Multiple System Atrophy‐like Phenotype Accompanied by Prominent Weight Loss and Fatigue

Multiple system atrophy (MSA) is a progressive neurodegenerative disease that clinically presents with autonomic failure, parkinsonism, and a cerebellar syndrome in varying combinations. ¹ The updated diagnostic criteria for MSA defined the novel category of “clinically established MSA” for diagnostic certainty at the clinical level. ¹ However, the diagnosis and differential diagnosis of MSA remain challenging. Here, we describe a unique case of X‐linked adrenoleukodystrophy (X‐ALD) that met the criteria for “clinically established MSA”.

Case Report

A 58‐year‐old man had a history of unstable walking with wide‐based gait since the age of 46. The gait difficulty progressed slowly, accompanied by other symptoms including slurred speech, dysphagia, amaurosis fugax when standing up, erectile disfunction, urinary retention requiring an indwelling catheter and progressive lower limb stiffness. He became wheelchair‐bound eight years after symptom onset. Initial brain magnetic resonance imaging (MRI) at age 48 revealed cerebellum and pons atrophy and he was diagnosed with probable MSA‐cerebellar type (MSA‐C). In recent years, he experienced a 10 kg weight loss within 2 years, along with prominent fatigue and apathy. Worsening lower limb stiffness prompted him to visit our clinic. He had no family history of similar symptoms and his medical history included nasopharyngeal carcinoma at age 46, treated with radiotherapy, and a septic shock due to recurrent urinary tract infections.

Neurologic examination (Video 1) revealed cerebellar dysarthria, upper limb dysmetria and impaired rapid alternating movements. His lower limbs exhibited hypertonia with clasp‐knife response and hyperreflexia. Bilateral pyramidal signs, including Hoffmann's sign, Chaddock's sign, and spontaneous Babinski's sign were observed but no bradykinesia, resting tremor or muscle atrophy were noted. Cognition was preserved.

Video 1.

The video demonstrates a 58‐year‐old male presenting with cerebellar dysarthria, bilaterally dysmetria in the finger‐to‐nose test, bilaterally Hoffmann's sign, tendon hyperreflexia in lower limbs, clasp‐knife phenomenon in lower limbs, bilaterally positive Chaddock's sign, and bilaterally spontaneous Babinski's sign.

Brain MRI showed atrophy of the cerebellum, pons and corticospinal tract in tegmentum, with midbrain‐to‐pons ratio of 0.71. The “hot cross bun sign” was also noted. Additionally, multiple white matter hyperintensities (WMH) were observed in the bilateral oval region, frontal parietal cortex, lateral ventricle, corticospinal tracts, middle cerebellar peduncle and cerebellar white matter (left > right). ¹⁸F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging revealed predominant hypometabolism in bilateral cerebellum (left > right) and pons, and slight hypometabolism in right putamen and right thalamus (Fig 1A–C).

Figure 1.

Radiographic results of the patient. (A) The “hot cross bun sign” is shown in the transverse section of brain MRI T2WI. The atrophy of the cerebellum can also be noted (left > right). (B) Brain MRI T2FLAIR image shows white matter hyperintensities in corticospinal tracts. (C) ¹⁸F‐FDG‐PET revealed predominant hypometabolism in bilateral cerebellum (left > right).

The patient met the criteria for “clinically established MSA”, ¹ but atypical features such as predominant weight loss, fatigue, a longstanding history and spastic diplegia raised suspicion for another diagnosis. Given his history of recurrent infections and septic shock, we detected low serum cortisol (78.6 nmol/L) and high corticotropin (79.3 pg/mL) in the early morning, suggesting Addison's disease. A fasting plasma very long chain fatty acid (VLCFA) assay was performed, which revealed the following: C26:0 5.61 nmol/ml (normal <1.3); C24/C22 ratio 1.86 (normal <1.39) and C26/C22 ratio 0.138 (normal <0.023). A whole‐genome sequencing (WGS) was performed detecting a hemizygote mutation in ABCD1 gene [c.1534G > A (p.G512S)], confirming the diagnosis of X‐ALD. The patient was prescribed baclofen and pregabalin, which alleviated his lower limb cramping pain. He was also given hydrocortisone for corticosteroid replacement therapy to improve his symptoms of fatigue and apathy.

