BRIEF REPORT
Frontotemporal Dementia-amyotrophic Lateral Sclerosis Complex is Simulated by Neurodegeneration With Brain Iron Accumulation Alexander Frizell Santillo, MD,* Lena Skoglund, MSc,* Maria Lindau, PhD,* Karin Edebol Eeg-Olofsson, MD, PhD,w Metin Tovi, MD, PhD,z Henry Engler, MD,y Rose-Marie Brundin,* Sofie Ingvast, MSc,* Lars Lannfelt, MD, PhD,* Anna Glaser, PhD,* and Lena Kilander, MD, PhD*
Abstract: We describe a case of late onset neurodegeneration with brain iron accumulation (NBIA) presenting as frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS). A male patient presented at age 66 with change of personality: disinhibition, emotional blunting, and socially inappropriate behavior, coupled with dysarthria, dystonia, and corticospinal tract involvement. Magnetic resonance imaging showed general cortical atrophy, iron deposits in the globus pallidus, and the ‘‘eye of the tiger’’ sign. Neuropsychologic performance was globally reduced, especially executive functions. Fluorodeoxyglucose positron emission tomography showed hypometabolism predominantly in frontal and temporal areas. Repeated neurophysiologic examinations showed signs of chronic denervation. The patient was diagnosed with NBIA but fulfilled consensus criteria for FTD and had a clinical picture of ALS, without neurophysiologic confirmation. Our finding introduces NBIA as a possible cause of FTD and as a differential diagnosis of the FTD-ALS complex. Key Words: neurodegeneration with brain iron accumulation, Hallervorden-Spatz disease, frontotemporal dementia, amyotrophic lateral sclerosis
(Alzheimer Dis Assoc Disord 2009;23:298–300)
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eurodegeneration with brain iron accumulation (NBIA) is a rare autosomal recessive or sporadic neurodegenerative disorder that was previously known as Hallervorden-Spatz disease. Typically dystonia, dysarthria, rigidity, and choreoathetosis start in the first decade of life, progress and culminate in early death.1 Atypical forms have later onset, with slower progression, and are clinically much more heterogeneous. A combination of cognitive decline and psychiatric symptoms such as personality change and disinhibition, ‘‘reminiscent of frontotemporal dementia’’ (FTD), is prominent in about one-third of atypical cases.1 Also, NBIA have been described to mimic amyotrophic lateral sclerosis (ALS) clinically and with regard to electromyography (EMG).2 Received for publication November 13, 2007; accepted January 7, 2009. From the Departments of *Public Health/Geriatrics; wNeuroscience/ Clinical Neurophysiology; yMedical Sciences/Clinical Physiology, Uppsala University, Uppsala; and zDepartment of Diagnostic Radiology, Karolinska University Hospital, Stockholm, Sweden. Reprints: Alexander Frizell Santillo, MD, Department of Public Health/ Geriatrics, Uppsala University, Uppsala Science Park, 751 85 Uppsala, Sweden (e-mail:
[email protected]). Copyright r 2009 by Lippincott Williams & Wilkins
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METHODS AND RESULTS A 70-year-old man presented at a neurologic clinic for gait problems and postural instability since the age of 64. Three years before admission he had a subdural hematoma after a fall, which resolved spontaneously. His family history included a younger brother with FTD, a maternal uncle with ALS, a mother and grandmother with dementia of unknown type and bulbar dysfunction, and a sister with Alzheimer disease (AD) (all clinical diagnoses, Fig. 1). There was no consanguinity. A first neurologic examination showed broad based, slowed gait without ataxia, muscular atrophy of the legs with fasciculations, generalized hyperreflexia, and positive extensor palmar response bilaterally. Pursuit eye movements were slow but otherwise normal, and speech was mildly dysarthric. Magnetic resonance imaging (MRI) of the brain showed mild general cortical atrophy and the ‘‘eye of the tiger’’ sign.3 The diagnosis of NBIA was thus suggested radiologically but at this time judged to be clinically unprobable and ignored. Serum ceruloplasmine, iron, ferritin levels, and urine copper levels were within normal range. MRI of the cervical spine was normal. Nerve conduction studies of upper and lower extremities showed slightly increased F-wave latencies, possibly a sign of discrete neuropathy. EMG yielded normal findings except for a slight inactive neurogenic change in the left thigh, where motor unit potentials were slightly increased in amplitude. On subsequent examinations the condition had progressed. Speech became more effortful, dysarthric, ‘‘pseudobulbar’’ in quality, spontaneous verbal production diminished, and swallowing had become effortful. Walking was increasingly difficult, and he had several forward falls. Mild ataxia of the lower extremities was noted, and a generalized limb paratonia had emerged. Fluorodeoxyglucose positron emission tomography showed global cerebral and cerebellar hypometabolism more pronounced in the frontal, temporal, and anterior cingulum cortex bilaterally, whereas parietal and occipital cortices and putamina were relatively spared (Fig. 2). Single photon emission computed tomography with 123I-ioflupane (DaTSCAN) showed reduced activity bilaterally in concordance with presynaptic dopaminergic degeneration. Cerebrospinal fluid examination revealed high tau (660 ng/L), slightly increased phospho-tau (97 ng/L), normal b amyloid (880 ng/L) concentrations, and no increase in leukocyte or protein content. Levodopa stimulation test was negative. On interview the patient stated no subjective symptoms except a slight gait difficulty, which hampered his ability to bowl. An interview with his
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FIGURE 1. Pedigree. Individuals who have not yet reached age of onset have been omitted. Diagnoses have been set as indicated for all affected individuals with * describing dementia of unknown type with bulbar dysfunction for individuals 20 and 40.
