Targeted genetic testing is critical for accurate diagnosis of X-linked adrenoleukodystrophy (ALD), particularly in cases with atypical presentation, the case of an adult male with mild symptoms demonstrates.
The case, presented by Mayo Clinic researchers, was described in a study titled “Targeted gene approach with biochemical assay confirms ABCD1 mutation of X-linked adrenoleukodystrophy in a 62-year-old man with gait imbalance,” published in the journal Neuromuscular Disorders.
The man had an atypical clinical presentation of X-linked ALD with family history suggesting a genetic cause.
He had experienced progressive gait imbalance for 17 years, and had loss of sensation in his feet since the symptoms’ onset. He complained of pain affecting the upper arm and calf, and reported to have had difficulty rising from a seated position for two to three years.
Physical examination revealed that he had difficulty squatting, with moderate muscle weakness. He also showed signs of altered balance and gait, which could be linked to central nervous system impairment.
Additional tests showed that he had about 5-20% reduced responsiveness in all motor-sensory nerves. He was found to have reduced reactivity of the nerve that controls some muscles in the lower leg, and reduced reactivity of muscles on his back.
Evaluation of his spine by magnetic resonance imaging (MRI) showed mild degenerative changes but without cord abnormalities.
His family already had a clinical history of weakness and/or sensory loss, with four younger brothers and two sisters being affected. The family history was negative for adrenal gland insufficiency.
Two of the brothers had previously been evaluated by a neurologist, and one was diagnosed with demyelinating neuropathy (nerve cell damage due to loss of the protective myelin layer). The patient’s mother had lower extremity weakness diagnosed when she was 70-80 years old, and dementia diagnosed by her 90s.
Given the extensive clinical family history, the team suspected that the patient could have a genetic condition involving nerve degeneration.
To explore this hypothesis, the researchers conducted genetic analysis for a panel of 102 genes related to peripheral neuropathy. The patient was found to carry a mutation on the ABCD1 gene, known to be associated with X-linked ALD.
X-linked ALD is a progressive disorder characterized by impaired production of the ABC transporter that is encoded by the ABCD1 gene, and consequent accumulation of very long-chain fatty molecules in tissues throughout the body. When the disease has its onset in adulthood, it is known as adrenomyeloneuropathy (AMN).
Lab analysis confirmed the fatty molecules’ accumulation in the patient, supporting a final diagnosis of X-linked AMN. Still, he did not have cerebral involvement and his adrenal gland was functioning within normal patterns — two features common among AMN patients.
Genetic analysis of other family members confirmed that his four brothers and his mother were all carriers of the identified ABCD1 gene variant. No additional genetic alterations were detected in the family.
“Targeted genetic approaches are helpful in the evaluation of suspected genetic neuropathies as seen in this case where AMN was not initially clinically considered,” researchers stated.
“As gene panel testing expands and more variants of unclear significance are found,” it becomes evident that “combining targeted gene approaches with functional assay confirmation, especially for atypical clinical presentations,” are necessary, the team concluded.