What is the recommended management approach for an adult patient with a possible sqstm1 (sequestosome 1) gene mutation and a potential neurodegenerative condition or autophagy-related disorder?

Management of SQSTM1 Gene Mutations

Immediate Clinical Recognition and Genetic Confirmation

Biallelic loss-of-function mutations in SQSTM1 cause a distinct childhood- or adolescence-onset neurodegenerative disorder requiring immediate multidisciplinary evaluation and longitudinal surveillance. 1

The core clinical phenotype includes:

• Gait abnormalities and ataxia 1
• Dysarthria and dystonia 1
• Vertical gaze palsy 1
• Progressive cognitive decline 1
• Locomotor deficits with motor neuron axonal defects 2

Genetic confirmation should utilize:

• Exome sequencing to identify biallelic SQSTM1 variants 1
• Confirmation of protein absence in patient fibroblasts 1
• Fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), or chromosomal microarray analysis 3

Pathophysiological Understanding

The molecular mechanism involves:

• SQSTM1/p62 functions as a selective autophagy receptor linking ubiquitinated proteins to LC3, and regulates KEAP1 degradation controlling NFE2L2/NRF2 antioxidant responses 4
• Loss-of-function causes defects in early response to mitochondrial depolarization and autophagosome formation 1
• Increased mTOR levels occur with SQSTM1 knock-down, indicating dysregulated autophagy 2
• Disease mutations abolish KEAP1-SQSTM1 interaction, diminishing NFE2L2-targeted gene expression and increasing stress granule formation 5

Therapeutic Intervention

Rapamycin treatment should be strongly considered as it ameliorates the locomotor phenotype by inhibiting the mTOR pathway. 2

The rationale for rapamycin:

• Knock-down of sqstm1 leads to increased mTOR levels 2
• Rapamycin treatment yields amelioration of locomotor deficits in SQSTM1 knock-down models 2
• The therapeutic effect targets the misregulation of autophagic processes 2

Comprehensive Multidisciplinary Evaluation

Given the phenotypic overlap with other contiguous gene deletion syndromes, systematic evaluation should include:

Neurological assessment:

• Screening for psychiatric disorders including anxiety, attention deficits, and psychotic disorders 3
• Developmental and cognitive reassessment at ages 1-5 years, 6-12 years, and 13-18 years 6
• Surveillance for early signs of parkinsonism in adults, particularly after 35 years 3

Cardiac evaluation:

• Comprehensive echocardiography and ECG annually to monitor for cardiomyopathy development 6
• Transition to adult congenital heart disease specialists when reaching adulthood 3

Ophthalmologic monitoring:

• Examination with intraocular pressure monitoring for glaucoma risk 6

Auditory assessment:

• Comprehensive audiometry with tympanometry to detect sensorineural or conductive hearing loss 6

Renal evaluation:

• Renal and bladder ultrasound as part of initial evaluation 6

Longitudinal Monitoring

Regular evaluations (annual or biannual) of all potentially affected systems are essential. 3

Laboratory surveillance should include:

• Complete blood count, electrolytes, ionized calcium, magnesium, parathyroid hormone 3
• Creatinine, liver function, lipid profile, glucose, and HbA1c 3

Transition Planning and Genetic Counseling

Structured transition planning from pediatric to adult care should begin during puberty. 6, 3

Coordination requirements:

• Integration between neurology, psychiatry, cardiology, ophthalmology, and primary care providers 6
• Genetic counseling at diagnosis with adaptation according to age and cognitive abilities 3
• Clear information on the 50% risk of transmission for each pregnancy in affected individuals 3
• Reproductive health counseling, contraception, and pregnancy planning 6
• Discussion on variability of clinical manifestations and impossibility of predicting severity in offspring 3

Critical Pitfalls to Avoid

When interpreting decreased SQSTM1 levels, pan-caspase inhibitors must be used to exclude caspase-induced cleavage. 4

SQSTM1 accumulation indicates autophagy inhibition but requires confirmation with additional markers. 4

Heterozygous SQSTM1 variants are associated with Paget disease of bone and may contribute to ALS/FTD, but the childhood neurodegenerative phenotype requires biallelic loss-of-function mutations. 1

Human SQSTM1 constructs carrying ALS/FTLD-related mutations do not rescue the loss-of-function phenotype, confirming these are true loss-of-function pathogenic variants. 2