Andermann syndrome

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Andermann syndrome
Other namesKCC3 axonopathy, agenesis of corpus callosum with neuronopathy, Charlevoix disease
Autosomal recessive - en.svg
This condition is inherited in an autosomal recessive manner.
Specialty Medical genetics, neurology   OOjs UI icon edit-ltr-progressive.svg

Andermann syndrome, also known as agenesis of corpus callosum with neuronopathy (ACCPN), Charlevoix disease and KCC3 axonopathy among other names, [1] is a very rare neurodegenerative genetic disorder that damages the nerves used to control muscles and related to sensation and is often associated with agenesis of the corpus callosum. [1] [2] [3] [4] [5]

Contents

It was first described in 1972 by Frederick and Eva Andermann et al. [3] [6] [7]

Symptoms and signs

Symptoms and signs involve both the central and peripheral nervous systems starting in infancy: [2] [4]

Genetics

The inheritance pattern is autosomal recessive [4] and involves nonsense [8] and missense [9] mutations of the SLC12A6 gene which codes for an axonal cell membrane protein of the same name, that functions as a co-transporter of potassium ions and chloride ions. The normal presence of these channels [10] in axons of both the central nervous system [11] and peripheral nervous system accounts for the symptoms and signs arising from brain [12] and nerves. [13]

The disease has been modelled in transgenic mice. [14] Dogs show a different phenotype from humans, with predominantly spinocerebellar ataxia. [15]

Neuropathology

Autopsy examination of eight cases has shown both developmental and degenerative neuropathologic features in this disease, consistent with clinical duality as both a neurodevelopmental and neurodegenerative disorder. [16]

In the central nervous system, accompanying the hypotonia at birth is hypoplasia of the corticospinal tracts. Another developmental feature is seen in the corpus callosum, which varies from absent to hypoplastic. The anterior commissure is almost always absent, but occasionally hypoplastic. A bundle of Probst can be found running anteroposterior rather than crossing the midline. The axonal damage due to the channel deficiency can cause a reactive axonal overgrowth leading to small, tumor-like growths, or tumorlets, called axonomas, or balls of aberrant axons attempting regrowth. [17] Damaged axons can also show a sign of inhibition of axonal transport, forming axonal spheroids. These spheroids can occur throughout the cerebral hemispheres, explaining the psychotic symptoms by disconnection of the brain from itself by axonal functional disruption. [16]

In the peripheral nervous system (PNS), the disease is more severe. While most nervous system diseases affect either central nervous system (CNS) or PNS, this disease affects both, but the changes in the PNS lead to death. This occurs by axonal disease paralyzing the skeletal muscles, including the respiratory muscles, as a result of axonal damage in peripheral nerves. Changes in the axons are more severe in the PNS than CNS, and under the electron microscope, some axons look necrotic, by virtue of containing mitochondrial flocculent densities and other irreversible changes. [16] The lack of innervation of the body musculature during development gives rise to small body weights, often below 40 kg (88 lb), remarkable in view of the preserved brain weights. [16]

Diagnosis

A typical diagnostic workup includes: [18]

Treatment

Currently, no cure is known, but some symptoms may be treated, such as neuroleptics for the psychiatric problems. [5]

Prognosis

The prognosis is poor. Patients are usually wheelchair bound by their 20s and die by their 30s. [4] [5]

Prevalence

The prevalence rate has been estimated to be less than one per 1,000,000 worldwide, [4] and is much more common in the French-Canadian population of the Saguenay and Lac-St-Jean regions of Quebec, Canada, where it has a frequency of about one in 2100 in live births, and a carrier rate of one in 23. [5] This genetic disease, along with the SLC12A6 mutation, has also been described in Turkey, [19] Algeria, [20] Tanzania, [21] Bulgaria [22] and Norway. [23]

Related Research Articles

<span class="mw-page-title-main">Axon</span> Long projection on a neuron that conducts signals to other neurons

An axon or nerve fiber is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action potentials away from the nerve cell body. The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons, such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body and from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction can be the cause of many inherited and acquired neurological disorders that affect both the peripheral and central neurons. Nerve fibers are classed into three types – group A nerve fibers, group B nerve fibers, and group C nerve fibers. Groups A and B are myelinated, and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only the sensory fibers as Type I, Type II, Type III, and Type IV.

