Psychiatric Annals

Case Report 

Adult-Cerebral X-linked Adrenoleukodystrophy: A Mirage of Psychosis, Mania, and Substance Use

Hina Makkar, MBBS; Celine C. Corona, MD; Abhishek Wadhawan, MD; John W. Stiller, MD

Abstract

We report the case of a patient with adult-onset cerebral variant of X-linked adrenoleukodystrophy (XALD) who initially presented with psychotic and mood symptoms in the background of an extensive history of substance use that resulted in multiple psychiatric hospitalizations. Neurology consultation for abnormal stereotypical movement of his head led to the correct diagnosis.

The patient was an unmarried homeless man in his early 30s. He had a history of schizoaffective disorder, substance use disorder, nonadherence with medications, urinary incontinence, and hypercholesterolemia. He had an inpatient psychiatric hospitalization at another facility for disorganized behavior characterized by walking into traffic, using profanities, and urinating and defecating on the streets, together with racing thoughts, irritable mood, paranoid delusions, and auditory hallucinations. During that hospitalization (at the other facility) he was started on risperidone, which was titrated to 50 mg intramuscular every 2 weeks, but he showed no improvement.

He was transferred to our facility for further psychiatric stabilization. He reportedly had developed an abnormal stereotypic circular head movement 2 weeks after initiating risperidone, which prompted its discontinuation at our hospital.

On review of his history, it was reported that at age 18 years, the patient had begun using multiple recreational drugs, including cocaine, methamphetamine, ecstasy, synthetic cannabinoids, cannabis, alcohol, and ketamine. He was diagnosed with schizophrenia and bipolar disorder during his early 20s while attending college. In addition, during his late 20s, he was involved in multiple motor vehicle accidents (without any reported serious sequelae), displayed hypersexual tendencies, and experienced a general decline in social and occupational functioning that led to dismissal from his job and then homelessness. He deteriorated more in his early 30s, with marked manic symptoms including insomnia, racing thoughts, grandiosity, pressured speech, and impulsive spending. He also developed urinary and fecal incontinence during this time, was nonadherent with medications, and was hospitalized seven times for psychiatric care. During this time period he failed treatment trials with aripiprazole at a dose of 15 mg daily, aripiprazole at a dose of 400 mg intramuscular monthly, trazodone at a dose of 150 mg at bedtime, and mirtazapine at a dose of 45 mg at bedtime.

His family history was significant for his maternal grandmother being diagnosed with late-onset multiple sclerosis. Prenatal and developmental histories were unremarkable.

The stereotypic circular head motion, history of incontinence, less than optimal motor functioning, and poor response to multiple psychotropic medications precluded a primary psychiatric disorder as the sole diagnosis and prompted a referral to the neurology service for further evaluation.

Upon assessment by the neurology team, it was noted that his hair was spiked with a sticky white substance at the tips and he had scant hair posteriorly. He had multiple flesh colored skin tags on his back and unknowingly urinated on himself during the examination.

On mental status examination, his affect was flat with poor eye contact associated with circular motion of his head that he reported helped him to relax but that could be abated voluntarily. His speech was monotone with impaired modulation. His judgment was poor. His score on the Montreal Cognitive Assessment was 17 of 30, consistent with a significant decline in cognitive functioning.

There was mild anisocoria (unequal size of pupils), impaired smooth pursuit eye movements with saccadic intrusions, and bilateral exophoria (tendency for the eyes to deviate outwards). Myerson's sign (persistent blinking on tapping glabella) was present.

On motor examination, there was bilateral limb spasticity with brisk deep tendon reflexes and “up-going” toes. In addition, there was superimposed gait and appendicular ataxia, and bradykinesia with loss of amplitude when attempting to increase the speed of repetitive movements. On sensory examination,…

We report the case of a patient with adult-onset cerebral variant of X-linked adrenoleukodystrophy (XALD) who initially presented with psychotic and mood symptoms in the background of an extensive history of substance use that resulted in multiple psychiatric hospitalizations. Neurology consultation for abnormal stereotypical movement of his head led to the correct diagnosis.

