Clinical practice guidelines for the diagnosis, management, and surveillance of people with LMNB1 related autosomal dominant leukodystrophyA Consensus-Based Approach
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical-Adult
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Secondary Categories:
- Clinical-Adult & Pediatric
Introduction:
Autosomal dominant leukodystrophy (ADLD) is an adult-onset progressive neurodegenerative genetic disorder caused by variants in LMNB1 with limited published evidence to guide clinical care recommendations making diagnosis and management challenging and inconsistent.
Methods:
We used a modified Delphi process to systematically combine literature evidence with international consensus experts (10) recommendations to determine best-practice clinical care guidelines.
We identified 10 clinicians and scientists (Europe and USA) from 5 different institutions as expert panel members (EPM), one biostatistician (DH), as well as a guidelines methodologist (HB) with expertise in medical guideline development using the modified Delphi approach. The EPM included neurologists, neuroradiologist, clinical geneticists, and molecular geneticists. Representatives from the ADLD Center (2) were also included to review the clinical guideline statements for patient relevance, review final recommendations, and provide feedback. Final recommendations from the EPM were also sent to additional clinicans and scientist (3) for feedback.
Results:
Diagnosis
ADLD should be suspected in a patient with characteristic brain MRI findings (symmetric T2-weighted hyperintensities in the cerebral white matter extending from below the motor cortex, following corticospinal tracts toward the pyramids in the medulla oblongata, in the cerebrum, symmetric T2 hyperintense areas spread into frontal and parietal lobes first, followed by occipital and temporal lobes, periventricular areas are less affected) and clinical symptoms of autonomic dysfunction, with or without a positive family history of autosomal dominant inheritance. The typical course of the disease is insidious onset with gradual progression, acute worsening with illness followed by recovery to baseline can be seen.
Genetic testing
Diagnosis of ADLD should be established in a patient with suggestive clinical and MRI findings, positive family history and either a pathogenic LMNB1 duplication or rarely a heterozygous deletion upstream of the LMNB1 promoter identified on genetic testing. Single gene testing that can identify LMNB1 structural variants (duplications/deletions) at a high resolution should be used for diagnosis. Whole exome is not recommended as a first-tier test
Surveillance Careful physical examination, tilt table testing, brain and C spine MRI, and neuropsychometric assessment should be obtained at baseline and based on disease progression thereafter to monitor progression.
Management A neurologist, physiotherapist and a genetic counselor and/or geneticist should be involved in care at the minimum. Additional providers including a urologist, mental health specialists, PMR physician, and dietician can be involved as needed for the patient. For management of myelopathy, non invasive treatments like oral antispasticity medications, followed by botulinum toxin, followed by invasive treatments like intrathecal baclofen therapy should be considered. All patients with ADLD and at-risk individuals who wish to conceive should be offered prenatal genetic counseling.
Conclusion:
Our consensus-based approach utilizing ADLD experts allowed us to formulate guideline recommendations despite limited scientific evidence.Our EPM have put forth these recommendations to promote uniform care for this ultra-rare disease and pave the way for future collaborative research efforts towards a natural history study, defining end points for future clinical trials and a cure.
Autosomal dominant leukodystrophy (ADLD) is an adult-onset progressive neurodegenerative genetic disorder caused by variants in LMNB1 with limited published evidence to guide clinical care recommendations making diagnosis and management challenging and inconsistent.
Methods:
We used a modified Delphi process to systematically combine literature evidence with international consensus experts (10) recommendations to determine best-practice clinical care guidelines.
We identified 10 clinicians and scientists (Europe and USA) from 5 different institutions as expert panel members (EPM), one biostatistician (DH), as well as a guidelines methodologist (HB) with expertise in medical guideline development using the modified Delphi approach. The EPM included neurologists, neuroradiologist, clinical geneticists, and molecular geneticists. Representatives from the ADLD Center (2) were also included to review the clinical guideline statements for patient relevance, review final recommendations, and provide feedback. Final recommendations from the EPM were also sent to additional clinicans and scientist (3) for feedback.
Results:
Diagnosis
ADLD should be suspected in a patient with characteristic brain MRI findings (symmetric T2-weighted hyperintensities in the cerebral white matter extending from below the motor cortex, following corticospinal tracts toward the pyramids in the medulla oblongata, in the cerebrum, symmetric T2 hyperintense areas spread into frontal and parietal lobes first, followed by occipital and temporal lobes, periventricular areas are less affected) and clinical symptoms of autonomic dysfunction, with or without a positive family history of autosomal dominant inheritance. The typical course of the disease is insidious onset with gradual progression, acute worsening with illness followed by recovery to baseline can be seen.
Genetic testing
Diagnosis of ADLD should be established in a patient with suggestive clinical and MRI findings, positive family history and either a pathogenic LMNB1 duplication or rarely a heterozygous deletion upstream of the LMNB1 promoter identified on genetic testing. Single gene testing that can identify LMNB1 structural variants (duplications/deletions) at a high resolution should be used for diagnosis. Whole exome is not recommended as a first-tier test
Surveillance Careful physical examination, tilt table testing, brain and C spine MRI, and neuropsychometric assessment should be obtained at baseline and based on disease progression thereafter to monitor progression.
Management A neurologist, physiotherapist and a genetic counselor and/or geneticist should be involved in care at the minimum. Additional providers including a urologist, mental health specialists, PMR physician, and dietician can be involved as needed for the patient. For management of myelopathy, non invasive treatments like oral antispasticity medications, followed by botulinum toxin, followed by invasive treatments like intrathecal baclofen therapy should be considered. All patients with ADLD and at-risk individuals who wish to conceive should be offered prenatal genetic counseling.
Conclusion:
Our consensus-based approach utilizing ADLD experts allowed us to formulate guideline recommendations despite limited scientific evidence.Our EPM have put forth these recommendations to promote uniform care for this ultra-rare disease and pave the way for future collaborative research efforts towards a natural history study, defining end points for future clinical trials and a cure.