Spectrum of Clinical and Imaging Characteristics of 48 X-Linked Adrenoleukodystrophy Patients: Our Experience from a University Hospital
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.355099
Source of Support: None, Conflict of Interest: None
Keywords: Lysophosphatidylcholines, VLCFA, very-long-chain fatty acids, X-linked adrenoleukodystrophy
X-linked adrenoleukodystrophy (X-ALD, OMIM #300100) is a rare metabolic peroxisomal disorder with an estimated incidence of 1 in 17,000 live births. Mutations of adenosine triphosphate binding cassette, subfamily D, member-1 (ABCD1) gene located on chromosome Xq28 results in X-ALD. It is characterized by impaired peroxisomal beta-oxidation of very-long-chain fatty acids (VLCFA; ≥C22) which accumulate in the plasma, body fluids, and tissues including brain, spinal cord, and adrenal cortex. In X-ALD, MRI not only is important for diagnostic purposes, but it plays an important role in the follow-up and prognostication of patients. The correlation of the MRI patterns with clinical features is required to stratify patients and modify appropriate therapies. We herewith describe the clinical attributes and MRI patterns in 48 biochemically proven X-ALD patients who were referred to our institute in the last 7 years.
This is a retrospective chart review of patients with clinical and imaging features of X-ALD who were confirmed by biochemical indices. The demographic characteristics, age of onset, and other clinical features were studied to segregate the data into the phenotypic variants of X-ALD, namely childhood cerebral ALD (CCALD: 3-10 years), adolescent cerebral ALD (Ado-CALD: 11–20 years), adult-cerebral ALD (ACALD: >21 years), adrenomyeloneuropathy (AMN), and Addisonian only. The following investigations of the patients were analyzed: hematological, biochemical parameters, serum cortisol, serum VLCFA levels, evoked potentials (visual-evoked potentials—VEP, BAER—brainstem auditory evoked response, SSEP—somatosensory-evoked potentials), and nerve conduction studies (NCS). The estimation of plasma VLCFA was performed by VLCFA-LPCs (lysophosphatidylcholines) by tandem mass spectrometry.,,, The panel of VLCFA-LPCs–(C26:0, C24:0, C22:0, C20:0) and their ratios were estimated in the blood spots collected on Whatman S&S 903 (Schleicher and Schuell) filter paper.,,,, We reviewed the MRI features in all the patients from PACS (picture archiving and communication systems) and tabulated the data. The siblings and parents of the affected patients were clinically evaluated. The patients signed a consent form before the estimation of the LPCs.
Data and statistical analysis
Data were analyzed using IBM SPSS statistical software version 22 and Graph Pad Prism 5.1. and a P value of <0.05 was taken as significant. Data were expressed using descriptive statistics such as for continuous variables, mean and standard deviation and categorical variables, frequency, and percentage. The normality of the distribution was assessed by the skewness of the values. The normality of the VLCFA-LPC data was checked using the Kolmogorov-Smirnov test. One-way Analysis of Variance (ANOVA) (Kruskal-Wallis test) with post hoc Dunn's multiple comparison test was performed to check if there was any significant difference in the mean/medians VLCFA-LPC concentration of the three cerebral ALD phenotypes. The concentration of VLCFA- LPCs and their ratios were compared between the posterior and cerebellar MRI variants by using the t-test (Mann–Whitney U test). The VLCFA-LPC concentrations and their ratios were represented as the median with the 1st and the 99th percentile concentration range.
Demographic profile: Our cohort was predominantly the male (47) population with a solitary female patient. There were 28 (58.3%) patients with childhood cerebral form, 7 (14.6%) with adolescent cerebral form, and 10 (20.8%) patients were of adult-cerebral form. Two (4.2%) patients presented with Addisonian only variant and one (2.1%) patient was diagnosed with AMN. The median duration of illness was 12 months with a range of 1–144 months.
Clinical features: The various clinical features noted in the study population have been described in [Table 1]. Notable among them was that hearing impairment and movement disorders (dystonia, tics, and myoclonus) were exclusively seen in CCALD. There were three patients with very-late-onset of the illness (<50 years) who were misdiagnosed as limbic encephalitis and later ALD diagnosis was confirmed.
Family history: Consanguineous parentage was noted in 5 (10.2%) patients and positive family history in 13 (27.1%) patients. Screening of other asymptomatic family members revealed that (i) out of the 26 mothers evaluated, 12 demonstrated an elevation in VLCFA-LPCs, while in five others, the elevations were borderline and normal in the rest. Only the mother of patient number 29 had a history of psychiatric features [Case 1; [Figure 1]]. (ii) Patient number 29's maternal aunt had an elevation in VLCFA-LPC. (iii) The daughter of patient number 41 showed an elevation in the VLCFA-LPC (asymptomatic). Cranial and spinal MRI was performed in two mothers, which were non-contributory.