<span class="mw-page-title-main">Myelin</span> Fatty substance that surrounds nerve cell axons to insulate them and increase transmission speed

Myelin is a lipid-rich material that surrounds nerve cell axons to insulate them and increase the rate at which electrical impulses pass along the axon. The myelinated axon can be likened to an electrical wire with insulating material (myelin) around it. However, unlike the plastic covering on an electrical wire, myelin does not form a single long sheath over the entire length of the axon. Rather, myelin ensheaths the axon segmentally: in general, each axon is encased in multiple long sheaths with short gaps between, called nodes of Ranvier. At the nodes of Ranvier, which are approximately one thousandth of a mm in length, the axon's membrane is bare of myelin.

<span class="mw-page-title-main">Schwann cell</span> Glial cell type

Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle. The two types of Schwann cells are myelinating and nonmyelinating. Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. The Schwann cell promoter is present in the downstream region of the human dystrophin gene that gives shortened transcript that are again synthesized in a tissue-specific manner.

<span class="mw-page-title-main">Corpus callosum</span> White matter tract connecting the two cerebral hemispheres

The corpus callosum, also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental mammals. It spans part of the longitudinal fissure, connecting the left and right cerebral hemispheres, enabling communication between them. It is the largest white matter structure in the human brain, about 10 in (250 mm) in length and consisting of 200–300 million axonal projections.

<span class="mw-page-title-main">Somatic nervous system</span> Part of the peripheral nervous system

The somatic nervous system (SNS) is made up of nerves that link the brain and spinal cord to voluntary or skeletal muscles that are under conscious control as well as to skin sensory receptors. Specialized nerve fiber ends called sensory receptors are responsible for detecting information within and outside of the body.

<span class="mw-page-title-main">Polyneuropathy</span> Medical condition

Polyneuropathy is damage or disease affecting peripheral nerves in roughly the same areas on both sides of the body, featuring weakness, numbness, and burning pain. It usually begins in the hands and feet and may progress to the arms and legs and sometimes to other parts of the body where it may affect the autonomic nervous system. It may be acute or chronic. A number of different disorders may cause polyneuropathy, including diabetes and some types of Guillain–Barré syndrome.

<span class="mw-page-title-main">MASA syndrome</span> Medical condition

MASA syndrome is a rare X-linked recessive neurological disorder on the L1 disorder spectrum belonging in the group of hereditary spastic paraplegias a paraplegia known to increase stiffness spasticity in the lower limbs. This syndrome also has two other names, CRASH syndrome and Gareis-Mason syndrome.

Agenesis of the corpus callosum (ACC) is a rare birth defect in which there is a complete or partial absence of the corpus callosum. It occurs when the development of the corpus callosum, the band of white matter connecting the two hemispheres in the brain, in the embryo is disrupted. The result of this is that the fibers that would otherwise form the corpus callosum are instead longitudinally oriented along the ipsilateral ventricular wall and form structures called Probst bundles.

<span class="mw-page-title-main">Giant axonal neuropathy</span> Medical condition

Giant axonal neuropathy is a rare, autosomal recessive neurological disorder that causes disorganization of neurofilaments. Neurofilaments form a structural framework that helps to define the shape and size of neurons and are essential for normal nerve function. A distinguishing feature is its association with kinky, or curly, hair; in such cases it has been called Giant axonal neuropathy with curly hair.

