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Adult-onset autosomal dominant demyelinating leukodystrophy(ADLD)

MedGen UID:
356995
Concept ID:
C1868512
Disease or Syndrome
Synonyms: Autosomal Dominant Leukodystrophy with Autonomic Disease; Leukodystrophy, adult-onset, autosomal dominant; Multiple sclerosis-like disorder; Pelizaeus-Merzbacher disease, autosomal dominant or late-onset type; Pelizaeus-Merzbacher disease, late-onset type
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): LMNB1 (5q23.2)
 
Monarch Initiative: MONDO:0008215
OMIM®: 169500
Orphanet: ORPHA99027

Disease characteristics

LMNB1-related autosomal dominant leukodystrophy (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 by pyramidal and cerebellar abnormalities resulting in spasticity, ataxia, and tremor. Autonomic dysfunction can include bladder dysfunction, constipation, postural hypotension, erectile dysfunction, and (less often) impaired sweating. Pyramidal signs are often more prominent in the lower extremities (e.g., 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 include gait ataxia, dysdiadochokinesia, intention tremor, dysmetria, and nystagmus. Many individuals have sensory deficits starting in the lower limbs. Pseudobulbar palsy with dysarthria, dysphagia, and forced crying and laughing may appear in the seventh or eighth decade. 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. [from GeneReviews]
Authors:
Raili Raininko  |  Michael Gosky  |  Quasar S Padiath   view full author information

Additional descriptions

From OMIM
Autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) is a slowly progressive and fatal disorder that presents in the fourth or fifth decade of life and is characterized clinically by early autonomic abnormalities, pyramidal and cerebellar dysfunction, and symmetric demyelination of the CNS. ADLD differs from multiple sclerosis and other demyelinating disorders in that neuropathology shows preservation of oligodendroglia in the presence of subtotal demyelination and lack of astrogliosis (summary by Padiath et al., 2006). Characteristic MRI findings include T2-weighted hyperintense changes in the upper corticospinal tract and cerebellar peduncles, with later development of confluent white matter changes in the frontoparietal area with relative sparing of the periventricular white matter (summary by Schuster et al., 2011).  http://www.omim.org/entry/169500
From MedlinePlus Genetics
Autosomal dominant leukodystrophy with autonomic disease (ADLD) is one of a group of genetic disorders called leukodystrophies. Leukodystrophies are characterized by abnormalities of the nervous system's white matter, which consists of nerve fibers covered by a fatty substance called myelin. Myelin insulates and protects nerve fibers and promotes the rapid transmission of nerve impulses.

People with ADLD develop signs and symptoms of the condition in adulthood, typically in their forties or fifties. The first signs of the condition often involve problems with the autonomic nervous system, which controls involuntary body processes such as the regulation of blood pressure and body temperature. These problems include difficulty with bowel and bladder function, a sharp drop in blood pressure upon standing (orthostatic hypotension), and erectile dysfunction in men. Rarely, people experience an inability to sweat (anhidrosis), which can lead to a dangerously high body temperature.

In ADLD, movement difficulties often develop after the autonomic nervous system problems. Affected individuals can have muscle stiffness (spasticity) or weakness and involuntary rhythmic shaking, called intention tremor because it worsens during movement. People with ADLD often have difficulty coordinating movements (ataxia), including movements that involve judging distance or scale (dysmetria), such as picking up a distant object, and rapidly alternating movements (dysdiadochokinesis), including hand clapping or foot stomping. These movement problems usually first affect the legs, but as the condition worsens, the arms and eventually the face become involved. In some people with ADLD, the symptoms worsen during episodes of fever, infection, or exposure to heat. Due to difficulty walking and an unsteady gait, many affected individuals need a cane, walker, or wheelchair for assistance.

Intelligence is usually unaffected; however, people who have had ADLD for a long time may have a decline in intellectual function (dementia). ADLD worsens slowly, and affected individuals usually survive 10 to 20 years after the onset of symptoms.  https://medlineplus.gov/genetics/condition/autosomal-dominant-leukodystrophy-with-autonomic-disease

