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Disease Profile

Autosomal dominant leukodystrophy with autonomic disease

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Adult

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ICD-10

E75.2

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Adult-onset autosomal dominant demyelinating leukodystrophy; Pelizaeus-Merzbacher disease, autosomal dominant or late-onset type; Leukodystrophy, demyelinating, adult-onset, autosomal dominant;

Categories

Congenital and Genetic Diseases; Eye diseases; Nervous System Diseases

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 99027

Definition
A rare, slowly progressive neurological disorder involving centralnervous systemdemyelination, leading to autonomic dysfunction, ataxia and mild cognitive impairment.

Epidemiology
More than 20 families in different ethnic groups have been reported to date. Exact prevalence and incidence data are however lacking.

Clinical description
Unlike mostforms of leukodystrophy which appear in childhood, ADLD occurs in the 4th to 6th decade of life. ADLD may clinically resemble multiple sclerosis in the initial phase. In most patients, the initial manifestation of the disease is autonomic dysfunction resulting in micturitionurgency, bladder retention, constipation, postural hypotensionanderectile dysfunction in affected males. Decreased sweating is reported in some cases. Some patients develop autonomic dysfunction later in the disease course. The other features are cerebellardysfunction (gait ataxia, nystagmus, dysmetria, loss of fine motor control, and action tremors), pyramidal signs (spasticity, weakness of both upper and lower extremities, hyperreflexia), and cognitive impairment possibly with personality changes. These manifestations may not develop for years following initial presentation. Neuroradiologicalcharacteristics include extensive symmetrical white matter changes, corpus callosum atrophy, and brain stem and spinal cord atrophy. The disease follows a slow progressive course with an eventual loss of walking ability and slightly shortened lifespan.

Etiology
ADLD is caused by chromosomal rearrangements with duplications of the LMNB1 gene (5q23.2) or a ''position effect'' due to a genomic deletion upstream of the gene causing its upregulation. Overexpression of LMNB1 causes myelin disruptionin the central nervous system for which the precise underlying pathogenic mechanisms have not been elucidated. Alteration of splicing patterns suggests that ADLD is a spliceopathy.

Genetic counseling
Genetic counseling should be provided to affected families indicating the autosomal dominant pattern of inheritance.

Visit the Orphanet disease page for more resources.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Ataxia
0001251
30%-79% of people have these symptoms
Abnormal pyramidal sign
0007256
Constipation
0002019
Dilatation of the bladder
0010955
Gait disturbance
Abnormal gait
Abnormal walk
Impaired gait

[ more ]

0001288
Hyperreflexia
Increased reflexes
0001347
Hypotension
Low blood pressure
0002615
Impotence
Difficulty getting a full erection
Difficulty getting an erection

[ more ]

0000802
Nystagmus
Involuntary, rapid, rhythmic eye movements
0000639
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
Tetraparesis
0002273
Tremor
0001337
Urinary urgency
Overactive bladder
0000012
5%-29% of people have these symptoms
Atrophy of the spinal cord
Degeneration of the spinal cord
0006827
Cerebral cortical atrophy
Decrease in size of the outer layer of the brain due to loss of brain cells
0002120
Corpus callosum atrophy
0007371
Dysarthria
Difficulty articulating speech
0001260
Dysphagia
Poor swallowing
Swallowing difficulties
Swallowing difficulty

[ more ]

0002015
Global developmental delay
0001263
Hearing impairment
Deafness
Hearing defect

[ more ]

0000365
Hypohidrosis
Decreased ability to sweat
Decreased sweating
Sweating, decreased

[ more ]

0000966
Intellectual disability, mild
Mental retardation, borderline-mild
Mild and nonprogressive mental retardation
Mild mental retardation

[ more ]

0001256
Visual loss
Loss of vision
Vision loss

[ more ]

0000572
Percent of people who have these symptoms is not available through HPO
Abnormal cerebellum morphology
Abnormality of the cerebellum
Cerebellar abnormalities
Cerebellar abnormality
Cerebellar anomaly

[ more ]

0001317
Abnormality of the urinary system
Urinary tract abnormalities
Urinary tract abnormality
Urinary tract anomalies

[ more ]

0000079
Adult onset
Symptoms begin in adulthood
0003581
Autonomic bladder dysfunction
0005341
Autonomic erectile dysfunction
0008652
Autosomal dominant inheritance
0000006
Babinski sign
0003487
Decreased sweating due to autonomic dysfunction
0007480
Depressivity
Depression
0000716
Diffuse leukoencephalopathy
0006994
Gliosis
0002171
Leukodystrophy
0002415
Orthostatic hypotension due to autonomic dysfunction
0004926
Personality changes
Personality change
0000751
Progressive
Worsens with time
0003676
Progressive neurologic deterioration
Worsening neurological symptoms
0002344
Pseudobulbar paralysis
0007024
Symmetric peripheral demyelination
0007262

Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Providing General Support

      Learn more

      These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

      Where to Start

      • Genetics Home Reference (GHR) contains information on Autosomal dominant leukodystrophy with autonomic disease. This website is maintained by the National Library of Medicine.

        In-Depth Information

        • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
        • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
        • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
        • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
        • PubMed is a searchable database of medical literature and lists journal articles that discuss Autosomal dominant leukodystrophy with autonomic disease. Click on the link to view a sample search on this topic.