Late-onset neurological manifestations of X-linked adrenoleukodystrophy in a male with childhood-onset Addison’s disease: A case report

Abstract

BACKGROUND

Primary adrenal insufficiency [Addison’s disease (AD)] is a rare but potentially life-threatening endocrine disorder caused by impaired cortisol and aldosterone production. While autoimmune adrenalitis is the most common etiology in adults, genetic causes account for a substantial proportion of childhood-onset cases and should be actively investigated. Among inherited etiologies, X-linked adrenoleukodystrophy (X-ALD) is one of the most important genetic causes of primary adrenal insufficiency in males. X-ALD is a peroxisomal disorder caused by pathogenic variants in the ABCD1 gene, leading to impaired degradation of very long-chain fatty acids. Its clinical spectrum ranges from isolated adrenal insufficiency to progressive cerebral demyelination or adrenomyeloneuropathy.

CASE SUMMARY

We report a 27-year-old male diagnosed with AD in early childhood who remained neurologically asymptomatic for more than two decades, consistent with the so-called “Addison-only” phenotype. In adulthood, he developed progressive psychiatric and neurological manifestations, including behavioral changes and motor symptoms, prompting further evaluation.

CONCLUSION

This case illustrates that childhood-onset AD in males may represent the earliest manifestation of X-ALD and that the “Addison-only” phenotype does not confer long-term neurological protection. The late emergence of psychiatric and neurological symptoms underscores the need for systematic screening for X-ALD in males with idiopathic early-onset adrenal insufficiency and highlights the importance of lifelong neurological surveillance to avoid delayed diagnosis.

Key Words: X-linked adrenoleukodystrophy; Addison-only; Late-onset; Psychiatric symptoms; ABCD1 gene; Case report

Core Tip: Adrenoleukodystrophies are a heterogeneous neurological occurrence and sometimes their differential diagnosis might be difficult. Addison disease among other background conditions might be related to such a progressive disorder that could lead to severe neurological injury. We present a case where the nervous symptomatology was delayed vis-à-vis the initial and main disease, and whose psychiatric signs preceded gait instability, impaired balance, and dysarthria. Imaging and genetic studies are of particular diagnostic importance in this setting.

INTRODUCTION

Primary adrenal insufficiency (PAI) also known as Addison’s disease (AD) is a rare but potentially life-threatening endocrine disorder resulting from impaired cortisol and aldosterone production due to dysfunction or destruction of the adrenal cortex. In adults, the most common etiology is autoimmune adrenalitis; however, in childhood-onset cases, genetic causes account for a substantial proportion and should be actively investigated[1].

Among inherited causes, X-linked adrenoleukodystrophy (X-ALD) is among the most critical genetic etiologies of primary adrenal insufficiency in males[2]. X-ALD is a peroxisomal disorder caused by pathogenic variants in the ABCD1 gene located on chromosome Xq28, leading to defective transport and degradation of very long-chain fatty acids (VLCFAs)[3].

The clinical spectrum of X-ALD is highly heterogeneous, ranging from isolated adrenal insufficiency to progressive inflammatory cerebral demyelination or adrenomyeloneuropathy (AMN). In many affected boys, adrenal insufficiency is the first manifestation and may remain the only clinical feature for years or even decades, a presentation commonly referred to as the “Addison-only” phenotype[2].

Despite an initial endocrine-only presentation, studies have demonstrated that a significant proportion of patients eventually develop neurological involvement later in life, including adult-onset cerebral adrenoleukodystrophy (ALD) or AMN, even after prolonged periods of apparent clinical stability[2].

Furthermore, psychiatric and behavioral symptoms are increasingly recognized as early manifestations of cerebral disease in adolescents and adults and may precede overt neurological decline, frequently leading to diagnostic delay[2].

We report the case of a young man diagnosed with AD in early childhood who developed psychiatric and neurological manifestations more than two decades later, ultimately leading to the diagnosis of X-ALD. This case underscores the importance of considering X-ALD in males with early-onset primary adrenal insufficiency and highlights the need for systematic screening and lifelong neurological surveillance, even in patients with long-standing endocrine-only disease.

CASE PRESENTATION

Chief complaints

A 27-year-old male, diagnosed with AD at age five and maintained on fludrocortisone therapy, remained in good health until presentation to our neurological facility.

Chief complaints

At this age, he developed prominent psychiatric and behavioral changes, including marked disinhibition; aggressive and irritable behavior toward family members, friends, and colleagues; and socially inappropriate conduct in professional settings.