Clinical features

From HPO
Bowel incontinence
MedGen UID:
41977
Concept ID:
C0015732
Disease or Syndrome
Involuntary fecal soiling in adults and children who have usually already been toilet trained.
Autonomic erectile dysfunction
MedGen UID:
358232
Concept ID:
C1868524
Finding
Impotence (inability to develop or maintain an erection) resulting from abnormal functioning of the autonomic nervous system.
Impotence
MedGen UID:
1720680
Concept ID:
CN208474
Finding
Inability to develop or maintain an erection of the penis.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior.
Gliosis
MedGen UID:
4899
Concept ID:
C0017639
Pathologic Function
Gliosis is the focal proliferation of glial cells in the central nervous system.
Leukodystrophy
MedGen UID:
6070
Concept ID:
C0023520
Disease or Syndrome
Leukodystrophy refers to deterioration of white matter of the brain resulting from degeneration of myelin sheaths in the CNS. Their basic defect is directly related to the synthesis and maintenance of myelin membranes. Symmetric white matter involvement at MRI is a typical finding in patients with leukodystrophies.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Pseudobulbar paralysis
MedGen UID:
10989
Concept ID:
C0033790
Disease or Syndrome
Bilateral impairment of the function of the cranial nerves 9-12, which control musculature involved in eating, swallowing, and speech. Pseudobulbar paralysis is characterized clinically by dysarthria, dysphonia, and dysphagia with bifacial paralysis, and may be accompanied by Pseudobulbar behavioral symptoms such as enforced crying and laughing.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Personality changes
MedGen UID:
66817
Concept ID:
C0240735
Mental or Behavioral Dysfunction
An abnormal shift in patterns of thinking, acting, or feeling.
Corpus callosum atrophy
MedGen UID:
96560
Concept ID:
C0431370
Finding
The presence of atrophy (wasting) of the corpus callosum.
Progressive neurologic deterioration
MedGen UID:
381506
Concept ID:
C1854838
Finding
Abnormal cerebellum morphology
MedGen UID:
400925
Concept ID:
C1866129
Anatomical Abnormality
Any structural abnormality of the cerebellum.
Diffuse leukoencephalopathy
MedGen UID:
358229
Concept ID:
C1868514
Finding
Orthostatic hypotension due to autonomic dysfunction
MedGen UID:
358344
Concept ID:
C1868528
Finding
Symmetric peripheral demyelination
MedGen UID:
870468
Concept ID:
C4024914
Anatomical Abnormality
A symmetric loss of myelin from the internode regions along myelinated nerve fibers of the peripheral nervous system.
Autonomic bladder dysfunction
MedGen UID:
870755
Concept ID:
C4025212
Disease or Syndrome
Abnormal bladder function (increased urge or frequency of urination or urge incontinence) resulting from abnormal functioning of the autonomic nervous system.
Decreased sweating due to autonomic dysfunction
MedGen UID:
358343
Concept ID:
C1868527
Finding
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAdult-onset autosomal dominant demyelinating leukodystrophy

Professional guidelines

PubMed

Giorgio E, Lorenzati M, Rivetti di Val Cervo P, Brussino A, Cernigoj M, Della Sala E, Bartoletti Stella A, Ferrero M, Caiazzo M, Capellari S, Cortelli P, Conti L, Cattaneo E, Buffo A, Brusco A
Brain 2019 Jul 1;142(7):1905-1920. doi: 10.1093/brain/awz139. PMID: 31143934

Recent clinical studies

Etiology

Vaia Y, Mura E, Tonduti D
Mol Genet Metab 2023 Mar;138(3):107540. Epub 2023 Feb 10 doi: 10.1016/j.ymgme.2023.107540. PMID: 36804850
Sassi C, Nalls MA, Ridge PG, Gibbs JR, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, Bras J; ARUK Consortium, Blumenau S, Thielke M, Josties C, Freyer D, Dietrich A, Hammer M, Baier M, Dirnagl U, Morgan K, Powell JF, Kauwe JS, Cruchaga C, Goate AM, Singleton AB, Guerreiro R, Hodges A, Hardy J
Neurobiol Aging 2018 Jun;66:179.e17-179.e29. Epub 2018 Feb 2 doi: 10.1016/j.neurobiolaging.2018.01.015. PMID: 29544907Free PMC Article
Köhler W, Curiel J, Vanderver A
Nat Rev Neurol 2018 Feb;14(2):94-105. Epub 2018 Jan 5 doi: 10.1038/nrneurol.2017.175. PMID: 29302065Free PMC Article
Padiath QS
Nucleus 2016 Nov;7(6):547-553. doi: 10.1080/19491034.2016.1260799. PMID: 27854160Free PMC Article
Finnsson J, Sundblom J, Dahl N, Melberg A, Raininko R
Ann Neurol 2015 Sep;78(3):412-25. Epub 2015 Jul 27 doi: 10.1002/ana.24452. PMID: 26053668Free PMC Article

Diagnosis

Pasquetti D, Gazzellone A, Rossi S, Orteschi D, L'Erario FF, Concolino P, Minucci A, Dionisi-Vici C, Genuardi M, Silvestri G, Chiurazzi P
Int J Mol Sci 2023 Dec 29;25(1) doi: 10.3390/ijms25010495. PMID: 38203665Free PMC Article
Vaia Y, Mura E, Tonduti D
Mol Genet Metab 2023 Mar;138(3):107540. Epub 2023 Feb 10 doi: 10.1016/j.ymgme.2023.107540. PMID: 36804850
Chen S, Zou JL, He S, Li W, Zhang JW, Li SJ
Neurol Sci 2022 Aug;43(8):1-9. Epub 2022 Apr 14 doi: 10.1007/s10072-022-06057-0. PMID: 35419641
Sassi C, Nalls MA, Ridge PG, Gibbs JR, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, Bras J; ARUK Consortium, Blumenau S, Thielke M, Josties C, Freyer D, Dietrich A, Hammer M, Baier M, Dirnagl U, Morgan K, Powell JF, Kauwe JS, Cruchaga C, Goate AM, Singleton AB, Guerreiro R, Hodges A, Hardy J
Neurobiol Aging 2018 Jun;66:179.e17-179.e29. Epub 2018 Feb 2 doi: 10.1016/j.neurobiolaging.2018.01.015. PMID: 29544907Free PMC Article
Köhler W, Curiel J, Vanderver A
Nat Rev Neurol 2018 Feb;14(2):94-105. Epub 2018 Jan 5 doi: 10.1038/nrneurol.2017.175. PMID: 29302065Free PMC Article

