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Table of Contents    
Year : 2017  |  Volume : 65  |  Issue : 4  |  Page : 887-889

Long-term follow-up of a case of adult-onset Alexander disease presenting with cognitive impairment as the initial symptom

1 Department of Neurology, Oyamada Memorial Spa Hospital, 5538-1 Yamadacho, Yokkaichi City, Mie Prefecture 512-1111, Japan
2 Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
3 Department of Neurology, Yokkaichi Municipal Hospital, 2-2-37 Shibata, Yokkaichi City, Mie Prefecture 510-8567, Japan

Date of Web Publication5-Jul-2017

Correspondence Address:
Yoshinari Kawai
Department of Neurology, Oyamada Memorial Spa Hospital, 5538-1 Yamadacho, Yokkaichi City, Mie Prefecture 512-1111
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/neuroindia.NI_630_16

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How to cite this article:
Kawai Y, Hattori M, Mori K, Ieda T. Long-term follow-up of a case of adult-onset Alexander disease presenting with cognitive impairment as the initial symptom. Neurol India 2017;65:887-9

How to cite this URL:
Kawai Y, Hattori M, Mori K, Ieda T. Long-term follow-up of a case of adult-onset Alexander disease presenting with cognitive impairment as the initial symptom. Neurol India [serial online] 2017 [cited 2019 Dec 7];65:887-9. Available from:


Alexander disease (AxD) is a leukodystrophy disorder associated with mutations in the coding region of the glial fibrillary acidic protein (GFAP) gene. Three age-dependent clinical subtypes are known, i.e., infantile, juvenile, and adult.[1],[2] Adult-onset AxD shows progressive ataxia, bulbar and pseudobulbar signs, such as palatal myoclonus, dysphagia, and dysarthria,[3] and the radiological appearance of a unique tadpole-like feature of the brain stem and upper cervical cord, which is characterised by marked atrophy of the medulla oblongata and cervical spinal cord, although the pontine base remains intact.[4] Here we report a patient with an adult-onset AxD presenting with cognitive impairment as the initial symptom.

In March 2000, a 39-year old woman, the child of non-consanguineous healthy parents, presented with cognitive disturbances over a 5-year period. Her early development was normal. Her academic records in junior and senior high school were at mid-to-low levels. At 14 years of age, she underwent an operation for scoliosis. Subsequently, she graduated from a technical college. At 30 years of age, she got married, and at that time, her husband found her to be healthy. Four years later, he noticed that she was becoming forgetful and apathetic. She was disorientated, often got lost, and could no longer pick her children from kindergarten. She would go shopping but would buy too much and repetitively purchase the same goods. Her family history was negative for neurological diseases, with the exception of her grandson suffering from epilepsy since the age of 13 months. On neurological examination, she politely interacted with the medical staff. She often answered questions without any great thought. Ocular movement was slightly saccadic, and she had rotatory nystagmus when looking towards the left or right side. Other cranial nerve functions, limb muscle power, coordination, and cutaneous sensations were intact. Her tendon reflexes were systemically increased, and plantar responses were extensor with signs of spasticity. On neuropsychological examination conducted at 39 years of age, her Hasegawa Dementia Scale-Revised (HDS-R)[5] score was 19/30 and the Mini-Mental State Examination (MMSE) score was 21/30. The HDS-R, a screening test for patients with dementia in Japan, is similar to the MMSE. A score of <20 out of 30 is indicative of dementia. Her verbal and performance intelligence quotient scores in the Wechsler Adult Intelligence Scale-Revised test were 67 and 62, respectively. Her information, digit span, vocabulary, arithmetic, comprehension, and similarity subscores were 3, 7, 5, 5, 4, and 5, respectively, whereas her picture completion, picture arrangement, block design, object assembly, and digit symbol subscores were 7, 4, 5, 4, and 3, respectively. This suggested the presence of a prominent executive dysfunction, attentional deficit, and impaired global cognition. Verbal and visual memories were mildly impaired. Laboratory findings, including hematology, routine blood chemistry, blood pyruvate/lactate levels, and thyroid function tests, were all unremarkable. Enzyme activity of arylsulfatase A, β-hexosaminidase A, and β-galactocerebrosidase in leukocytes as well as the concentrations of very long-chain fatty acids and their respective ratios were normal. Magnetic resonance imaging (MRI) revealed regions with high-signal intensity in the bilateral frontal white matter around the anterior horn of the lateral ventricle on T2-weighted images and atrophy of the corpus callosum [Figure 1]. The 99mTc-ethyl cysteinate dimer single photon emission computed tomography showed hypoperfusion of both frontal areas. At that time, her findings remained inconclusive. At 41 years of age, she could not adequately wash dishes. At 42 years, she sang without feeling self-conscious. At 45 years, she was unable to stand without support in our medical office. At 50 years, she attended a local care center for day service and had to be bathed. At 51 years, her HDS-R score had decreased to 9/30. At 53 years, she wore an adult diaper. In 2014, at 53 years, she fell down the stairs and was immobile. MRI revealed cervical atrophy and high intramedullary signal changes in the medulla oblongata and cervical spinal cord. She was diagnosed with a spinal cord injury without radiographic abnormalities related to trauma. A retrospective review of her imaging studies revealed that in addition to progressive extensive changes in the cerebral white matter, she showed a tadpole-like brainstem, which was caused by marked atrophy from the medulla oblongata to the cervical spinal cord, sparing the pontine base [Figure 1]. After obtaining informed consent from the patient and her husband, GFAP gene analysis was performed, revealing a heterozygous c. 745C>T mutation predictive of a p.A244V amino acid substitution. Thus, we diagnosed AxD.
Figure 1: The first, second, third, and fourth rows show magnetic resonance imaging of our case performed at 39, 45, 48, and 51 years of age. The far-right column shows sagittal sections of T1- or T2-weighted images, whereas the rest of the columns show axial T2-weighted images

