Gaucher's disease is a rare, autosomal recessive, glycosphingolipid storage disease caused by mutations in the gene coding for lysosomal enzyme glucocerebrosidase.1 Although almost 300 unique mutations have been identified,2 clinical presentation can be categorized into three subtypes based on the absence (Type 1) or presence (Types 2 and 3) and extent of neurological symptoms. Type 1 (non-neuronopathic) is characterized by anemia, thrombocytopenia, hepatosplenomegaly, and skeletal complications, whereas Type 2 (infantile, acute neuronopathic) has severe fetal and central nervous system complications in addition to clinical manifestations of Type 1.3 Symptoms include abnormal eye movements, dystonia, myoclonic seizures, hydrops fetalis, and ichthyosis. Unlike Type 2 (infantile, acute neuronopathic), which reduces lifespan to 1 to 3 years, Type 3 (chronic, neuronopathic) has a more indolent and progressive course of illness with neurological complications predominating in later years. This report describes a person who developed Gaucher's disease and, some years later, a psychotic disorder. Phenomenology in previous case reports and possible links between these disorders are discussed.
The patient was a 44-year-old man who was admitted to the inpatient psychiatric unit for management of acute psychosis. His clinical presentation was significant for loud speech, paranoid ideations, somatic delusions, irritable mood, and marked affective lability.
Medical history revealed diagnoses of left eye amblyopia in early childhood and Gaucher's disease at age 17 years. He was diagnosed with Gaucher's disease after he had multiple episodes of epistaxis and bruising during rigorous physical training. On evaluation, he was found to have anemia, thrombocytopenia, and pathological bone fractures. Radioisotope scanning also confirmed hepatosplenomegaly. Bone marrow biopsy was performed, which showed macrophages with “wrinkled paper” appearance and that were positive for periodic acid-Schiff stain. Subsequent beta-glucocerebrosidase level assay confirmed the diagnosis of Type 1 Gaucher's disease (mild, adult onset). He had received enzyme replacement therapy until age 36 years.
Psychiatric history indicated that the patient had his first psychotic episode 6 years after being diagnosed with Gaucher's disease. A review of records revealed a diagnosis of schizophrenia and relative stability of psychiatric presentations during hospitalizations with predominant persecutory and somatic delusions, loud speech, affective lability, and poor impulse control. Over the course of illness, he had shown best response to first-generation antipsychotics, especially haloperidol, whereas his psychiatric condition had worsened upon trials of second-generation antipsychotics such as quetiapine. At the time of admission, the patient had been medication noncompliant for the past 3 months.
Physical examination at the time of admission was significant for tall stature, thin and lean body, hypermobile joints, skin bruises, and facial asymmetry. Neurological examination revealed mask-like face, hippus of the left pupil, and decreased vision of the left eye. Neurological soft signs were absent as evidenced by absent primitive reflexes and intact sensory integration and complex motor task performance. In addition, he demonstrated bilateral resting tremors (3–5 Hz) of upper extremities and brisk reflexes (3+) at knee and ankle.
Mental status examination demonstrated loud speech, labile affect, illogical thought process, concrete thinking, paranoid and somatic delusions, and grossly intact attention, concentration, and memory.
Selective neuropsychological testing, including the Test of Premorbid Functioning, Wide Range Achievement Test 4, and the Repeatable Battery for the Assessment of Neuropsychological Status form A, were performed to assess neurocognitive functioning. His performance yielded scores for most cognitive parameters in the average range, but attention and delayed memory skills had scores in borderline and extremely low ranges, respectively. Overall, he was found to have adequate neurocognitive functioning (Table 1).
Significant laboratory investigations showed mild normocytic normochromic anemia, thrombocytopenia (50,000–100,000/mm3), elevated thyroid-stimulating hormone (6.97 mIU/L), and normal thyroxine (1 ng/dL) (subclinical hypothyroidism). A computed tomography scan of his head was unremarkable.
