Adult-onset cerebello-brainstem-dominant form of X-linked adrenoleukodystrophy with auditory pathway involvement: A case report

Abstract

X-linked adrenoleukodystrophy (X-ALD) is classified into several clinical subtypes. Among them, the cerebello-brainstem-dominant form is rare, and its symptoms and imaging findings can mimic spinocerebellar degeneration (SCD), making diagnosis difficult. Herein, we report a case that we initially diagnosed as SCD but was eventually diagnosed as the cerebello-brainstem-dominant form of X-ALD. The patient presented with psychiatric symptoms in adulthood. He subsequently developed gait disturbance and was referred to the neurology department of our hospital. Initial magnetic resonance imaging (MRI) showed atrophy of the cerebellum and pons, and abnormal signals in various regions, including the middle cerebellar peduncles, the corpus callosum, infero-posterior part of the bilateral thalami, and lateral edges of the midbrain, on T2-weighted imaging. The patient was followed up as SCD; however, his symptoms and MRI findings worsened. Further examination was performed, and the diagnosis of X-ALD was made. Abnormal signals in the thalami and midbrain on MRI are considered to correspond to the medial geniculate bodies and the brachia of the inferior colliculus, respectively. They constitute the auditory pathway, which is an evaluation item in Loes score, an imaging-based scoring system for patients with X-ALD. Recognizing abnormalities in the bilateral auditory pathway may aid accurate diagnosis of X-ALD.

Translated Abstract

副腎白質ジストロフィーはさまざまな臨床病型に分類される．その中で小脳・脳幹型は頻度がまれである上に症状や画像が脊髄小脳変性症と似ており，診断が難しい．我々は脊髄小脳変性症として経過観察を行い，最終的に小脳・脳幹型の副腎白質ジストロフィーと診断した症例を報告する．彼は成人後精神症状が出現して精神科かかりつけとなり，その後歩行障害が出現したために当院の脳神経内科を受診した．初回のMRIでは小脳と橋の萎縮や，中大脳脚や脳梁，視床下後方，中脳外側など様々な部位にT2強調像で異常信号を認めた．SCDとして経過観察中に，症状やMRI所見の増悪が出現したために再度精査を行い，副腎白質ジストロフィーと診断した．視床や中脳の異常信号はそれぞれ内側膝状体や下丘腕に相当すると考える．それらは聴覚路を構成しており，副腎白質ジストロフィーの画像評価法であるLoes scoreの評価項目の一つである．両側聴覚路の異常信号を認識することがX-ALDの正確な診断の助けになる可能性がある．

INTRODUCTION

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ATP-binding cassette subfamily D member 1 (ABCD1) gene located on Xq28.¹ The ABCD1 gene encodes ALD protein (ALDP), a peroxisomal membrane protein that is responsible for the β-oxidation of very long-chain fatty acids (VLCFAs) in multiple tissues including the adrenal gland, central nervous system myelin, and Leydig cells of the testicles.² A defect of ALDP results in the accumulation of VLCFAs in plasma and tissues.³ Clinical manifestations range from isolated adrenocortical insufficiency and slowly progressive myelopathy to severe cerebral demyelination. X-ALD is classified into the following forms with presymptomatic and symptomatic forms, especially in female carriers: childhood cerebral, adolescent cerebral, adrenomyeloneuropathy, adult cerebral, cerebello-brainstem-dominant, and Addison’s disease.^{4, 5} Cerebral X-ALD exhibits characteristic magnetic resonance imaging (MRI) findings.^{5, 6} However, diagnosing the cerebello-brainstem-dominant form can be challenging. This type is rare, estimated to account for 8% of ALD,⁴ and mainly involves infratentorial structures. Patients with this type present with progressive cerebellar dysfunction that can mimic spinocerebellar degeneration (SCD) .^{7, 8} Herein, we present a case of the cerebello-brainstem-dominant form of X-ALD that showed abnormal MRI findings in the auditory pathway in addition to the brainstem and cerebellum.