Therapy

Ratti S, Rusciano I, Mongiorgi S, Neri I, Cappellini A, Cortelli P, Suh PG, McCubrey JA, Manzoli L, Cocco L, Ramazzotti G
Cells 2021 Sep 28;10(10) doi: 10.3390/cells10102566. PMID: 34685544Free PMC Article
Giorgio E, Lorenzati M, Rivetti di Val Cervo P, Brussino A, Cernigoj M, Della Sala E, Bartoletti Stella A, Ferrero M, Caiazzo M, Capellari S, Cortelli P, Conti L, Cattaneo E, Buffo A, Brusco A
Brain 2019 Jul 1;142(7):1905-1920. doi: 10.1093/brain/awz139. PMID: 31143934
Jaklin C, Heiliger K, Hempel M, Sollacher D, Cohen M, Makowski CC, Meitinger T, Jauch A, Oexle K
Eur J Med Genet 2012 Oct;55(10):568-72. Epub 2012 Jul 7 doi: 10.1016/j.ejmg.2012.06.010. PMID: 22776853
Keegan BM, Giannini C, Parisi JE, Lucchinetti CF, Boeve BF, Josephs KA
Neurology 2008 Mar 25;70(13 Pt 2):1128-33. Epub 2008 Feb 20 doi: 10.1212/01.wnl.0000304045.99153.8f. PMID: 18287567

Prognosis

Vaia Y, Mura E, Tonduti D
Mol Genet Metab 2023 Mar;138(3):107540. Epub 2023 Feb 10 doi: 10.1016/j.ymgme.2023.107540. PMID: 36804850
Köhler W, Curiel J, Vanderver A
Nat Rev Neurol 2018 Feb;14(2):94-105. Epub 2018 Jan 5 doi: 10.1038/nrneurol.2017.175. PMID: 29302065Free PMC Article
Adams SJ, Kirk A, Auer RN
J Clin Neurosci 2018 Feb;48:42-49. Epub 2017 Nov 6 doi: 10.1016/j.jocn.2017.10.060. PMID: 29122458
Finnsson J, Sundblom J, Dahl N, Melberg A, Raininko R
Ann Neurol 2015 Sep;78(3):412-25. Epub 2015 Jul 27 doi: 10.1002/ana.24452. PMID: 26053668Free PMC Article
Finnsson J, Melberg A, Raininko R
Neuroradiology 2013 Aug;55(8):933-939. Epub 2013 May 1 doi: 10.1007/s00234-013-1174-5. PMID: 23636437

Clinical prediction guides

Alturkustani M, Sharma M, Hammond R, Ang LC
J Neuropathol Exp Neurol 2013 Nov;72(11):1090-103. doi: 10.1097/NEN.0000000000000008. PMID: 24128683
Columbaro M, Mattioli E, Maraldi NM, Ortolani M, Gasparini L, D'Apice MR, Postorivo D, Nardone AM, Avnet S, Cortelli P, Liguori R, Lattanzi G
Biochim Biophys Acta 2013 Mar;1832(3):411-20. Epub 2012 Dec 20 doi: 10.1016/j.bbadis.2012.12.006. PMID: 23261988
Brussino A, Vaula G, Cagnoli C, Panza E, Seri M, Di Gregorio E, Scappaticci S, Camanini S, Daniele D, Bradac GB, Pinessi L, Cavalieri S, Grosso E, Migone N, Brusco A
Eur J Neurol 2010 Apr;17(4):541-9. Epub 2009 Dec 4 doi: 10.1111/j.1468-1331.2009.02844.x. PMID: 19961535
Itoh K, Shiga K, Shimizu K, Muranishi M, Nakagawa M, Fushiki S
Acta Neuropathol 2006 Jan;111(1):39-45. Epub 2005 Nov 23 doi: 10.1007/s00401-005-1113-6. PMID: 16328511
Coffeen CM, McKenna CE, Koeppen AH, Plaster NM, Maragakis N, Mihalopoulos J, Schwankhaus JD, Flanigan KM, Gregg RG, Ptácek LJ, Fu YH
Hum Mol Genet 2000 Mar 22;9(5):787-93. doi: 10.1093/hmg/9.5.787. PMID: 10749986

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