Adrenoleukodystrophy presenting as glue sniffing

Abstract

Adrenoleukodystrophy classically presents in childhood with bronze skin, spastic tetraparesis, dysphagia, behavioural abnormalities and adrenal insufficiency. However, atypical presentations are known. Here we report an adolescent with adrenoleukodystrophy who first sought medical attention for glue sniffing.

Background

X-linked adrenoleukodystrophy (ALD) is a complex uncommon peroxisomal disorder with prevalence of 0.5–3.3 in 100 000 men.¹ Affected male members of the same family may present with different phenotypes—cerebral adrenoleukodystrophy (childhood, juvenile or adult forms), adrenomyeloneuropathy or isolated adrenal insufficiency.² The clinical presentation varies depending on the neuropathology which in turn is influenced by epigenetic, environmental and stochastic factors.² Isolated cerebral ALD is the presenting feature in about 60% of affected men. In its most common form, it presents with neurobehavioural symptoms beginning in childhood (35%–40%) and MRI features of symmetric white matter lesions progressing in a caudo-rostral pattern.³ Adolescent onset cerebral ALD is uncommon,⁴ and often presents with atypical features. Here we report an adolescent with cerebral ALD who was first evaluated for glue sniffing.

Case presentation

A 12-year-old boy was brought to the department of psychiatry with complaints of glue sniffing, truancy and running away. During interview parents revealed him to be a well-adjusted child with normal development up until a year ago when he started having these symptoms. The child was diagnosed as conduct disorder with glue sniffing and managed with counselling and risperidone for behavioural disturbances. About a year later, the child came to the emergency department with seizures. MRI of brain was done (figure 1). A diagnosis of acute glue sniffing encephalopathy was made in view of MRI and seizures. Abstinence was advised and antiepileptic drug (valproate) was added. The child continued to follow-up with counselling and antiepileptic medications. Meanwhile, declining cognitive performance and recurrent seizures caused the child to discontinue school. As the child became restricted to home, glue sniffing ceased. Despite abstinence from glue sniffing, these symptoms continued to worsen until he presented to the neurology department with subacute onset gait difficulty about 2 years later. Examination at that time revealed a mute child with pseudo bulbar affect, spastic asymmetric quadriparesis with greater involvement of left side and bilateral up-going plantars.

Figure 1.

MRI during initial presentation with seizures showing symmetrical fluid-attenuated inversion recovery (FLAIR) sequence hyperintensities involving the grey matter, subcortical and deep white matter of bilateral frontal lobes.

Investigations

Repeat MRI showed progression of lesions with typical pattern of contrast enhancement (figure 2). Other investigations revealed normal nerve conduction studies, normal serum cortisol levels, but high adrenocorticotropic hormone (ACTH) (1249 pg/mL; normal: 0–46 pg/mL). Lysophosphatidylcholine, a metabolite of very long chain fatty acids (VLCFA) was found to be 1.00 µmol/L (cut-off value 0.25 µmol/L). Further genetic tests could not be done due to financial reasons.

Figure 2.

(A) MRI brain 2 years later showing progression of lesions on fluid-attenuated inversion recovery (FLAIR) sequence. (B) T1-axial contrast-enhanced MRI sequence showing contrast enhancement.

Differential diagnosis

The presence of history of glue sniffing and seizures with a corresponding MRI showing a lesion in bilateral frontal white matter lead to a diagnosis of acute glue sniffing encephalopathy. However, the neuropsychiatric manifestations, frequent seizures, progressive cognitive decline and spastic quadriparesis despite abstinence in an adolescent male caused us to suspect a leukodystrophy. The elevated ACTH, corroborative imaging and high lysophosphatidylcholine confirmed our diagnosis of adrenoleukodystrophy.

Treatment

Genetic counselling was offered to the family. The patient was managed with baclofen for spasticity, percutaneous endoscopic gastrostomy (PEG) was done to facilitate feeding and antiepileptic drugs were continued.

Outcome and follow up

At last follow-up, he was seizure free, bedbound, mute and on PEG feeds.

Discussion

This is the first report to present glue sniffing and conduct disorder as the initial manifestations of adolescent ALD. The atypical frontal predominant pattern in the setting of glue sniffing caused the patient to be wrongly labelled as glue sniffing encephalopathy but subsequent course and imaging helped establish the diagnosis that was confirmed by VLCFA metabolites.

Simons et al reviewed 71 papers for psychiatric childhood disorders secondary to inborn errors of metabolism. They reported ALD to be associated only with learning disorders;⁵ while Sedel et al reported that psychiatric symptoms like mania, depression and acute psychosis may precede motor symptoms in late onset ALD.⁶ Ray et al presented a 15-year old with ALD presenting as treatment resistant mania.⁷ Other psychiatric manifestations reported include exhibitionism⁸ and attention deficit hyperactivity disorder with acute psychosis.⁹ However, glue sniffing and conduct disorder as the initial presentation of ALD have not been reported so far.

Loes et al studied MRI features in ALD and reported that the most common pattern of involvement was symmetric white matter lesions of parieto occipital lobes and it was seen in 66% of their subjects.¹⁰ Primary involvement of frontal lobe was seen in only 15.5% of their subjects in particular those aged 10–16 years. This was similar to our patients first MRI. However, these features may also be seen with glue encephalopathy.¹¹ The follow-up MRI scan of brain showed progression of lesions (figure 2), and an enhancement pattern that was highly suggestive of ALD.

Glue sniffing adds an additional layer of complexity to the diagnosis of ALD as chronic abuse and the resulting toluene toxicity may itself present as subcortical dementia and leukoencephalopathy.¹² This leukoencephalopathy is often associated with peripheral neuropathy¹³ and improvement is seen in the neurological features with abstinence.¹⁴ Consequently when our subject presented with seizures and MRI features of white matter involvement, he was diagnosed as glue sniffing encephalopathy. However, he had no evidence of peripheral nerve involvement either clinically or on nerve conduction studies. Also, there was progressive clinical deterioration despite abstinence. The presence of epilepsy, findings on follow-up imaging were also clues that the patient was not suffering from glue sniffing encephalopathy. Disturbance of the lipid bilayer and thereby the integral membrane proteins, and oxidative stress have been implicated in mediating the neurotoxic effects of toluene and other organic solvents.¹⁵ However, it is not known what effect toluene has on the lipid metabolism in subjects with mutations in the ABCD1 gene or its effects on levels of VLCFA in blood. Whether glue sniffing in our subject accelerated progression or precipitated the initial presentation is unknown, and these will be interesting areas for future work.

Learning points.

• Inborn errors of metabolism should be considered in the differential diagnosis of all childhood and adolescent onset psychiatric disorders.

• Presence of atypical features like epilepsy should prompt neuroimaging.

• Close follow-up including repeat neuroimaging may be warranted in select cases to establish correct diagnosis.