FTDP-17: 2-Year Follow-Up of Motor and Cognitive Features After Autologous Stem-Cell Transplantation

To the Editor: Autologous stem-cell transplantation is a regenerative therapeutic modality that holds great promise for the treatment of neurological disorders characterized by neurodegeneration, although its development is currently still largely at the experimental stage. Nonetheless, commercial facilities offering stem-cell transplantation that patients may access are available. We present the case of a patient with frontotemporal dementia with parkinsonism linked to chromosome 17 due to a tau gene mutation who underwent stem cell transplantation.

Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17; OMIM#157140) has been associated with over 40 different pathogenic mutations in the gene encoding the microtubule-associated protein tau (MAPT), including splice site and missense mutations and deletions in both coding regions and introns.¹

Clinical and neuropathological heterogeneity of FTDP-17 cases is recognized, with some cases manifesting a predominantly cognitive phenotype, sometimes akin to Alzheimer’s disease, and others, a movement-disorder phenotype, sometimes akin to progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD).² Inter- and intrafamilial phenotypic heterogeneity with the same MAPT mutation has been reported.³ Treatment options are limited, with no reliable response of parkinsonism to dopaminergic therapies.

Stem-cell transplantation (SCTx) as a treatment for neurological disorders (“brain repair”) has attracted much attention in recent years, although formidable barriers remain to clinical application. These include the generation, appropriate anatomical distribution, survival, and function of appropriately-differentiated stem cells.⁴ Nonetheless, possible applications of SCTx in various neurological disorders, including Parkinson’s disease, have been anticipated, and controlled clinical trials have been initiated.⁴ Institutions offering SCTx have opened in various parts of the world, mostly in the commercial sector.⁵ We present the case of a patient with FTDP-17 who underwent SCTx.

Case Report

A 45-year-old man presented with poor balance, difficulty concentrating at work, and occasional slurring of speech. In the family history, his mother had been diagnosed with a frontal lobe dementia with onset in her early 60s, and his maternal grandmother was said to have had “Parkinson’s with dementia” (age at onset unknown).³ The patient had facial hypomimia and mild bradykinesia, but no tremor or rigidity. MR brain imaging was within normal limits. On initial neuropsychological assessment, Mini-Mental State Exam (MMSE) and Addenbrooke’s Cognitive Examination-Revised (ACE-R) scores were 28/30 and 93/100, respectively, indicating no dementia, and the Frontal Assessment Battery (FAB) score was 18/18. Formal neuropsychological assessment showed no evidence for decline in intellectual function (WTAR predicted FSIQ 105; WASI FSIQ 106) and no frontal lobe dysfunction (Delis-Kaplan Executive Functioning System: average range on Trail-Making Test, Color Word Interference Test, and letter fluency, borderline on category fluency; Hayling Sentence Completion Test and Brixton Spatial Anticipation Test within normal limits), but some impairment on sustained attention (Test of Everyday Attention). No significant changes were observed on repeat neuropsychological assessment 1 year later, but he had developed slow voluntary saccades and reduced arm swing when walking, but rigidity was still not observed. The initial provisional diagnosis of a parkinsonian syndrome, possibly early Parkinson’s disease, was revised to FTDP-17 after identification of the IVS10+16C>T splice site mutation in the MAPT gene, the most prevalent MAPT mutation in populations of British descent.⁶ The parkinsonian features showed no response to dopamine agonists or levodopa.³

The patient elected to undergo autologous stem-cell transplantation (SCTx), funded by himself (at about €7000) and against independent medical advice, at a commercial facility in Europe that advertises SCTx for the treatment of parkinsonian disorders, among other conditions. The procedure involved bone marrow collection from the iliac crest, laboratory processing to “measure the quantity and quality of the stem cells,” followed by implantation of stem cells by lumbar puncture. There were no immediate procedure-related complications.

At follow-up, cognitive and motor functions were monitored. Cognition remained stable: MMSE score was 29/30 at 9 months and Mini-Mental Parkinson (MMP) score was 30/32; at 18 months MMSE and ACE-R scores were 30/30 and 92/100, respectively. FAB score remained at 18/18 at 3 and 12 months post-SCTx. Examining motor function, some dystonic head tremor was evident 3 months post-SCTx. By 9 months, the patient was increasingly hypophonic and monotonic and had evident levator inhibition (pretarsal blepharospasm) in addition to slow horizontal and vertical saccades. At 1-year post-SCTx, he complained of swallowing problems, which required advice from speech and language therapy and dieticians to ensure suitable food consistency. Repeat MR brain imaging 12 months post-SCTx was within normal limits and unchanged from the pre-SCTx imaging. By 18 months, he was falling backward on a weekly basis. The phenotype was increasingly typical of PSP.

Just under 2 years post-SCTx, the patient was admitted to the hospital with evidence of compensated type II respiratory failure ascribed to hypoventilation. Despite non-invasive ventilatory support, he died. Permission for autopsy was not granted.

Discussion

This patient with FTDP-17 caused by the IVS10+16C>T splice site mutation in the MAPT gene initially presented in his mid-40s with subtle parkinsonism and essentially intact cognition, an age at onset and clinical phenotype apparently different from that of his affected progenitors, who had cognitive problems of later onset, with or without parkinsonism, indicating intrafamilial clinical heterogeneity.³ Over time, he developed a typical PSP motor phenotype, which has been previously reported with this MAPT mutation,^7,8 developing in the context of a dementing disorder in one patient.⁸ PSP phenotype has also been observed with other MAPT mutations, including R5L, N279K, ΔN296, G303V, and S305S.^1,2 Respiratory failure as a feature of FTDP-17 has also been reported, in a highly inbred family from the traveling community in Yorkshire, England, with a recessively-inherited MAPT mutation (S352L): two individuals presented with stridor, dyspnea, aspiration pneumonia, and respiratory failure, and one had additional mild parkinsonism and eye-movement signs.⁹

SCTx holds great hope for the treatment of many disorders, including chronic neurological conditions, such as multiple sclerosis and motor neuron disease.⁴ It is an established treatment for a variety of hematological disorders. However, research into the neurological applications of SCTx is still at a relatively early, experimental, stage, with no high-quality evidence of clinical efficacy yet available. Nonetheless, commercial clinics providing SCTx have opened, and a phenomenon of “stem-cell tourism”⁵ has developed as patients desperately searching for treatment patronize these units.

Although idiopathic Parkinson’s disease may be deemed a good candidate for neurotransplantation because the pathology is site-specific, with single cell-type loss,⁴ this may not be true of FTDP-17. Previous reports of FTDP-17 patients undergoing SCTx have not been identified. Sadly, this patient’s experience of progressive parkinsonism has provided no evidence for benefit of SCTx in FTDP-17.