Adrenoleukodystrophy siblings with a novel ABCD1 missense variant presenting with phenotypic differences: a case report and literature review.

Adrenoleukodystrophy (ALD) is an X-linked disease that affects primarily the white matter of the central nervous system and adrenal cortex. A correlation between genotypes and phenotypes has not been observed. Here, we present two Japanese siblings with a novel missense variant (c.1887T > G) in the ABCD1 gene who presented with different clinical phenotypes, i.e., adolescent cerebral and cerebello-brainstem types. We also review the literature focusing on the variation in the clinical phenotypes within ALD families. In our review, 61.9% of sibling pairs presented with the same clinical type of ALD and 59.1% of sibling pairs presented with a similar age of onset. Conversely, 15.4% of sibling pairs had a similar age of onset, but different clinical types of ALD. To observe the correlation between genotypes and phenotypes, it is important to diagnose early and to accumulate reports describing age of onset, first onset symptom, and progression of the symptom.

X-linked Adrenoleukodystrophy, The Tunisian Experience.

BACKGROUND: X-linked adrenoleukodystrophy is a genetic disease affecting the degradation of very long chain fatty acids. This study aims to describe the clinical phenotype and biochemical feature of Tunisian patients; it also seeks to describe recognition of pattern analysis on the level of very long chain fatty acids in plasma for the visual discrimination of X-linked patients from a healthy group. METHODS: During the last 21 years, 19 patients were diagnosed with X-linked adrenoleukodystrophy based on the clinical features combined with the area percentage of hexacosanoic acid (C26:0) as well as the ratio of C26:0 and lignoceric acid (C24:0) relative to behenic acid (C22:0) by gas chromatography. For the biochemical diagnosis of X-ALD with better accuracy, it has been desired to transform the numerical values of these biochemical markers into visually discriminating patterns. RESULTS: The clinical features of 19 patients aged between 4 to 47 years were classified into cerebral form (57.8%), adrenomyeloneuropathic (26.3%), and a few patients were asymptomatic. The ratio C24:0/C22:0 ranged from 1.12 to 2.41 (normal value: 0.46 - 0.9) and C26:0/C22:0 ratio ranged from 0.03 to 0.36 (normal value: 0.003 - 0.009). The concentration of fatty acids with 22 or more carbons in body fluid did not change with age in control subjects and patients. For the visual diagnostic of patients, the Scatter plot was a reliable method for the diagnostic patterns of very long chain fatty acids of patients with X-linked adrenoleukodystrophy disorders. CONCLUSIONS: The incidence of X-linked adrenoleukodystrophy disorders is under diagnosed in Tunisia. The diagnosis was confirmed by enzymatic activity study and molecular analysis but the analysis of very long chain fatty acids by gas chromatography remains a reliable tool for the diagnosis and early initiation of the treatment.

X-linked adrenoleukodystrophy in heterozygous female patients: women are not just carriers.

UNLABELLED: X-linked adrenoleukodystrophy (X-ALD) is a recessive X-linked disorder associated with marked phenotypic variability. Female carriers are commonly thought to be normal or only mildly affected, but their disease still needs to be better described and systematized. OBJECTIVES: To review and systematize the clinical features of heterozygous women followed in a Neurogenetics Clinic. METHODS: We reviewed the clinical, biochemical, and neuroradiological data of all women known to have X-ADL. RESULTS: The nine women identified were classified into three groups: with severe and aggressive diseases; with slowly progressive, spastic paraplegia; and with mildly decreased vibratory sensation, brisk reflexes, and no complaints. Many of these women did not have a known family history of X-ALD. CONCLUSIONS: Heterozygous women with X-ADL have a wide spectrum of clinical manifestations, ranging from mild to severe phenotypes.