CASE REPORT

A 43-year-old male was admitted to our hospital because of difficulty climbing stairs. He had been neuropsychologically stable until he began exhibiting psychiatric symptoms at age 32 such as vacant smiles and excessive nodding while watching television. These symptoms disrupted his career, and he began excessive alcohol consumption. At age 37, he sought psychiatric treatment and was diagnosed with schizophrenia. Subsequently, his symptoms improved with antipsychotics, and his pathological drinking habits also stopped. Further consultation revealed that he started having difficulty climbing stairs around the age of 32. He was referred to the neurology department of our hospital. Neurological examination revealed decreased muscle tone and slight ataxic gait with shuffling steps. Impaired postural reflexes were also observed. His father had a history of epilepsy; however, the details were unclear.

Brain MRI demonstrated atrophy of the cerebellum and pons (Figure 1a), T2 hyperintensity in the middle cerebellar peduncles (Figure 1b), and cruciform hyperintensity in the pons (hot cross bun sign) (Figure 1c). There was also T2 hyperintensity in the lateral edges of the midbrain and infero-posterior part of the bilateral thalami (Figure 1d, e). Additionally, the left periventricular white matter and the splenium and genu of the corpus callosum showed hyperintensity on T2-weighted imaging (Figure 1f, g). Some hyperintense areas on T2-weighted imaging, such as the splenium and genu of the corpus callosum, showed hypointensity on T1-weighted imaging (Figure 1a). Based on the findings in the cerebellum and brainstem, SCD, especially spinal cerebellar ataxia (SCA) type 3 and multiple system atrophy cerebellar type (MSA-C) were initially suspected. Demyelinating disorders; alcohol-related conditions, such as Marchiafava-Bignami disease and Wernicke encephalopathy; toluene abuse; and mitochondrial disease were also considered as differential diagnoses. Genetic testing was performed, and the results were negative for SCA1, 2, 3, and 6, and dentatorubropallidoluysian atrophy (DRPLA). A definitive diagnosis was not made; therefore, we decided to monitor the patient's progress as SCD in the outpatient setting.

Figure 1.

(a–g) MRI on first admission. (a) Sagittal T1-weighted MRI shows atrophy of the cerebellum and pons, and hypointensity in the splenium and genu of the corpus callosum (arrow). (b–f) Axial T2-weighted MRI shows hyperintensity in the bilateral middle cerebellar peduncles (b, arrow), infero-posterior part of the bilateral thalami (d, arrow), lateral edges of the midbrain (e, arrow), the splenium and genu of the corpus callosum (f, g, arrow), and the left periventricular white matter (f, arrowhead). Cruciform hyperintensity is observed in the pons (hot cross bun sign) (c, arrow).

Over ten years, his walking difficulties worsened, and he developed a spastic gait with narrow steps and was at risk of falling without a cane. MRI showed worsening atrophy of the cerebellum and T1 hypointensity in the splenium and genu of the corpus callosum (Figure 2a). Atrophy of the corpus callosum was also detected (Figure 2a). T2-weighted imaging showed atrophy and attenuated hyperintensity of bilateral middle cerebellar peduncles and expanded hyperintensity in the periventricular white matter (Figure 2b, c). Diffusion-weighted imaging (b value = 1,000 sec/mm²) showed abnormal signals along the hyperintense area on T2-weighted imaging (Figure 2d). There was no significant change in ADC values. He was readmitted for further examination to review the working diagnosis of SCD. It was considered that demyelinating disorders, including X-ALD, may be the cause of the worsening white matter lesion. Laboratory tests showed elevated levels of adrenocorticotropic hormone (ACTH) and VLCFAs. ACTH loading test revealed subnormal cortisol elevation, indicating primary adrenal insufficiency. These findings met the definite diagnostic criteria for X-ALD, which was confirmed by a positive genetic test for X-ALD.

Figure 2.

(a–d) MRI 10 years after first admission. (a) Sagittal T1-weighted imaging (magnetization-prepared rapid gradient echo) shows exacerbation of atrophy of the cerebellum, and hypointensity in the splenium and genu of the corpus callosum (arrow). Atrophy of the corpus callosum is also detected. (b) T2-weighted imaging shows atrophy of the bilateral middle cerebellar peduncles and attenuated hyperintense area. (c) T2-weighted imaging shows expanded hyperintensity in the periventricular white matter (arrow). (d) Diffusion-weighted imaging (b value = 1,000 sec/mm²) shows abnormal signal along the hyperintense area on the T2-weighted imaging (arrow).

