Two uncommon cases of adult-onset adrenoleukodystrophy (ALD) with congenital brain developmental defects and damage to small nerve fibers were described in a new study.
The study, “Broadening the Spectrum of Adulthood X-Linked Adrenoleukodystrophy: A Report of Two Atypical Cases,” was published in the journal Frontiers in Neurology.
ALD, also known as X-linked ALD, has variable clinical presentations, which may include childhood, adolescent, and adult cerebral ALD, as well as myelopathy (spinal cord injury) with or without damage to peripheral nerve fibers.
A team from Italy reported the cases of two patients with adult-onset ALD, both without family history of neurological or endocrinological diseases, and with normal psychomotor development.
Patient 1 was a 37-year-old man who started experiencing progressive gait disturbances because of rigidity and weakness in both legs at age 35. He also complained of urinary urgency with incontinence and erectile dysfunction.
A neurological examination revealed mild dysarthria (a speech disorder), spastic paraparesis (partial paralysis and muscle stiffness of both legs), and brisk deep tendon reflexes (a higher response of nerve reflexes upon tapping).
A magnetic resonance imaging (MRI) scan showed multiple congenital brain development defects, including impaired development of the white matter tract that connects the two cerebral hemispheres, called posterior commissure, as well as the white matter in the posterior portion of the brain (a condition called colpocephaly), and thickening in the right frontal part of the brain cortex. A spinal MRI revealed spinal cord atrophy, or shrinkage.
Assessment of somatosensory evoked potentials (SEPs) of peripheral nerves — the electrical activity of the nervous system upon sensory stimulation — showed that neural impulses required more time to travel from the right arm and left leg. No response was recorded from the right leg. Motor evoked potentials (MEPs) — recorded in muscles after stimulation of the brain’s motor cortex — were absent in both legs.
Genetic analysis revealed a mutation in the ABCD1 gene, which led to the diagnosis of ALD. This specific mutation (c.1394-2A > G) had only been reported once in a patient with childhood cerebral ALD. Further genetic testing for mutations linked to cortical development defects excluded other possible genetic causes.
The patient showed normal cortisol amounts, but higher-than-normal levels of adrenocorticotropic hormone (ACTH), in line with subclinical adrenocortical insufficiency. He also had increased plasma levels of very long chain fatty acids (VLCFA), a typical finding in ALD cases.
The second reported case was that of a 63-year-old man who had a six-year history of progressive gait impairment and a tendency to drag both feet. He had been diagnosed with Addison’s disease, a type of ALD, at age 13.
Similar to patient 1, he also showed spastic paraparesis and brisk deep tendon reflexes. SEPs showed increased latency in the responses from the upper and lower limbs. No motor responses were recorded from the lower limbs.
An MRI revealed signs of brain lesions, including evidence of active and past inflammation. As in patient one, a spinal MRI scan showed spinal cord atrophy.
Plasma levels of VLCFA were increased. Genetic analysis also revealed a mutation in the ABCD1 gene, leading to an amino acid substitution from threonine to methionine. This confirmed the diagnosis of ALD.
From age 65, the patient began complaining of severe burning pain and abnormal painful hypersensitivity (dysesthesia) in the lower limbs and feet, which impaired his quality of life.
A subsequent skin biopsy revealed the presence of small fiber neuropathy (SFN), or nerve damage. All parameters assessed on new blood tests were within normal range, except for risk factors associated with this form of nerve damage.
Whole exome sequencing — an analysis of the DNA bits containing the information to make proteins, called exons — identified two variants in one copy each of SBF1 and WNK1. These two genes had been previously associated with hereditary neuropathies, Charcot-Marie-Tooth disease type 4B3 in the case of SBF1, and hereditary sensory and autonomic neuropathy type II in WNK1. In both cases, the mutations found were predicted to disrupt the encoded protein function.
As a result, the researchers considered that, although not being the cause, these gene variants may have contributed to the SFN.
Of note, despite the fact that WNK1 mutations are known to be associated with pseudohypoaldosteronism type 2, an illness characterized by an imbalance of sodium and potassium blood levels, the patient did not show changes in blood or urine electrolytes or pH.
“In conclusion, while noting that extensive genetic analyses should be interpreted with caution in patients whose symptoms are related to different coexisting causes, our two cases expand the observed clinical heterogeneity of adult X-ALD, including the possible presence of brain development defects and clinically relevant SFN,” researchers stated.