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Autosomal Dominant Leukodystrophy with Autonomic Disease

Synonyms: ADLD, Adult-Onset Autosomal Dominant Leukodystrophy with Autonomic Symptoms, Autosomal Dominant Adult-Onset Demyelinating Leukodystrophy, LMNB1-Related Adult-Onset Autosomal Dominant Leukodystrophy

, MD, , MD, , MD, and , MBBS, PhD.

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Summary

Clinical characteristics.

Autosomal dominant leukodystrophy with autonomic disease (ADLD) is a slowly progressive disorder of central nervous system white matter characterized by onset of autonomic dysfunction in the fourth to fifth decade, followed in months to years by pyramidal and cerebellar involvement. Autonomic dysfunction can include bladder dysfunction, constipation, postural hypotension, feeding difficulties, erectile dysfunction, and (less often) impaired sweating. Pyramidal signs are often more prominent in the lower extremities (i.e., spastic weakness, hypertonia, clonus, brisk deep tendon reflexes, and bilateral Babinski signs). Cerebellar signs typically appear at the same time as the pyramidal signs and can include gait ataxia, dysdiadochokinesia, intention tremor, dysmetria, and nystagmus. Although cognitive function is usually preserved or only mildly impaired early in the disease course, dementia and psychiatric manifestations can occur as late manifestations. Affected individuals may survive for decades after onset.

Diagnosis/testing.

The diagnosis of ADLD is established in a proband with suggestive clinical and MRI findings and either an LMNB1 duplication or (more rarely) a large heterozygous deletion upstream of the LMNB1 promoter.

Management.

Treatment of manifestations: Treatment is symptomatic. Autonomic dysfunction:

  • Neurogenic bladder may require management of urinary retention and/or urgency and recurrent urinary tract infection.
  • Constipation may require good hydration, increased dietary fiber, stool softeners, and/or laxatives.
  • Hypotensive events can be minimized by pharmacologic intervention, physical therapy, and increased dietary salt.
  • Feeding difficulties can be managed with speech therapy and appropriate feeding interventions to assure adequate nutrition while preventing aspiration pneumonia.

Spasticity may be treated with medications and physical therapy. Ataxia can be managed with strategies to minimize falls and increase strength, and adaptive equipment such as walkers or wheelchairs.

Surveillance: Routine assessment of: weight, nutrition, and feeding; pulmonary status (re possible recurrent pneumonia); bladder and erectile function; psychosocial well-being; and medications and their doses to avoid iatrogenic polypharmacy. At least yearly assessment: by a neurologist for disease manifestations and progression; and by a physiatrist, orthopedist, physical therapist, and occupational therapist to address orthopedic, equipment, and functional needs.

Genetic counseling.

ADLD is inherited in an autosomal dominant manner. To date all individuals with ADLD have inherited a large LMNB1 duplication (or large deletion upstream of LMNB) from an affected parent. Each child of an individual with ADLD has a 50% chance of inheriting the ADLD-related LMNB1 pathogenic variant. When the ADLD-related LMNB1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible.

Diagnosis

No formal diagnostic criteria exist.

Suggestive Findings

Autosomal dominant leukodystrophy with autonomic disease (ADLD) should be suspected in adults with the following clinical and neuroimaging features:

Clinical features

  • Onset in the fourth to fifth decade of signs and symptoms of autonomic dysfunction including bladder dysfunction, constipation, erectile dysfunction, and postural hypotension
  • Subsequent onset of motor and cerebellar impairment resulting in spasticity, ataxia, and tremor

MRI findings. Specific brain and spine MRI findings that suggest the diagnosis of ADLD [Bergui et al 1997, Melberg et al 2006, Sundblom et al 2009] include the following:

