Considering Inherited, Basal Ganglia Diseases in the Differential Diagnosis of First-Episode Psychosis
• Psychosis is a very rare symptom of Huntingon’s disease and most commonly occurs in the childhood-onset form of the disease.
• Since Huntington’s disease is inherited in an autosomal dominant fashion, virtually all patients will have a family history of the illness.
• Wilson’s disease can lead to irreversible hepatic and neurological damage that can be prevented by available treatment.
• Although diagnosis of Wilson’s disease by genetic testing is impractical due to the fact that it is caused by many different mutations, straightforward laboratory tests are available to evaluate this illness.
• Basal ganglia calcification is a common incidental finding on computed tomography and is frequently of unclear clinical significance.
• Fahr’s disease describes an inherited, idiopathic, bilateral basal ganglia calcification that has been associated with neurological and psychiatric symptoms.
This article reviews three inherited basal ganglia diseases—Huntington’s disease, Wilson’s disease, and Fahr’s disease. Although these diseases are rare causes of psychiatric symptoms, they can initially present with psychosis in the absence of the neurological and systemic signs and symptoms that are more typical of these illnesses. In other words, it is possible that these illnesses could present with a syndrome that is very difficult to clinically distinguish from a first break of schizophrenia. All three illnesses are fairly straightforward to diagnose in the presence of an appropriate index of clinical suspicion. Diagnosis is most critical for Wilson’s disease, as effective treatment exists that can prevent irreversible organ damage.
The diagnostic evaluation of a first episode of psychosis in a young adult includes not only a consideration of a first break of schizophrenia and other psychiatric illnesses, but also a consideration of medical and neurological etiologies of psychosis. Despite this, illnesses such as Huntington’s disease, Wilson’s disease, and Fahr’s disease, for which there are some straightforward diagnostic tests, are not routinely screened for as part of a diagnostic work-up for first-episode psychosis. It is simply not cost effective to perform diagnostic procedures to rule them out because these exotic causes of psychosis are relatively rare.
When is it therefore reasonable to seriously consider a rare, exotic illness, such as Wilson’s disease, as a possible etiology of a first episode of psychosis in a young adult who has no other neurological or systemic signs or symptoms? This article attempts to address this question as it pertains to three inherited basal ganglia diseases—Huntington’s disease, Wilson’s disease, and Fahr’s disease. These three diseases are considered because they can present initially with psychosis in the second or third decade of life, which is also the typical time of onset for a first break of schizophrenia.
Although typically dominated by neurological symptoms, including dementia and chorea, the initial presentation of Huntington’s disease, especially of so-called childhood-onset Huntington’s disease, may consist of psychiatric symptoms that can be clinically difficult to distinguish from a primary psychiatric illness. Huntington’s disease is an autosomal dominant disorder that causes degeneration of parts of the basal ganglia by unclear mechanisms. The genetic defect is an abnormal trinucleotide repeat, also known as a dynamic or expansion mutation,1 of a gene on chromosome 4 that leads to abnormal production of the protein huntingtin. Both the normal function of huntingtin and the mechanism by which its abnormal production leads to disease is not well elucidated. Huntington’s disease occurs in 5–10 persons per 100,000.2
The basal ganglia degeneration associated with Huntington’s disease can cause movement disorders, including the chorea that is classically associated with the disease, dementia, and psychiatric disturbances. The classic presentation of the disease, with its onset in the fourth decade of life and predominant neurological symptoms, should not be confused with a first break of schizophrenia. Also, the typical presentation of so-called childhood-onset Huntington’s disease, characterized by rigidity instead of chorea, cerebellar signs, and rapidly progressive dementia, should not be confused with a first break of schizophrenia.
It has been estimated that psychiatric disturbances are the initial symptoms in 24% to 79% of Huntington’s disorder cases. Affective symptoms are most common, but psychotic symptoms have been estimated to occur in 5% to 17% of patients.3 Recently, Lovestone and colleagues3 described a family in which psychiatric symptoms, including psychosis in three cases, were the first manifestation of Huntington’s disease in four members of the family. At the time of publication of the research of Lovestone and colleagues,3 one member of the family had been treated for a presumptive diagnosis of schizoaffective disorder, while having no other signs or symptoms of Huntington’s disease. Tsuang and colleagues,4 in a study of 22 Huntington’s disease patients with psychosis and 22 Huntington’s disease patients without psychosis, found that patients with psychosis were more likely to have first-degree relatives who had psychosis (in the context of Huntington’s disease).
