for cerebellar dysfunction in this patient, it is notable that collaterals of noradrenergic neurons in the locus ceruleus have extensive innervation in the cerebellum as well as the cerebral cortex. Future work should include structural and functional neuroimaging studies to investigate potential correlations between neuroanatomic changes and psychiatric symptoms. Treatment studies should use prospective assessment with structured psychiatric and neurologic rating scales to better quantify efficacy and neurologic effects of psychotropics, respectively. Also of particular interest would be the potential efficacy of novel antipsychotic agents with reported minimal extrapyramidal side effects (at therapeutic doses compared with the traditional agents) in treating the associated psychosis in these patients.
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L. C. Frey, S. P. Ringel, and C. M. Filley
The Natural History of Cognitive Dysfunction in Late-Onset GM2 Gangliosidosis
Arch Neurol,
June 1, 2005;
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989 - 994.
[Abstract]
[Full Text]
[PDF]
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