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Here, we report a case of adult-onset AxD patient presenting with cognitive impairment as the initial symptom at 34 years of age. At the time of her first medical examination, our knowledge of AxD was limited; therefore, she did not receive a confirmed diagnosis. In 2010, Namekawa et al., revealed that a typical tadpole-like appearance of the brainstem is strongly suggestive of adult-onset AxD and should lead to a genetic investigation of the GFAP gene.[3] A retrospective review of our patient's imaging studies revealed that she had a tadpole-like brainstem. Thus, we were able to confirm AxD. This finding suggests the importance of the re-examination of patients based on the acquisition of novel information. Our patient showed primary pathology in her subcortical region, and her presentation was characterized by a prominent executive dysfunction and attention deficit. This suggests that executive dysfunction is caused by a disconnection in the frontal–subcortical circuit. Infantile AxD is characterized by developmental delay, seizures, megalencephaly, and progressive deterioration with increased severity in neonatal patients, whereas adult AxD is characterized by bulbar symptoms, ataxia, palatal myoclonus, and spasticity. Our case was adult-onset AxD; however, the patient had less brainstem symptoms and presented with cognitive impairment as the initial symptom, presumably resulting from cerebral involvement; these findings are inconsistent with those of previous cases. The incidence of muscle weakness, hyperreflexia, dysarthria, dysphonia, dysphagia, and sphincteric abnormalities is high; however, dementia has only been observed in 25% of adult AxD patients.[2] This finding suggests that when adult-onset leukodystrophy cases develop cognitive impairment, the possibility of AxD should be considered.

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  References Top

Prust M, Wang J, Morizono H, Messing A, Brenner M, Gordon E, et al. GFAP mutations, age at onset, and clinical subtypes in Alexander disease. Neurology 2011;77:1287-94.  Back to cited text no. 1
Yoshida T, Sasaki M, Yoshida M, Namekawa M, Okamoto Y, Tsujino S, et al. Nationwide survey of Alexander disease in Japan and proposed new guidelines for diagnosis. J Neurol 2011;258:1998-2008.  Back to cited text no. 2
Pareyson D, Fancellu R, Mariotti C, Romano S, Salmaggi A, Carella F, et al. Adult-onset Alexander disease: A series of eleven unrelated cases with review of the literature. Brain 2008;131:2321-31.  Back to cited text no. 3
Namekawa M, Takiyama Y, Honda J, Shimazaki H, Sakoe K, Nakano I. Adult-onset Alexander disease with typical “tadpole” brainstem atrophy and unusual bilateral basal ganglia involvement: A case report and review of the literature. BMC Neurol 2010;10:21.  Back to cited text no. 4
Hosokawa T, Yamada Y, Isagoda A, Nakamura R. Psychometric equivalence of the Hasegawa Dementia Scale-Revised with the Mini-Mental State Examination in stroke patients. Percept Mot Skills 1994;79:664-6.  Back to cited text no. 5


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