Psychotic symptoms, when present in Huntington’s disease, are most common in childhood-onset Huntington’s disease. By a process that has been called “anticipation,”2 people with Huntington’s disease tend to have more trinucleotide repeats than the parents from whom they inherited the disorder. Trinucleotide repeats have been associated not only with an earlier age of presentation of Huntington’s disease, but also with an earlier age of onset of psychotic symptoms. Tsuang and colleagues4 replicated this finding in their study of Huntington’s disease patients with psychosis. Huntington’s disease can be definitively diagnosed by genetic testing that detects the characteristic trinucleotide repeats on chromosome 4 (Table).
Although antipsychotic medication is standard treatment for psychosis due to Huntington’s disease, few studies have looked specifically at the efficacy of this practice.2 Madhusoodanan and colleagues5 described the successful treatment of psychotic symptoms with risperidone in a 55-year-old woman whose Huntington’s disease first manifested with psychotic and cognitive symptoms.
Although Wilson’s disease can cause a variety of symptoms attributable to multiple organ systems, approximately one third of cases will present initially with psychiatric symptoms that can be mistaken for a primary psychiatric illness. Early diagnosis is critical, as timely treatment can prevent irreversible organ damage.
Hepatolenticular degeneration, or Wilson’s disease, is an autosomal recessive disorder of copper metabolism leading to the deposition of copper in the liver, cornea, kidney, and brain, particularly in the lenticular nuclei of the basal ganglia (putamen and globis pallidus). Over 100 different mutations that cause Wilson’s disease have been identified.6 The mutations affect a gene on chromosome 13.7 Of the mutations identified, no one mutation accounts for >30% of mutations present.8 Because of this, most people with clinical illness are compound heterozygotes.8
Hepatic deposition of copper can result in a variety of signs and symptoms, including hepatitis, splenomegaly, hemolytic anemia, and portal hypertension. Deposition of copper in the brain can result in neurological and/or psychiatric signs and symptoms. Neurologic symptoms are the result of basal ganglia dysfunction and include tremors, dysarthria, and dysphagia.
The prevalence of Wilson’s disease is 1 in 40,0008; approximately 2% of these patients with Wilson’s disease have psychosis.9 The carrier frequency is approximately 1 in 90.7 The age of onset ranges from childhood to adulthood with a mean onset of 17 years of age. Gow and colleagues,10 in a series of 30 patients, reported an age range of 7–58 years. Wilson’s disease can initially present with either hepatic, neurological, or psychiatric manifestations. Adolescents tend to initially present with hepatic disease, while young adults tend to initially present with neuropsychiatric disease, but there is great variability.
There is no definitive diagnostic test for Wilson’s disease. Instead, diagnosis relies on clinical signs and a number of laboratory tests. Because there are so many different mutations that lead to Wilson’s disease, genetic diagnosis is impractical. Granular, pigmented deposits in the cornea—Kayser-Fleischer rings—are pathognomonic but not always present. They are present in 50% of persons with only hepatic presentations, but are more frequently present in persons with neurologic or psychiatric presentations.8 Specific laboratory findings include increased urinary copper excretion and low serum ceruloplasmin. These tests, however, are not specific for Wilson’s disease and are not always abnormal. Ceruloplasmin is normal 25% of the time with hepatic presentations and 10% of the time in neurologic or psychiatric presentations.8 Also, 10% of clinically normal heterozygotes (ie, not requiring treatment) will have abnormally low ceruloplasmin. High 24-hour urine copper is a much more sensitive and specific screen (Table).8 Liver function tests may be abnormal, but this of course is even less specific. Other laboratory tests, including measurement of radio-labeled copper incorporation into ceruloplasmin, 24-hour urine copper measurement after penicillamine challenge, and serum copper, are not reliable for a variety of reasons and should be avoided.8 Demonstration of increased hepatic copper concentration requires biopsy and probably should not be routinely performed unless there is other evidence for presence of disease.
