Mutations in SQSTM1 gene have been recently identified as a rare cause of progressive childhood neurodegenerative disorder. So far, only 25 patients from 10 unrelated families were reported.
We report on the first Tunisian case of an 11-year-old girl with cerebellar ataxia, chorea and ophthalmoparesis. Brain MRI was normal. Whole-exome sequencing revealed a homozygous mutation c.823_824del(p.Ser275Phefs*17) in SQSTM1 gene (GenBank: NM_003900.4).
By pooling our data to the data of literature, we delineated the phenotypic spectrum and stressed on genetic heterogeneity of this rare neurodegenerative disease.

BACKGROUND: Accumulating evidence shows that SQSTM1 plays a vital role in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which represent a neurodegenerative disease continuum. Here, we report a novel SQSTM1 variant in a patient presenting with progressive nonfluent aphasia (PNFA) and progressive bulbar palsy (PBP). Relevant literature about FTD and FTD-ALS caused by SQSTM1 mutation was reviewed to better understand its clinical features.
METHODS: We collected data from a 66-year-old male patient with a novel heterozygous variant (c.995C > G, p.S332X) in the SQSTM1 gene who was diagnosed with PNFA and PBP and performed a PubMed literature search using the advanced research criteria: [(\"frontotemporal lobar degeneration\") OR (\"frontotemporal dementia\") OR (\"amyotrophic lateral sclerosis\") OR (\"motor neuron disease\")] AND (\"SQSTM1\"). The clinical features of FTD and FTD-ALS related to SQSTM1 mutation were summarized based on previous cases and our new case.
RESULTS: The initial symptom of the current patient was progressive verb finding difficulties and effortful speech output, which developed into dysarthria and dysphagia in subsequent months. The results, including tongue atrophy, fasciculations, neurogenic changes, and mild left dominant hypometabolism of 18F-fluorodeoxyglucose PET in the frontal cortex, suggest the possibility of PNFA and PBP. A novel likely pathogenic heterozygous variant (c.995C > G, p.S332X) in the SQSTM1 gene was identified. The literature search revealed a total of 33 FTD and FTD-ALS cases related to the SQSTM1 mutation with detailed clinical information. The mean age of onset (including our patient) was 63.5 ± 9.7 years. bvFTD was the most common clinical phenotype. The missense mutation in the SQSTM1 gene coding region and the UBA domain involvement are its main genetic characteristics.
CONCLUSIONS: Although rare, mutations in SQSTM1 can lead to various clinical subtypes of FTD and FTD-ALS, including the rare combination of PNFA and PBP. Exon missense mutation is the main type of mutation, which is common in the UBA domain.

p62/SQSTM1 is the scaffold protein implicated in selective autophagy, which is induced by cellular stress. Research has shown that p62 is highly expressed in cancer. Moreover, p62 can easily promote tumor metastasis. However, studies have not reached a consensus on the relationship of p62 expression with the diagnosis and prognosis of lung cancer. We conducted a systematic review and meta-analysis of studies on p62 expression in the prognosis and clinical-pathological parameters of lung cancer patients. Literature search was performed with PubMed, Web of Science, EMBASE, Cochrane Library, and SpringerLink databases. Fixed-effects and random-effects models were used to study the relationship of p62 expression with patients\' overall survival (OS) and clinical-pathological parameters. I2 was used to test for heterogeneity. Egger\'s test was used to assess publication bias. The meta-analysis collected and considered 13 articles, which included 1393 lung cancer patients. The studies show that the high expression of p62 is associated with poor OS in lung cancer patients. The clinical-pathological parameters of patients show that p62 is more highly expressed in high TNM stage (II + III + IV VS. I), Lymph node metastasis (N1 VS. N0), and distant metastases (D1 VS. D0). However, there is no correlation between the p62 expression and the Beclin 1 and LC3B in lung cancer patients. In conclusion, the over-expression of p62 is associated with poor OS in lung cancer patients and can be used as a biomarker for lung cancer diagnosis and prognosis.

