Likely inborn error of metabolism

Gene: HMBS

Based on the review from Sharon Whatley (International Porphyria Network) a mode of inheritance change has been suggested, from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.

Created: 24 Apr 2025, 12:34 p.m. | Last Modified: 24 Apr 2025, 12:34 p.m.

Panel Version: 7.27

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
PMID: 38940544 Aasand The acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, including acute intermittent porphyria (AIP), usually become symptomatic in early adulthood.
In a patient with symptoms consistent with a porphyria disorder, the definitive diagnosis depends on the demonstration of increased accumulation and excretion of porphyrins and porphyrin precursors during an acute attack. If a patient is no longer symptomatic it may be difficult to diagnose an acute porphyria.
PMID: 27539938 Chen reports that the HMBS gene has very low penetrance (<1%) so that genetic testing alone may be misleading and cause misdiagnosis.
PMID: 14262853 De Villeneuve, 1577472 Llewellyn, 15534187 Solis, 14970743 Hessels, 27558376 Kevelam, 31153822 Dixon and 34089223 Stutterd, reported biallelic variants in the HMBS gene in six children (5 families) five children with severe progressive neurological disease and in six adults (3 families) with leukoencephalopathy. A biallelic finding may lead to diagnosis in these very rare patients.
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, 3:49 p.m. | Last Modified: 4 Apr 2025, 3:49 p.m.

Panel Version: 7.21

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

Phenotypes
176000; 620711; 620704

Publications

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

Green List (high evidence)

HMBS is the third enzyme of the biosynthetic pathway leading to the production of heme. >3 unrelated cases from multiple populations providing gene:disease association. Plus animal model.

Created: 23 Feb 2017, 5:14 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Porphyria, acute intermittent, 176000; Porphyria, acute intermittent, nonerythroid variant, 176000

Publications

• 2511016
• 1714233