SQSTM1 mutation: Description of the first Tunisian case and literature review

Abstract Background 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. Methods and results 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). Conclusion By pooling our data to the data of literature, we delineated the phenotypic spectrum and stressed on genetic heterogeneity of this rare neurodegenerative disease.


| OBSERVATION
An 11-year-old girl was referred to our department for evaluation of movement disorders. She was born to unrelated healthy parents. The pregnancy was complicated by maternal CMV infection in the 4th month. Serologic tests of CMV were repeatedly negative in the amniotic fluid and a fetal infection was ruled out. Our patient had a normal psychomotor development: she was able to walk independently at the age of 13 months. At the age of 9 years, the teacher remarked writing difficulties. Visual problem was suspected, however, ophthalmologic examination was normal. Subsequently, she developed deterioration in school performance, involuntary movement disorders, gait instability as well as balance and coordination problems.
Clinical examination revealed cerebellar signs with dysarthria, ataxic gait without enlargement of the support polygon, a postural instability, hypotonia, Dysdiadochokinesia, and dysmetria in finger-to-nose test. She also had generalized chorea. The study of oculomotricity revealed a downgaze palsy with a restriction of abduction. She had no telangiectasias and no pyramidal signs. A standardized intelligence quotient (IQ) assessment revealed a full scale IQ of 90 but working memory difficulties. Brain and spine MRI were normal. Laboratory tests, including hemogram, creatine kinase, IgA, and thyroid function tests were unremarkable. Electromyography and muscle biopsy were normal.
A written informed consent was obtained from the parents and whole-exome sequencing was performed using a SureSelect Human All Exon 38 Mb enrichment kit. Cosegregation analysis revealed homozygous frameshift variant c.823_824del(p.Ser275Phefs*17) in SQSTM1 (GenBank: NM_003900.4) as the likely candidate and confirmed that the mutation was inherited from heterozygous carrier parents. No other mutations were detected. The analysis of the gene dosage using exome depth did not indicate any copy-number variation. Our patient has been treated with coenzyme Q10 (100 mg daily), L-carnitine (1 g daily), vitamin E (200 mg twice daily), vitamin C (500 mg per day), and Piracetam (600 mg twice daily). She also underwent occupational and speech therapies.

| DISCUSSION
We report on the first Tunisian child with cerebellar ataxia, chorea, and ophthalmoparesis due to recessive mutation in SQSTM1. Sequestosome 1 (SQSTM1), encoding for p62 protein, is an adaptor protein involved in a variety of key cellular processes including oxidative stress response, apoptosis, and cell differentiation (Le Ber et al., 2013;Seibenhener et al., 2007). In addition, it plays a critical role in the degradation of ubiquitinated substrates, by its function as a selective autophagy receptor (Katsuragi et al., 2015). Therefore, mutations of SQSTM1 are closely linked to neurodegenerative diseases through the autophagy failure (Zhou et al., 2013).
This progressive childhood neurodegenerative disease caused by SQSTM1 mutations is rare. Indeed, so far, only 25 patients related to 10 families have been reported (Haack et al., 2016;Muto et al., 2018;Vedartham et al., 2019;Zúñiga-Ramírez et al., 2019). Demographic, clinical, imaging, and genetic findings of our patient and those of the 25 published cases are summarized in Table 1.
By pooling our case with those of the literature, the phenotypic spectrum seems very large. This neurodegenerative disease, caused by biallelic SQSTM1 mutations, is panethnic. In fact, reported patients were from Europe, Mexico, India, and the Middle East (Haack et al., 2016;Muto et al., 2018;Vedartham et al., 2019;Zúñiga-Ramírez et al., 2019). To date, this is the first case reported in Africa. Consanguinity was found in seven families. The mean age of onset was 9 years (extreme 6-15 years). Sex ratio was 1.27. Cerebellar Ataxia was found in all patients regardless of origin. Ophthalmoparesis and cognitive impairment were the commonest presenting symptoms (22 patients).
Dystonia and chorea were noted in 15 and five cases, respectively. Dysautonomic features such excessive sweating and orthostatic hypotension with additional features like iridoplegia and anisocoria were reported by Zuniga-Ramirez et al (two patients) (Zúñiga-Ramírez et al., 2019). Three patients presented a hearing loss (Haack et al., 2016), and two presented a hypergonadotropic hypogonadism (Muto et al., 2018).
These findings were not observed in our patient. Brain MRI revealed a cerebellar atrophy in six patients and signal abnormalities in basal ganglia with iron accumulation in two individuals (Haack et al., 2016).
The mean age at last examination was 27.7 years. In these studies, the course of this disease is characterized by a relatively slow progression, and only a fifth of reported patients lost their ability to walk between the age of 16 and 32 years.
Recently, heterozygous SQSTM1 mutations have also been found in other diseases like Paget's disease (PDB), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTLD). Furthermore, causal relationships have been found between mutations of SQSTM1 and the occurrence of these diseases (Le Ber et al., 2013): Recent studies have confirmed the presence of p62-positive inclusions in spinal motor neurons and frontal cortex, in SQSTM1 mutation carriers (Teyssou et al., 2013).
In contrast to PDB-associated SQSTM1 mutations predominantly affecting the Ubiquitin-Associated domain, the coding mutations in ALS/FTLD patients are widespread, affecting the regions essential for p62's functions such as the promoter regions (Rubino et al., 2012). Further studies are necessary to better investigate the role of p62 in the pathogenesis of these diseases. | 3 of 5 AKKARI et Al.

T A B L E 1 Demographic and genetic data of index patient and reported patients with SQSTM1
mutations (Haack et al., 2016;Majcher et al., 2015;Muto et al., 2018;Vedartham et al.,

| CONCLUSION
SQSTM1 mutation is a rare cause of neurodegenerative disease characterized by progressive ataxia movement disorders and gaze palsy. Through our study, we highlight the importance of whole-exome sequencing in the diagnosis of rare neurodegenerative disorders. Description of further cases, will allow to better understand the disease and to develop therapeutic trials. T A B L E 1 (Continued)