Amid concerns of worsening extrapyramidal symptoms, the patient was initially started on olanzapine 5 mg orally twice daily. Thyroxine supplementation (levothyroxine 25 mg orally daily) was initiated to correct subclinical hypothyroidism. His psychiatric condition deteriorated significantly with worsening of paranoid delusions, affective lability, and aggressive episodes. Medication was switched to haloperidol 5 mg orally twice daily and benztropine 1 mg orally twice daily after 1 week. In addition, thyroxine supplementation was discontinued after consistent medication refusals, as the patient attributed his worsening of delusions and aggressive episodes to thyroxine. Initiation of haloperidol led to significant improvement in affective lability, impulse control, anger outbursts, and preoccupation with delusions, but also to worsened resting tremors of bilateral upper extremities and face. In response to worsening extrapyramidal symptoms, the dose of benztropine was increased to 2 mg orally twice daily, which resulted in partial improvement of symptoms.
Gaucher's disease was described by Philippe Gaucher in 1882, yet the diversity of its phenotypic presentations still inspires case reports.1 The main finding of this report is the rare concurrence of schizophrenia, Gaucher's disease, and neurological symptoms. Although absence of neurological symptoms is considered a sine qua non for the diagnosis of Type 1 (adult-onset) Gaucher's disease, Miller et al.4 in 1973 first reported two siblings with Gaucher's disease who also had a neurologic dysfunction characterized by seizures, intellectual deterioration, disturbances of extraocular movements, and abnormal electroencephalograms.4 McKeran et al.5 in 1985 also reported a case that extended the neurological spectrum to include a late-onset, progressive, tapeto-retinal degeneration and a dopamine-responsive extrapyramidal syndrome.5 Similarly, Capablo et al.6 in 2008 systematically evaluated 31 patients with Type 1 Gaucher's disease and reported that 30.7% of adult patients had neurological deficits, including psychomotor delay, parkinsonism, dementia, impaired saccadic ocular movements, and peripheral nerve dysfunction. In this prospective study, three patients had extrapyramidal signs and six patients had immediate relatives with Parkinson disease.
The first case series on psychosis in Gaucher's disease was published by Neil et al.7 in 1979, who described a family with atypical psychosis, neurological problems, and Gaucher's disease. Like the case presented here, psychiatric presentation was characterized by marked affective lability, delusions, behavioral problems, depression, impaired concentration, and concrete thinking. Neurological problems included facial immobility, hyperreflexia, hypertonicity, muscle wasting, and extraocular movement disturbance. Electroencephalography showed sharp wave transients in the right hemisphere, excessive theta activity, and paroxysms of sharp and slow wave complexes after photic stimulation in one patient, and paroxysmal bursts of delta activity and sharp transients over the left temporal area in another patient. Interestingly, full scale IQ on the Wechsler Adult Intelligence Scale was normal for all patients, with discrepancy between verbal and performance scores, and selective deficits in attention, memory, visuospatial perception, and abstraction. Our patient also showed selective deficits in attention and delayed memory skills. Because GBA1 mutations have been associated with Lewy body disease,8,9 it remains to be explored whether selective deficits in attention and memory, as observed in our patient and other case reports, are stable over time or represent early markers of neurocognitive disorder (primarily dementia with Lewy bodies).
