Adrenoleukodystrophy: The Importance of Early MRI Findings and Serial Imaging
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.273651
Source of Support: None, Conflict of Interest: None
Adrenoleukodystrophy is a rare metabolic disorder that predominantly affects white matter of central nervous system, with involvement of the adrenal glands and testis as well. The childhood X-linked variety is the most common and severe type. It results in severe neurological dysfunction and has fairly classical MRI features. However, atypical MRI patterns have been described. These may not be readily by clinicians and thus the diagnosis may be delayed, as in our case. Serial imaging in our case highlighting this is presented.
Childhood adrenoleukodystrophy is an uncommon X-linked metabolic disorder caused by deposition of very long chain fatty acids (VLCFAs) in body tissues, that result in progressive demyelination of the white matter of the central nervous system. It shows predilection for parieto-occipital white matter and adrenal insufficiency. The majority of patients show normal development till they reach 4–8 years of age, at which time symptoms resulting from the demyelination of cerebral white matter start to appear. In addition to the CNS manifestations, patients may develop symptoms of adrenal and gonadal insufficiency. It is a fatal condition; however, with dietary modification, medication and bone marrow transplant, a patient's quality of life may become better and clinical course and prognosis can also be improved. MRI is the imaging modality of choice which shows a characteristic diagnostic pattern in the majority of cases. Atypical MRI features are seen in some. Serial imaging in our patient with an initial unusual atypical pattern is presented.
A 10-year-old male child presented with the complaints of severe progressive weakness of bilateral lower limbs, imbalance in walking and slurred speech for the past 3 years, and with recent development of visual disturbance, behavioral symptoms and rapid progression of motor weakness.
The first MRI was performed two years previously at an unknown clinic when the patient was eight years of age. It revealed bilateral, symmetrical hyper-intense signal in the posterior limb of internal capsule, substantia nigra and along the pyramidal tracts in the pons and medulla on T2 weighted and FLAIR sequences. There was a hypo-intense signal on T1. DWI images showed no evidence of restricted diffusion, though post-contrast images showed subtle patchy enhancement. No obvious white matter lesions were noted [Figure 1] and [Figure 2]. Given these atypical findings, the diagnosis of ALD was not suggested and specific biochemical tests were not performed. In the follow-up, the patient showed progressive neurological deterioration. An MRI study at ten years of age showed characteristic findings of adrenoleukodystrophy such as bilateral symmetrical T2/FLAIR hyper-intensity in parieto-occipital periventricular white matter and strong contrast enhancement along the outer edges of white matter signal. Altered signal intensity in bilateral internal capsule, thalamus, substantia nigra, and along cortico-spinal tract in pons and medulla oblongata persisted as before with some progression [Figure 1] and [Figure 2]. On the basis of MRI findings, the possible diagnosis of adrenoleukodystrophy was given. For confirmation of diagnosis a genetic test for a specific mutation was performed along with several biochemical tests for VLCFA. It was found to be positive and appropriate treatment was initiated.
Adrenoleukodystrophy is a rare X-linked metabolic disorder. Various clinical forms have been described in the literature including childhood, adolescent, adrenomyeloneuropathy, adult cerebral and Addison only. The childhood cerebral variety is the most common type. It results from a mutation in the ALD gene which is reponsible for the coding of a peroxisomal membrane protein and results in accumulation of VLCFAs in tissues. Under normal circumstances, VLCFAs are metabolized in short chain fatty acids and can be used for biosynthesis of complex lipids and proteins, which are necessary for the normal development of cerebral white matter.,,,
The classical childhood cerebral variety is seen almost exclusively in male children due to its X-linked inheritance and usually becomes symptomatic around 5–10 years of age, until when the child shows normal development. Many patients present with problems of learning difficulty in school, which is frequently attributed to other behavioral conditions. They gradually start developing weaknesses in their limbs and disturbance in their gait later on. Impairment in visual acuity, intellect, skin pigmentations and seizures is also seen in some patients.
Cross-sectional imaging findings are fairly typical involving peritrigonal parieto-occipital white matter. In the majority of patients, the CT scan reveals a symmetric hypo-density in bilateral parieto-occipital white matter with involvement of splenium of corpus callosum, enhancement seen along the anterior edge of hypo-density, Magnetic resonance imaging demonstrate T2/FLAIR hyper-intense signal in same areas as that of CT scan with hypo-intense signal on T1. There was is no evidence of restricted diffusion or blooming on susceptibility weighted images. In the majority of patients, three distinct zones of white matter involvement is seen, a fact which corroborates the radiological appearance. Zone A in the inner most and is represented by scarring, while zone B is the inflammatory zone and is represented by the perivascular inflammatory cells and demyelination, zone C is a zone of ongoing demyelination and is situated at the periphery, where myelin is breaking down in the absence of inflammation. These areas are very well appreciated in contrast MRI images, where zone B shows strong contrast enhancement due to ongoing inflammation.
Around 15% of patients may show atypical findings with predominant frontal involvement and occasional involvement of the cerebellar white matter. Other less common atypical patterns are described (Kim et al., and Loes et al.) in the form of the internal capsule and long tract involvement as an isolated pattern (pattern 3) and predominant cerebellar white matter as another distinct pattern., In our case pattern, three changes were not identified as that due to ALD initially. The diagnosis could be made after the typical peritrigonal changes were noticed in MRI 2 years later. Progression from pattern 3 to peritriogonal pattern later is not previously described which was seen in our case. In addition, our report highlights the importance of identifying the less common patterns of ALD to avoid missing early diagnosis.
MR spectroscopy may show prominent choline peak with occasional increase in lactate. NAA is typically reduced. Daniel Warren and others have found usefulness of MRS in the mapping of brain metabolic changes after hematopoietic stem cell transplantation and demonstrated a complete reversal of metabolic abnormality in two patients.
Like in other demyelination conditions, DTI shows an increased mean diffusivity (MD) and decreased fractional anisotropy. Schneider et al also showed these changes in normal-appearing white matter on conventional MRI and suggested its important role in identifying early changes.
Adrenoleukodystrophy is a rare metabolic condition associated with severe neurological dysfunction. Due to the availability of newer treatment modalities and associated high morbidity and mortality, early diagnosis is of paramount importance. The contrast-enhanced MRI is the imaging investigation technique of choice, which in addition to showing typical involvement of the peritrigonal parieto-occipital white matter in the majority of patients, can also reveal early changes in the posterior limb of the internal capsule and long tracts. Hence, knowledge of early MRI findings and performance of serial imaging certainly will lead to a better prognosis and allow for appropriate management of the disease.
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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.
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[Figure 1], [Figure 2]