These symptoms were accompanied by intrusive and recurrent sexual thoughts and impaired impulse control, including the expression of sexually inappropriate comments in the workplace. The behavioral disturbances led to significant conflicts at home and work, and were initially managed with neuroleptic treatment prescribed by a psychiatrist.

History of present illness

Approximately one year prior to presentation, the patient developed insidious psychiatric and behavioral changes. Family members reported progressive disinhibition, irritability, and reduced emotional regulation, with episodes of verbal aggressiveness toward relatives, friends, and colleagues. These behavioral changes were accompanied by impaired impulse control and hypersexual behavior, characterized by intrusive sexual thoughts and socially inappropriate comments, including inappropriate remarks in the workplace. The patient demonstrated limited insight into these behaviors, leading to significant interpersonal conflict and occupational difficulties. Psychiatric evaluation led to initiation of risperidone therapy (titrated to 2 mg/day) for behavioral dysregulation and impulse control symptoms. Although mild reduction in irritability was reported, hypersexual behavior and the other symptoms persisted.

History of past illness

Nothing worth to mention was reported.

Personal and family history

Notably, his younger brother had been diagnosed with AD at the age of 22 and was receiving similar treatment, raising suspicion of a familial disorder. Genetic testing confirmed the presence of a hemizygous pathogenic variant [c.1415_1416del p. (Gln472ArgfsTer83)] in the ABCD1 gene, thereby establishing the diagnosis of X-ALD.

Physical examination

Two years after the onset of psychiatric symptoms, the patient experienced progressive gait instability, impaired balance, and dysarthria.

On neurological examination, the patient was alert and oriented but exhibited mild executive dysfunction and reduced verbal fluency. Speech was dysarthric with a scanning quality. Cranial nerve examination was normal. Motor examination showed normal muscle strength and bulk, with mildly increased tone in the lower extremities. Deep tendon reflexes were brisk bilaterally, more pronounced in the lower limbs, with equivocal plantar responses. Sensory examination was largely preserved, though the patient reported intermittent distal paresthesias in the lower extremities. Coordination testing revealed bilateral dysmetria on finger-to-nose and heel-to-shin maneuvers, along with impaired rapid alternating movements. Gait was broad-based and unsteady, with impaired tandem walking and postural instability.

Laboratory examinations

Endocrine evaluation confirmed persistent primary adrenal insufficiency. Baseline morning serum cortisol levels were markedly reduced, with inappropriately elevated plasma adrenocorticotropic hormone concentrations, consistent with long-standing primary adrenal failure. Electrolyte levels were within normal limits under chronic replacement therapy. There was no clinical or biochemical evidence of adrenal crisis at presentation.

Imaging examinations

Brain magnetic resonance imaging (MRI) revealed bilateral, nearly symmetrical white matter hyperintensities on T2-weighted, fluid-attenuated inversion recovery (FLAIR) sequences, while spinal MRI was unremarkable. These radiologic findings suggested ALD (Figure 1).

Figure 1 Brain magnetic resonance imaging showing bilateral nearly symmetrical white matter hyperintensities on T2-weighted, fluid-attenuated inversion recovery sequences. A and B: Infratentorial images; C and D: Supratentorial images.

FINAL DIAGNOSIS

Given the clinical suspicion of X-ALD, plasma VLCFA analysis was performed and revealed elevated concentrations of hexacosanoic acid (C26:0) and increased C24:0/C22:0 and C26:0/C22:0 ratios, consistent with a peroxisomal β-oxidation defect.

TREATMENT

With no definitive curative genetic treatment at hand, the patient was referred for continuous psychiatric monitoring and was suggested yearly imaging control of the brain.

OUTCOME AND FOLLOW-UP

The next imaging examination still to be scheduled; while the patient is under antipsychotic therapy.

DISCUSSION

This case illustrates the clinically challenging association between childhood-onset AD and X-ALD, highlighting the potential for very late neurological manifestations after a prolonged “Addison-only” phenotype[2]. The patient developed neuropsychiatric and motor symptoms more than two decades after the diagnosis of PAI, underscoring the importance of lifelong neurological surveillance in male patients with early-onset AD of unknown etiology.