Discussion

X‐linked adrenoleukodystrophy (X‐ALD) is the most common peroxisomal disorder and it is caused by a mutation in the ABCD1 gene, with an estimated birth incidence of about 1/14,700. ² X‐ALD presents with variable clinical phenotypes, including childhood cerebral, adult cerebral, adrenomyeloneuropathy (AMN) and Addison‐only type. In female patients, isolated myelopathies is common. A rare subtype, “olivo‐ponto‐cerebellar (OPC)” type, involving the cerebellar and brainstem in adulthood onset patients might be misdiagnosed as MSA, ³ , ⁴ particularly in the absence of other X‐ALD manifestations or family history.

In the present case, the patient's clinical presentation fulfilled the criteria for “clinically established MSA”, including cerebellar syndrome, autonomic dysfunction, and MRI findings. However, signs of adrenal insufficiency served as the crucial clue to differentiate X‐ALD from MSA. The WMH lesions, most conspicuous in the corticospinal tracts, pons and middle cerebellar peduncle, may be the characteristics of X‐ALD OPC type, which were observed in 82.4% of the patients. ⁴ The ¹⁸F‐FDG PET findings were compatible with both MSA‐C and X‐ALD, as metabolic abnormalities have been described in various forms of X‐ALD and they are related to clinical severity. ¹ , ⁵

Diagnosing X‐ALD might be challenging. In this case, the onset of the manifestations occurred around the time the patient was diagnosed and treated for a nasopharyngeal carcinoma. Given the progression of the neurological symptoms after the carcinoma was treated and considered in remission, the paraneoplastic cerebellar degeneration was considered unlikely. Genetically‐driven cerebral small vessel disease, eg, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy), was a differential diagnosis in our patient, given the combination of movement disorders and multiple WMH. ⁶ Furthermore, some types of hereditary spastic paraplegia that might mimic MSA were also considered, given the association of ataxia and spastic diplegia (eg, SPG7 and SPG11). ⁷ Nevertheless, no mutations for such suspicious diseases were found in the patient's whole‐genome sequencing data.

In summary, we reported a unique case of X‐ALD with manifestations that fulfilled the “clinically established MSA” criteria. It took 12 years and multiple medical center visits before the patients received an accurate diagnosis due to his late onset of Addison's disease‐related symptoms. Although the latest MSA criteria are stringent, without genetic test, X‐ALD patients may still mimic “clinically established MSA”. Therefore, X‐ALD should be considered in the differential diagnosis of MSA‐C patients with suggestive “red flags” (Table 1). Molecular genetics techniques are crucial for the early identification.

TABLE 1.

Suggestive “Red Flags” for VLCFA Test in Patients with MSA‐C Phenotype

A longstanding history of MSA‐C

Leukoencephalopathy in the corticospinal tracts and cerebellar hemispheres

Spastic diplegia due to spinal cord atrophy

Addisonian features such as fatigue and weight loss etc.

Abbreviations: VLCFA, very long chain fatty acid; MSA‐C, Multiple system atrophy‐cerebellar type.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

X.C.: 1B; 1C; 3A

Z.C.: 1B; 1C; 3B

B.W.: 1C; 3B

P.L.: 3B

W.L.: 1A; 3B

Disclosures

Ethical Compliance Statement: Ethical guidelines were followed in the absence of an institutional review board. Written informed patient consent was obtained for this publication. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: Wei Luo is supported by the Science Technology Department of Zhejiang Province (2019C03017) and the National Natural Science Foundation of China (No. 81571089).