<span class="mw-page-title-main">Chronic inflammatory demyelinating polyneuropathy</span> Medical condition

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired autoimmune disease of the peripheral nervous system characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder is sometimes called chronic relapsing polyneuropathy (CRP) or chronic inflammatory demyelinating polyradiculoneuropathy. CIDP is closely related to Guillain–Barré syndrome and it is considered the chronic counterpart of that acute disease. Its symptoms are also similar to progressive inflammatory neuropathy. It is one of several types of neuropathy.

<span class="mw-page-title-main">Frederick Andermann</span> Canadian neurologist and epileptologist (1930–2019)

Frederick Andermann was a Canadian neurologist and epileptologist.

In molecular biology, the electroneutral cation-Cl family of proteins are a family of solute carrier proteins. This family includes the products of the Human genes: SLC12A1, SLC12A1, SLC12A2, SLC12A3, SLC12A4, SLC12A5, SLC12A6, SLC12A7, SLC12A8 and SLC12A9.

<span class="mw-page-title-main">Myelin protein zero</span> Protein-coding gene in the species Homo sapiens

Myelin protein zero is a single membrane glycoprotein which in humans is encoded by the MPZ gene. P0 is a major structural component of the myelin sheath in the peripheral nervous system (PNS). Myelin protein zero is expressed by Schwann cells and accounts for over 50% of all proteins in the peripheral nervous system, making it the most common protein expressed in the PNS. Mutations in myelin protein zero can cause myelin deficiency and are associated with neuropathies like Charcot–Marie–Tooth disease and Dejerine–Sottas disease.

Antiganglioside antibodies that react to self-gangliosides are found in autoimmune neuropathies. These antibodies were first found to react with cerebellar cells. These antibodies show highest association with certain forms of Guillain–Barré syndrome.

<span class="mw-page-title-main">GJB1</span> Protein-coding gene in humans

Gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32), is a transmembrane protein that in humans is encoded by the GJB1 gene. Gap junction beta-1 protein is a member of the gap junction connexin family of proteins that regulates and controls the transfer of communication signals across cell membranes, primarily in the liver and peripheral nervous system. However, the protein is expressed in multiple organs, including in oligodendrocytes in the central nervous system.

<span class="mw-page-title-main">SLC12A6</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 12 member 6 is a protein that in humans is encoded by the SLC12A6 gene.

Hereditary sensory neuropathy, type II also known as HSN2 is a region of a parent protein which in humans is encoded by the WNK1 gene. It is a transcript variant of the WNK1 gene that is selectively expressed in nervous system tissues, and during development. Mutations in this exon of the WNK1 gene have been identified as causative in genetic neuropathy syndromes, and in inherited pain insensitivity.

Anti-MAG peripheral neuropathy is a specific type of peripheral neuropathy in which the person's own immune system attacks cells that are specific in maintaining a healthy nervous system. As these cells are destroyed by antibodies, the nerve cells in the surrounding region begin to lose function and create many problems in both sensory and motor function. Specifically, antibodies against myelin-associated glycoprotein (MAG) damage Schwann cells. While the disorder occurs in only 10% of those afflicted with peripheral neuropathy, people afflicted have symptoms such as muscle weakness, sensory problems, and other motor deficits usually starting in the form of a tremor of the hands or trouble walking. There are, however, multiple treatments that range from simple exercises in order to build strength to targeted drug treatments that have been shown to improve function in people with this type of peripheral neuropathy.

<span class="mw-page-title-main">Congenital mirror movement disorder</span> Medical condition

Congenital mirror movement disorder(CMM disorder) is a rare genetic neurological disorder which is characterized by mirrored movement, sometimes referred to as associated or synkinetic movement, most often in the upper extremity of the body. These movements are voluntary intentional movements on one, ipsilateral, side of the body that are mirrored simultaneously by involuntary movements on the contralateral side.

Proud syndrome is a very rare genetic disorder which is characterized by severe intellectual disabilities, corpus callosum agenesis, epilepsy, and spasticity. It is a type of syndromic X-linked intellectual disability.

