Case 1: A six-year-old with hyperactivity

A six-year-old boy was referred to the child neurology clinic by his paediatrician for hyperactivity and aggressive behaviour that started a few months before presentation. His paediatrician attempted to modify his behaviour with stimulant medication. However, the family noted progressive worsening, with increasing distractibility in the classroom and marked irritability toward his siblings. His parents, as well as teachers, noted a decline in his academic performance in the first grade.

The parents did not indicate any changes in their social situation and the family history was unremarkable for psychosis or bipolar disease.

Physical examination revealed a tanned young boy in no pain or distress. On neurological examination, he was found to have a very short attention span, had difficulty reading from a grade-level reading word list and required frequent redirection. Mild increase in tone was noted in his lower extremities, with exaggerated deep tendon reflexes and positive Babinski sign bilaterally. His gait was awkward with short shuffling steps, and he could not walk in a tandem manner.

His initial laboratory work-up included electrolyte levels and blood counts, which were normal. Magnetic resonance imaging (MRI) of the brain was performed the next day and indicated the likely diagnosis.

CASE 1 DIAGNOSIS: X-LINKED ADRENOLEUKODYSTROPHY

MRI showed bright signals on axial inversion recovery sequences in the pons, internal capsule and the subcortical white matter of the parietal and occipital areas suggesting a leukodystrophy (Figures 1A and 1B). X-linked adrenoleukodystrophy (X-ALD) was subsequently confirmed by genetic testing. The patient was later found to have Addison disease – explaining his darker skin tone. He started hormone replacement therapy and was referred to the bone marrow transplant program. Unfortunately, he was not considered to be a suitable candidate and is currently in a home-based hospice program.

Figure 1).

AAxial fluid-attenuated inversion recovery image showing white matter hyperintensity in bilateral parietal occipital white matter (solid arrow). The dotted arrow indicates involvement of the splenium of the corpus callosum.BAxial fluid-attenuated inversion recovery image demonstrating lesions in the internal capsules (solid arrow). The dotted arrow indicates cavum septum pellucidum, which was an incidental finding

X-ALD is a genetically determined condition, caused by a mutation in the ABCD1 gene, which maps to chromosome Xq28. This genetic defect leads to impaired oxidation of very long chain fatty acids (VLCFA). The resultant accumulation of VLCFA is most prominent in the central nervous system and adrenal cortex.

The exact mechanism whereby the accumulation of VLCFA results in demyelination is unclear. Nonetheless, VLCFA are known to build up in specific lipid fractions of brain tissue, including gangliosides and phosphatidylcholine. Gangliosides, by virtue of their function in cell adhesion and signalling pathways, have been implicated in several immunological disorders and have been postulated to play a role in the disease pathogenesis of X-ALD (1). Furthermore, pathological studies have noted the presence of lymphocytes and the expression of proinflammatory markers at the edge of the lesion, which further contribute to the destruction of myelin.

The prevalence of X-ALD is one in 17,000. The recognized phenotypes of X-ALD in childhood are as follows:

1. Childhood-onset cerebral ALD – is the most commonly encountered form (45%). The onset usually occurs between five and 10 years of age. The disease often presents with behaviour changes, progressive cognitive decline and associated neurological symptoms such as spasticity and gait abnormalities. The average interval to death or vegetative state is three years. The neuropsychological features are reflective of subcortical dementia and include deficits in verbal fluency, naming during visual stimulus and executive function (2).

2. Adolescent-onset cerebral type – is similar to childhood-onset cerebral ALD but is slower to progress.

3. Primary adrenal insufficiency – two-thirds of all males with central nervous system manifestations have adrenal insufficiency.

4. Adrenomyeloneuropathy – is usually limited to the spinal cord and is uncommon in childhood.

Definitive diagnosis is achieved by demonstration of elevated VLCFA in plasma and DNA mutation analysis. Prenatal diagnosis, although available, is not routinely performed as part of the newborn screening process for metabolic diseases.

Hematopoietic stem cell transplant, using bone marrow, is currently accepted as the most effective treatment option for children who are in the early stages of the disease. Scoring of MRI patterns using the criteria set forth by Loes et al (3) and detailed neuropsychological analysis assist with selecting children suitable for bone marrow transplant.

Adrenal hormone replacement therapy, with upward adjustments for intercurrent illnesses, is obligatory for children who have associated adrenocortical insufficiency – although it does not influence ultimate survival.

CLINICAL PEARLS

• Inborn errors of metabolism can present in childhood with behaviour disturbances, psychosis and/or depression and, therefore, psychiatric symptoms of new onset, or cognitive deterioration, especially in a previously healthy male child, warrant thorough neurological evaluation including consideration of X-ALD. Other metabolic defects that can present in this manner include metachromatic leukodystrophy, Niemann-Pick disease, Wilson disease and urea cycle disorders (4).

• Special attention must be devoted to subtle signs of spasticity, visual impairment and gait disturbances.

• Siblings of children with X-ALD should be screened, even if asymptomatic, with genetic testing because they may be candidates for bone marrow transplant, which is potentially curative. While providing genetic counselling, the fact that female carriers can develop myelopathy should be kept in mind.