From one fifth to one third of people with Wilson’s disease present initially with psychiatric symptoms in isolation (ie, without hepatic or neurologic manifestations). Psychiatric symptoms are variable and include behavioral and personality changes, affective symptoms, and psychosis. It has been estimated that one half of patients with Wilson’s disease may be hospitalized for psychiatric symptoms before Wilson’s disease is diagnosed.11 Rathburn12 reported that 50% of a sample of 34 patients with Wilson’s disease received psychiatric treatment prior to a diagnosis of Wilson’s disease. Muller13 described a case of an adolescent boy who first had psychiatric symptoms at 13 years of age but was not diagnosed with Wilson’s disease until almost 7 years later. By the time treatment for Wilson’s disease was begun (with penicillamine) psychiatric and neurologic symptoms had become irreversible.
Of the three diseases discussed in this article, it is probably most important to diagnose Wilson’s disease because, if treated properly, symptom progression can be stopped and even reversed. On the other hand, if diagnosed too late, neurologic damage leading to neurologic and psychiatric symptoms can become irreversible. Until recently, penicillamine, a copper chelator that results in the elimination of copper via urine, was practically the only therapy available for acute and maintenance therapy of Wilson’s disease. Unfortunately, penicillamine treatment is often complicated by side effects, including hypersensitivity reactions, bone-marrow suppression, proteinuria, autoimmune disorders, collagen disorders, and teratogenicity.8 Penicillamine even sometimes initially worsens the neurological symptoms of Wilson’s disease.8 A newer copper chelator called trientine has fewer side effects than penicillamine but may still initially worsen the neurological symptoms of Wilson’s disease; its effectiveness in the acute phase of treatment is untested.8 The experimental drug tetrathiomolybdate shows promise as an agent that may be both safer and more effective than penicillamine.8 Zinc, which reduces the gastrointestinal absorption of copper, is proving to be a safe and effective agent for maintenance therapy of Wilson’s disease.8
To date, there is very little research supporting specific treatment for psychiatric symptoms associated with Wilson’s disease. Anecdotal reports have suggested persons with Wilson’s disease are predisposed to extrapyramidal side effects of antipsychotics.11
Basal ganglia calcification, which has many causes, including a familial, idiopathic presentation known as Fahr’s disease, has long been associated with psychiatric disturbance. Although neurological symptoms clearly attributable to basal ganglia dysfunction are often associated with basal ganglia calcification, this is also a common incidental finding in asymptomatic persons. Because of this, there is debate about the clinical significance of basal ganglia calcification in persons with psychiatric symptoms in the absence of neurologic symptoms.
Basal ganglia calcifications have many causes. Fahr’s syndrome refers to bilateral, symmetrical, basal ganglia calcification of any etiology. Fahr’s disease refers to familial, idiopathic, bilateral calcification of the basal ganglia. By definition, Fahr’s disease should not be accompanied by perturbations of calcium or phosphorous metabolism. Other etiologies of Fahr’s syndrome, the so-called secondary basal ganglia calcification, include hypoparathyroidism, lupus, tuberous sclerosis, Alzheimer’s disease, myotonic muscular dystrophy, and mitochondrial encephalopathies.11
Basal ganglia calcification is often associated with neurological symptoms that are clearly the result of basal ganglia dysfunction. These include headache, vertigo, movement disorders, paresis, seizures, dysarthria, syncope, and cognitive abnormalities.