References

  1. 1 2 "Andermann syndrome". Genetics Home Reference. NIH. Retrieved 19 January 2017.
  2. 1 2 "Andermann syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2017-01-19.
  3. 1 2 "AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY; ACCPN". www.omim.org. Retrieved 2017-01-19.
  4. 1 2 3 4 5 RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Corpus callosum agenesis neuronopathy syndrome". www.orpha.net. Retrieved 2017-01-19.{{cite web}}: CS1 maint: numeric names: authors list (link)
  5. 1 2 3 4 Dupré, Nicolas; Howard, Heidi C.; Rouleau, Guy A. (1993-01-01). "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum". In Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Ledbetter, Nikki; Mefford, Heather C. (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID   20301546.
  6. ↑ Andermann, E; Andermann, F; Joubert, M (1972). "Familial agenesis of the corpus callosum with anterior horn cell disease. A syndrome of mental retardation, areflexia and paraplegia". Transactions of the American Neurological Association. 97: 242-244.
  7. ↑ Andermann, E; Andermann, F; Joubert, D; Melançon, D; Karpati, G; Carpenter, S (1975). "Three familial midline malformation syndromes of the central nervous system: agenesis of the corpus callosum and anterior horn-cell disease; agenesis of cerebellar vermis; and atrophy of the cerebellar vermis". Birth Defects Original Article Series. 11 (2): 269–293. PMID   1227532.
  8. ↑ Howard, HC; Mount, DB; Rochefort, D; Byun, N; Dupré, N; Lu, J; Fan, X; Song, L; Rivière, JB; Prévost, C; Horst, J; Simonati, A; Lemcke, B; Welch, R; England, R; Zhan, FQ; Mercado, A; Siesser, WB; George, AL Jr; McDonald, MP; Bouchard, J-P; Mathieu, J; Delpire, E; Rouleau, GA (2002). "The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum". Nature Genetics. 32 (3): 384–392. doi:10.1038/ng1002. PMID   12368912.
  9. ↑ Uyanik, G.; Elcioglu, N.; Penzien, J.; Gross, C.; Yilmaz, Y.; Olmez, A.; Demir, E.; Wahl, D.; Scheglmann, K. (2006). "Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome". Neurology. 66 (7): 1044–1048. doi:10.1212/01.wnl.0000204181.31175.8b. ISSN   1526-632X. PMID   16606917. S2CID   280621.
  10. ↑ Garneau, AP; Marcoux, AA; Frenette-Cotton, R; Mac-Way, F; Lavoie, JL; Isenring, P (2017). "Molecular insights into the normal operation, regulation, and multisystemic roles of K+-Cl- cotransporter 3 (KCC3)". American Journal of Physiology. Cell Physiology. 313 (5): C516–C532. doi:10.1152/ajpcell.00106.2017. hdl: 1866/33307 . PMID   28814402.
  11. ↑ Shekarabi, M; Salin-Cantegrel, A; Laganière, J; Gaudet, R; Dion, P; Rouleau, GA (2011). "Cellular expression of the K+-Cl- cotransporter KCC3 in the central nervous system of mouse". Brain Research. 1374: 15–26. doi:10.1016/j.brainres.2010.12.010. PMID   21147077.
  12. ↑ Filteau, MJ; Pourcher, E; Bouchard, RH; Baruch, P; Mathieu, J; Bédard, F; Simard, N; Vincent, P (1991). "Corpus callosum agenesis and psychosis in Andermann syndrome". Archives of Neurology. 48 (12): 1275–1280. doi:10.1001/archneur.1991.00530240079027. PMID   1668979.
  13. ↑ Larbrisseau, A; Vanasse, M; Brochu, P; Jasmin, G (1984). "The Andermann syndrome: agenesis of the corpus callosum associated with mental retardation and progressive sensorimotor neuronopathy". Canadian Journal of Neurological Sciences. 11 (2): 257–261. doi:10.1017/s0317167100045509. PMID   6329500.
