Childhood onset hereditary spastic paraplegia

Gene: HMBS

Green List (high evidence)

Relevant metabolic investigation: urine porphobilinogen
Although HMBS biallelic pathogenic variants are very rare (8 families worldwide to date) four families have been reported to have spasticity.
PMID: 14262853 De Villeneuve described a patient retrospectively confirmed to have biallelic HMBS pathogenic variants (c.500G>A, p.(Arg167Gln) and c.518G>A, p.(Arg173Gln)). At 8 months she was noted to have abnormalities of the brain. At 5 years she had learning disabilities and neurological aberrations. Her teeth showed red fluorescence on exposure to UV light. Biochemical studies over a period of 3 years, showed persistently highly elevated levels of ALA, PBG and uroporphyrin and slightly elevated levels of coproporphyrin. These were extremely raised even in comparison to AIP patients. Further clinical features of this child included spasticity with contractures of arms and legs. She died at 8 years of age due to a seizure.
PMID: 27558376 Kevelam reports 3 siblings see previous review.
PMID: 34089223 Stutterd reported 2 siblings and an unrelated patient see previous review.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the HMBS gene, due to its low clinical penetrance.

Created: 4 Apr 2025, 3:37 p.m. | Last Modified: 4 Apr 2025, 3:37 p.m.

Panel Version: 7.8

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
620711; 620704

Publications

• 14262853

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 26 Sep 2024, 1:01 p.m. | Last Modified: 26 Sep 2024, 1:01 p.m.

Panel Version: 6.3

Comment on list classification: There are three unrelated families reported with spastic paraparesis. Hence, this gene can be promoted to green rating in the next GMS review.

Created: 30 Jan 2024, 3:54 p.m. | Last Modified: 30 Jan 2024, 3:54 p.m.

Panel Version: 4.39

PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

Monoallelic variants in HMBS gene have been associated with acute intermittent porphyria (MIM #176000) in OMIM, but biallelic variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature

Created: 30 Jan 2024, 3:52 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leukoencephalopathy, HP:0002352; hereditary spastic paraplegia, MONDO:0019064

Publications

• 27558376
• 34089223