Adult-onset adrenoleukodystrophy presenting with status epilepticus and psychosis

Abstract

Adrenoleukodystrophy (ALD) is an X linked recessive genetic disorder caused by an abnormality in the ABCD1 gene on the X chromosome, that affects 1 in 20 000 people. In X linked adrenoleukodystrophy (X-ALD), a defect in lignoceroyl-coenzyme A ligase causes pathognomonic tissue accumulation of very long chain fatty acids (VLCFA) in the adrenal cortex and nervous system. The phenotypic variability ranges from cerebral inflammatory demyelination of childhood onset, leading to death within 5 years, to adults remaining presymptomatic through more than five decades. Our case is that of a man who was previously diagnosed with bipolar affective disorder presented with dystonic posturing. During transit, he had an episode of generalised convulsive status epilepticus. He presented with spasticity and exaggerated reflexes. Three important signs of adrenal insufficiency were observed: hypotension, hyperpigmentation and comatose state. The diagnosis of X-ALD should be considered in young men presenting with gradually progressive unexplained cognitive and behavioural problems, a strong family history, adrenal insufficiency, bilateral upper motor signs with absent ankle reflexes.

Background

Adrenoleukodystrophy (ALD) is an X linked disorder affecting approximately 1 in 20 000 people.¹ It is characterised by accumulation of very long chain fatty acids (VLCFA). Three major phenotypic forms are childhood ALD, adult adrenomyeloneuropathy (AMN) and Addison’s disease.² In the adult form young men usually present with behavioural disturbance and Addison’s disease.

We report here a very rare case of adult-onset X linked adrenoleukodystrophy (X-ALD) accompanied with status epilepticus and symptoms of Addison’s disease.

Our aim is to describe the initial presentation, diagnosis, imaging and management of this rare case in order to highlight the multidisciplinary approach involved as well as the importance of an early diagnosis and treatment of this debilitating disease.

Case presentation

A man who was previously diagnosed with bipolar affective disorder was referred to our hospital. He had an unremarkable birth and developmental history. He was diagnosed to have bipolar disorder 8 years back and was started on antipsychotics. With those medications, he could do activities of daily living. However, there was a gradual cognitive decline.

There was history of changing his psychiatric medications the week prior to admission. This was accompanied with dystonic posturing. Soon thereafter he developed fever and his sensorium deteriorated. The treating physician suspected meningoencephalitis and referred the patient to our hospital.

During transit, he had an episode of generalised convulsive status epilepticus, aspirated, and presented with hypotension. On examination he was comatose, frothing from the mouth, and hyperpigmentation was present on the knuckles of both hands and the flexor surface of both upper limbs.

His entire body was spastic with exaggerated reflexes. He was intubated in view of type 1 respiratory failure and airway protection. He was kept in the intensive care unit.

Investigations

A plain CT brain was done which revealed bilateral frontal cortical white matter hypodensities.

A lumbar puncture was performed. Opening pressure was not measured. CSF volume was 2 mL. The fluid was clear with no WBCs. CSF glucose was normal (78 mg/dL) while CSF protein and lactate were elevated (84 mg/dL and 21.3 mg/dL, respectively). CSF cultures were sterile.

Initial blood laboratory reports revealed leukocytosis. Hepatic parameters were normal; however, renal parameters showed low serum creatinine (0.55 mg/dL) possibly due to reduced muscle mass and ill health. Serum cortisol level was normal and ranged from 7.33 µg/dL to 13.39 µg/dL during the hospital stay. Bacterial cultures sent came back sterile. Viral panel that was sent came back negative. However, procalcitonin levels were elevated (3.047 µg/L), and ESR was raised (69 mm/hr). An EEG was also done which revealed bi-hemispherical diffuse encephalopathy changes.

An MRI brain was performed which revealed extensive confluent T2 hyperintensities involving the deep and periventricular white matter of bilateral parieto-temporal and frontal lobes, the splenium of corpus callosum, with white matter showing post contrast enhancement in the peripheral edge of the structures involved (figure 1).

Figure 1.