  14. ↑ Shekarabi, M; Moldrich, RX; Rasheed, S; Salin-Cantegrel, A; Laganière, J; Rochefort, D; Hince, P; Huot, K; Gaudet, R; Kurniawan, N; Sotocinal, SG; Ritchie, J; Dion, PA; Mogil, JS; Richards, LJ; Rouleau, GA (2012). "Loss of neuronal potassium/chloride cotransporter 3 (KCC3) is responsible for the degenerative phenotype in a conditional mouse model of hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum". Journal of Neuroscience. 32 (11): 3865–3876. doi:10.1523/JNEUROSCI.3679-11.2012. PMC   6703451 . PMID   22423107.
  15. ↑ Van Poucke, M; Stee, K; Sonck, L; Stock, E; Bosseler, S; Van Dorpe, J; Van Nieuwerburgh, F; Deforce, D; Peelman, LJ; Van Ham, L; Bhatti, SFM; Broeckx, BJG (2019). "Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs". European Journal of Human Genetics. 27 (10): 1561–1568. doi:10.1038/s41431-019-0432-3. PMC   6777613 . PMID   31160700.
  16. 1 2 3 4 Auer RN, Laganière JL, Robitaille YO, Richardson J, Dion PA, Rouleau GA, Shekarabi M (2016). "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system". Modern Pathology. 29 (9): 962–976. doi: 10.1038/modpathol.2016.90 . PMID   27230413.
  17. ↑ Sung, JH (1987). "Tangled masses of central axons (central axonomas) in the brain stem: anatomical evidence for the regenerative growth of human central axons". Journal of Neuropathology and Experimental Neurology. 46 (2): 200–213. doi:10.1097/00005072-198703000-00007. PMID   3819774.
  18. ↑ Dupré, Nicolas (12 June 2014). "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum". University of Washington, Seattle. Retrieved 18 April 2020.
  19. ↑ Demir, E; Irobi, J; Erdem, S; Demirci, M; Tan, E; Timmerman, V; De Jonghe, P; Topaloglu, H (2003). "Andermann syndrome in a Turkish patient". Journal of Child Neurology. 18 (1): 76–79. doi:10.1177/08830738030180011901. PMID   12661946.
  20. ↑ Lesca, G; Cournu-Rebeix, I; Azoulay-Cayla, A; Lyon-Caen, Q; Barois, A; Dulac, O; Fontaine, B (2001). "Andermann syndrome in an Algerian family: suggestion of phenotype and genetic homogeneity". Revue Neurologique. 157 (10): 1279–1281. PMID   11885521.
  21. ↑ Deleu, D; Bamanikar, SA; Muirhead, D; Louon, A (1997). "Familial progressive sensorimotor neuropathy with agenesis of the corpus callosum (Andermann syndrome): a clinical, neuroradiological and histopathological study". European Neurology. 37 (2): 104–109. doi:10.1159/000117419. PMID   9058066.
  22. ↑ Pacheva, I; Todorov, T; Halil, Z; Yordanova, R; Todorova, A; Geneva, I; Galabova, F; Ivanov, I (2019). "First case of Roma ethnic origin with Andermann syndrome: A novel frameshift mutation in exon 20 of SLC12A6 gene". American Journal of Medical Genetics Part A. 179 (6): 1020–1024. doi:10.1002/ajmg.a.61110. PMID   30868738.
  23. ↑ Løseth, S; Høyer, H; Le, K-M; Delpire, E; Kinge, E; Lande, A; Hilmarsen, HT; Fagerheim, T; Nilssen, Ø; Braathen, GJ (2023). "Late-onset sensory-motor axonal neuropathy, a novel SLC12A6-related phenotype". Brain. 146 (3): 912–922. doi:10.1093/brain/awac488. hdl: 10037/28541 . PMC   9976957 . PMID   36542484.
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