X-linked adrenoleukodystrophy and primary adrenal insufficiency
X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene (ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estima...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1309053/full |
| _version_ | 1797626709274525696 |
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| author | Marco Cappa Tommaso Todisco Carla Bizzarri |
| author_facet | Marco Cappa Tommaso Todisco Carla Bizzarri |
| author_sort | Marco Cappa |
| collection | DOAJ |
| description | X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene (ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females), and there is no evidence that this prevalence varies among regions or ethnic groups. ALDP deficiency results in a defective peroxisomal β-oxidation of very long chain fatty acids (VLCFA). As a consequence of this metabolic abnormality, VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex. All X-ALD affected patients carry a mutation on the ABCD1 gene. Nevertheless, patients with a defect on the ABCD1 gene can have a dramatic difference in the clinical presentation of the disease. In fact, X-ALD can vary from the most severe cerebral paediatric form (CerALD), to adult adrenomyeloneuropathy (AMN), Addison-only and asymptomatic forms. Primary adrenal insufficiency (PAI) is one of the main features of X-ALD, with a prevalence of 70% in ALD/AMN patients and 5% in female carriers. The pathogenesis of X-ALD related PAI is still unclear, even if a few published data suggests a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity. The reason why PAI develops only in a proportion of ALD/AMN patients remains incompletely understood. A growing consensus supports VLCFA assessment in all male children presenting with PAI, as early diagnosis and start of therapy may be essential for X-ALD patients. Children and adults with PAI require individualized glucocorticoid replacement therapy, while mineralocorticoid therapy is needed only in a few cases after consideration of hormonal and electrolytes status. Novel approaches, such as prolonged release glucocorticoids, offer potential benefit in optimizing hormonal replacement for X-ALD-related PAI. Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood. This paper aims to explore the multifaceted relationship between PAI and X-ALD, shedding light on shared pathophysiology, clinical manifestations, and potential therapeutic interventions. |
| first_indexed | 2024-03-11T10:14:03Z |
| format | Article |
| id | doaj.art-ad1af5f6b7e1432791382669afe65135 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-03-11T10:14:03Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-ad1af5f6b7e1432791382669afe651352023-11-16T12:05:59ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-11-011410.3389/fendo.2023.13090531309053X-linked adrenoleukodystrophy and primary adrenal insufficiencyMarco Cappa0Tommaso Todisco1Carla Bizzarri2Research Area for Innovative Therapies in Endocrinopathies, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyResearch Area for Innovative Therapies in Endocrinopathies, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyUnit of Paediatric Endocrinology, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyX-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene (ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females), and there is no evidence that this prevalence varies among regions or ethnic groups. ALDP deficiency results in a defective peroxisomal β-oxidation of very long chain fatty acids (VLCFA). As a consequence of this metabolic abnormality, VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex. All X-ALD affected patients carry a mutation on the ABCD1 gene. Nevertheless, patients with a defect on the ABCD1 gene can have a dramatic difference in the clinical presentation of the disease. In fact, X-ALD can vary from the most severe cerebral paediatric form (CerALD), to adult adrenomyeloneuropathy (AMN), Addison-only and asymptomatic forms. Primary adrenal insufficiency (PAI) is one of the main features of X-ALD, with a prevalence of 70% in ALD/AMN patients and 5% in female carriers. The pathogenesis of X-ALD related PAI is still unclear, even if a few published data suggests a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity. The reason why PAI develops only in a proportion of ALD/AMN patients remains incompletely understood. A growing consensus supports VLCFA assessment in all male children presenting with PAI, as early diagnosis and start of therapy may be essential for X-ALD patients. Children and adults with PAI require individualized glucocorticoid replacement therapy, while mineralocorticoid therapy is needed only in a few cases after consideration of hormonal and electrolytes status. Novel approaches, such as prolonged release glucocorticoids, offer potential benefit in optimizing hormonal replacement for X-ALD-related PAI. Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood. This paper aims to explore the multifaceted relationship between PAI and X-ALD, shedding light on shared pathophysiology, clinical manifestations, and potential therapeutic interventions.https://www.frontiersin.org/articles/10.3389/fendo.2023.1309053/fullX-linked adrenoleukodystrophyprimary adrenal insufficiencyvery long chain fatty acidsadrenal functioncortisol replacement |
| spellingShingle | Marco Cappa Tommaso Todisco Carla Bizzarri X-linked adrenoleukodystrophy and primary adrenal insufficiency Frontiers in Endocrinology X-linked adrenoleukodystrophy primary adrenal insufficiency very long chain fatty acids adrenal function cortisol replacement |
| title | X-linked adrenoleukodystrophy and primary adrenal insufficiency |
| title_full | X-linked adrenoleukodystrophy and primary adrenal insufficiency |
| title_fullStr | X-linked adrenoleukodystrophy and primary adrenal insufficiency |
| title_full_unstemmed | X-linked adrenoleukodystrophy and primary adrenal insufficiency |
| title_short | X-linked adrenoleukodystrophy and primary adrenal insufficiency |
| title_sort | x linked adrenoleukodystrophy and primary adrenal insufficiency |
| topic | X-linked adrenoleukodystrophy primary adrenal insufficiency very long chain fatty acids adrenal function cortisol replacement |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1309053/full |
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