Ataxia and cerebellar anomalies - narrow panel

Gene: HMBS

Green List (high evidence)

Relevant metabolic investigation: urine porphobilinogen
Although HMBS biallelic pathogenic variants are very rare (8 families worldwide to date) three families (7 individuals) have been shown to have cerebellar ataxia.
PMID: 1577472 Llewellyn reported two siblings with HMBS biallelic pathogenic variants c.499C>T, p.(Arg167Trp) and c.500G>A, p.(Arg167Gln). At the age of 18 months one patient had ataxia with intention tremor and dysarthria secondary to partial agenesis of the cerebella vermis, bilateral cataracts and right optic nerve hypoplasia. Biochemical studies showed excessive excretion of PBG with normal faecal porphyrin and very low erythrocyte PBG deaminase activity. At 3 years of age, she was admitted to hospital following febrile convulsions. When assessed one year later, she had had no further convulsions or symptoms of acute porphyria. She died at 8 years of age.
PMID: 15828996 Sheppard reported on the sibling of the above patient. He had no cataracts or other abnormalities with a normal cerebral ultrasound at birth. Urine PBG was raised and erythrocyte PBG-deaminase activity was very low. Developmental progress was normal up to 18 months old. At 10 years of age clinical signs included severe ataxia, peripheral neuropathy and dysarthria. Urinary porphyrins were continuously elevated in this patient.
PMID: 27558376 Kevelam reports 3 siblings with cerebellar ataxia see previous review.
PMID: 34089223 Stutterd reported two siblings and an unrelated patient with ataxia 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, 2:44 p.m. | Last Modified: 4 Apr 2025, 2:44 p.m.

Panel Version: 7.25

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leukoencephalopathy, HP:0002352, cerebellar ataxia, MONDO:0000437

Publications

• 1577472
• 15828996

Green List (high evidence)

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

Created: 26 Sep 2024, 12:35 p.m. | Last Modified: 26 Sep 2024, 12:35 p.m.

Panel Version: 6.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

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

Created: 30 Jan 2024, 3:56 p.m. | Last Modified: 30 Jan 2024, 3:56 p.m.

Panel Version: 4.54

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; cerebellar ataxia, MONDO:0000437

Publications

• 27558376
• 34089223