Case Description

The patient was an unmarried homeless man in his early 30s. He had a history of schizoaffective disorder, substance use disorder, nonadherence with medications, urinary incontinence, and hypercholesterolemia. He had an inpatient psychiatric hospitalization at another facility for disorganized behavior characterized by walking into traffic, using profanities, and urinating and defecating on the streets, together with racing thoughts, irritable mood, paranoid delusions, and auditory hallucinations. During that hospitalization (at the other facility) he was started on risperidone, which was titrated to 50 mg intramuscular every 2 weeks, but he showed no improvement.

He was transferred to our facility for further psychiatric stabilization. He reportedly had developed an abnormal stereotypic circular head movement 2 weeks after initiating risperidone, which prompted its discontinuation at our hospital.

On review of his history, it was reported that at age 18 years, the patient had begun using multiple recreational drugs, including cocaine, methamphetamine, ecstasy, synthetic cannabinoids, cannabis, alcohol, and ketamine. He was diagnosed with schizophrenia and bipolar disorder during his early 20s while attending college. In addition, during his late 20s, he was involved in multiple motor vehicle accidents (without any reported serious sequelae), displayed hypersexual tendencies, and experienced a general decline in social and occupational functioning that led to dismissal from his job and then homelessness. He deteriorated more in his early 30s, with marked manic symptoms including insomnia, racing thoughts, grandiosity, pressured speech, and impulsive spending. He also developed urinary and fecal incontinence during this time, was nonadherent with medications, and was hospitalized seven times for psychiatric care. During this time period he failed treatment trials with aripiprazole at a dose of 15 mg daily, aripiprazole at a dose of 400 mg intramuscular monthly, trazodone at a dose of 150 mg at bedtime, and mirtazapine at a dose of 45 mg at bedtime.

His family history was significant for his maternal grandmother being diagnosed with late-onset multiple sclerosis. Prenatal and developmental histories were unremarkable.

The stereotypic circular head motion, history of incontinence, less than optimal motor functioning, and poor response to multiple psychotropic medications precluded a primary psychiatric disorder as the sole diagnosis and prompted a referral to the neurology service for further evaluation.

Upon assessment by the neurology team, it was noted that his hair was spiked with a sticky white substance at the tips and he had scant hair posteriorly. He had multiple flesh colored skin tags on his back and unknowingly urinated on himself during the examination.

On mental status examination, his affect was flat with poor eye contact associated with circular motion of his head that he reported helped him to relax but that could be abated voluntarily. His speech was monotone with impaired modulation. His judgment was poor. His score on the Montreal Cognitive Assessment was 17 of 30, consistent with a significant decline in cognitive functioning.

There was mild anisocoria (unequal size of pupils), impaired smooth pursuit eye movements with saccadic intrusions, and bilateral exophoria (tendency for the eyes to deviate outwards). Myerson's sign (persistent blinking on tapping glabella) was present.

On motor examination, there was bilateral limb spasticity with brisk deep tendon reflexes and “up-going” toes. In addition, there was superimposed gait and appendicular ataxia, and bradykinesia with loss of amplitude when attempting to increase the speed of repetitive movements. On sensory examination, decreased appreciation of vibration distally in bilateral lower extremities was noted.

Management

Because the presentation was one of an adult-onset neuropsychiatric disorder with significant cognitive, motor, and sphincteric dysfunction, the differential diagnoses were broad so neuroimaging, including magnetic resonance imaging (MRI) of the brain and cervical spine, was obtained. On T2/fluid-attenuated inversion recovery sequences, the MRI of the brain revealed a confluence of deep white matter hyperintensities involving bilateral occipital and parietal lobes, splenium of the corpus callosum, bilateral subcortical U-fibers (ie, short association fibers), bilateral posterior limbs of the internal capsules, deep white matter adjacent to bilateral bodies of the lateral ventricles, pyramidal tracts, bilateral middle cerebellar peduncles, and bilateral cerebellar white matter (Figure 1). These findings on brain MRI were concerning for XALD. The MRI of the cervical spinal cord was unremarkable.

