Childhood onset hereditary spastic paraplegia

Gene: OGDHL

Green List (high evidence)

Comment on list classification: This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly heterogeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.

Created: 10 Oct 2025, 1:41 p.m. | Last Modified: 10 Oct 2025, 1:41 p.m.

Panel Version: 8.13

There are at least 24 individuals from 21 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363; 38031187). The individuals present with a childhood-onset complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases, including spasticity, hypotonia and muscle atrophy.

PMIDs: 28017472; 34800363: 10 individuals from 9 unrelated families identified with biallelic variants in OGDHL with Yoon-Bellen Syndrome. Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14), spasticity (3/14). One individual was reported to have spastic cerebral palsy, another presented with spastic quadriplegia.
Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Sources: Literature

Created: 10 Oct 2025, 1:37 p.m. | Last Modified: 10 Oct 2025, 1:40 p.m.

Panel Version: 8.13

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221

Publications

• 28017472
• 34800363
• 38031187