X-linked adrenoleukodystrophy in heterozygous female patients: women are not just carriers / Adrenoleucodistrofia ligada ao X em pacientes femininas heterozigotas: mulheres não são meras portadoras

X-linked adrenoleukodystrophy (X-ALD) is a recessive X-linked disorder associated with marked phenotypic variability. Female carriers are commonly thought to be normal or only mildly affected, but their disease still needs to be better described and systematized. OBJECTIVES: To review and systematize the clinical features of heterozygous women followed in a Neurogenetics Clinic. METHODS: We reviewed the clinical, biochemical, and neuroradiological data of all women known to have X-ADL. RESULTS: The nine women identified were classified into three groups: with severe and aggressive diseases; with slowly progressive, spastic paraplegia; and with mildly decreased vibratory sensation, brisk reflexes, and no complaints. Many of these women did not have a known family history of X-ALD. CONCLUSIONS: Heterozygous women with X-ADL have a wide spectrum of clinical manifestations, ranging from mild to severe phenotypes.

A adrenoleucodistrofia ligada ao X (ADL-X) é uma doença recessiva ligada ao X, associada à grande variabilidade clínica. Mulheres heterozigotas portadoras do gene causador da doença são consideradas, tradicionalmente, como clinicamente normais ou com fenótipo clínico muito discreto. No entanto, a apresentação clínica deste grupo necessita ser melhor caracterizada e sistematizada. OBJETIVOS: Revisar e sistematizar as principais características clínicas de mulheres heterozigotas para ADL-X, seguidas em serviço de neurogenética. MÉTODOS: Foram revisados os principais achados clínicos, bioquímicos e neurorradiológicos das mulheres seguidas no serviço com o diagnóstico bioquímico de ADL-X. RESULTADOS: Nove mulheres foram identificadas e classificadas em três grupos: com doença grave e incapacitante; com evolução mais insidiosa e sintomas de paraparesia espástica; e com sintomas discretos apresentando diminuição da sensibilidade vibratória, reflexos vivos, mas sem queixas clínicas. A maioria dessas mulheres não possuía história familiar positiva para ALD-X. CONCLUSÕES: Mulheres heterozigotas para ALD-X apresentam um amplo espectro de manifestações clínicas, variando desde um fenótipo leve, subclínico até apresentações graves e incapacitantes.

Methionine metabolism and phenotypic variability in X-linked adrenoleukodystrophy.

A combined genotype of polymorphisms of methionine metabolism has been associated with CNS demyelination in methotrexate-treated patients. Within a sample of 86 patients with X-linked adrenoleukodystrophy, this genotype was overrepresented in a subgroup of 15 patients with adrenomyeloneuropathy (AMN) with CNS demyelination (adrenoleukomyeloneuropathy) in comparison to 49 AMN patients without CNS demyelination ("pure" AMN; p = 0.002), suggesting that methionine metabolism might contribute to the phenotypic variability in adrenoleukodystrophy.

Assessment of adrenoleukodystrophy lesions by high field MRS in non-sedated pediatric patients.

BACKGROUND: Early detection of white matter lesions in childhood-onset cerebral adrenoleukodystrophy (ALD) is important as hematopoietic cell transplantation (HCT), currently the only effective treatment, is beneficial only if performed early in the disease course. OBJECTIVE: To establish reliable biochemical markers of cerebral disease progression in patients with ALD to aid in treatment planning. METHODS: The authors used proton magnetic resonance spectroscopy (MRS) in combination with LCModel analysis to quantify brain metabolites in small volumes (3 to 16 mL) in the occipital and frontal white matter and the splenium of the corpus callosum of 17 unsedated patients and 26 healthy volunteers (adult n = 21, age-matched n = 5) at 4 tesla. RESULTS: Absolute concentrations of 12 metabolites were reliably determined, seven of which were established as markers of lesion development. Among these, creatine and choline containing compounds were the weakest markers while N-acetylaspartate, glutamine, and lipids + lactate were the strongest. The large extent of changes in the markers enabled detection of early neurochemical changes in lesion formation prior to detection of abnormalities by conventional MRI. Concentrations of a number of metabolites were also significantly different between normal appearing white matter of patients and controls indicating biochemical alterations in the absence of cerebral disease. Neurochemical improvements following HCT were measured in six patients. CONCLUSIONS: The progression of adrenoleukodystrophy, as well as effectiveness of its treatment, can be assessed with high precision using high field 1H magnetic resonance spectroscopy in individual patients without the need for sedation.

