X-linked adrenoleukodystrophy in two male siblings; Endocrinological aspects of the disease, and therapeutic approaches

Kyriaki Hatziagapiou; Maria Dolianiti; Sakka Sofia D.; Eleftheria Kokkinou; Roser Pons; Christina Kanaka-Gantenbein

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ESPE Abstracts (2024) 98 P2-13

ESPE2024 Poster Category 2 Adrenals and HPA Axis (25 abstracts)

X-linked adrenoleukodystrophy in two male siblings; Endocrinological aspects of the disease, and therapeutic approaches.

Kyriaki Hatziagapiou ¹ , Maria Dolianiti ¹ , Sofia D. Sakka ¹ , Eleftheria Kokkinou ² , Roser Pons ² & Christina Kanaka-Gantenbein ¹

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¹Division of Endocrinology, Diabetes and Metabolism and ENDO-ERN Center for rare pediatric Endocrine disorders, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Aghia Sophia Children’s Hospital, Athens, Greece. ²Division of Pediatric Neurology, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Aghia Sophia Children’s Hospital, Athens, Greece

Introduction: X-linked adrenoleukodystrophy (X-ALD) is a cause of primary adrenocortical insufficiency. It is associated with accumulation of very long chain fatty acids (VLCFA), due to peroxisome dysfunction. X-ALD is caused by pathogenic variants of the ABCD1, which encodes an ATP-binding cassette transport protein, and is inherited in X-linked recessive mode. There is no known genotype-phenotype correlation, and the degree of VLCFA elevation does not correlate with the onset of adrenal insufficiency or the severity of the neurologic disease.

Patients and Methods: We present the cases of two male brothers, aged 6 and 3^9/12-years with suspected X-ALD. Measurements of plasma VLCFA, Magnetic Resonance Imaging (MRI), and Whole Genome Sequencing (WGS) for the definite diagnosis, complete endocrinological and biochemical panel were performed.

Results: The older sibling demonstrated signs of attention-deficit disorder, gait instability, visual difficulties, skin and mucosal pigmentation, whereas the younger only mucosal pigmentation. Both had elevated VLCFA C24, C26, C24/C22 C26/C22 ratios. Brain MRI of the older brother showed extensive cerebral white matter demyelination, whereas the younger brother’s was negative. WGS identified the pathogenic ABCD1 variant c.1213T>C (p.Ser405Pro), which has been detected in only one patient of Chinese origin so far. The endocrinological and biochemical screening is presented in the Table. Both children were started on substitution with hydrocortisone (10 mg/m²) and fludrocortisone. The older brother due to extensive MRI lesions is not eligible for hematopoietic stem cell transplantation (HSCT). He is receiving experimental treatment with leriglitazone, a selective PPAR-γ (peroxisomal proliferator activating receptor gamma) agonist. During the last follow-up, three months after leriglitazone initiation, clinical deterioration was observed, and ΑCTH was increased to 683pg/ml, thus hydrocortisone replacement was increased to 16 mg/m². Also, fludrocortisone was suspended, as it was incompatible with leriglitazone. However, electrolytes remained normal. The younger brother is under follow-up to perform HSCT at the appropriate time.


	Sibling 1 (6 years)	Sibling 2 (3^9/12years)	Normal range
Sodium	140	138	135-150mmol/1
Chloride	101	101	95-110mmol/1
Potassium:	4.2	4.8	3.5-5.5mmol/1
Cortisol (8.00 am)	7.17	13.1	5-25µg/dl
ACTH	776	295	9-52pg/ml
Aldosterone	10.9	25.3	4-76ng/dl
PRA	3.48	4.37	0.5-2.95ng/ml/h

Conclusion: VLCFA are thought to be directly cytotoxic to adrenocortical cells or disrupt their response to ACTH, leading to cortical atrophy. Early diagnosis of X-ALD, and administration of proper replacement therapy with hydrocortisone and fludrocortisone is important, as electrolyte fluctuations are associated with demyelination acceleration. Increases in ACTH, even with normal cortisol, are early signs of establishment of primary adrenal insufficiency.