Haploidentical hematopoietic stem cell transplantation with busulfan, cyclophosphamide, and fludarabine conditioning for X-linked adrenal cerebral leukodystrophy.

OBJECTIVE: We investigated the safety and efficacy of haploidentical stem cell transplantation (SCT) in pediatric patients with X-linked adrenoleukodystrophy (ALD). METHODS: A retrospective analysis of transplantation data from 29 cases of ALD, treated between December 2014 and April 2022, was conducted. Neurologic function scores (NFS) were assessed. The conditioning regimen was busulfan 9.6 mg/kg, cyclophosphamide 200 mg/kg, and fludarabine 90 mg/m2 (BFC). Graft-versus-host disease prophylaxis consisted of anti-human thymocyte globulin, cyclosporine A, mycophenolate mofetil, and short course of methotrexate. RESULTS: Among the 29 cases, 14 cases (NFS = 0) were asymptomatic, and 15 (NFS ≥ 1) were symptomatic. The median age at SCT was 8 years (range: 4-16 years); the median follow-up time was 1058 days (range: 398-3092 days); 28 cases were father donors and 1 case was a grandfather donor. Hematopoietic reconstitution was successful in all patients, and all of them achieved complete donor chimerism at the time of engraftment. The leading cause of death was still primary disease progression (n = 4). Survival free of major functional disabilities was 100% in asymptomatic patients versus 66.67% in the symptomatic group (p = .018). CONCLUSION: BFC regimen used in haploidentical SCT was administered safely without major transplant-related complications even in symptomatic patients, and neurological symptoms were stabilized after SCT.

Adrenomyeloneuropathy manifesting as adrenal insufficiency and bilateral lower extremity spastic paraplegia: A case report and literature review.

RATIONALE: Adrenomyeloneuropathy (AMN) is a variant type of X-linked adrenoleukodystrophy, and it is a genetic metabolic disease with strong clinical heterogeneity so that it is easily misdiagnosed and underdiagnosed. Moreover, most patients with AMN have an insidious clinical onset and slow progression. Familiarity with the pathogenesis, clinical features, diagnosis, and treatment of AMN can help identify the disease at an early stage. PATIENT CONCERNS: We present a case of 35-year-old male, who was admitted to our hospital due to "immobility of the lower limbs for 2 years and worsening for half a year," accompanied by skin darkening and hyperpigmentation of lips, oral mucosa, and areola since puberty. DIAGNOSIS: The level of very long-chain fatty acids was high and genetic testing depicted that exon 1 of the ABCD1 gene had a missense mutation of C.761c>T, which was diagnosed as AMN. INTERVENTIONS: Baclofen was administered to improve muscle tension combined with glucocorticoid replacement therapy. OUTCOMES: The condition was relieved after half a year. LESSONS: The clinical manifestations of AMN are diverse. When patients with adrenocortical dysfunction complicated with progressive spastic paraplegia of lower limbs are involved, AMN should be highly suspected, and the determination of very long-chain fatty acids and genetic testing should be performed as soon as possible to confirm the diagnosis because early treatment can help prevent or delay the progression of the disease.

Accelerated Course of Cerebral Adrenoleukodystrophy After Coronavirus Disease 2019 Infection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can not only infect the respiratory system but also affect the nervous system through the release of inflammatory factors. Our study aimed to investigate the effect of COVID-19 infection on cerebral adrenoleukodystrophy (ALD). METHODS: Changes in the neurological symptoms of cerebral ALD after infection with COVID-19 from January 2022 to February 2023 were retrospectively analyzed. The primary assessment indicator was the Neurologic Function Scale (NFS) score. RESULTS: A total of 17 male patients with cerebral ALD were enrolled, with a median age of 101 months (80 to 151 months). Among them, 11 (11 of 17, 64.7%) developed an exacerbation of neurological symptoms after COVID-19 infection. Two patients with NFS = 0 started presenting with neurological symptoms after infection. Fifteen patients were in the advanced stage (NFS >1 and/or Loes score >9), of which nine did not progress to major functional disabilities (MFDs). Seven of the nine patients (77.8%) experienced an increase in NFS scores, ranging from 1 to 9 points, within two weeks of COVID-19 infection, with four of them experiencing MFDs. For the other six patients who had progressed to MFDs, there was not much room for further degeneration, so the NFS score did not increase after COVID-19 infection. No deaths related to COVID-19 infection occurred. CONCLUSIONS: COVID-19 infection may aggravate neurological symptoms of cerebral ALD, particularly among patients who have not yet progressed to MFDs. Therefore, COVID-19 may accelerate the course of cerebral ALD, so protecting patients from infection is essential for maintaining the stability of the disease.