  • The cerebral white matter demonstrates symmetric T2-weighted hyperintensities extending from the motor cortex, following corticospinal tracts downward through the posterior limb of the internal capsule toward the medulla oblongata. Over time the signal abnormalities extend from the frontoparietal lobe to the occipital lobe and finally the temporal lobe to become completely confluent (Figure 1C, thick arrow).
  • U-fibers and optic radiations are usually spared.
  • The periventricular white matter is usually spared or mildly affected.
  • The upper and middle cerebellar peduncles are almost always involved with marked T2-weighted hyperintensity; however, in rare instances they can be spared [Bergui et al 1997] (Figure 1A, thin arrow).
  • Brain stem atrophy is present with increased signal intensity of the medulla oblongata. There is diffuse thinning and atrophy of the spinal cord, often with diffuse homogeneous T2-weighted hyperintensity.
  • Atrophy of the cerebrum, cerebellum, and corpus callosum may develop over time.
  • No pathologic enhancement is seen after contrast administration.
    Note: The brain and spinal cord MRI findings can precede clinical manifestations by decades.
Figure 1. . T2-weighted MRI from a male age 55 years with ADLD with sections through the brain stem (A), internal capsule (B), and parietal regions (C).

Figure 1.

T2-weighted MRI from a male age 55 years with ADLD with sections through the brain stem (A), internal capsule (B), and parietal regions (C). Characteristic involvement of the middle cerebellar peduncles and brain stem features (A, thin arrow), and confluent (more...)

Establishing the Diagnosis

The diagnosis of ADLD is established in a proband with suggestive clinical and MRI findings and either an LMNB1 duplication or (more rarely) a large heterozygous deletion upstream of the LMNB1 promoter [Giorgio et al 2015] (see Molecular Genetics and Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

  • Single-gene testing. Gene-targeted duplication/deletion analysis of LMNB1 should be performed in individuals with classic clinical and neuroimaging features of ADLD.
  • A multi-gene panel that includes LMNB1 and other genes of interest (see Differential Diagnosis) may also be considered.
    Note: (1) Attention should be given to whether the panel includes duplication/deletion analysis, as sequence variants of LMNB1 are not known to be associated with ADLD. (2) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time.
  • More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes LMNB1) fails to confirm a diagnosis in an individual with features of ADLD. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Autosomal Dominant Leukodystrophy with Autonomic Disease (ADLD)

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
LMNB1Gene-targeted deletion/duplication analysis 3, 4
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

4.

To include analysis upstream of the LMNB1 promoter (see Molecular Genetics)

5.
6.

Clinical Characteristics

Clinical Description

Autosomal dominant leukodystrophy with autonomic disease (ADLD) is a slowly progressive neurologic disorder of central nervous system white matter. Adults show autonomic dysfunction, the first evidence of the disorder, in the fourth to fifth decade of life, followed by pyramidal and cerebellar abnormalities resulting in spasticity, ataxia, and tremor [Finnsson et al 2015].

Specific clinical features, as described in more than 70 affected individuals with a molecularly confirmed diagnosis, include the following:

Autonomic dysfunction, a nearly constant feature [Padiath & Fu 2010], includes bladder dysfunction, constipation, postural hypotension, erectile dysfunction, and less often impaired sweating. Symptoms of autonomic dysfunction may be the initial disease presentation and can precede the motor and cerebellar manifestations by months to years.

  • Neurogenic bladder is commonly complicated by urinary urgency and/or incomplete bladder emptying, which is often complicated by urinary tract infection.
  • Orthostatic hypotension can be asymptomatic or symptomatic (frequent fainting results in significant functional disability) [Finnsson et al 2015].
  • Although less commonly reported, anhidrosis can lead to body temperature dysregulation (mainly hypothermia), which can be severe and even fatal. Infection may exacerbate temperature instability; for example, body temperature decreased to 29.5° C in one individual with a urinary tract infection [Meijer et al 2008, Finnsson et al 2015].
  • It has been hypothesized that spinal cord white matter involvement [Finnsson et al 2015] and isolated noradrenergic failure [Guaraldi et al 2011] result in the autonomic dysfunction seen in this disorder.

