Bilateral congenital or childhood onset cataracts

Gene: HMBS

Green List (high evidence)

Published evidence quoted by Sharon Whatley (International Porphyria Network), supports a green rating for HMBS gene on this panel - Bilateral congenital or childhood onset cataracts.

Created: 24 Apr 2025, 12:04 p.m. | Last Modified: 24 Apr 2025, 12:04 p.m.

Panel Version: 6.8

Green List (high evidence)

Biallelic inheritance of HMBS pathogenic variants is very rare. PMID: 14262853 De Villeneuve, 1577472 Llewellyn, 15534187 Solis, 14970743 Hessels and 31153822 Dixon. It has been reported in six children (from 5 families) four children (from 3 families) children have been reported to have cataracts.
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 and no symptoms of acute porphyria. She died at 8 years of age.
PMID: 15534187 Solis reported a 28 month old patient with homozygous HMBS variants c.499C>T, p.(Arg167Trp), bilateral capsular cataracts and a unique pattern of deep cerebral white matter injury, with relative preservation of the corpus callosum, anterior limb of the internal capsule, cerebral grey matter, and infratentorial structures. He had no history of seizures. Neurologic examination confirmed peripheral neuropathy, psychomotor delay and revealed occasional dystonic head positioning and dystonic arm movements. The proband had approximately 1% of normal mean erythrocyte HMBS activity, and urinary ALA and PBG were markedly elevated. He died at 40 months.
PMID: 34089223 Stutterd reported two siblings (45 and 54 years old) with homozygous HMBS variants c.251C > A, p.(Ala84Asp).
Sibling 1, was diagnosed with cataracts at 4 years of age and slowly progressive ataxia at 7. At 36 years, she had spastic/ataxic paraparesis, distal sensory impairment, mild dysarthria, and normal cognitive function. Nerve conduction studies confirmed a mild generalized sensorimotor peripheral neuropathy with reduction in the sural and ulnar sensory nerve action potentials and mild prolongation of F waves in the lower limbs. She was independent. Over a period of 16 months, her ataxia and dysarthria worsened and she underwent liver transplantation which initially gave some improvement after which her neurological function began to decline.
Sibling 2 was diagnosed with cataracts in early childhood and in late childhood, developed slowly progressive ataxia, dysarthria, and mild cognitive impairment. At 53 he had predominantly truncal ataxia and mild peripheral ataxia. He had lower limb spasticity and evidence of a mild peripheral neuropathy.
Both had extensive, mainly confluent, symmetrical signal abnormalities in the periventricular and deep cerebral white matter with relative sparing of the U-fibers. All individuals had bilateral involvement of the thalami with sparing of the basal nuclei, internal capsule, and corpus callosum.
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.
Sources: Expert Review

Created: 4 Apr 2025, 4:25 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
620711; 620704

Publications

• 14262853
• 1577472
• 15534187
• 14970743
• 31153822