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 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 ß-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.

Clinical course and endocrine dysfunction in X-linked adrenoleukodystrophy: A case series.

BACKGROUND AND PURPOSE: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder affecting particularly the nervous tissue and adrenal cortex. Adrenomyeloneuropathy (AMN) is the most frequent phenotype, although adrenal insufficiency is usually the first manifestation in male patients. We set out to describe the clinical and biochemical features, together with the clinical course of X-ALD patients, focusing particularly on endocrine dysfunction. PATIENTS AND METHODS: A retrospective study of 10 male X-ALD patients followed up at the Endocrinology Department. Epidemiologic data, phenotype evolution, endocrine and neurological findings and family history were analysed. RESULTS: All the patients presented with adrenal insufficiency, 4 of them during adulthood, with a mean age of 19.6±17.1 years (6-64 years). Six patients had mineralocorticoid deficiency. At diagnosis, 8 patients had Addison-only phenotype and 2 AMN phenotype. In the course of follow-up (24.9±16.1 years), 4 patients developed AMN about 25.0±7.4 years after the initial diagnosis and 2 patients presented the cerebral adult form 11 and 17 years after the initial diagnosis. Testosterone levels were within the normal range in all patients. There were 7 families, and age of onset and clinical course were similar in 3 of them. CONCLUSIONS: The presentation of X-ALD varied widely, 40% of the patients presented with adrenal insufficiency in adulthood, 60% had mineralocorticoid deficiency, and the onset and progression of neurological manifestations showed no pattern. Nevertheless, some similarities in the clinical course were found in some families. Our findings reinforce the need for screening for X-ALD at any age when approaching adrenal insufficiency and the importance of a multidisciplinary approach between endocrinologists and neurologists.

Nutritional status of children affected by X-linked adrenoleukodystrophy.

BACKGROUND: Adrenoleukodystrophy (ALD) is a rare X-linked metabolic disorder that causes the accumulation of very-long-chain fatty acids (VLCFAs) (C26:0) and the subsequent variety of clinical and neurological symptoms. Little is known about nutritional status and dietary habits of children affected by ALD, and so the present study aimed to assess nutritional status and food intake in children with ALD, also exploring the relationship between food intake and the consumption of disease-specific dietary supplements to reduce blood C26:0 concentrations and increase monounsaturated fatty acids (C26:1). METHODS: All patients underwent a clinical and neurological evaluation and a comprehensive nutritional assessment. The association of VLCFA concentrations with dietary lipids was assessed. RESULTS: Nine boys (11.49 ± 3.61 years) were enrolled in a cross-sectional study. All patients were normal weight, with normal resting energy expenditure. Only six of nine patients followed the low-fat diet and dietary supplements. An inverse association was found between the food intake of polyunsaturated lipids and C26:0; conversely, the C26:0 was positively associated with the dietary saturated lipids. When consumed, dietary supplement consumption correlated positively with C26:1 (ρ = 0.917, p = 0.029) and no correlation was found with C26:0 (ρ = 0.410, p = 0,493). CONCLUSIONS: No children were found to be malnourished or overweight or obese; however, half of the children reported excessive body fat, probably as a result of the pharmacotherapies. A low-fat diet could be adjuvant in the management of the accumulation of VLCFAs, but poor dietary compliance to disease-specific nutritional guidelines appears to be a major problem of this condition and underlines the need for a structured and personalised nutritional management in ALD disease.

Neonatal lupus is a novel cause of positive newborn screening for X-linked adrenoleukodystrophy.