Pyramidal signs and symptoms usually develop after manifestations of autonomic dysfunction; however, gait difficulties have been reported as the first manifestations [Finnsson et al 2015]. Pyramidal manifestations include signs of upper motor neuron dysfunction, often more prominent in the lower extremities (e.g., spastic weakness, hypertonia, clonus, brisk deep tendon reflexes, and bilateral Babinski signs). Spasticity can cause muscle pain and joint contractures. Over time, pyramidal dysfunction extends to the upper extremities.

Cerebellar signs that typically appear at the same time as the pyramidal signs include gait ataxia, dysdiadochokinesia, intention tremor, dysmetria, and nystagmus. Upper extremity postural tremor accompanied by neck tremor (resulting in head titubation) or jaw tremor (affecting speech and chewing) can also be seen [Schwankhaus et al 1988].

Cognitive function is usually preserved or mildly impaired early in the disease course; however, dementia and psychiatric manifestations can occur as late manifestations [Dos Santos et al 2012, Finnsson et al 2015].

Additional features include:

  • Pseudobulbar palsy with dysarthria, dysphagia, and forced crying and laughing [Quattrocolo et al 1997], which can affect feeding and lead to aspiration pneumonia and/or malnutrition;
  • Loss of position and vibration sensation attributed to extensive involvement of the spinal cord;
  • In rare cases, sensorineural hearing loss [Schwankhaus et al 1994].

Affected individuals may survive for decades after onset of symptoms. Motor manifestations are usually slowly progressive without acute exacerbations; however, some affected individuals report reversible worsening of cognitive function and gait with fever [Finnsson et al 2015].

Neurophysiologic studies are largely non-contributory.

  • Electromyograms (EMG), visual evoked potentials (VEP), and nerve conduction studies (NCS) are normal [Padiath & Fu 2010].
  • Brain stem auditory evoked potential (BAEP) and somatosensory evoked potentials (SEP) demonstrate nonspecific conductive delays [Schwankhaus et al 1994].
  • Electroencephalograms (EEG) are normal or show diffuse slowing of electrical activity with no epileptic discharges [Schwankhaus et al 1994].

Laboratory findings

  • CSF analysis is usually normal with no oligoclonal bands; rarely, however, slight increases in protein and Immunoglobulin levels are observed [Schwankhaus et al 1994].
  • Orthostatic hypotension has prompted measurements of catecholamines. Blood norepinephrine levels are in the low normal range and drop further when individuals with ADLD stand. In 24-hour urine samples excretion of epinephrine was low [Eldridge et al 1984].
  • Peripheral nerve biopsy is normal.

Genotype-Phenotype Correlations

Genotype-phenotype correlations are not observed.

Penetrance

The disease presents in the fourth to fifth decades of adulthood with no gender variation. Penetrance is not known but is thought to be 100%.

Nomenclature

ADLD was originally referred to as “autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis” or “adult-onset leukodystrophy simulating chronic progressive multiple sclerosis” [Eldridge et al 1984, Schwankhaus et al 1994].

Prevalence

The exact prevalence of autosomal dominant leukodystrophy with autonomic disease (ADLD) is unknown. Published cases include 24 families with more than 70 affected individuals; it is likely that many more unpublished families have now been identified.

Families of different origins have been reported:

Differential Diagnosis

See Leukodystrophy Overview.

The differential diagnosis of autosomal dominant leukodystrophy with autonomic disease (ADLD) includes other leukodystrophies with adult onset as well as acquired demyelinating disorders such as multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory disease that affects central nervous system white matter. The age of presentation, combination of motor, cerebellar, and autonomic manifestations make this disorder in some instances similar to ADLD [Eldridge et al 1984]. Unlike the brain MRI in ADLD, the brain MRI in MS is characterized by multifocal lesions mainly around the periventricular area, brain stem, cerebellum, and spinal cord [Noseworthy et al 2000]. CSF contains high IgG and oligoclonal bands [Poser et al 1983]. Available data suggest that multiple sclerosis is inherited as a complex multifactorial disorder that results from the interaction of genetic and environmental factors.

