A six-year-old male presented to the emergency department (ED) with an eight-week history of clumsiness, falls, behavioural changes and global developmental regression. On examination he was alert and orientated but with poor attention and single-word answers. Neurological examination revealed subtle abnormalities. Subsequent neuroimaging and plasma very long-chain fatty acid (VLCFA) levels confirmed the diagnosis of adrenoleukodystrophy (ALD). 

Background

ALD is a rare presentation of neurological deficit with an incidence ranging between 1/20,000-1/100,000.¹ Time between onset and diagnosis is also delayed, particularly in probands.²

Case presentation

A six-year-old male patient of sallow complexion presented to the ED with an eight-week history of global developmental regression. His mother first noticed the patient having staring episodes which slowly progressed to declining content and character of speech, behavioural changes and attention deficit. There was also a history of urinary incontinence. 

Neurological examination proved unremarkable with the exception of an unsteady gait, positive heel to toe walking and past pointing. Birth history was unremarkable; the patient was born at 39 weeks by elective Caesarean section as one male of dizygous male twins. His neonatal period and developmental milestones were completely normal. 

With regard to family history, the mother reported that two of her father’s siblings died of motor neuron disease (MND), one female at 54 years old and one male at 69 years old.

Investigations

Audiology and visual assessment tests performed prior to admission were normal. Biochemical and haematological investigations were unremarkable. 

Electroencephalography (EEG) revealed abnormal photoparoxysmal response to intermittent flash stimulation during waking and drowsy states only, though this was not associated with any clinical changes. 

The remainder of the waking record showed no definite epileptiform features. Subsequent magnetic resonance imaging (MRI) of the brain demonstrated extensive diffuse deep white matter high signal change extending inferiorly along the white matter tracts as far as the superior aspect of the pons and brain stem on axial fluid attenuated inversion recovery (FLAIR) and axial T2-weighted sequences. 

Extensive high signal changes were seen in the posterior corpus callosum. These extensive changes were bilateral and symmetrical showing moderate peripheral rim enhancement post-gadolinium administration. 

Adrenocorticotropic hormone (ACTH) stimulation test was performed and confirmed adrenal insufficiency with cortisol level at 0 minutes: 282, at 30 minutes: 284 and at 60 minutes: 289. 

Differential diagnosis

Early behavioural changes are described in 13% of patients diagnosed with ALD and hyperactivity in 6% often leading to the diagnosis of hyperactivity or attention deficit disorders in the early stage of the disease.³

Seizures are the presenting complaint in 7% of ALD patients often leading to the suspicion of epilepsy.¹ In the later stages, the disease emulates encephalitis and brain tumours, other neurodegenerative disorders such as arylsulfatase deficiency (metachromatic leukodystrophy) and Krabbe disease (globoid cell leukodystrophy); subacute sclerosing encephalitis, multiple sclerosis, Lyme disease, and other dementing disorders including juvenile neuronal ceroid-lipofuscinosis (Batten disease) and Creutzfeldt-Jakob disease. 

Brain MRI studies and plasma VLCFA assay will lead to definitive diagnosis.⁴

Treatment

A definitive cure does not yet exist for ALD but three treatment options significantly improve prognosis if initiated in the early stage of the disease. 

Dietary treatment with Lorenzo’s oil was shown to decrease plasma VLCFAs to undetectable levels at four weeks post-therapy but so far has been unsuccessful in preventing progression in neurologically symptomatic patients. However, asymptomatic patients may still benefit. Haematopoietic stem cell transplants (HSCTs) have proven therapeutic benefit in patients with mild cerebral impairment, where a suitable donor can be found.²

The third treatment option, adrenal replacement therapy, which was initiated in this case with hydrocortisone and fludrocortisone, prevents life-threatening adrenal events but has not been shown to slow neurological progression.⁵

Figure 1. Axial T-weighted image showing bilateral extensive white matter lesion in the occipital lobe(click to enlarge)

Figure 2. Sagittal T2-MRI image showing extensive white matter lesions affecting posterior lobe, pons and midbrain(click to enlarge)

Outcome and follow-up

The patient was referred to a multidisciplinary team including neurology, geneticist, endocrine and metabolic specialists for assessment of further treatment options.

Discussion

ALD is an x-linked inherited disorder with a defect in the ALD gene causing defective peroxisomal oxidation of VLCFAs leading to their accumulation in the central nervous system, adrenal glands and testis; there are at least six phenotypic distinctions of the ALD gene. 

Childhood-onset ALD (CCALD), as in this case, accounts for 31-57% of presentations.⁶ Other types include adolescent-onset ALD (AdolALD), adrenomyeloneuropathy (AMN), Addison only type, adult-onset cerebral ALD (ACALD) and pre- or asymptomatic ALD. Of the various phenotypes, CCALD presents with rapidly progressive demyelination of the white matter.^7,8

Peak incidence is between three and 10 years of age. Common neurological symptoms include attention deficit/hyperactivity, regression in school, gradual visual and auditory impairment. There is continuous ongoing clinical deterioration resulting in seizures, spastic tetraplegia and dementia within months of onset of symptoms. 

Clinical prognosis is guarded with most patients dying within two to three years of manifestation of neurological disease.³ Nevertheless, some patients live longer, though in a persistent vegetative state. 

The most common finding in MRI neuroimaging is extensive demyelination in the occipital periventricular white matter.³ Plasma VLCFA assay is the recommended diagnostic procedure in male patients.⁹ Heterozygous females can be identified by plasma VLCFA assay in 83% of cases but DNA-based diagnosis has a higher detection rate.¹⁰ AMN, a phenotypic variant of ALD, usually presents in the third to fourth decade of life with patients developing a spastic paraparesis and cerebral demyelination (50% of cases).¹¹

With the diagnosis of CCALD in this child, the illness described in his maternal grandfather’s siblings as MND was most probably a phenotype of ALD, namely AMN. 

The only treatment which has been shown to improve survival and slow progression to disability is HSCT treatment. Overall five-year survival reported by Peters et al for patients who received HSCT was 56% compared to 40% of non-treated patients. The authors concluded that patients with minimal signs of neurological damage were most suitable (minimal changes on MRI and IQ > 80).¹² In the literature, Auborg et al presented a case of a male born with a dizygous twin who presented with adrenal insufficiency at first but rapidly progressed to dystonia, attention deficit, behaviour problems with normal audiometry and visual tests. The patient’s dizygous twin provided bone marrow suspension for transplant. Twelve-month and 18-month follow-up assessments post-transplantation revealed complete normal neurological and psychometric tests. Neuroimaging at 18 months showed no pathology as had been previously shown prior to HSCT. 

This similar case emphasises the need for better awareness of ALD and the significance of early diagnosis.¹³

Learning points

• ALD should be excluded in cases where neurological progression occurs in patients with previous diagnosis of ADHD
• Consider ALD in Addison’s disease in male patients
• ALD should be considered in all patients presenting with developmental regression
• Early detection allows for aggressive treatment, slowing progression.

References 

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