[Endocrine disease in adrenoleukodystrophy]. / Généralités et atteintes endocriniennes de l'adrénoleucodystrophie.

X-linked adrenoleukodysrophy is the most frequent genetic disorder affecting central and peripheral nervous system myelin. One of the biochemical abnormalities is the accumulation of very long chain fatty acids (VLCFA) in tissues and body fluids subsequent to defective catabolism in the peroxysomes. The principal characteristic of the disease is an association between a neurological disorder and an endocrine disorder: primary adrenal insufficiency and testicular failure. Clinical manifestations are variable. There are two main forms, one affecting boys between the age of 5 and 10 years with severe rapidly fatal cerebral involvement, and the other affecting young adults between the age of 20 and 30 years with degeneration of the anterior and posterior long spinal cord tracts, similar to the disorders observed in multiple sclerosis. About 20% of the heterozygous women may develop a syndrome which resembles adrenomyeloneuropathy, rarely adrenal insufficiency. Adrenal insufficiency is present in 85% of the childhood cerebral forms and in about 70% of the adult forms. It may occur before, after or at the same time as the neurological disease but is not correlated with the severity of the neurological disorder. Careful screening is required to avoid missing subclinical forms. Adrenoleukodystrophy should be envisaged in young boys with primary adrenal insufficiency, accounting for about 30% of the cases of primary adrenal insufficiency in children under 3 years of age and about 13% of those in adults. Experience with dietary therapy (low-VLCFA diet and supplementation with unsaturated fatty acids such as glyceryl trioleate (GTO) and glyceryl trierucate (GTE), commonly called Lorenzo's oil) has not demonstrated any clinical improvement in the cerebral forms. Bone marrow transplantation is recommended for children who show early evidence of cerebral involvement. Gene therapy is a promising perspective. Lovastatin and 4-phenlbutyrate have recently been shown to normalize plasma VLCFA levels. Their therapeutic efficacy must be assessed in a randomized trial.

Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy.

BACKGROUND: The childhood-onset cerebral form of X-linked adrenoleukodystrophy, a demyelinating disorder of the central nervous system, leads to a vegetative state and death within 3-5 years once clinical symptoms are detectable. The hypothesis to be tested was whether bone-marrow transplantation can over an extended period of time halt the inexorable progressive demyelination and neurological deterioration. METHODS: 12 patients with childhood onset of cerebral X-linked adrenoleukodystrophy have been followed for 5-10 years after bone-marrow transplantation. Magnetic resonance imaging (MRI), neurological, neuropsychological, electrophysiological, and plasma very-long-chain fatty acid (VLCFA) measurements were used to evaluate the effect of this treatment. FINDINGS: MRI showed complete reversal of abnormalities in two patients and improvement in one. One patient showed no change from baseline to last follow-up. All eight patients who showed an initial period of continued demyelination stabilised and remained unchanged thereafter. Motor function remained normal or improved after bone-marrow transplantation in ten patients. Verbal intelligence remained within the normal range for 11 patients. Performance (non-verbal) abilities were improved or were stable in seven patients. Decline in performance abilities followed by stability occurred in five patients. Plasma VLCFA concentrations decreased by 55% and remained slightly above the upper limits of normal. INTERPRETATION: 5-10-year follow-up of 12 patients with childhood-onset cerebral X-linked adrenoleukodystrophy shows the long-term beneficial effect of bone marrow transplantation when the procedure is done at an early stage of the disease.

[Backache as the initial symptom of adrenomyeloneuropathy]. / Lumbalgia como síntoma inicial de una adrenomieloneuropatía.