MRI brain-extensive confluent T2 hyperintensities involving white matter of parietal, temporal and frontal lobes.

These features were suggestive of demyelination. A possibility of leukodystrophy was kept in mind. Early morning plasma adrenocorticotropic hormone (ACTH) was done which was elevated (716 pg/mL) in the presence of hyponatremia (ranging from 112 mEq/L to 121 mEq/L during the hospital stay). Retrospective analysis revealed that the patient had a strong family history of psychiatric illness and sudden deaths in the maternal side of the family.

A genetic consultation was sought and genetic testing revealed the presence of ABCD1 gene mutation. Nerve conduction studies and MRI spine were not done.

A diagnosis of adult-onset cerebral ALD with adrenal insufficiency was made.

Differential diagnosis

The differential diagnosis includes myelopathies which may be congenital, infectious, immunological, neoplastic or degenerative. Others include leukodystrophies such as metachromatic leukodystrophy, Krabbe disease, gangliosidosis and the neurological diseases such as familial spastic paraparesis and primary lateral sclerosis.³ Women who are heterozygous for the condition can be misdiagnosed with multiple sclerosis due to the overlap of symptoms.

The above differentials should be ruled out by measurement of VLCFA in the serum which is the definitive diagnostic test to detect ALD.⁴

By characteristic CT/MRI findings as well as genetic testing for ABCD gene mutation, these conditions can be ruled out, highlighting that genetic testing is paramount in the diagnosis of this rare condition.

Treatment

Intravenous levetiracetam was started. He was started on broad spectrum antibiotics after sending cultures of venous blood, endotracheal aspirate and urine. Intravenous acyclovir was started following the lumbar puncture due to the presence of temporal lobe involvement on imaging which is a characteristic feature of Herpes encephalitis. In addition, injection hydrocortisone 50 mg intravenous every 6 hours was prescribed for 48 hours.

The patient gradually improved; he was weaned off the ventilator and was stepped down to a high dependency unit (HDU). Even though his sensorium improved, he was not oriented to time or place, and his word output was low. In the HDU he had a right lateral seizure with secondary generalisation. Intravenous phenytoin was added to his existing medications. The patient was continued on antiepileptic drugs, and he was started on oral prednisolone (7.5 mg-0-5mg daily) and fludrocortisone 50 mg daily supplementation.

Dietary advice given on discharge included RT feeds 100 mL every 2 hours.

The patient’s relatives were counselled regarding haematopoietic stem cell transplantation (HCT). Other family members were asked to come to our department of clinical genetics for screening. Prenatal counselling for family members who were planning conception was advised. The patient’s antiepileptic drugs and psychiatric medications were optimised, and he was discharged on oral corticosteroid supplementation.

Outcome and follow-up

Follow-up with our patient was not possible.

Discussion

X-ALD is a peroxisomal disorder of beta-oxidation. It is caused by an abnormality in the ATP-binding cassette (ABC), subfamily D, member 1 gene (ABCD1 gene) on the X chromosome.⁵ It affects about 1 in 20 000 people worldwide.¹ The disease most commonly presents in childhood and has a high mortality rate resulting in very few cases presenting in adulthood.

In X-ALD, there is a defect in lignoceroyl-coenzyme A ligase which causes tissue accumulation of VLCFA. VLCFA accumulate in Leydig cells of the testis, adrenal cortex and the central nervous system. The adrenoleukodystrophy protein (ALDP) is mapped in subcortical and cerebellar white matter, hypothalamus, ACTH producing cells in the pituitary and dorsal root ganglion (DRG). ALDP tend to spare the corticospinal tract and corpus callosum (except the splenium). In the nervous system, there is inflammatory demyelination which results in confluent and bilateral symmetric loss of myelin in the cerebral and cerebellar white matter.²

The phenotypic variability ranges from cerebral inflammatory demyelination of childhood onset, leading to death within 5 years, to adults remaining presymptomatic through more than five decades. There are three predominant phenotypic forms: childhood ALD, AMN and adrenal insufficiency.² Adult-onset ALD is rare (1%–3%) and have often been characterised by mainly psychiatric symptoms.⁶

