Brain Imaging, Tests Help Diagnose Rare Phenotype of X-linked ALD

Brain Imaging, Tests Help Diagnose Rare Phenotype of X-linked ALD

A combination of structural and functional brain imaging and tests assessing cognitive and behavioral functions may help assess damage progression in the frontal part of the brain in adult- onset X-linked adrenoleukodystrophy (ALD), a study based on a case report suggests.

The report study, titled “Late adult-onset adrenomyeloneuropathy evolving with atypical severe frontal lobe syndrome: Importance of neuroimaging” was published in the journal Radiology Case Reports.

ALD is a metabolic disease affecting different parts of the nervous system. The disorder is characterized by mutations in the ABCD1 gene — located on the X-chromosome — that is important in the breakdown of a group of fats called very long-chain fatty acids (VLCFAs).

The impaired VLCFA breakdown causes a damaging accumulation of fatty acids around the protective myelin sheath of nerve cells, affecting nerve communication. As a result, ALD can cause cognitive limitations, movement problems, and hormonal changes.

Standard ALD diagnosis relies primarily on genetic analysis of ABCD1 mutations, but also includes clinical examinations and assessment of plasma VLCFA levels. Other useful diagnostic tools include magnetic resonance imaging (MRI), and [18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET).

The case study presents results from molecular, functional, and brain-imaging analyses of a patient with adrenomyeloneuropathy (or AMN, an adult-onset form of ALD) with a rare progressive onset of frontal brain cognitive decline.

The 46-year-old Caucasian man came to the hospital with mild walking difficulties and urinary urgency (sudden urge to urinate due to involuntary contraction of bladder muscles).

The patient also showed mild cognitive limitations, scoring 27.89 on the 30-point Mini-Mental State Examination (MMSE) cognitive impairment test (low test scores indicate increased cognitive impairment severity).

MRI showed hyperintense areas in the brain’s frontal lobe, associated with spinal cord atrophy.

These observations, together with the patient’s family history of walking difficulties and child deaths, led the team to suspect ALD/AMN.

The patient had high plasma VLCFA levels, and a point mutation in the ABCD1 gene (c.1028G.T) was found.

These final observations confirmed the suspected diagnosis of ALD/AMN.

Five years after the diagnosis, the patient was readmitted to the hospital with progressive cognitive limitations (MMSE score, 24.99 of 30) and behavioral limitations, including disinhibition, distractibility, lack of understanding, apathy, inability to feel pleasure, as well as incontinence.

Follow-up MRI confirmed the findings from the first scan, showing signs of critical damage to the frontal part of the brain. The team found a strong correlation between clinical progression of the patient and the progressive damage of white matter (the area in the central nervous system that transmits information between different parts of the brain and between nerves) seen through MRI.

The ability of the brain to metabolize glucose (a sugar) can be a marker for cognitive dysfunction, with a lower glucose metabolism indicating a cognitive decline. Glucose metabolism can be assessed through brain FDG-PET scan.

FDG-PET scan of the patient showed reduced FDG metabolism, mainly in the brain’s gray matter, specifically on the frontal part of the brain. According to the team, the reduced brain metabolism found in this part of the brain is in line with the observed brain-associated cognitive impairments and white matter damage.

Together, the results show a correlation between the clinical decline of the patient and brain imaging results. The researchers argued that further studies might be able to link ALD-specific mutations and clinical outcomes measured by functional tests and brain scans.

“The degree and extent of these findings allow us to trace a direct line between loss of white matter integrity, altered connectivity, morphological and functional changes, and, finally, the resulting clinical picture,” the team stated.

“This also underlines how clinical examination, MRI and FDG PET all offer unique contributions to the description of this rare phenotype of [X-linked ALD],” the researchers said.