Hereditary neuropathy or pain disorder

Gene: HMBS

Based on review from Sharon Whatley (International Porphyria Network), the mode of inheritance of HMBS should be changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal on this panel - Hereditary neuropathy or pain disorder.

Created: 24 Apr 2025, 12:16 p.m. | Last Modified: 24 Apr 2025, 12:16 p.m.

Panel Version: 6.168

Comment on publications: Publications suggested by Sharon Whatley (International Porphyria Network): 27539938; 38940544; 35584894; 14262853; 1577472; 15534187; 31153822; 14970743; 34089223; 27558376

Created: 24 Apr 2025, 11:19 a.m. | Last Modified: 24 Apr 2025, 11:19 a.m.

Panel Version: 6.168

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Green List (high evidence)

Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyric attack)
PMID: 27539938 Chen reports that pathogenic HMBS allele frequency is high in the general population (1/1,782) and that the HMBS gene has very low penetrance (<1%) so that genetic testing alone may be misleading and cause misdiagnosis.
PMID: 38940544 Aarsand IPNET advises that an acute attack of acute intermittent porphyria is diagnosed using urine porphobilinogen as the penetrance is so low. Genetic testing of the HMBS gene should only be used for family testing where penetrance is higher (10-20%).
PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.
PMID: 14262853 De Villeneuve, 1577472 Llewellyn, 15534187 Solis, 31153822 Dixon and 14970743 Hessels reported the very rare finding of biallelic pathogenic variants in the HMBS gene in six children (5 families) five children with severe progressive neurological disease. Symptoms included spastic paraparesis, ataxia, dysarthria, nystagmus, peripheral neuropathy, decreased muscle tone and reflexes and Babinski signs.
PMID:34089223 Stutterd, 27558376 Kevelam reported in six adults (3 families) with biallelic pathogenic HMBS variants who had leukoencephalopathy with symptoms including spastic paraparesis and peripheral neuropathy.
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, 4:02 p.m. | Last Modified: 4 Apr 2025, 4:02 p.m.

Panel Version: 6.165

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
27539938; 38940544; 35584894; 14262853; 1577472; 15534187; 31153822; 14970743; 34089223; 27558376

Green List (high evidence)

The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 26 Sep 2024, 1:11 p.m. | Last Modified: 26 Sep 2024, 1:11 p.m.

Panel Version: 5.16

Comment on mode of inheritance: There is sufficient evidence available (three unrelated families) for the association of biallelic HMBS variants with peripheral neuropathy. Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS review.

Created: 30 Jan 2024, 4:09 p.m. | Last Modified: 30 Jan 2024, 4:09 p.m.

Panel Version: 3.82

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.

Created: 30 Jan 2024, 4:03 p.m. | Last Modified: 30 Jan 2024, 4:03 p.m.

Panel Version: 3.79

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Porphyria, acute intermittent, OMIM:76000; Porphyria, acute intermittent, nonerythroid variant, OMIM:176000; Leukoencephalopathy, HP:0002352; hereditary peripheral neuropathy, MONDO:0020127

Publications

• 27558376
• 34089223

Green List (high evidence)

Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Broader phenotype - acute intermittent porphyria As per CPOX usually presents more acutely but management implications. Promote to Green as management implications

Created: 6 Dec 2019, 8:47 p.m. | Last Modified: 6 Dec 2019, 8:47 p.m.

Panel Version: 0.73

Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.

Created: 6 Dec 2019, 8:45 p.m. | Last Modified: 6 Dec 2019, 8:45 p.m.

Panel Version: 0.73

Review and rating uploaded from file (Curation_Template_GMS_Neuro_AR_20190521.xlsx) submitted by Alex Rossor (UCL Institute of Neurology) on behalf of London North GLH for GMS Neurology specialist test group.

Created: 11 Jun 2019, 1:40 p.m.

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
AIP, Abdominal pain, psychosis, depression, seizures, axonal predominantly motor neuropathy