Vitamin B12 deficiency. While the first manifestation of vitamin B12 deficiency is typically megaloblastic anemia, on occasion the first manifestations can be the neurologic findings of subacute combined degeneration involving the spinal cord (myelopathy, loss of position and vibration sensation, bladder incontinence, and gait ataxia), peripheral nerves, and brain (neuropsychiatric disturbance). These neurologic findings can be confused with those of ADLD. In vitamin B12 deficiency, MRI changes include hyperintense T2-weighted changes in the spinal cord.

Because untreated vitamin B12 deficiency is associated with progressive neurologic deterioration and because early detection and treatment can improve the long-term outcome, it is important that vitamin B12 deficiency be considered in the differential diagnosis of ADLD [Rabhi et al 2011, Devalia et al 2014, Issac et al 2015].

Spinocerebellar ataxias types 2 and 3 (SCA2 and SCA3) are slowly progressive, adult-onset, autosomal dominant ataxias caused by CAG trinucleotide repeat expansions in ATXN2 and ATXN3, respectively. Manifestations of SCA2 and SCA3 that overlap with those of ADLD include cerebellar gait ataxia, autonomic disturbances, pyramidal involvement, and dysarthria; manifestations that do not overlap with ADLD include nystagmus, peripheral neuropathy, abnormal movements, and seizures. Unlike ADLD, no specific radiologic changes are observed in the SCAs. See also Hereditary Ataxia Overview.

Alexander disease is an autosomal dominant leukodystrophy that predominantly affects infants and children and is caused by mutation of GFAP. The adult form of Alexander disease (accounting for ~33% of cases) is associated with range of clinical manifestations that overlap with ADLD: bulbar/pseudobulbar signs, pyramidal signs, cerebellar signs, gait disturbance, sleep disturbance, and dysautonomia. Brain MRI in Alexander disease usually shows white matter signal changes in the frontal lobe, periventricular area, basal ganglia, thalami, and brain stem with contrast enhancement, changes that are quite different from those of ADLD.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an autosomal dominant adult-onset leukodystrophy caused by mutation of CSF1R. Frontal lobe syndrome and personality changes (which are not typical for ADLD) usually appear early in the ALSP disease course. Affected individuals subsequently develop motor impairment and gait dysfunction. Brain MRI changes include asymmetric bifrontal T2-weighted signal changes in the deep subcortical periventricular areas with cerebral atrophy and minimal involvement of the cerebellum and brain stem.

Adult polyglucosan body disease is an adult-onset autosomal recessive leukodystrophy caused by mutation of GBE1. Disease manifestations include neurogenic bladder, gait difficulties, muscle spasticity and weakness, and distal sensory loss mainly in the lower extremities. Cognitive function is mildly affected. Brain MRI signal changes occur in periventricular, subcortical, and deep white matter with brain and spinal cord atrophy. Nerve biopsy shows the characteristics intraneural polyglucosan bodies.

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is an autosomal recessive leukodystrophy caused by mutation of DARS2. LBSL usually presents in childhood or adolescence but may present in adulthood. The disease is characterized by progressive spasticity, cerebellar ataxia, and dorsal column abnormalities. Dysarthria develops over time. Occasional findings include: epilepsy; learning problems; cognitive decline; and reduced consciousness, neurologic deterioration, and fever following minor head trauma. MRI changes include non-homogeneous signal changes in the cerebral white matter, lateral corticospinal tracts, and dorsal columns in the spinal cord and pyramids including the medulla oblongata. Lactate is elevated in cerebral white matter.