DISCUSSION

In past reports of adult-onset cerebello-brainstem-dominant X-ALD, the following MRI findings have been reported: cerebellar atrophy; brainstem atrophy; and hyperintense areas in the dentate nuclei, cerebellar white matter adjacent to the dentate nuclei, middle cerebellar peduncles, and pons on T2-weighted imaging.^{8, 9} Bilateral symmetric involvement of the parieto-occipital white matter is the most common finding in the cerebral form, which is the most frequent and severe phenotype and may cause rapid neurologic deterioration and early death.^{6, 10}

In the present case, cerebellar and brainstem atrophy, T2 hyperintensity in the cerebellar white matter, and middle cerebellar peduncles support the findings of previous studies of the cerebello-brainstem-dominant form of X-ALD.^{9, 11} MRI of the present patient also showed cruciform hyperintensity in the pons, known as hyperintense cerebellar brainstem signal, and T2 hyperintensity in the corpus callosum, as previously reported.^{11, 12} In addition, abnormal signals on diffusion-weighted imaging and atrophy of middle cerebellar peduncles and corpus callosum were detected, which may indicate myelin breakdown, inflammatory cell infiltration, and tissue loss due to inflammation and demyelination.^{13, 14} Although there were some features consistent with imaging findings reported in cases diagnosed with the cerebello-brainstem-dominant form of X-ALD, the lack of specific imaging characteristics made diagnosis challenging. Cerebellar and brainstem atrophy have been reported in SCA, DRPLA, and MSA.¹⁵ T2 hyperintensity in the middle cerebellar peduncles has been reported in neurodegenerative diseases (MSA-C, SCA), cerebrovascular disease, demyelinating and inflammatory diseases (MS, acute disseminated encephalopathy, Behçhet disease, and HIV encephalopathy), neoplasms (lymphoma, glioma, meningeal carcinomatosis), and toxic and metabolic disorders (Wilson’s disease, hepatic encephalopathy, and toluene abuse).^{16, 17} T2 hyperintensity in the corpus callosum has been reported in neoplasms (glioblastoma multiforme, lymphoma), demyelinating and inflammatory diseases (MS, progressive multifocal leukoencephalopathy, and Marchiafava-Bignami disease), and cerebrovascular disease.^{18, 19}

The present case had abnormal signals in the lateral edges of the midbrain and infero-posterior part of the thalami. It is difficult to determine their anatomical location in conventional MRI; however, based on previous reports, we considered them to correspond to the medial geniculate bodies (Figure 1d) and brachia of the inferior colliculus (Figure 1e), which are components of the auditory pathway.²⁰ The auditory pathway transmits auditory information collected by the inner ear to the primary auditory cortex in the superior temporal gyrus via several intermediary pathways and structures. The principal auditory pathway leading to the cerebral cortex passes from the cochlea, via the cochlear nerve, cochlear nuclei, the inferior colliculus, and the medial geniculate body, to the contralateral auditory cortex in the temporal lobe.²¹ Auditory pathway involvement is sometimes observed in X-ALD patients, and T2 hyperintensity in the lateral lemniscus, brachium of the inferior colliculus, and medial geniculate body have been reported.^{11, 20} The auditory pathway is an important evaluation item in Loes score, which is an imaging-based scoring system for patients with X-ALD that is based on neuroanatomical involvement and the presence or absence of focal and global atrophy.²⁰ The auditory pathway can be involved in other diseases. Hocke et al. described auditory pathway involvement in patients with SCA2, SCA3, and SCA7 using a pathoanatomical investigation.²² Scarpa et al. reported that hearing loss and cervical vestibular-evoked myogenic potential abnormalities are frequently found in MSA patients.²³ However, to the best of our knowledge, no previous studies reported abnormal signals in the auditory pathway on conventional MRI in patients with SCA or MSA. Despite the fact that MS lesions can affect the auditory pathway and cause hearing loss,^{24, 25} MS brainstem lesions tend to be asymmetrical.²⁶ Thus, it is speculated that selective impairment along the bilateral fibers and structures of the auditory pathway, as seen in this case, is characteristic of X-ALD.

CONCLUSION

The adult-onset cerebello-brainstem-dominant form of X-ALD often mimics SCD clinically and radiologically. Hyperintensity in the bilateral auditory pathway on T2-weighted imaging may be useful for accurately diagnosing X-ALD.

DISCLOSURE STATEMENT

The authors report no conflicts of interest directly relevant to the content of this article.

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