Presentation and Diagnosis of Adolescent-Onset HMBS-Related Leukoencephalopathy
Biochemical/Metabolic and Therapeutics
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Introduction
Biallelic variants in HMBS, encoding porphobilinogen deaminase (PBGD), have been identified in individuals presenting with childhood or adolescent-onset progressive neurologic disease and white matter abnormalities, a rare phenotype termed HMBS-related leukoencephalopathy. PBGD catalyzes the condensation of porphobilinogen (PBG) to form hydroxymethylbilane in the third step of heme synthesis. Monoallelic HMBS variants are known to cause acute intermittent porphyria (AIP), an autosomal dominant condition with incomplete penetrance. Biallelic HMBS variants are exceedingly rare and have only been identified in five children with severe infantile or early childhood-onset disease, and more recently, in at least six individuals with later childhood or adolescent-onset disease. Neurologic features include progressive spastic paraparesis, cerebellar ataxia and peripheral neuropathy. Imaging findings include extensive symmetrical abnormalities in the periventricular and deep white matter and thalami. To date, treatment for HMBS-related leukoencephalopathy remains supportive.
Here we present the presentation and diagnosis of another individual with adolescent-onset HMBS-related leukoencephalopathy.
Case Presentation
A 17-year-old male with mild learning difficulties presented with five months of progressive gait changes and lower extremity paresthesias. He experienced tripping, falling and unsteadiness. Subsequently, he developed painful numbness of his bilateral lower extremities. He became nonambulatory and was unable to attend school in the month prior to presentation. Examination revealed hyperreflexia of the lower extremities, bilateral ankle clonus, wide-based gait, and preserved sensation. There were hand tremors and titubation.
Diagnostic Workup
Brain magnetic resonance imaging (MRI) revealed bilateral thalamic, subcortical white matter and corpus callosum lesions. Thoracic spine MRI was unremarkable. Ophthalmologic evaluation was only notable for red-green color blindness. Neuroinflammatory work-up was negative. Metabolic screening labs and lysosomal enzyme storage disease panel were unrevealing.
Exome and mitochondrial sequencing revealed biparentally inherited variants in HMBS: a paternally inherited pathogenic variant (c.499C>T, p.Arg167Trp) and a maternally inherited variant of uncertain significance (c.674G>A, p.Arg225Gln).
Follow-up biochemical testing revealed normal plasma aminolevulinic acid (ALA) and PBG levels, normal urine ALA, elevated urine PBG and decreased erythrocyte PBGD activity. Both parents were found to have mildly decreased PBGD activity.
Treatment and Management
Physical therapy, occupational therapy and care through physical medicine and rehabilitation is ongoing. Baclofen was prescribed for spasticity. Ankle foot orthotic braces and botulinum injections were initiated for heel tightness. Given reported mitochondrial dysfunction in individuals with monoallelic and biallelic variants in HMBS, treatment with a mitochondrial cocktail was also started.
Outcome and Follow-Up
Spasticity and tremors have improved with therapies and baclofen. No changes were observed on repeat brain MRI.
Discussion
This case describes another individual with HMBS-related leukoencephalopathy and is consistent with previous reports of childhood-onset ataxia and neuropathy, as well as symmetrical deep white matter and thalamic signal abnormalities on MRI. Interestingly, the c.499C>T variant has been reported in individuals with infantile and early childhood-onset disease, while the c.674G>A variant has been reported in later-onset disease; an individual with the combination of both variants has not been previously reported.
Conclusion
This case adds to our understanding of the clinical spectrum of HMBS-related leukoencephalopathy. The pathophysiology of HMBS-related leukoencephalopathy remains unclear. Givosiran is a small interfering RNA targeting ALA synthase 1, the first and rate-limiting enzyme in heme synthesis. Givosarin treatment has been shown to reduce accumulation of the neurotoxic heme intermediates ALA and PBG and to improve outcomes in individuals with AIP. Future work will investigate the impact of givosarin on this individual’s symptoms and laboratory and imaging findings.