Adult PD of bone is the second commonest metabolic bone condition after osteoporosis. The condition is characterized by increased bone cell activity, with bone-resorbing osteoclasts often larger and containing more nuclei than normal, and osteoblasts producing increased amounts of disorganized bone. This leads to expanded bone of poor quality possessing both sclerotic and lytic areas. PD of bone has a strong genetic element, with a family history being noted in 10-20% of cases. A number of genetic defects have been found to be associated with the condition. The most common disease-associated variants identified affect the SQSTM1 gene, providing insights into disease aetiology, with the clinical value of knowledge of SQSTM1 mutation status currently under active investigation. The diagnosis may be suggested by an isolated raised total ALP without other identifiable causes. This can be confirmed on plain X-rays and the extent determined by isotope bone scan. The mainstays of treatment are the bisphosphonates, especially i.v. zoledronate, which results in long-term suppression of bone turnover. ALP is the usual means of monitoring the condition, although more specific bone turnover markers can be helpful, especially in coincident liver disease. Patients should be followed up to monitor for biochemical relapse or development of complications, which may require medical or surgical intervention.

Paget\'s disease was first described more than 150 years ago, but the exact cause is still unknown--genes and the environment are both important. This article explores the basic science and clinical aspects of this intriguing condition.

Paget\'s disease (PD) is a focal disorder of bone remodelling that occurs commonly in older people. In this article, we review clinical aspects of PD with an emphasis on recent findings. The epidemiology of PD appears to be changing rapidly, with several groups in different parts of the world reporting a marked reduction in the prevalence and incidence of PD, as well as in the severity of disease seen by clinicians. These findings seem most likely to be caused by changes in exposure to unknown environmental factors that have a role in the development of PD. However, genetic factors are also important. Mutations in SQSTM1 occur in 25-50% of familial PD. Genotype-phenotype relationships are present, as PD develops at an earlier age and is more extensive and severe in those with SQSTM1 mutations, and these findings are more pronounced in those with truncating mutations. However, the prevalence of PD in adults with SQSTM1 mutations is uncertain, and it is not known how such mutations might cause PD. Ultimately, if the cause of PD is determined, it seems likely that it will include both genetic and environmental factors. Lastly, clinical trials have shown that potent bisphosphonates are highly effective treatments for active PD, and reduce pain, improve quality of life, normalise bone turnover and heal lytic lesions on radiographs. They can also induce sustained remission that persists for many years.

OBJECTIVE: New acquisitions have been recently obtained on molecular pathogenesis, genetics and treatment of the Paget\'s disease of bone. Utmost importance to the skeletal manifestations of this disease has been given, even though extraskeletal abnormalities have been reported over the years. Consequently, the clinical aspects of extraskeletal complications have been less extensively investigated. This review will focus primarily on epidemiological, clinical and diagnostic features of skeletal and extra-skeletal clinical manifestations and will include either the hypotheses or new findings on their underlying molecular pathophysiology. A practical suggestion for an optimal management path of Paget\'s disease of bone is given.
RESULTS: It has been revealed that osteoblasts and osteocytes participate in impaired bone remodeling; in a North American study on pagetic patients, the survival rate was better than expected; the frequency of neurological complications and hearing loss could be different than previously reported; and somatically acquired mutations of SQSTM1/p62 gene have been found in both the diseased bone and tumor samples from sporadic patients with Paget\'s disease of bone.
CONCLUSIONS: Through an improved and more complete clinical characterization the \'old\' complications could be better managed and new ones could emerge as entities potentially associated with Paget\'s disease.

Paget\'s disease of bone (PDB) is a condition of unknown etiology characterized by excessive and abnormal bone remodeling. It may be localized to one or several skeletal segments. The disease seldom appears before the age of 40 years, but its prevalence tends to double each decade from the age of 50 onwards, reaching about 10% after ninth decade. PDB may virtually affect every bone in the skeleton. Affected bones are involved right away with no new involvement during the evolution. The basic symptom of the disease is bone pain, while complications depend on skeletal sites involved and range from secondary osteoarthritis to malignant degeneration. Diagnosis is usually based upon clinical features, imaging, and laboratory analyses. Therapeutic approach is currently based on second-generation bisphosphonates. Their use is recommended when bone alkaline phosphatase is high and/or when the disease localizations are highly suspected for determining complications.