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Neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP) is a rare childhood-onset multisystem disorder characterized by cerebellar ataxia, dystonic movements, and vertical supranuclear gaze palsy. Biallelic loss-of-function variants in the sequestosome-1 gene (SQSTM1) have been implicated in NADGP, expanding its phenotypic spectrum beyond Paget’s disease of bone and amyotrophic lateral sclerosis.
Genetic Evidence
NADGP displays autosomal recessive inheritance. Two affected siblings in a Japanese pedigree were identified as compound heterozygotes for SQSTM1 variants: c.1A>G (p.Met1Val) and c.969G>A (p.Glu323=) (PMID:39587727). Both parents, who are phenotypically normal, each carried one of these variants, consistent with segregation of recessive alleles. No other unrelated families have been reported to date, yielding a total of two probands across one pedigree.
Variant Spectrum
The c.1A>G (p.Met1Val) change abolishes the initiation codon, and the c.969G>A (p.Glu323=) synonymous alteration creates a cryptic splice site leading to premature truncation. Both variants result in loss-of-function alleles.
Functional Evidence
Urine-derived cell (UDC) assays demonstrated that transcripts from both SQSTM1 alleles undergo aberrant splicing, resulting in absent or truncated p62 protein in patient cells, corroborating a loss-of-function mechanism (PMID:39587727). This in vitro evidence aligns with the observed recessive phenotype.
Clinical Validity and Integration
Based on two probands from a single family with clear biallelic segregation and functional confirmation, the SQSTM1–NADGP association currently meets a Limited level of clinical validity. Genetic findings and UDC-based functional assays provide a coherent mechanistic link between SQSTM1 loss of function and early-onset neurodegeneration featuring ataxia, dystonia, and vertical supranuclear gaze palsy.
Key Take-Home
Biallelic SQSTM1 loss-of-function variants cause childhood-onset NADGP; genetic testing of SQSTM1 should be considered in cases of unexplained cerebellar ataxia with dystonia and gaze palsy.
Gene–Disease AssociationLimitedTwo probands in a single family with compound heterozygous variants and functional confirmation Genetic EvidenceLimitedAutosomal recessive segregation in one pedigree with two affected siblings and loss-of-function alleles Functional EvidenceModerateUDC assays demonstrate aberrant splicing and absence of normal p62 protein |