Investigation details: The hematological, biochemical, and electrolytes of all patients were within normal limits. The serum cortisol levels were available in 30 patients and a quarter (26.7%) of them had low cortisol, less than 5 μg/dL. The plasma VLCFA levels, measured by stable isotope dilution gas chromatography-mass spectrometry (GC/MS), were available in 15 patients. It was abnormal with elevated VLCFA levels in all with a normal level of pristanic acid and low levels of phytanic acid. NCS done in 31 patients in both upper and lower limbs detected abnormalities in three (9.7%) patients in the form of sensorimotor neuropathy in the lower limbs. The evoked potentials (visual-evoked potential: VEP, brainstem auditory evoked response: BAER, somatosensory evoked potential: SSEP) were available in 15 patients; prolonged latency was present in three (20%) patients in VEP, and one each in BAER and SSEP.
MRI Patterns: The imaging features were divided into five patterns [Table 2] and [Table 3]; [Figure 1] as per Loes et al., The correlation between MRI variants and clinical phenotypes is given in [Figure 1]; [Table 1]. A few unusual features noted were hyperintensity of the anterior commissure, optic tracts, and signal changes in the cervicodorsal spinal cord. Interestingly, the lobar white matter lesions showed a tigroid appearance in one patient of a combined pattern.
Measurement of Lysophosphatidylcholines in Dried Blood Spots for the identification of X-ALD: The diagnosis of X-ALD was confirmed for 48 patients by measuring the VLCFA-LPCs (LC-MS/MS method). The median values with the 1st and the 99th percentile concentration range of LPCs expressed in μmol/L and their ratios were represented in a Box and Whisker plot for normal subjects and X-ALD patients [Figure 2] and [supplementary Figure 1]. There was a significant elevation in the concentration of LPCs and their ratios in X-ALD patients when compared to the normal subjects, P < 0.0001 (14). Only C26:0-LPC concentration was significant in CCALD when compared to adolescent CALD (P < 0.05). The concentration of VLCFA- LPCs and their ratios were compared between the posterior and cerebellar MRI variants; C22:0-LPC (P < 0.05) showed a significant difference.
Genetic analysis: Three patients underwent genetic analysis. The sequence analysis of the ABCD1 gene was available in two patients: (i) Of the solitary female patient showed homozygous mutation for c. 253 dup (p. Arg85Profs*110) in exon 1. (ii) Of an adult-onset CALD showed hemizygous mutation for c. 838C > T (p. Arg280Cys) in exon-1.
Treatment details: Patients were treated symptomatically with antispastic agents and oral steroids (12). In view of the profound neurological disturbances, none of them underwent HSCT (hemopoietic stem cell therapy).
Follow-up details: Follow-up information was available in 36 patients (elicited by a telephonic call). The follow-up duration was a median of 3.5 years with a range of 0.5–14 years. Subjective improvement or static course was observed in 13 (36.1%) patients; 6 (16.7%) patients showed worsening over the course of time and 17 (47.2%) patients had expired.
Case Illustrations: [Supplementary Figure 2]
Patient No. 29:
Patient No. 42: A 53-year-old gentleman born out of non-consanguineous parentage was brought with a 3-month history of cognitive, behavior, and gait disturbances. His brother had a similar illness and died at 36 years of age. The MRI of the brain was suggestive of a cerebellar variant of ALD (Pattern-4). The NCS was suggestive of sensorimotor neuropathy in the lower limbs, VEP was normal. He expired after 6 months of illness.
Patient No. 15: A 4-year-old girl born out of non-consanguineous parentage was brought with a history of speech disturbances, seizures, visual disturbance, gait instability, global developmental delay, hearing, and visual problems at 2 years of age. Her neurological examination revealed optic pallor and spasticity in the lower limbs. Her family history was unremarkable except for her grandfather with late-onset seizures. The investigations revealed MRI of the brain: posterior variant (Pattern-1), NCS, and EP were normal. The Electroencepahlography (EEG) showed left frontal spike and wave discharges. The patient expired after 2 years of illness. Her genetic analysis of the sequence analysis of the ABCD1 gene revealed homozygous mutation for c. 253 dup (p. Arg85Profs*110) in exon 1.
Phenotypic heterogeneity: It was observed in one family. Patients nos. 46 and 47. Patient no. 47 is a 9-year old boy detected to have Addison's only phenotype genetically confirmed. While his maternal uncle was diagnosed with adult-cerebral ALD with features of myeloneuropathy (ACALD + AMN). The boy's MRI of the brain and spine were normal. The uncle's MRI of the brain showed unilateral corticospinal tract hyperintensity.
Different MRI variants in the same family: Patients nos. 17 and 43. Patient number 17 is a 13-year-old boy diagnosed with CCALD with age at onset of 8 years. His MRI of the brain had Pattern-1 posterior variant changes. His elder brother had seizures, cognitive decline, and hyperpigmentation and died at the age of 7.5 years. The third sibling had seizures, cognitive decline with MRI showing a combined variant (Pattern-5).