wife revealed a story of progressive emotional blunting and loss of motivation, impulsiveness and restlessness, social inappropriate behavior, high risk taking, and he ate faster than before. Empathy had diminished, and he had very rudimentary insight regarding his condition. Memory had worsened for day-to-day events. The change in personality had been insidious, came simultaneously with the gait difficulties, and had gradually worsened. The results of the neuropsychologic examination are presented in Table 1.4-11 The patient scored considerably lower than expected (according to age and education) in
Frontotemporal Dementia
practically all tests, with most marked reductions in executive ability and visuospatial memory. The test behavior was denoted by impulsivity, perseverations, and lack of planning. An EMG was repeated after 6 months, 41=2 year after first reported symptom of disease, and showed no signs of denervation. However, there were now slight inactive neurogenic changes (ie, slight chronic denervation) proximally and distally in both lower limbs and left arm, as well as in the right hand. Nerve conduction studies showed at this time no signs of neuropathy. Transcranial magnetic stimulation with registration of muscle responses bilaterally in hand and lower limb muscles showed normal findings for hand muscles, whereas response from left lower leg was absent; and in the right lower leg corticomuscular latency at muscle rest was prolonged but normalized after voluntary activation. The diagnosis of this patient was set to be neurodegeneration with brain iron accumulation. In view of previous reports of genetic causes for NBIA, identified as mutations within the genes for pantothenate kinase PANK212and PLA2G6,13 a sample from this patient was sequenced for all exons within these 2 genes, revealing no mutations. Given the family history, we sequenced samples from the NBIA patient and the 2 siblings affected by FTD and AD, respectively, within selected coding exons for microtubuleassociated protein tau, exons 9 to 13; superoxide dismutase1, exons 1 to 5; progranulin, exons 0 to 12; a-synuclein, exons 1 to 6; amyloid precursor protein,exons 16 to 17; ferritin light chain; and presenilin 1, but no pathogenic mutations were identified.
DISCUSSION Cognitive decline and dementia are known features of adult NBIA, and have been described in detail.14 Also, psychiatric symptoms and aberrant behavior resembling that in FTD are common in NBIA.1,15 This is the first case described where a patient with probable NBIA have fulfilled current criteria for FTD after modern neuropsychiatric investigations. Behaviorally our patient showed loss of empathy, emotional blunting, hyperorality, inadequate social, and increased risk taking behavior, which all are typical features of FTD.16 His cognitive profile was generally reduced but even more in executive, verbal, and mnestic aspects, which is not entirely typical but well in accordance with FTD.16 This corresponded with the
FIGURE 2. A, T2 weighted magnetic resonance imaging and B, Fluorodeoxyglucose positron emission tomography examination, both transversal slides at the level of the third ventricle (for comments, see text). r
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TABLE 1. Neuropsychological Assessment
Verbal ability FAS, totally Boston naming Information Similarities Logical reasoning Calculation Visuospatial ability Clock drawing Rey-Osterrieth complex figure Block design Psychomotor function Digit symbol TMT A, number of connections Time, seconds TMT B, number of connections Time, seconds Executive ability Wisconsin Card Sorting Test, correct answers Short-term memory Digit span, forwards, maximum items Digit span, backwards, maximum items Corsi Block-tapping Test Verbal episodic memory Word list, encoding Word list, recognition, d Visuospatial episodic memory Rey-Osterrieth figure, immediate recall
Raw Value
Z-score/ Stanine
10 46 14 21
3.3/1 1.8/1 0.3/4 0.0/5
10
0.7/4
2 21 24
2.0/1 3.8/1 0.3/4
29 23 91 23 205
1.3/2 3.3/1 2.0/1
0* 5 4 4.4
0.9/3 0.8/3 1.4/2
1 0.9
1.8/2 3.8/1
0
2.6/1
The patient’s raw values and Z-scores are shown, (corresponding to specific intervals on the stanine scale on the normal probability curve4). Reference values are from a database at Karolinska University Hospital, Huddinge, Stockholm.5 *The patient did not understand the testing procedure and could thus not perform the test.
fluorodeoxyglucose positron emission tomography scan performed which showed global deterioration markedly worse in the frontotemporal and anterior cingulum cortex bilaterally, also typical of FTD.17 Age at first symptoms, 66 years, is also in accordance with FTD, as is notably the patients striking family history of FTD and ALS. Our patient did develop clinical signs of ALS such as muscle wasting, fasciculations, pseudobulbar speech, emergence of plantar extensor response, and primitive reflexes, but repeated neurophysiologic examination, of which the last was 5.5 years after onset did not show any signs of ongoing denervation, which is one of the neurophysiologic criteria for the diagnosis of ALS.18 In this case the reevaluation of the MRI finding lead to the diagnosis of probable NBIA. The ALS-like symptomatology fitted well given that NBIA often show findings such as generalized hyperreflexia, positive extensor palmar responses, and that NBIA also has been described to mimic ALS on EMG, showing neurogenic motor unit potentials with neurogenic motor unit recruitment.2 NBIA could explain the entire family history of FTD and ALS, or, less likely, this is a case of sporadic NBIA within a family suffering from the FTD/
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ALS complex. Our genetic investigation of this patient included genes previously have been reported to contain mutations in patients with NBIA, and in addition we also screened the patient and his 2 siblings with FTD and AD, for mutations within a selection of dementia/neurodegeneration-related genes. This investigation served to exclude these genes as disease causing in the NBIA patient, and to examine possible heterogeneity within the family. To summarize, this case introduces NBIA as a possible cause of FTD and as a differential diagnosis of the FTD/ALS complex.
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