Hereditary neuropathy

Gene: HMBS

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 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, 3:56 p.m. | Last Modified: 4 Apr 2025, 3:56 p.m.

Panel Version: 1.497

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

Phenotypes
176000; 620711; 620704

Publications

• 27539938
• 38940544
• 35584894
• 14262853
• 1577472
• 15534187
• 31153822
• 14970743
• 34089223
• 27558376

Green List (high evidence)

The Neurology Specialist Test Group agreed that this gene was recommended for the WGS panel based on a broader phenotype view to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP. This panel includes conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation. This panel as going to be used for R78, 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 and as a result a new panel was created https://panelapp.genomicsengland.co.uk/panels/846/ for this purpose.

Created: 7 Dec 2019, 6:08 p.m. | Last Modified: 7 Dec 2019, 6:08 p.m.

Panel Version: 1.352

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