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Autosomal recessive spastic paraplegia 50 (SPG50; MONDO:0013048) is caused by bi-allelic loss-of-function variants in AP4M1 (HGNC:574), encoding the mu subunit of the adaptor protein complex-4. A core phenotype of neonatal hypotonia progressing to spastic paraplegia is accompanied by severe intellectual disability and seizures, often with postnatal microcephaly and neuroimaging abnormalities. The inheritance is autosomal recessive, with multiple reports of consanguineous pedigrees and a recurrent founder variant in Middle Eastern and Turkish families.
In a multicenter case series, three unrelated consanguineous families from the Middle East carried homozygous NM_004722.4:c.1012C>T (p.Arg338Ter) in AP4M1, with core features of early hypotonia, spasticity, intellectual disability and seizures ([PMID:36371792]). Subsequent identification of four additional patients in three other families worldwide bearing the same truncating variant supports a founder effect. A shared SNP haplotype spanning AP4M1 in all six families confirms a common ancestor most likely of Turkish origin.
Independent reports expand the AP4M1 variant spectrum. A patient with prenatal‐onset severe microcephaly and progressive spasticity was homozygous for c.1012C>T (p.Arg338Ter) with predicted loss of the Mu homology domain ([PMID:28464862]). Two siblings from a consanguineous family carried a canonical splice donor mutation c.1137+1>T, segregating with an AP4-deficiency–like neurodevelopmental phenotype ([PMID:26029708]). A recent exome study identified bi-allelic loss-of-function AP4M1 variants in three additional families with syndromic intellectual disability and microcephaly ([PMID:36371492]). Across these reports at least eight unrelated probands from six families carry AP4M1 truncating or splice mutations.
The variant spectrum is dominated by loss-of-function alleles: five families with the recurrent nonsense variant c.1012C>T (p.Arg338Ter), and other homozygous splice or stop mutations. No missense-only cases have been reported in SPG50. Segregation of AP4M1 variants with disease in multiple siblings and families confirms recessive inheritance and pathogenicity.
Mechanistically, truncating and splice mutations are predicted to abolish AP4M1 function, consistent with a loss-of-function disease model. Haplotype analysis demonstrates a founder effect for the Arg338Ter allele. To date, no in vitro or animal models have been published for AP4M1-related SPG50, and functional assays remain limited.
A single-patient phase 1 trial of intrathecal AAV-mediated AP4M1 gene replacement demonstrated safety and tolerability at 12 months, with no serious adverse events and preliminary stabilization of motor function ([PMID:38942994]). Although efficacy data are early, this personalized therapy underscores the feasibility of gene replacement for SPG50.
Given at least eight unrelated probands with bi-allelic loss-of-function variants, consistent autosomal recessive segregation, and concordant clinical phenotypes across multiple families, the gene–disease association for AP4M1 and SPG50 is classified as Strong. Genetic evidence is Strong based on eight probands and recurrent LoF variants; functional evidence is Limited pending in vivo or in vitro modeling. AP4M1 testing should be included in diagnostic panels for early-onset spastic paraplegia and intellectual disability. Gene replacement therapy offers a promising future avenue for clinical intervention.
Gene–Disease AssociationStrongEight probands in six unrelated families with segregating LoF variants and clinical concordance Genetic EvidenceStrongEight probands with bi-allelic LoF variants across multiple consanguineous and non-consanguineous families; founder variant in six pedigrees Functional EvidenceLimitedHaplotype and predicted loss-of-function support mechanism; no in vitro or animal models published |