Axial fluid-attenuated inversion recovery image showing confluent deep white matter hyperintensity involving the bilateral occipital and parietal lobes, splenium of the corpus callosum, bilateral occipital medial subcortical U-fibers, bilateral posterior limbs of the internal capsules, deep white matter adjacent to bilateral bodies of the lateral ventricles, pyramidal tracts, bilateral middle cerebellar peduncles, and the bilateral cerebellar white matter. Gray matter and the deep nuclei are preserved. There was mild heterogeneous enhancement at the T2 hyperintensity of the deep white matter of the left frontal lobe adjacent to the left lateral ventricle and the T2 hyperintensity of the bilateral cerebellar white matter. This was concerning for a demyelinating disorder, most likely adrenoleukodystrophy.

Figure 1.

Axial fluid-attenuated inversion recovery image showing confluent deep white matter hyperintensity involving the bilateral occipital and parietal lobes, splenium of the corpus callosum, bilateral occipital medial subcortical U-fibers, bilateral posterior limbs of the internal capsules, deep white matter adjacent to bilateral bodies of the lateral ventricles, pyramidal tracts, bilateral middle cerebellar peduncles, and the bilateral cerebellar white matter. Gray matter and the deep nuclei are preserved. There was mild heterogeneous enhancement at the T2 hyperintensity of the deep white matter of the left frontal lobe adjacent to the left lateral ventricle and the T2 hyperintensity of the bilateral cerebellar white matter. This was concerning for a demyelinating disorder, most likely adrenoleukodystrophy.

Formal neuropsychological testing was consistent with a progressive decline in intelligence and impairment in learning new information.

Laboratory investigations revealed the presence of elevated very long chain fatty acids (VLCFAs): tetracosanoic acid, C24-114.90 mcmol/L (normal range: 31.26–84.11 mcmol/L); hexacosanoic acid, C26-4.11 mcmol/L (normal range: <0.94 mcmol/L); ratio of C24 to C22 of 1.75 (normal range: 0.64–0.99). Plasma adrenocorticotropic hormone level (53 pg/mL [normal range: 6–50 pg/mL]) was slightly high with low-normal evening cortisol levels (level at 6:50 am of 17.9 mcg/dL [normal range: 4–22 mcg/dL]; and cortisol level at 3 pm of 5 mcg/dL [normal range: 4–22 mcg/dL]), indicative of suboptimal adrenal function.

The patient's clinical presentation, neuroimaging studies and laboratory investigations were consistent with a diagnosis of XALD, cerebral phenotype. Genetic testing confirmed the diagnosis by demonstrating a hemizygous frameshift mutation in the ABCD1 gene (ATP-binding cassette, sub-family D, member 1).

The patient's psychiatric symptoms were treated with quetiapine at a dose of 100 mg at bedtime, olanzapine at a dose of 2.5 mg daily, escitalopram at a dose of 10 mg at bedtime, benztropine at a dose of 0.5 mg twice a day, and nicotine patch at a dose of 14 mg transdermal daily. The patient was also referred to an endocrinologist and a urologist. His medical comorbidities were treated with desmopressin at a dose of 10 mcg via nasal spray twice a day, prednisone at a dose of 5 mg twice a day (added for suboptimal adrenal function), tamsulosin at a dose of 0.4 mg twice a day, atorvastatin at a dose of 20 mg at bedtime, megesterol at a dose of 400 mg daily, fish oil at a dose of 1,000 mg twice a day, thiamine at a dose of 100 mg daily, and vitamin D3 at a dose of 1,000 units daily. He was placed on a high-calorie diet and started on physical therapy.

The primary care practitioner for the patient's mother was informed of his genetic disorder and there was a discussion on the appropriate screening of the family members.

The patient's cognitive and motor functioning continued to decline. He had an epileptic seizure associated with an acute intracerebral hemorrhage that was the proximate cause of his death about 1 year after admission to our facility.