INTRODUCTION: Adrenoleukodystrophy is a paroxysmal disorder, with recessive linking to the X chromosome, characterized biochemically by the accumulation of extra-long-chain fatty acids. Six phenotypes are distinguished: pre-symptomatic, infantile, adolescent and adult cerebral forms, adrenomyeloneuropathy and isolated Addison's disease. We describe a patient with adrenomyeloneuropathy in whom the presenting symptom was lumbago. CLINICAL CASE: A 23 year old man with no significant previous clinical history complained of having lumbago for over two years. On examination he had pyramidal signs and reduced epicritic sensitivity of the legs. Laboratory investigations showed adrenal failure, increased plasma extra-long-chain fatty acids concentration, mononuclear cells and fibroblasts. On MR there was a hyperintense lesion of the genu of the corpus callosum. SSEP were pathological while the electroneurogram showed bilateral increase in latency of the F wave. The patient was diagnosed as having adrenomyeloneuropathy and treatment started with hydrocortisone, a diet low in extra-long-chain fatty acids and 'Lorenzo's oil'. The lumbago gradually disappeared while the plasma extra-long-chain fatty acids concentration dropped. The oil was stopped because of moderate thrombocytopenia, and treatment was started with lovastatin 40 mg/day. Two years later the patient has no lumbago and is neurologically stable. CONCLUSIONS: The lumbago associated with adrenomyeloneuropathy is probably due to demyelination of the spinal tracts. Although lumbago is usually a benign condition, a careful history and examination is necessary in all such cases.

Quantitative proton magnetic resonance spectroscopy of childhood adrenoleukodystrophy.

Cerebral metabolic disturbances in patients with childhood adrenoleukodystrophy (ALD) were assessed by quantitative localized proton MRS. Patient monitoring by follow-up MRS studies served to identify putative markers for disease onset and progression. Whereas normal-appearing white matter of neurologically asymptomatic patients is characterized by slightly elevated concentrations of choline-containing compounds (Cho), an increase of both Cho and myo-inositol (Ins) seems to indicate the onset of demyelination. Markedly elevated concentrations of Cho, Ins, and glutamine in affected white matter reflect active demyelination and glial proliferation. A simultaneous reduction of the concentrations of N-acetylaspartate and glutamate is consistent with neuronal damage or loss. The observation of elevated lactate is in line with inflammation and/or macrophage infiltration. The more severe metabolic disturbances in cerebral ALD correspond to progressive demyelination, neuroaxonal loss and gliosis leading to clinical deterioration and eventually death. The detection of MRS abnormalities before the onset of neurological symptoms may help in the selection of patients for bone marrow transplantation (BMT). Stabilization and partial reversal of metabolic abnormalities is demonstrated in a patient after BMT.

Intrathecal IgA synthesis in X-linked cerebral adrenoleukodystrophy.

Cerebrospinal fluid data on 25 patients suffering from various phenotypes of X-linked adrenoleukodystrophy have been evaluated neurochemically including cerebrospinal fluid/serum quotient diagrams. Intrathecal IgA production in 13 of 14 patients with cerebral adrenoleukodystrophy was the most sensitive parameter in cerebrospinal fluid and was not seen in any of the neurologically asymptomatic patients or in the patients with adrenomyeloneuropathy. A blood-cerebrospinal fluid barrier dysfunction was found in 9 of these 14 patients. Additional intrathecal IgG or IgM synthesis was observed in 3 patients each. In 1 patient with lumbar punctures before and after onset of neurologic symptoms intrathecal IgA synthesis was seen only after the appearance of neurologic symptoms. Repetition of lumbar punctures in 5 neurologically symptomatic patients with cerebral adrenoleukodystrophy revealed a similar pattern of intrathecal IgA synthesis with a tendency of decreasing IgA concentration. The pathophysiologic aspects of intrathecal IgA synthesis are discussed in relation to other demyelinating and inflammatory neurologic diseases.

Predominance of the adrenomyeloneuropathy phenotype of X-linked adrenoleukodystrophy in The Netherlands: a survey of 30 kindreds.

