Inherited white matter disorders

Gene: HMBS

Green List (high evidence)

Relevant metabolic investigation: urine porphobilinogen
Although HMBS biallelic pathogenic variants are very rare (8 families worldwide to date) five have been shown to have white matter anomalies on MRI.
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: 27558376 Kevelam reports 3 siblings (between 58, 63 and 57 years old) from a single family with HMBS biallelic pathogenic variants c.500G.A, p.(Arg167Gln) and c.674G.A, p.(Arg225Gln). Patient 1 developed a slowly progressive spastic paraparesis as a teenager. At 58 years of age he had a normal cognition and his vision was normal with glasses. His neurologic examination showed a spastic paraparesis and a distal peripheral neuropathy of his legs.
Gross motor development was mildly delayed in patient 2. She suffered progressive spastic paraparesis, leading to wheelchair dependency at the age of 4. She had optic atrophy together with a slowly progressive neurologic deterioration and mild cognitive impairment. At 63 years of she had peripheral neuropathy in her arms and legs, a severe cerebellar ataxia and apraxia and loss of vision.
Patient 3 had progressive vision loss due to optic atrophy and from 12 years of age he developed progressive gait problems leading to wheelchair dependency at 35 years. At 57 years, he had spastic paraparesis, a distal peripheral neuropathy of legs and arms, cerebellar ataxia and also apraxia.
All 3 patients had extensive, confluent, symmetrical signal abnormalities in the periventricular and deep cerebral white matter with relative sparing of the U-fibers. In patients 2 and 3, the abnormalities were most extensive. The thalami were affected, but the basal nuclei, internal capsule, and corpus callosum were spared. All patients had mild widening of the lateral ventricles and subarachnoid spaces. Patients 2 and 3 had signal abnormalities in the central part of the pons.
PMID: 31153822 Dixon reported an 11-month-old patient with biallelic HMBS variants (c.500G > A, p.(Arg167Gln) and c.104C>T, p.(Thr35Met)). At 4-6 weeks of age, he was noted to have developmental delays and later apnoeic episodes. At 3 months he had seizures and feeding difficulty. At 11 months no dysmorphic features were noted. He had an abnormal neurological exam with slight left lower facial droop, hypotonic throughout, absent reflexes in both lower extremities. Magnetic resonance spectroscopy of the brain, revealed an abnormal lactate peak in the cerebral white matter and enlarged bilateral fronto-parietal subarachnoid spaces (BESSI). He had an abnormal electroencephalogram with focal seizure activity but a comprehensive epilepsy panel was negative.
PMID: 34089223 Stutterd reported two siblings (45 and 54 years old) with homozygous HMBS variants c.251C>A, p.(Ala84Asp) and a 45 year old individual with compound heterozygous variants c.500G>A, p.(Arg167Gln) and c.674G>A, p.(Arg225Gln).
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.
Individual 3 had onset of an unsteady gait at the age of 13. At 22 years, he had bilateral lower limb spasticity with normal strength and otherwise normal neurological function. His gait deteriorated over time with progressive leg weakness and peripheral numbness. At 46 years, he had moderate spastic paraparesis and peripheral neuropathy
All three individuals 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.

Created: 4 Apr 2025, 3:28 p.m. | Last Modified: 4 Apr 2025, 3:28 p.m.

Panel Version: 1.184

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
620711; 620704

Publications

• 27539938
• 31153822
• 34089223

Comment on list classification: This gene is awaiting curator evaluation and rating.

Created: 19 Dec 2018, 1:03 p.m.

Green List (high evidence)

Please note that while heterozygous variants in this gene cause acute intermittent porphyria, bi-allelic variants can cause paediatric onset leukoencephalopathy. Consider Amber if not Green.

Created: 24 Jul 2018, 1:54 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 27558376, 27271711

Variants in this GENE are reported as part of current diagnostic practice