It is worth exploring if these neuropsychiatric manifestations share common underlying pathophysiology with Gaucher's disease. Both clinical and genetic association studies suggest that mutations in the glucocerebrosidase (GBA) gene confer increased vulnerability to developing Parkinsonism.10 Lewy bodies have been found in the brains of people who are homozygous or heterozygous carriers of the GBA1 gene.11 Goker-Alpan et al.12 in 2010 reported that glucocerebrosidase was present in 32% to 90% of Lewy bodies present in brain tissue obtained from three people with Gaucher's disease. More recently, Zunke et al.13 found that glycosphingolipids, which accumulate in increased amounts in Gaucher's disease, can cause structural changes in alpha-synuclein, thereby causing aggregation and toxicity.13 Glucosylceramide was involved in conversion of alpha-synuclein from oligomers to pathological nucleated polymers and amyloid fibrils. In addition, reduction of glycosphingolipids in midbrain dopaminergic neurons restored alpha-synuclein to its physiological conformers.13
Although the link between Gaucher's disease and parkinsonism has been well established, its relationship with psychosis and affective disorders is less established. Goodmann14 in 1994 reported that 50% higher rates of schizophrenia among European people of Jewish ancestry might be attributable to genes causing lysosomal storage diseases, including Gaucher's disease.14 The present report highlights the significance of metabolic processes in neuropsychiatric illnesses. Generally, metabolic disorders appear to disrupt late neurodevelopmental processes (eg, in metachromatic leukodystrophy and adrenoleukodystrophy) and, therefore, manifest neuropsychiatric symptoms early in life (usually in first decade).15 However, many disorders with inborn errors of metabolism also have mild and later-onset forms that can present in adolescence and adulthood without any preceding overt clinical symptoms in childhood.16 A critical step in the pathogenesis of almost all inborn errors of metabolism involves accumulation of toxic metabolic products resulting from deficiency or dysfunction of relevant enzymes. For example, common lysosomal storage diseases affect complex sphingolipids, which share a ceramide core formed mainly by a sphingosine base linked to a long-chain fatty acid.17 The primary group of ceramides can be attached to phosphorylcholine or saccharides, producing sphingomyelin and glycosphingolipids, respectively. This sphingomyelin and glycosphingolipid then play a major role in intracellular signal transduction, apoptosis, and neurotransmission.17 However, deficiency of one of the enzymes involved in biosynthesis or degradation of sphingolipids leads to increased levels of precursor metabolites. For example, in Gaucher's disease there is an elevation of glucosylceramide and its deacylated form glucosylsphingosine, which leads to neuronal injury.17 Interestingly, chronic haloperidol administration led to decreased plasma sphinganine and sphingosine levels in mice models,18 whereas olanzapine increased hepatic sphingomyelin levels in female rats. Although translation of these findings in humans has yet to happen,19 it is interesting to note that our patient responded well to haloperidol but showed poor response to olanzapine.
At present, both enzyme replacement and substrate reduction therapies have not proven to be of benefit for management of neuronopathic forms of Gaucher's disease. However, novel strategies such as central nervous system accessible inhibitors of glucosylceramide synthase may provide benefit in the future. For example, treatment in a mouse model of neuronopathic Gaucher's disease with glucosylceramide synthase inhibitor reduced the hepatic and neural glycolipids (>70% and >20%, respectively), extent of gliosis, and severity of ataxia.20 Other therapies that target protein misfolding and endoplasmic reticulum associated degradation,21 such as pharmacological chaperones for Gaucher's disease,22 have also been under investigation.
One major limitation of this case report is that electroencephalography and magnetic resonance imaging of the brain were not performed to rule out other causes of psychosis or identify a prodromal phase of neurocognitive disorder. In addition, we did not perform a dopamine transporter single photon emission computerized tomography imaging scan to confirm whether symptoms of bilateral resting tremors and masked-like face were due to Parkinson's disease in addition to drug-induced parkinsonism.
During the first two decades of twentieth century, not only was “dementia praecox” made distinct from “manic depressive insanity,”23 but a diagnostic classification system of exogenous and endogenous psychoses was also proposed by Bonhoeffer.24 The present report is a reminder of Bonhoeffer's view that “the diversity of the underlying medical conditions stands facing a great sameness of mental conditions. The conclusion is reached that we deal with typical forms of mental reactions which prove to be relatively independent of specific forms of noxae ... one is legitimated to speak of exogenous reaction types.”24
More research will further enhance our understanding of GBA1 gene function in dopaminergic transmission, which can provide new insights into the complex neuropsychiatric disorders collectively known as schizophrenia.
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- Hruska KS, LaMarca ME, Scott CR, Sidransky E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat. 2008;29(5):567–583. doi:10.1002/humu.20676 [CrossRef] PMID:18338393
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- Miller JD, McCluer R, Kanfer JN. Gaucher's disease: neurologic disorder in adult siblings. Ann Intern Med. 1973;78(6):883–887. doi:10.7326/0003-4819-78-6-883 [CrossRef] PMID:4713569
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- Nalls MA, Duran R, Lopez G, et al. A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol. 2013;70(6):727–735. doi:10.1001/jamaneurol.2013.1925 [CrossRef] PMID:23588557
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