It has been estimated that ≤40% of patients with basal ganglia calcification present initially with psychiatric symptoms.11 When psychosis occurs in Fahr’s disease, it usually presents in persons 20–40 years of age as part of the so-called early adult-onset Fahr’s disease.11 Classic schizophrenia-like symptoms have been described, including auditory hallucinations, paranoid delusions, delusions of reference, and catatonia. Psychotic symptoms that are not typically associated with schizophrenia have also been described, including musical auditory hallucinations and complex visual hallucinations.11
The finding of basal ganglia calcification on computed tomography (CT) scans, however, is not uncommon and is often an incidental finding in patients with no symptoms attributable to basal ganglia derangement. Traditional estimates place this rate at between 0.3% and 1.2% of routine CT scans. Because of this, the correlation between the finding of idiopathic basal ganglia calcification on CT scans and psychiatric syndromes remains unclear. Gomille and colleagues14 reported a basal ganglia calcification incidence rate of 12.5% in a series of 2,318 CT scans and detected no correlation between this finding and symptoms. Yamada and Hayashi15 even reported a series of asymptomatic familial basal ganglia calcification. Brodaty and colleagues16 studied a family with two members who had basal ganglia calcification, dementia, bipolar disorder, and parkinsonism, and found 10 other family members with basal ganglia calcification but no neurologic or psychiatric symptoms. They concluded that the etiology of calcification and the neurologic and psychiatric illness were inherited independently. On the other hand, Lopez-Villegas and colleagues17 found significant neuropsychological dysfunction in a group of 18 people who had an incidental finding of basal ganglia calcification compared to a control group. Chabot and colleagues18 found a correlation between the amount of basal ganglia calcification and the presence and severity of schizophrenia-like illness in a family with a familial pattern of idiopathic basal ganglia calcification. Manyam and colleagues19 also concluded that the amount of basal ganglia calcification was predictive of the presence of neurological or psychiatric symptoms in a series of 99 patients with bilateral, basal ganglia calcification.
Fahr’s disease, or familial, idiopathic basal ganglia calcification, has been inherited in an autosomal, dominant pattern in most families studied but also in an autosomal, recessive pattern.16 The genetic derangement has been mapped to a region of chromosome 14 (Table).16
Even if it can be determined that psychosis is due to basal ganglia calcification, there is no treatment to limit calcification due to Fahr’s disease. Treatment of secondary basal ganglia calcification should focus on the underlying disease (eg, hypoparathyroidism). Psychosis has responded variably to antipsychotics and lithium.11 Some patients have proved refractory to treatment. Also, patients whose psychosis is due to basal ganglia calcification seem to be more sensitive to the extrapyramidal side effects of antipsychotics.11
The three inherited, basal ganglia diseases presented in this article—Huntington’s disease, Wilson’s disease, and Fahr’s disease—will rarely present initially with a psychotic syndrome that is difficult to distinguish clinically from a first break of schizophrenia.
People with Huntington’s disease typically suffer with chorea and progressing dementia. Psychiatric symptoms, especially affective symptoms, are not uncommon and usually occur alongside neurological symptoms. Despite this, psychiatric symptoms, including psychosis, can be the initial symptoms of Huntington’s disease, especially when the illness presents early. Since Huntington’s disease is inherited in an autosomal dominant fashion, a family history of the disease will be present in virtually all carriers. Definitive diagnosis can be made by genetic testing even before the onset of symptoms.
Wilson’s disease most commonly affects the liver and brain. Although an extremely rare cause of isolated psychosis, Wilson’s disease is perhaps the most important of these three illnesses to diagnose because of the presence of effective treatment that can prevent irreversible organ damage. Kayser-Fleischer rings are virtually pathognomonic but are not always present. Two straightforward laboratory tests, a low-serum ceruloplasmin and an elevated 24-hour urine copper, are sensitive and specific enough to screen for Wilson’s disease if there is a clinical suspicion of disease. Measurement of hepatic copper by biopsy is the gold standard diagnostic test. The presence of over 100 identified mutations and both symptomatic and asymptomatic compound heterozygotes make genetic testing an impractical diagnostic tool.
Attributing psychiatric symptoms, including psychosis, to basal ganglia calcification in Fahr’s disease remains debatable. Basal ganglia calcification is a common incidental finding on CT scans and has even been demonstrated in a family with asymptomatic inheritance of this finding. On the other hand, there is evidence of an association between psychosis and idiopathic basal ganglia calcification in some families. Unfortunately, to date, there is no way to reverse idiopathic basal ganglia calcification.
As described above, these three basal ganglia diseases are not difficult to diagnose. Because they are such rare causes of psychosis in isolation, however, catching them requires a high index of suspicion and vigilance. Although diagnosing Huntington’s disease and Fahr’s disease is of limited clinical value, as there is no way to reverse the effects of either illness, it is crucial to diagnose Wilson’s disease as prevention of irreversible organ damage is possible. PP
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