PMC:4337967 / 7759-11662
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4337967","sourcedb":"PMC","sourceid":"4337967","source_url":"http://www.ncbi.nlm.nih.gov/pmc/4337967","text":"DISCUSSION\nWe describe a new family carrying a heterozygous p.Lys238del mutation in SQSTM1 gene segregating with FTD. This study further demonstrates the implication of SQSTM1 in FTLD spectrum of diseases. Clinically, the three patients of the family were affected by atypical forms of FTD. Two patients had hip and femoral fractures, but none presented severe bone symptoms and deformations. The patients were not investigated specifically with biological testing or bone scintigraphy but no radiological signs of PDB were present on radiography. Furthermore, although the p.Lys238del mutation has been previously identified in ALS patients [4], motor neuron symptoms were absent in the three patients. ALS patients are often not tested for FTD symptoms, which could be the case for the ALS patient with the same mutation. This family thus illustrates the variability of bone and motor phenotype that can be moderate or absent in SQSTM1 families. We propose that SQSTM1 gene should be integrated in the ‘multisystem proteinopathies’ (MSP4), an emerging group of genetic diseases clinically characterized by variable association of FTD, ALS, PDB, and myopathy, and so far including VCP (MSP1), hnRNPA2/B1 (MSP2), and hnNPA2 genes (MSP3) [7].\nThe three patients exhibited a similar neuropsychological profile associating dysexecutive syndrome and early visuo-constructional disabilities. The episodic memory was for a long time preserved. The patients were mainly apathetic and one initially presented psychotic symptoms with hallucinations at onset. Brain imaging showed major opercular and perisylvian involvement. None of the three patients completely fit with the clinical criteria of bvFTD of Rascovsky [2] at onset. Patient 009 was the only one to fulfil these criteria after several years of evolution.\nMore interestingly, patient 007 presented apraxia of speech, with buccofacial apraxia dysarthria and anomia at onset. The patient 008 also had moderate symptoms of apraxia of speech. Apraxia of speech can be the initial sign of PNFA [2]. However, even if two patients presented with language problems, both of them presented early visuo-constructional disorders and, therefore, do not completely fit with the diagnosis of primary progressive aphasia according to the criteria of Gorno-Tempini et al. [2, 8]. They also showed different neuroimaging patterns, and neither of them presents the typical neuroimaging of nfv-PPA [2, 8].\nMany genetic cases of FTD do not present with the typical features of sporadic FTD, or do not strictly meet the criteria for any of the clinical variants. Notably, in previous studies, all FTD patients carrying SQSTM1 mutations presented a behavioral variant of FTD [5, 6]. This family demonstrates that the phenotypes associated with SQTM1 mutations are more heterogeneous, and that this gene should also be studied in patients presenting with speech apraxia or behavioral disorders associated with visuo-constructive deficit at onset, even in absence of PDB or ALS.\nPredicting the underlying pathology in patients with FTD is difficult but will be particularly important for future treatments targeting tau or TDP-43 proteins. A pathological study previously showed that SQSTM1 mutation carriers had TDP-43 and p62-immunoreactive neuronal inclusions in the prefrontal cortex [9]. So far, PNFA and more precisely, apraxia of speech, was rather considered predictive of FTLD-tau [10–12]. Our study supports a possible link between speech apraxia and FTLD-TDP. This finding is supported by a recent pathological study in 11 patients showing that nonfluent/agrammatic primary progressive aphasia could be associated with FTLD-TDP pathology [13].\nIn conclusion, our report widens the phenotypic spectrum of SQSTM1 mutations, and further illustrates the variability of phenotypes associated with SQSTM1 mutations thus supporting a pleiotropic effect of the 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