Childhood ataxia with central nervous system hypomyelination/vanishing white matter is an autosomal recessive leukodystrophy caused by mutation of one of the five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5), encoding the eukaryotic translation initiation factor 2B (eIF2B). Adult-onset cases have been reported. Clinical presentation includes mild alteration of intellectual ability and behavioral changes as well as progressive neurologic features such as ataxia, spasticity, and brisk deep tendon reflexes. Optic atrophy and amenorrhea have also been reported. MRI changes include diffuse cerebral white matter signal changes isointense with CSF on T2-weighted images.

Krabbe disease and arylsulfatase A deficiency (metachromatic leukodystrophy). These autosomal recessive lysosomal storage disorders (caused by mutation of GALC and ARSA, respectively) in which onset is typically infantile may also manifest initially in adults with nonspecific clinical features.

In adult-onset Krabbe disease [Farina et al 2000, Wang et al 2007, Abdelhalim et al 2014, Ahmed et al 2014, van Rappard et al 2015]:

  • MRI signal changes are sometimes confined to the corticospinal tracts, similar to the findings in asymptomatic individuals with ADLD.
  • Characteristic MRI findings are discrete T2-weighted hyperintensities along the corticospinal tracts, in contrast to the more widespread changes in symptomatic individuals with ADLD.
  • When MRI findings are more extensive the T2-weighted hyperintensities tend to have a more posterior distribution than those seen in ADLD.

In adult-onset metachromatic leukodystrophy MRI T2-weighted hyperintensities have a predominantly frontal, periventricular distribution.

X-linked adrenoleukodystrophy, caused by mutation of ABCD1, can have several phenotypes. The adrenomyeloneuropathy (AMN) phenotype demonstrates overlapping clinical features with ADLD: gait disturbance, sphincter control abnormalities, and sexual dysfunction can be seen in affected males. Approximately 20% of females who are heterozygous for a pathogenic variant in ABCD1 develop neurologic manifestations that resemble AMN but have later onset (age ≥35 years) and milder disease than do affected males. Clinical or radiologic brain involvement can be seen in 40%-45% of affected individuals.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with autosomal dominant leukodystrophy with autonomic disease (ADLD), the following evaluations are recommended:

  • Evaluation by a neurologist for evidence of autonomic dysfunction (e.g., orthostatic hypotension), abnormal tone, and/or tremor
  • Psychological evaluation and neuropsychological assessment
  • Assessment by rehabilitation specialists including equipment needs
  • Evaluation of swallowing function and communication
  • Gastroenterology evaluation for bowel dysfunction
  • Urologic evaluation for urinary dysfunction, recurrent urinary tract infection, and erectile dysfunction
  • Audiologic assessment
  • Consultation with clinical geneticist and/or genetic counselor

Treatment of Manifestations

Primary treatment is not possible, but management of symptoms can improve the comfort and care of individuals with this disorder [Van Haren et al 2015].

Autonomic dysfunction

  • Neurogenic bladder:
    • Recurrent urinary tract infections should be addressed with attention to bladder regimens for managing neurogenic bladders and in rare case antibiotic prophylaxis.
    • Urinary urgency may require spasmolytics (e.g., solifenacine succinate).
  • Constipation can be managed by good hydration and dietary fiber, although sometimes stool softeners (e.g., docusate) or a laxative is needed.
  • Hypotensive events can be minimized by pharmacologic treatment (mineralocorticoids such as fludrocortisone or vasopressors such as hydrochloride), compressive stockings, physical therapy (to help with rising from supine positions), and increased salt in the diet.
  • Feeding difficulties can be managed with speech therapy and appropriate feeding interventions to assure adequate nutrition while preventing aspiration pneumonia.
  • Sexual dysfunction can be alleviated with sildenafil.
  • Anhidrosis is managed by avoiding overheating.
  • Intensive management of infections should include adequate antipyretic treatment, as symptoms may worsen significantly with fever.