X-ALD is an X-linked recessive disorder with marked phenotypic variability frequently observed in boys, especially during early childhood. It has seven major clinical subtypes: childhood cerebral ALD (CCALD), (ii) adolescent CALD, (iii) adult CALD, (iv) AMN >21 years, (v) adrenal insufficiency, (vi) women with ALD, and (vii) asymptomatic. Our cohort had predominantly childhood cerebral form of ALD followed by adult and adolescent variants. Hearing impairment and movement disorders were the exclusive features in the childhood cerebral form of ALD and were not seen in other phenotypes. Whether it is because of the involvement of the auditory pathway consequent to the posterior fibers in the temporoparietal region needs to be considered as most of the CCALD patients had posterior predominant MRI patterns.
Reports of women with X-CALD are rare. Usually, female carriers present as AMN. Nine women with X-CALD were reported by Lourenco et al. They found the disease severity to range from mild to severe phenotypes of cognitive and behavioral changes; brain MRI was abnormal in three-quarters of them. Our patient was a 4-year-old child with an age of onset of 2 years, without any positive family history. She was initially misdiagnosed as a mitochondrial disorder. Her MRI [Figure 1] showed a few atypical changes, her LPCs were elevated, and genetic analysis revealed ABCD1 mutation, thus, confirming the diagnosis of X-ALD. Her MRI of the brain demonstrated incredibly unique features besides the typical T2/ Fluid attenuated inversion recovery (FLAIR) hyperintensities in the peritrigonal areas and splenium of the corpus callosum. Her post-contrast scan showed a band-like area of solid homogeneous enhancement in the splenium and peritrigonal areas which is different from the classical peripheral pattern of enhancement seen in X-ALD patients. The previous studies on females with X-ALD have described MRI findings identical to males with X-ALD but this type of enhancement has not been described., It is also to be noted that the age of onset of our female patient was 2 years. The youngest symptomatic patient described in the literature is a 7-year-old.
In 2003, Loes et al. modified their initial description of imaging patterns in X-ALD and devised a five-pattern MRI classification. Loes et al. also described atypical MRI findings that did not conform to any of these five patterns. The commonest pattern described in the literature is pattern-1 comprising 66% of the cases; in our cohorts, it was found in 68.75%. Apart from the typical involvement of peritrigonal white matter and splenium of the corpus callosum, there were a few unique features in our patients with Pattern-1 MRIs: (i) Two patients demonstrated T2/FLAIR hyperintensity of the anterior commissure which enhanced on contrast study [Figure 1]a and [Figure 1]b. This imaging finding is uncommon and has been described in one patient with frontal variant MRI previously. (ii) Optic tract hyperintensity was noted in three patients; all were childhood-onset CALD [Figure 1]c. None of the patients had visual impairment clinically but one patient had optic pallor on fundoscopic examination. Visual-evoked potentials in one patient were unremarkable. Optic tract involvement is not commonly encountered and has been described in one series previously. (iii) The entire anterior aspect of the pons was involved in four cases, indicating the involvement of corticospinal tract, transverse pontine fibers, and corticopontine fibers. The involvement of the anterior pons has been described in two instances previously., (iv) One patient showed T2-hyperintensity involving the anterior and lateral columns of the cervicodorsal cord [Figure 1]e and [Figure 1]f. The spinal cord signal changes have not been described in the X-ALD patients previously. (v) Eight patients in the posterior variant group showed signal changes extending from the deep white matter to the subcortical U fibers, and in one patient, the cortex was also involved, however, cortical involvement, has been demonstrated in one instance in the literature. The other unique features in the other patterns were (i) Tigroid pattern of white matter involvement in a patient of combined pattern group, (ii) involvement of bilateral central tegmental tracts in a patient of combined pattern group, (iii) involvement of basal ganglia. This finding is infrequently reported.,,
Biochemical identification of X-ALD was done using C26:0-LPC that is a more sensitive and specific marker for the identification of X-ALD,,,, The usage of this in our study is more economical, especially in economically-constraint countries, which forms one of the strengths of our study. The other strengths include a comprehensive clinical, biochemical, and imaging analysis with follow-up information constituting one of the largest series of X-ALD patients from a single tertiary center. The description of the youngest female child with CALD, the rare and wide range of typical and atypical imaging features, validation of low-cost biochemical studies of the VLCFA, description of families with this rare disorder. A retrospective review, absence of the genetic confirmation in all, and the non-availability of stem cell therapy are the limitations of our study.
In conclusion, X-linked ALD is a rare genetic disorder characterized by cognitive and behavioral changes and gait disturbances independent of the age at onset. Hearing impairment and movement disorders are more common in childhood ALD. The posterior predominant T2 hyperintensity forms the most common MRI finding in the whole cohort and children and adolescent age groups. The cerebellar variant is more common in adults resulting in diagnostic difficulties. Hence, the knowledge regarding the clinical features and imaging is of paramount importance for early diagnosis and treatment.
Patients for better understanding of the illness.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Department of Biotechnology, Ministry of Science and Technology, New Delhi, Government of India (Grant No. BT/PR26150/MED/12/768/2017).
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]