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal beta-oxidation associated with accumulation of saturated very long-chain fatty acids, which results in central and peripheral demyelination and in impaired function of adrenal cortex and testes. The phenotypic expression is highly variable, childhood cerebral ALD (CCALD) and adrenomyeloneuropathy (AMN) being the main variants. We explored the 30 Dutch kindreds well known to the Dutch X-ALD/AMN Study Group and phenotyped 77 male patients: 35 (46%) had AMN and 24 (31%) CCALD or adolescent cerebral ALD (AdolCALD). These percentages differ significantly from previous reports, in which 25 to 28% of the patients developed AMN and 53 to 57% CCALD or AdolCALD. Our findings indicate that--at least in the Netherlands--AMN may be the most frequent phenotype of X-ALD.

Adrenoleukodystrophy: a scoring method for brain MR observations.

PURPOSE: To develop a scoring method for brain observations in patients with X-linked adrenoleukodystrophy. METHODS: One hundred seventy-five brain MR scans in 83 male subjects less than 20 years of age with proved biochemical defects were reviewed. A severity score (0 to 34), based on a point system derived from location and extent of disease and the presence of focal and/or global atrophy, was calculated for each exam. RESULTS: Fifty-five of the 83 patients showed MR findings consistent with adrenoleukodystrophy. Two major patterns were observed. A posterior pattern (mean score, 9; range, 0.5 to 25) was present in 80% of patients, and an anterior pattern (mean score, 10; range, 2 to 18) was present in 15% of patients. Serial MR imaging, positive for adrenoleukodystrophy in 34 patients (mean follow-up, 23 months; range, 2 months to 6 years 11 months), showed progressive disease in 52%, progressive disease with subsequent stabilization in 18%, stable disease in 24%, and minimal improvement in 6%. CONCLUSION: The adrenoleukodystrophy MR severity scoring method is a measure that can be used with standard MR images. When used in conjunction with clinical parameters, this scoring method may help define better the natural history of adrenoleukodystrophy and monitor response to developing therapies.

[Clinical types of adrenoleukodystrophy].

With gas chromatography, we established a method of determining plasma very long-chain fatty acids (VLCFA). Eight cases with adrenoleukodystrophy (ALD) were confirmed by using plasma VLCFA assay as the diagnostic method. The phenotypes of the 8 patients are as follows: 1. Childhood ALD; 2. Adolescent ALD; 3. Adult cerebral ALD: 4. Adrenomyeloneuropathy; 5. Addison's disease without neurologic involvement; 6. Asymptomatic ALD. We do not agree with Moser's classification of ALD as presymptomatic and asymptomatic, but would suggest to have a subclinical type of ALD.

The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications.

Prominent inflammation in the demyelinative lesion of adreno-leukodystrophy (ALD) has suggested an immune-mediated pathogenetic component. Commercially available antibodies to T cells, B cells, macrophages, class I and II molecules, complement, IgG, IgM, IgA, interleukin-1 (IL-1), intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-alpha (TNF) were applied to paraffin sections of formaldehyde-fixed postmortem samples. Twenty-five primary demyelinative lesions from five juvenile ALD, three adult ALD, and three adrenomyeloneuropathic patients were evaluated with appropriate positive and negative controls. Macrophages and astrocytes were the predominant cells detected at the active edge; T lymphocytes, including T4 and CD45R subsets, were nearly as numerous but usually located around vessels within the lesion. B cells and plasma cells, usually containing IgG, were uncommon. The expression of class II molecules, restricted to one adult, was problematic; class I expression was increased in microvascular and other cells. Degraded myelin was labeled with antibodies to C3d and IL-1; IL-1 and ICAM-1 immunoreactivity was seen on microvessels and astrocytes. Tumor necrosis factor-alpha immunoreactivity was detected in macrophages, but more prominently in astrocytes. These data support a natural immune response in the demyelinative lesion of ALD, consisting predominantly of reactive astrocytes, macrophages, T cells and cytokines. A two-stage pathogenetic theory is discussed. The postulated roles of TNF and reactive astrocytes, in concert with a fundamental myelinolytic biochemical defect, suggest a different pathogenetic mechanism and raise novel therapeutic possibilities.