Autosomal Dominant Leukodystrophy With Autonomic Disease

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.

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). 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 multigene 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 multigene 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 are likely to change over time. (3) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype.
  For an intoduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here
• 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.

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:

• Irish-American [Eldridge et al 1984]
• Italian [Quattrocolo et al 1997, Brussino et al 2009]
• Swedish [Marklund et al 2006]
• French-Canadian [Meijer et al 2008]
• German [Dos Santos et al 2012]
• Israeli [Schuster et al 2011]
• Serbian [Potic et al 2013]
• Japanese [Padiath et al 2006]

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 in the US and EU Clinical Trials Register in Europe 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.