Unlike the childhood form of ALD, the adult form is more slowly progressive. The patient can present with non-specific psychiatric features that may be difficult to distinguish from primary psychiatric disorders like bipolar disorder and schizophrenia, highlighting the importance of a thorough history and examination.^{7 8} Patients present with psychiatric problems prior to neurological problems. In our case the psychiatric problems preceded the neurological manifestations (status epilepticus, upper motor signs) by over 8 years. Thus, in the light of a long duration between the neurological and psychiatric symptoms, ALD must be considered, despite the older age group. Psychosis and seizures are rare presenting symptoms for adult-onset cases of ALD, making our case unique.

Patients with ALD are also more vulnerable to the side effects of antipsychotic medications and often show atypical drug responses.⁹ Our patient also presented with dystonia, which may have been a side effect of the antipsychotic medication that he was prescribed. However, the dystonia could have been a result of the disease process itself.⁴

The diagnosis of X-ALD should be considered in young men presenting with gradually progressive unexplained cognitive and behavioural problems, a strong family history, adrenal insufficiency, bilateral upper motor signs with absent ankle reflexes. Our patient presented with three important signs of adrenal insufficiency namely hypotension, hyperpigmentation and comatose state. Serum cortisol was normal; however, early morning ACTH was elevated in the presence of hyponatremia. These findings point towards the diagnosis of ALD given the adrenal and cerebral symptoms. It is of paramount importance to diagnose and treat such cases early in order to avoid irreversible damage resulting in death.

Laboratory investigations should include testing for VLCFA and genetic testing for ABCD gene mutation. Imaging should include nerve conduction studies, MRI spine, MRI brain, proton MR spectroscopy of the brain at baseline and at follow-up of about 3.5 years. Loes J has developed an MRI severity scale for X-ALD. Features like patients age, MRI severity scale and anatomic location of lesions can be used to predict course of disease.⁵ Studies of magnetic resonance perfusion imaging suggest that changes in local brain perfusion might be one of the earliest signs of lesion development.¹⁰ Characteristic MRI findings in the adult-onset cerebral phenotype include demyelination in the white matter (parietal and occipital lobes), splenium of corpus callosum (earliest finding), visual and auditory tracts.³

Allogenic HCT has emerged as the treatment of choice for individuals with early stages of cerebral involvement in ALD; however, this does not lead to improvement in adrenal insufficiency.¹¹ Other treatment modalities include supportive care, physiotherapy and occupation therapy, treatment of associated conditions. Data on long-term efficacy of gene therapy is lacking.

Treatments such as low-fat diet and Lorenzo’s oil may reduce VLCFA levels but neither affect the disease progression nor provide symptomatic relief.^{12 13}

No disease slowing therapy has proven any benefit for AMN. Up to 60% of patients develop cerebral ALD. There is progressive cognitive and behavioural decline and leads to total disability and early death.

Finally, genetic testing of the family members is crucial in order to identify at-risk patients prior to the onset of neurological problems.

Learning points.

• This case is interesting for several reasons. First, the patient was misdiagnosed with bipolar affective disorder indicating the importance of ruling out metabolic causes of psychosis. Close attention should be paid to accompanying symptoms such as hypotension and hyperpigmentation.

• Second, the age of the patient highlights the fact that adrenoleukodystrophy (ALD) should be included in the differential diagnosis of psychosis in the setting of adrenal dysfunction in adult patients as well since adult ALD remains undiagnosed in many cases. This rare diagnosis should be identified early and appropriate genetic counselling should be offered.

• Third, lab tests revealed normal cortisol levels but further investigations revealed an elevated adrenocorticotropic hormone level and hyponatremia, thus highlighting that normal cortisol levels do not rule out adrenal insufficiency. Furthermore, the absence of an increase in cortisol levels in the setting of sepsis should raise suspicion of adrenal insufficiency.

• Finally, mood disorders with manic depressive symptoms such as psychosis and seizures have rarely been described as the inciting primary symptoms of ALD. To the best of our knowledge, this is the first adult-onset case of ALD in India presenting with status epilepticus and manic-depressive symptoms.

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