Biallelic variants in HMBS, encoding porphobilinogen deaminase (PBGD), have been identified in individuals presenting with childhood or adolescent-onset progressive neurologic disease and white matter abnormalities, a rare phenotype termed HMBS-related leukoencephalopathy. PBGD catalyzes the condensation of porphobilinogen (PBG) to form hydroxymethylbilane in the third step of heme synthesis. Monoallelic HMBS variants are known to cause acute intermittent porphyria (AIP), an autosomal dominant condition with incomplete penetrance. Biallelic HMBS variants are exceedingly rare and have only been identified in five children with severe infantile or early childhood-onset disease, and more recently, in at least six individuals with later childhood or adolescent-onset disease. Neurologic features include progressive spastic paraparesis, cerebellar ataxia and peripheral neuropathy. Imaging findings include extensive symmetrical abnormalities in the periventricular and deep white matter and thalami. To date, treatment for HMBS-related leukoencephalopathy remains supportive.
Here we present the presentation and diagnosis of another individual with adolescent-onset HMBS-related leukoencephalopathy.
Case Presentation
A 17-year-old male with mild learning difficulties presented with five months of progressive gait changes and lower extremity paresthesias. He experienced tripping, falling and unsteadiness. Subsequently, he developed painful numbness of his bilateral lower extremities. He became nonambulatory and was unable to attend school in the month prior to presentation. Examination revealed hyperreflexia of the lower extremities, bilateral ankle clonus, wide-based gait, and preserved sensation. There were hand tremors and titubation.
Diagnostic Workup
Brain magnetic resonance imaging (MRI) revealed bilateral thalamic, subcortical white matter and corpus callosum lesions. Thoracic spine MRI was unremarkable. Ophthalmologic evaluation was only notable for red-green color blindness. Neuroinflammatory work-up was negative. Metabolic screening labs and lysosomal enzyme storage disease panel were unrevealing.
Exome and mitochondrial sequencing revealed biparentally inherited variants in HMBS: a paternally inherited pathogenic variant (c.499C>T, p.Arg167Trp) and a maternally inherited variant of uncertain significance (c.674G>A, p.Arg225Gln).
Follow-up biochemical testing revealed normal plasma aminolevulinic acid (ALA) and PBG levels, normal urine ALA, elevated urine PBG and decreased erythrocyte PBGD activity. Both parents were found to have mildly decreased PBGD activity.
Treatment and Management
Physical therapy, occupational therapy and care through physical medicine and rehabilitation is ongoing. Baclofen was prescribed for spasticity. Ankle foot orthotic braces and botulinum injections were initiated for heel tightness. Given reported mitochondrial dysfunction in individuals with monoallelic and biallelic variants in HMBS, treatment with a mitochondrial cocktail was also started.
Outcome and Follow-Up
Spasticity and tremors have improved with therapies and baclofen. No changes were observed on repeat brain MRI.
Discussion
This case describes another individual with HMBS-related leukoencephalopathy and is consistent with previous reports of childhood-onset ataxia and neuropathy, as well as symmetrical deep white matter and thalamic signal abnormalities on MRI. Interestingly, the c.499C>T variant has been reported in individuals with infantile and early childhood-onset disease, while the c.674G>A variant has been reported in later-onset disease; an individual with the combination of both variants has not been previously reported.
Conclusion
This case adds to our understanding of the clinical spectrum of HMBS-related leukoencephalopathy. The pathophysiology of HMBS-related leukoencephalopathy remains unclear. Givosiran is a small interfering RNA targeting ALA synthase 1, the first and rate-limiting enzyme in heme synthesis. Givosarin treatment has been shown to reduce accumulation of the neurotoxic heme intermediates ALA and PBG and to improve outcomes in individuals with AIP. Future work will investigate the impact of givosarin on this individual’s symptoms and laboratory and imaging findings.