We report three unrelated individuals, each exposed to maternal autoantibodies during gestation and found to have elevated very long-chain fatty acids (VLCFAs) in the newborn period after screening positive by California newborn screening (NBS) for X-linked adrenoleukodystrophy (ALD). Two probands presented with clinical and laboratory features of neonatal lupus erythematosus (NLE); the third had features suggestive of NLE and a known maternal history of Sjogren's syndrome and rheumatoid arthritis. In all three individuals, subsequent biochemical and molecular evaluation for primary and secondary peroxisomal disorders was nondiagnostic with normalization of VLCFAs by 15 months of age. These cases add to the expanding differential diagnosis to consider in newborns who screen positive for ALD via elevated C26:0-lysophosphatidylcholine. Though the pathophysiology of how transplacental maternal anti-Ro antibodies damage fetal tissue is not well-understood, we postulate that the VLCFA elevations reflect a systemic inflammatory response and secondary peroxisomal dysfunction that improves once maternal autoantibodies wane after birth. Additional evaluation of this phenomenon is warranted to better understand the intricate biochemical, clinical, and possible therapeutic overlap between autoimmunity, inflammation, peroxisomal dysfunction, and human disease.

Experiences of patients and their family members with metachromatic leukodystrophy, adrenoleukodystrophy, and Krabbe disease: a qualitative systematic review protocol.

OBJECTIVE: The objective of this review is to synthesize the experiences of patients with metachromatic leukodystrophy (MLD), adrenoleukodystrophy (ALD), and Krabbe disease and the experiences of their family members. INTRODUCTION: MLD, ALD, and Krabbe disease are rare disorders that are classified as lysosomal storage or peroxisomal disorders, with similar presentations as leukodystrophy. As these diseases cause cognitive and neurological decline due to the progression of leukodystrophy associated with demyelination, they have significant impact on the lives of patients and their families. It is important to identify the impact and challenges of these diseases on patients' lives and on their families, as well as to synthesize qualitative studies regarding their experiences. INCLUSION CRITERIA: We will consider studies including patients with MLD, ALD, or Krabbe disease and their family members. These experiences will include the challenges, dissatisfactions, and frustrations with symptoms and treatments; complications of hematopoietic stem cell transplantation; and the increased caregiver burden with disease progression. This is important since the impacts of disease progression are experienced in a variety of settings beyond the hospital, such as in the community and at home. METHODS: The search strategy will follow JBI methodology and be conducted in 3 steps: an initial limited search, a comprehensive database search, and a reference search of the included articles. MEDLINE, CINAHL Plus, PsycINFO, and Scopus will be searched with no restriction on language or publication dates. The study selection, critical appraisal, data extraction, and data synthesis will be performed according to JBI guidelines for systematic reviews of qualitative research. Final syntheses will be assessed using the ConQual approach. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42022318805.

Neurocognitive and mental health impact of adrenoleukodystrophy across the lifespan: Insights for the era of newborn screening.

X-linked adrenoleukodystrophy (ALD) is a rare inherited neurological disorder that poses considerable challenges for clinical management throughout the lifespan. Although males are generally more severely affected than females, the time course and presentation of clinical symptoms are otherwise difficult to predict. Opportunities to improve outcomes for individuals with ALD are rapidly expanding due to the introduction of newborn screening programs for this condition and an evolving treatment landscape. The aim of this comprehensive review is to synthesize current knowledge regarding the neurocognitive and mental health effects of ALD. This review provides investigators and clinicians with context to improve case conceptualization, inform prognostic counseling, and optimize neuropsychological and mental health care for patients and their families. Results highlight key predictive factors and brain-behavior relationships associated with the diverse manifestations of ALD. The review also discusses considerations for endpoints within clinical trials and identifies gaps to address in future research.

Diagnosis, treatment and genetic analysis of a case of skin hyperpigmentation as the only manifestation with X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is an inherited disease caused by a mutation in the adenosine 5'-triphosphate binding cassette subfamily D member 1 (ABCD1) gene encoding a peroxisomal transmembrane protein, which has various clinical manifestations and a rapid progression from initial symptoms to fatal inflammatory demyelination. Therefore, identification of early clinical symptoms and further early diagnosis as well as treatment can effectively prevent disease development. In this study, we reported the laboratory and radiographic features in a rare case of X-ALD with 3-year skin hyperpigmentation as the only manifestation. And the ABCD1 gene was sequenced for the patient and his parents by a high-throughput sequencing method. The results of laboratory examination showed adrenocortical hypofunction and increased serum concentrations of very long-chain fatty acids. Brain MRI showed no obvious abnormal signal shadow. A hemizygous mutation of c.521A>C was detected in the ABCD1 gene of the patient, and his mother has the same site heterozygous mutation. Therefore, this patient was diagnosed as "X-linked adrenoleukodystrophy". During the follow-up, adrenocortical hypothyroidism did not improve, and brain MRI showed few high-FLAIR signals in the white matter of the right radial corona and left parietal lobe, suggesting possible brain injury. X-ALD patients with only skin manifestations but no neurological abnormalities are easily neglected, but early diagnosis and early intervention are important ways to delay the progression of this disease. Therefore, genetic testing for early X-ALD is recommended in all male children patients with skin pigmentation as the sole clinical presentation and subsequent diagnosis of adrenal hypofunction.