X-ALD is caused by pathogenic variants in the ABCD1 gene, located on Xq28[4]. This gene encodes the ALD protein, a peroxisomal membrane transporter responsible for the import of VLCFAs into peroxisomes for β-oxidation[2,4]. Dysfunction of this transporter leads to the accumulation of VLCFAs in the adrenal cortex, white matter, and spinal cord, resulting in adrenal insufficiency and progressive neurodegeneration. Adrenal involvement often precedes neurological disease and may represent the earliest or sole manifestation for years, particularly in boys[2,5].

The so-called “Addison-only” phenotype is well described. Approximately 80% of boys with X-ALD experience adrenal insufficiency in childhood, typically before the onset of neurological symptoms[2,6,7]. However, studies have demonstrated that neurological manifestations often emerge later in life, including adult-onset cerebral ALD or AMN, even after decades of apparent clinical stability[2]. This case exemplifies such delayed neurological progression, with symptom onset more than 20 years after initial endocrine presentation.

A notable feature of this case is the psychiatric prodrome, characterized by behavioral disinhibition and intrusive thoughts, which preceded overt neurological decline by approximately two years. Psychiatric and behavioral changes are increasingly recognized as manifestations of cerebral ALD, particularly in adults, and may mimic primary psychiatric disorders, leading to diagnostic delay[8,9]. Involvement of the frontal white matter is thought to underlie these symptoms[2,3,10].

Neuroimaging findings were essential in raising suspicion for X-ALD[11]. The presence of bilateral, nearly symmetrical white matter hyperintensities on T2-weighted and FLAIR sequences is characteristic of cerebral ALD and should prompt metabolic and genetic evaluation, particularly in patients with a history of adrenal insufficiency. Approximately 80% of patients initially develop demyelination in the splenium of the corpus callosum, with subsequent spread to the adjacent parieto-occipital white matter[2]. The most frequent presentation of the cerebral form is a lesion in the parieto-occipital white matter[11,12]. Although spinal MRI was unremarkable in this case, this does not exclude early AMN or evolving central nervous system involvement, as spinal cord pathology may develop later or remain clinically silent for prolonged periods.

The familial history of AD in the patient’s younger brother further supported a genetic etiology. Identification of a hemizygous pathogenic ABCD1 variant confirmed the diagnosis. Genetic testing revealed the ABCD1 variant c.1415_1416del p. (Gln472ArgfsTer83), which results in a shift in the reading frame starting at codon 472 in exon(s) no. 5 (of 10). According to HGMD professional 2024.4, this variant has previously been reported as disease-causing in ALD[12-14]. These findings highlight the importance of family screening, as male relatives may be at risk of developing neurological disease, and female carriers may develop late-onset symptoms.

From a clinical standpoint, this case reinforces several critical principles. First, all males with idiopathic AD, particularly those diagnosed in childhood, should be screened for X-ALD using VLCFA analysis and/or genetic testing[2]. Second, the emergence of psychiatric symptoms in such patients should prompt consideration of cerebral involvement[8,9,12,15]. Finally, lifelong neurological follow-up is essential, even in patients with long-standing endocrine-only disease, as early detection of neurological progression may allow timely referral to specialized centers and consideration of disease-modifying strategies in selected cases.

CONCLUSION

This case illustrates how X-ALD may remain clinically silent from a neurological standpoint for more than two decades after childhood-onset adrenal insufficiency, presenting initially with isolated psychiatric and behavioral changes before overt motor symptoms emerge. In this patient, progressive disinhibition, hypersexual behavior, and impaired executive function preceded cerebellar and pyramidal signs by approximately two years, leading to an initial psychiatric diagnosis and delayed neurological evaluation.

The case underscores that new-onset behavioral or psychiatric symptoms in adults with a history of childhood-onset AD should raise suspicion for cerebral involvement, even in the absence of early motor deficits. Characteristic symmetric white matter abnormalities on MRI can be a decisive diagnostic clue when psychiatric symptoms obscure the underlying neurological disorder. Rather than representing a purely endocrine disorder, the “Addison-only” phenotype may be a temporally limited stage of a multisystem disease. Recognition of subtle neuropsychiatric changes in such patients is critical to avoid misattribution to primary psychiatric illness and to facilitate timely neurological assessment.

Systematic screening for X-ALD should be considered in all males with idiopathic primary adrenal insufficiency, particularly when diagnosed in childhood, and lifelong neurological surveillance is essential even in clinically stable patients. Early recognition of neurological progression has critical implications for patient management, family counseling, and genetic screening, underscoring the need for close collaboration between endocrinologists, neurologists, and genetic specialists.