Spasticity. Medications that can help reduce muscle tone include oral baclofen or diazepam (GABA agonists) and injectable botulinum toxin for focal muscle spasticity. A good physical therapy regimen can be beneficial in improving joint mobility and function.

Ataxia. Although ataxia is difficult to treat, frequent falls can be managed with strategies to minimize falls and increase strength and adaptive equipment such as walkers or wheelchairs.

Cognitive dysfunction can affect social interactions and financial management. A social worker and financial planner can help anticipate issues of guardianship that may accompany progressive decline.

Family and patient support/advocacy groups can help address psychosocial consequences.

Prevention of Secondary Complications

The following are appropriate:

  • Physiotherapy and orthopedic follow-up to address bone health including Vitamin D and calcium supplementations and management of spasticity to prevent joint contractures and dislocation
  • Attention to pulmonary care, including the use of measures to address chronic lung disease from recurrent aspiration events
  • Yearly influenza immunizations

Agents/Circumstances to Avoid

Because disease manifestations may be exacerbated with fever and infection, care should be taken to avoid whenever possible exposure to those with infections.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Autosomal dominant leukodystrophy with autonomic disease (ADLD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • To date all individuals diagnosed with ADLD have inherited a large LMNB1 duplication (or large deletion upstream of LMNB) from an affected parent (see Molecular Genetics).
  • To date a de novo ADLD-related LMNB1 pathogenic variant has not been reported in a proband; however, it should be noted that not all affected individuals have parents available for testing.
  • The family history of some individuals diagnosed with ADLD may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband has an ADLD-related LMNB1 pathogenic variant, the risk to the sibs is 50%; clinical severity may vary within families.

Offspring of a proband. Each child of an individual with ADLD has a 50% chance of inheriting the ADLD-related LMNB1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

MRI findings suggestive of leukodystrophy may be seen many years before clinical manifestation of disease. This should perhaps be communicated to relatives at risk, as many persons may undergo MRI of the brain and spinal cord for a variety of unrelated reasons.

Molecular genetic testing of at-risk asymptomatic adult relatives of individuals with ADLD is possible once the ADLD-related LMNB1 pathogenic variant has been identified in an affected family member. Such testing should be performed in the context of formal genetic counseling. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing.

Molecular genetic testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of ADLD.

For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations can be explored; these include alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the ADLD-related LMNB1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for ADLD are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • European Leukodystrophy Association (ELA)
    2, rue Mi-les-Vignes
    B.P. 61024
    Laxou Cedex 54521
    France
    Phone: 03833093 34
    Fax: 03833000 68
    Email: ela@ela-asso.com
  • Leukodystrophy Australia
    P O Box 2550
    Mount Waverley Victoria 3149
    Australia
    Phone: 1800-141-400 (toll free)
    Email: info@leuko.org.au
  • United Leukodystrophy Foundation (ULF)
    224 North Second Street
    Suite 2
    DeKalb IL 60115
    Phone: 800-728-5483 (toll-free); 815-748-3211
    Fax: 815-748-0844
    Email: office@ulf.org
  • Myelin Disorders Bioregistry Project
    Email: myelindisorders@cnmc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Autosomal Dominant Leukodystrophy with Autonomic Disease: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
LMNB15q23​.2Lamin-B1Human Intermediate Filament Database LMNB1
LMNB1 database
LMNB1LMNB1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Autosomal Dominant Leukodystrophy with Autonomic Disease (View All in OMIM)

150340LAMIN B1; LMNB1
169500LEUKODYSTROPHY, DEMYELINATING, ADULT-ONSET, AUTOSOMAL DOMINANT; ADLD

Gene structure. LMNB1 (NM_005573.3) contains 11 exons and ten introns. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Giorgio et al [2013] evaluated 31 individuals with ADLD from 20 different families ascertained worldwide and determined that:

  • The duplicated region associated with ADLD ranged between ~128 kb (the smallest) and ~475 kb (the largest). Of note, the 475-kb duplication was in an inverted orientation and accompanied by a ~500-bp deletion;
  • The minimal duplication needed for ADLD development was ~72 kb extending from 9.8 kb upstream of LMNB1 to 1.8 kb downstream of LMNB1;
  • Three families had an LMNB1 pathogenic triplication;
  • Replication-based mechanisms may be responsible for the disease-causing LMNB1 duplications and genomic rearrangements.