Recurrent episodes of vomiting and diarrhoea in a male child: a rare presentation of X-linked adrenoleukodystrophy.

Recurrent episodes of vomiting and diarrhoea in a child can present as a diagnostic dilemma and be easily misdiagnosed as recurrent viral gastroenteritis episodes. Primary adrenal insufficiency can present with recurrent episodes of vomiting and diarrhoea with the presence of metabolic acidosis and can be life-threatening if left undiagnosed and untreated. A high index of suspicion should be kept for diagnosing primary adrenal insufficiency in a child presenting with recurrent episodes of vomiting and diarrhoea with laboratory evidence of metabolic acidosis and hypoglycaemia. Primary adrenal insufficiency, in a male child specifically, should raise alarm for X-linked adrenoleukodystrophy (X-ALD). Very-long-chain fatty acids and confirmatory genetic testing for an ABCD1 gene mutation can help confirm the diagnosis. Addison's disease often presents prior to the onset of the cerebral form of X-ALD. Early diagnosis of X-ALD allows for MRI screening for the development of cerebral disease in its early stages when treatment with stem cell transplant can halt the disease and be lifesaving.

Time to Transplant in X-Linked Adrenoleukodystrophy.

OBJECTIVES: Cerebral X-linked adrenoleukodystrophy (cALD) is an inflammatory demyelination of the brain that can lead to death unless treated by hematopoietic stem cell transplantation. Survival and improved outcomes for cerebral adrenoleukodystrophy are associated with hematopoietic stem cell transplantation at earliest evidence of disease on magnetic resonance imaging (MRI). Our goal was to determine average duration between diagnosis of cALD and hematopoietic stem cell transplantation. METHODS: This was a retrospective review of data of patients aged 18 years or younger, using a nationwide administrative health care database (Pediatric Health Information System), with an International Classification of Diseases, Tenth Revision (ICD-10) diagnosis of adrenoleukodystrophy. Time range was October 1, 2015, through June 30, 2021. We determined time to hematopoietic stem cell transplantation by duration between index brain MRI and a code for hematopoietic stem cell transplantation. RESULTS: We identified 27 patients with cerebral adrenoleukodystrophy. Total charges for the cohort was $53 million. Time to transplant averaged 97 days. For Hispanic patients, time to transplant was 117 days, compared with 80 days for White, non-Hispanic patients. Comparison of different hospitals showed significant variability in time to hematopoietic stem cell transplantation. DISCUSSION: We found that time to hematopoietic stem cell transplantation was >3 months for patients with cerebral adrenoleukodystrophy in the hospitals we evaluated. We noted differences in average time by race/ethnicity and by hospital. Our findings suggest opportunity to reduce time to transplant in cerebral adrenoleukodystrophy.

Restless Legs Syndrome in X-linked adrenoleukodystrophy.

OBJECTIVE/BACKGROUND: X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease that causes progressive gait and balance problems. Leg discomfort, sleep disturbances, and pain contribute to daily disability. We sought to investigate the prevalence and severity of Restless Legs Syndrome (RLS) in patients with ALD. PATIENTS/METHODS: We administered questionnaires and conducted diagnostic telephone interviews to assess RLS severity. We retrospectively extracted data from neurological examinations, functional gait measures, and laboratory assessments. RESULTS AND CONCLUSIONS: Thirty-two adults with ALD (21 female, 11 male) were recruited to participate. Thirteen patients (40.6%) had RLS (10/21 females and 3/11 males). The median age of RLS onset was 35 years [IQR = 22-54]. Patients with RLS had more signs and symptoms related to myelopathy, but not the brain demyelination seen in ALD. This pilot study suggests a high prevalence of RLS in adults with ALD, which may contribute to sleep problems and impair quality of life.

