Two pathogenetic intronic variants in SPG4/SPAST and expansion of the clinical presentation.

Abstract

Hereditary Spastic Paraplegia (HSP) is a group of inherited neurodegenerative disorders primarily characterized by progressive lower limb spasticity and weakness. Among the various genetic causes of HSP, pathogenetic variants in SPG4/SPAST are the most frequently identified, making them the leading molecular cause of autosomal dominant HSP. The SPAST gene encodes spastin, a protein involved in microtubule dynamics. In this study, we focused on the functional characterization of two specific intronic variants in SPAST absent or present at a very low frequency in GnomAD database and with conflicting classification of pathogenicity, c.1245 + 5G > A and c.1493 + 2_1493 + 5del respectively. These variants were identified in two independent families, one of Brazilian origin and the other of Japanese descent. Our data shows that the splicing variants impact splicing. Furthermore, through segregation analysis and clinical assessments, we provided a detailed description of the affected individuals, emphasizing the clinical presentation associated with these genetic changes. Notably, in both families, the identified variants co-segregated symptoms consistent with anorexia nervosa, suggesting a potential, previously unrecognized association between SPAST pathogenic variants and disordered eating behaviors. Our findings contributed to the expanding clinical spectrum of SPG4-associated HSP and highlighted the importance of characterizing intronic SPAST variants. The characterization of intronic pathogenetic variants enhanced our understanding of their potential pathogenic mechanisms, which may have implications for both genetic diagnosis and the broader clinical management of HSP.

AI evidence extraction

Main findings

Functional characterization indicated that the two intronic SPAST variants impact splicing. In both families, the variants co-segregated with HSP and symptoms consistent with anorexia nervosa, suggesting a potential association between SPAST pathogenic variants and disordered eating behaviors.

Outcomes measured

• Splicing impact of intronic SPAST variants (c.1245+5G>A; c.1493+2_1493+5del)
• Segregation of variants with clinical phenotype
• Clinical presentation of SPG4/SPAST-associated hereditary spastic paraplegia
• Co-segregation of symptoms consistent with anorexia nervosa/disordered eating behaviors

Limitations

• Sample size not stated in abstract (two families only)
• Association with anorexia nervosa described as potential; causality not established in abstract
• Details of functional assays and clinical assessment methods not provided in abstract

{
    "study_type": "other",
    "exposure": {
        "band": null,
        "source": null,
        "frequency_mhz": null,
        "sar_wkg": null,
        "duration": null
    },
    "population": "Two independent families with hereditary spastic paraplegia (one Brazilian origin; one Japanese descent) carrying intronic SPAST variants",
    "sample_size": null,
    "outcomes": [
        "Splicing impact of intronic SPAST variants (c.1245+5G>A; c.1493+2_1493+5del)",
        "Segregation of variants with clinical phenotype",
        "Clinical presentation of SPG4/SPAST-associated hereditary spastic paraplegia",
        "Co-segregation of symptoms consistent with anorexia nervosa/disordered eating behaviors"
    ],
    "main_findings": "Functional characterization indicated that the two intronic SPAST variants impact splicing. In both families, the variants co-segregated with HSP and symptoms consistent with anorexia nervosa, suggesting a potential association between SPAST pathogenic variants and disordered eating behaviors.",
    "effect_direction": "unclear",
    "limitations": [
        "Sample size not stated in abstract (two families only)",
        "Association with anorexia nervosa described as potential; causality not established in abstract",
        "Details of functional assays and clinical assessment methods not provided in abstract"
    ],
    "evidence_strength": "very_low",
    "confidence": 0.7399999999999999911182158029987476766109466552734375,
    "peer_reviewed_likely": "yes",
    "keywords": [
        "hereditary spastic paraplegia",
        "HSP",
        "SPG4",
        "SPAST",
        "spastin",
        "intronic variants",
        "splicing",
        "segregation analysis",
        "anorexia nervosa",
        "disordered eating"
    ],
    "suggested_hubs": []
}

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