In one family with typical manifestations of ADLD (except for later-onset autonomic findings [Bergui et al 1997]) but without an LMNB1 duplication [Brussino et al 2010], Giorgio et al [2015] identified a 660-kb deletion located 66 kb upstream of LMNB1 that also involved three additional genes (GRAMD3, ALDH7A1, and PHAX). Although GRAMD3, ALDH7A1, and PHAX are known to be involved in some diseases, their role in ADLD pathogenesis is not clear. One possible explanation is that the deletion results in LMNB1 overexpression by an enhancer adoption mechanism. Of note, an experimentally induced simultaneous single-copy loss did not affect lamin B1 expression.

Normal gene product. LMNB1 encodes lamin-B1, a member of the intermediate filament family of structural proteins and an integral component of the nuclear lamina. It not only provides structural integrity to the nucleus but also plays a role in essential cellular processes such as transcription, DNA replication, DNA repair, and epigenetic regulation [Butin-Israeli et al 2012, Stancheva & Schirmer 2014]. Lamin-B1 is widely expressed in various cell types and shows high levels of expression in the brain [Jung et al 2013].

The first LMNB1 exon encodes the amino terminal head domain of lamin-B1 and the beginning of the central red domain; the middle five exons encode the central red domain; and the last exons encode the carboxy terminal domain. The transcriptional unit contains 43-45 kbp and encodes 586 amino acids [Lin & Worman 1995, Maeno et al 1995, Wydner et al 1996].

Abnormal gene product. The pathology in ADLD is thought to be due to increased levels of lamin-B1 and, as such, there is no abnormal gene product, just an overexpression of the wild type protein.

In individuals with ADLD:

Overexpression of lamin-B1 was found to have deleterious effects in model organisms.

  • In a fruit fly model, over-expression of lamin-B1 resulted in lethality and a degenerative phenotype [Padiath et al 2006].
  • In an ADLD mouse model, targeted over-expression of lamin-B1 in oligodendrocytes, but not in neurons or astrocytes, resulted in demyelination and an age-dependent motor dysfunction reminiscent of the human disease [Heng et al 2013].
  • In an independently derived oligodendrocyte-specific lamin-B1 overexpressing mouse model, vacuolar demyelination of the spinal cord linked to an age-dependent reduction in lipid synthesis was responsible for the degenerative phenotype [Rolyan et al 2015].

References

Literature Cited

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  • Ahmed RM, Murphy E, Davagnanam I, Parton M, Schott JM, Mummery CJ, Rohrer JD, Lachmann RH, Houlden H, Fox NC, Chataway J. A practical approach to diagnosing adult onset leukodystrophies. J Neurol Neurosurg Psychiatry. 2014;85:770–81. [PubMed: 24357685]
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Chapter Notes

Author Notes

Quasar Padiath
ADLD – University of Pittsburgh Study
Email: ude.ttip@htaidapq

The major focus of the Padiath lab is to understand the molecular mechanisms underlying various neurologic diseases with an emphasis on disorders of myelin that are known as leukodystrophies. This work involves the use of clinical-based family studies to identify disease-related genes and the development of animal and cell culture models to elucidate disease mechanisms. As part of his post-doctoral research, Dr Padiath identified lamin B1 duplications as the cause of ADLD and understanding the molecular mechanisms of this disease remains an important area of research in his lab at the University of Pittsburgh.

Revision History

  • 7 January 2016 (me) Review posted live
  • 27 August 2015 (nn) Original submission
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