The clinical spectrum of X-linked adrenoleukodystrophy: from Addison's-only in men to middle-age neurologic manifestations in women.

X-linked adrenoleukodystrophy (X-ALD) is caused by a mutation in the ABCD1 gene which encodes for a peroxisomal very long-chain fatty acid (VLCFA) transporter. Clinically, X-ALD can present a wide range of phenotypes, from slowly progressive myelopathy to rapid demyelination of brain white matter (cerebral X-ALD-CALD). Adrenocortical insufficiency (AI) occurs mainly in the pediatric age group, and it can be the first manifestation of the disease. Female carriers may also develop manifestations of myelopathy, but later in life. We present two cases of patients who show the heterogeneous clinical manifestations of X-ALD. Case 1 was a man with AI diagnosed at 6 years old and with the first manifestations of myelopathy at 44 years old, which led to the diagnosis of X-ALD. At 47 years, he developed rapidly progressive CALD. Case 2 was a woman with progressive spastic gait disturbance that started at 49 years old. The diagnosis of X-ALD was confirmed at 54 years old after the discovery of a family history of the disease. Mild progression of the neurologic manifestations was noted, but with no signs of AI nor CALD. She is currently 60 years old and under surveillance. We review the current knowledge on X-ALD as concerns its genetic and pathophysiological mechanisms, clinical presentations, diagnosis, treatment, and follow-up. This condition is a real diagnostic challenge. The early detection of AI and CALD, potentially life-threatening complications in men, is very difficult. The surveillance of these complications in female patients still raises controversy.

Adult-onset adrenoleukodystrophy presenting with status epilepticus and psychosis.

Adrenoleukodystrophy (ALD) is an X linked recessive genetic disorder caused by an abnormality in the ABCD1 gene on the X chromosome, that affects 1 in 20 000 people. In X linked adrenoleukodystrophy (X-ALD), a defect in lignoceroyl-coenzyme A ligase causes pathognomonic tissue accumulation of very long chain fatty acids (VLCFA) in the adrenal cortex and nervous system. The phenotypic variability ranges from cerebral inflammatory demyelination of childhood onset, leading to death within 5 years, to adults remaining presymptomatic through more than five decades. Our case is that of a man who was previously diagnosed with bipolar affective disorder presented with dystonic posturing. During transit, he had an episode of generalised convulsive status epilepticus. He presented with spasticity and exaggerated reflexes. Three important signs of adrenal insufficiency were observed: hypotension, hyperpigmentation and comatose state. The diagnosis of X-ALD should be considered in young men presenting with gradually progressive unexplained cognitive and behavioural problems, a strong family history, adrenal insufficiency, bilateral upper motor signs with absent ankle reflexes.

Differential outcomes for frontal versus posterior demyelination in childhood cerebral adrenoleukodystrophy.

In the most common variant of childhood cerebral adrenoleukodystrophy (cALD), demyelinating brain lesions are distributed predominately in parieto-occipital white matter. Less frequently, lesions first develop in frontal white matter. This matched cohort study examined whether outcomes after standard treatment with hematopoietic cell transplantation (HCT) differ in patients with early stage frontal lesions as compared to parieto-occipital lesions. Retrospective chart review identified seven pediatric patients with frontal cALD lesions and MRI severity score < 10 who underwent a single HCT at our center between 1990 and 2019. Concurrent MRI, neurocognitive and psychiatric outcomes at last comprehensive follow-up (mean 1.2 years; range 0.5-2.1 years) were compared with a group of seven boys with the parieto-occipital variant matched on pre-HCT MRI severity score. Both groups showed similar rates of transplant complications and radiographic disease advancement. Neurocognitive outcomes were broadly similar, with more frequent working memory deficits among individuals with frontal lesions. Psychiatric problems (hyperactivity, aggression, and atypical behavior) were considerably more common and severe among patients with frontal lesions. Aligned with the critical role of the frontal lobes in emotional and behavioral regulation, functional disruption of self-regulation skills is widely observed among patients with frontal lesions. Comprehensive care for cALD should address needs for psychiatric care and management.