Discussion

Based on newborn screening1 for XALD in the United States, its incidence has been estimated to be about 1 in 15,000.2,3 XALD is a hereditary disorder involving a mutation in the ABCD1 gene4 that results in impairment of beta-oxidation of VLCFAs within the peroxisomes,5 leading to their accumulation in the body.6 The nervous system, adrenal cortex, and the testes are predominantly affected in XALD, which may present with various combinations of neuropsychiatric symptoms and adrenal and gonadal insufficiencies.7,8 Family history may be significant for multiple sclerosis as this is a frequent misdiagnosis for XALD.8

XALD has been reported to have seven different phenotypes among affected males and five different phenotypes among heterozygous females.8 The adult-onset cerebral phenotype of XALD manifests in about 2% to 5% of patients with XALD.9 Cerebral involvement occurs commonly and can initially present with psychiatric symptomatology,9,10 which can be misinterpreted as mania,11 schizophrenia,12 or attention-deficit/hyperactivity disorder,9,13 thereby creating a diagnostic dilemma for a psychiatrist. In patients with adrenomyeloneuropathy, a phenotype in affected males that develops in the adult-onset cerebral phenotype of XALD, hair is frequently scarce and thin with balding occurring prematurely.9

MRI of the brain in XALD with cerebral manifestations most commonly reveals white matter involvement in temporal lobes, parieto-occipital lobes, corpus callosum, frontal lobes, cerebellum, and in visual and auditory pathways.10 VLCFA build-up in XALD results in disruption in the function of cell membranes,8 oxidative stress, impaired mitochondrial function, and increased inflammation, ultimately leading to cell death and demyelination.14 In almost all XALD patients with cerebral involvement, rapid demyelination occurs along with the development of epilepsy, dysarthria, spastic paresis, sensory agnosia, and dysphagia. Once this process begins to occur it leads to a vegetative state in a few years or to death in about 4 years.8,9

Suspicion of XALD should prompt a clinician to test plasma VLCFA levels. A person with XALD would demonstrate considerably higher value of the ratio of C24:0 to C22:0, or C26:0 to C22:0, and higher levels of total C26:0 in patients with all XALD phenotypes.15 Genetic testing can confirm the diagnosis of XALD.16 Repeated MRI scans help to monitor the course of the illness using the Loes score.2,17

The psychopharmacologic treatment of psychiatric symptoms in XALD patients is challenging. Neuroleptics may augment free radical production in the brain18 and may lead to extrapyramidal side effects (EPS) that aggravate the functional impairment in XALD.19 Administration of anticholinergic agents to treat EPS may lead to dysphagia and hypotension and worsen cognitive functioning.19 Atypical antipsychotics may worsen the lipid profile, facilitate deterioration of cognitive functioning due to their anticholinergic properties, may induce hypotension in the setting of adrenal insufficiency, and may also lower the seizure threshold.19 Lithium levels may fluctuate in the setting of electrolyte disturbances secondary to adrenal insufficiency in XALD.19 Valproate11 and benzodiazepines19 may worsen ataxia, although, benzodiazepines may help in reducing spasticity.19 Prednisone for managing comorbid adrenal insufficiency may worsen psychosis.20

This case underscores the need for psychiatrists to be aware of the clinical presentation of XALD, as its cerebral manifestations may appear deceptively close to a primary psychotic or manic disorder complicated by substance use. An atypical clinical presentation of a psychiatric illness or treatment-resistant symptoms should alert the psychiatrist to perform a full neurological examination, radiological examination, and additional investigations to rule out possible underlying organic disorders.10

References

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Authors

Hina Makkar, MBBS, is a Neurology Extern, Neurology Consultation Services, Saint Elizabeth's Hospital. Celine C. Corona, MD, is a first-year Child Fellow, Bronx Care Health System, Icahn School of Medicine at Mount Sinai. Abhishek Wadhawan, MD, is an Attending Psychiatrist, Saint Elizabeth's Hospital. John W. Stiller, MD, is the Director, Neurology Consultation Services, Saint Elizabeth's Hospital; and the Chief Physician and Neurologist, Maryland State Athletic Commission.

Address correspondence to John W. Stiller, MD, Neurology Consultation Services, Saint Elizabeth's Hospital, 1100 Alabama Avenue SE, Room 122.03, Washington, DC 20032; email: john.stiller@dc.gov.

Disclaimer: This case report was reviewed by the Institutional Review Board (IRB) of Saint Elizabeths' Hospital, Washington, DC The authors were granted a waiver for an IRB approval as the patient's personal information was masked except for gender and race. The patient is now deceased.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/00485713-20200812-01

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