Endocrine Abstracts

Case history: We discuss a 40-year-old man with an unusual presentation of newly diagnosed Adrenoleukodystrophy following a family genetic screening test that was performed when his nephew aged 8 years was diagnosed with the same condition. He was struggling to articulate his thoughts and occasionally developed slurring of speech and these changes were noted over a period of 3 years preceding the diagnosis. The patient also reported symptoms of fatigue, clumsy gait and muscle stiffness. In contrast, his nephew developed features of the condition at a much younger age, initially presenting with a language development disorder which later rapidly progressed to recurrent falls and eventually to profound immobility.

Investigations and results: Genetic screening confirmed he was positive for ABCD1 gene alteration linked to X-linked Adrenoleukodystrophy (Hemizygous for ABCD1:c.901-5 C>A). 0900 hours cortisol level was low normal at 237 nmol/l, with a failed short Synacthen test demonstrating unsatisfactory cortisol response (0-minute: 74 nmol/l and 30-minute cortisol values of 308 nmol/l). MRI Brain and Spine did not reveal any gross sinister abnormalities.

Treatment: Hydrocortisone treatment was initiated, and subsequently his symptoms improved significantly, namely fatigue and muscle weakness.

Conclusion and discussion: Adrenoleukodystrophy (X-ALD) is an X-linked recessive disorder caused by mutations of the ABCD1 gene which codes for the adrenoleukodystrophy protein (ALDP). ALDP helps in the transport of very long chain fatty acids (VLCFA) to the peroxisomes for oxidative degradation. Due to the pathogenic variants and mutations of the ABCD1 gene, peroxisomes cannot oxidise VLCFA. It is characterised by the accumulation of VLCFA in the plasma and tissues, predominantly the adrenal gland, nervous system, and testes. Those affected with this mutation do not usually show signs or symptoms at birth, but males affected may develop adrenal insufficiency and spastic paraparesis. Previously, it was thought that females could only present as asymptomatic carriers as the condition is X-linked recessive. Despite this, more recent data show that heterozygous females can eventually develop signs of myelopathy. The three major phenotypes are cerebral adrenoleukodystrophy (CALD), primary adrenal insufficiency and adrenomyeloneuropathy (AMN). CALD is the most severe presentation of X-ALD resulting in demyelination within the cerebral white matter. It is characterised by a progressive and potentially fatal neurological decline, manifesting as seizures, paralysis and dysarthria. AMN typically presents in adulthood with a combination of myelopathy and peripheral neuropathy, with a more insidious course. In routine clinical practice, the implications of the ABCD1 mutation are well-recognised but less commonly perceived.