HACE1 – Spastic Paraplegia-Severe Developmental Delay-Epilepsy Syndrome

HACE1 encodes a HECT-type E3 ubiquitin ligase implicated in protein ubiquitination and regulation of small GTPases. Biallelic loss-of-function variants in HACE1 underlie an autosomal recessive neurodevelopmental disorder characterized by lower limb spasticity, global developmental delay, intellectual disability, hypotonia, and epilepsy (HACE1; spastic paraplegia-severe developmental delay-epilepsy syndrome).

Multiple independent reports describe 16 probands from five unrelated families with autosomal recessive inheritance, including 8 individuals in two consanguineous families (PMID:26424145), 3 patients from two families (PMID:31321300), 2 siblings in Saudi Arabia (PMID:38899231), a single male with gross deletions (PMID:36553453), and 2 siblings with a missense variant (PMID:38790209). Segregation analysis demonstrated 19 affected relatives with co-segregating biallelic variants.

The variant spectrum is dominated by loss-of-function alleles, including nonsense (e.g., c.994C>T (p.Gln209Ter)), frameshift, splice, and gross multi-exon deletions. The recurrent c.994C>T (p.Gln209Ter) allele has been observed in multiple families. To date, no hypomorphic or deep-intronic variants have been reported.

Functional studies in Hace1 knockout mice recapitulate human phenotypes, showing ventriculomegaly, hypoplastic corpus callosum, locomotor deficits, and learning impairment. Patient fibroblasts exhibit RAC1 hyperactivation, reduced synaptic puncta, impaired long-term potentiation, and disrupted autophagy and mitophagy, supporting a loss-of-function mechanism (PMID:31321300; PMID:32225089).

No conflicting evidence has been reported. The concordant genetic and experimental data firmly establish HACE1 haploinsufficiency as the pathogenic mechanism in SPPRS.

Key Take-home: Biallelic HACE1 loss-of-function variants cause a recessive spastic paraplegia–developmental delay–epilepsy syndrome with consistent clinical and experimental validation that informs diagnostic testing and genetic counseling.

References

• Journal of medical genetics • 2015 • HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome. PMID:26424145
• Neurology. Genetics • 2019 • HACE1 deficiency leads to structural and functional neurodevelopmental defects. PMID:31321300
• Cureus • 2024 • Autosomal Recessive Spastic Paraplegia and Psychomotor Retardation With or Without Seizures: A Case Report From Saudi Arabia. PMID:38899231
• Genes • 2022 • Previously Undescribed Gross HACE1 Deletions as a Cause of Autosomal Recessive Spastic Paraplegia. PMID:36553453
• Genes • 2024 • A Missense Variant in HACE1 Is Associated with Intellectual Disability, Epilepsy, Spasticity, and Psychomotor Impairment in a Pakistani Kindred. PMID:38790209

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