Complications
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| Autosomal dominant cerebellar ataxia, deafness and narcolepsy | |
|---|---|
| Other names | ADCADN, ADCA-DN, autosomal dominant cerebellar ataxia, deafness and narcolepsy, autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome, ADCA-DN syndrome. [1] |
| Specialty | Medical genetics, Neurology |
| Causes | Genetic mutation |
| Diagnostic method | Genetic testing |
| Prevention | none |
| Frequency | very rare |
Autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCADN) is a rare progressive genetic disorder that primarily affects the nervous system and is characterized by sensorineural hearing loss, narcolepsy with cataplexy, and dementia later in life. People with this disorder usually start showing symptoms when they are in their early-mid adulthoods. [2] [3] [4] [5] It is a type of autosomal dominant cerebellar ataxia. [2] [3] [4]
Usually, people with this disorder have ataxia, mild–moderate sensorineural hearing loss, narcolepsy, and cataplexy. These symptoms start happening when an affected person is about 30 years old. [6] [7]
A bit later in life, people with ADCADN start showing a decline in executive function known as dementia. Degeneration of the optic nerves, cataracts, sensory neuropathy, lymphedema of the arms and legs, urinary incontinence, depression, uncontrollable and inappropriate laughing or crying (e.g. sudden incontrollable laughing during a funeral), and psychosis are features that typically accompany it. People with this disorder only live to be 40–50 years old. [6] [7]
Other features of the disorder that may or may not occur in all patients include diabetes mellitus, spasticity, nystagmus, tremors, dilatation of the right ventricle, cerebral atrophy, and other generalized brain abnormalities. [8] [9]
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This condition is caused by mutations in exon 20–21 of the DNMT1 gene, located in chromosome 19. [10] [11] These mutations are inherited in an autosomal dominant manner, meaning that for someone to show symptoms of a condition, they must have at least one copy of the mutation. This can occur in two scenarios; it can be hereditary or it can be the result of a spontaneous error. [7] [12] [13] [14] [15] [16]
This gene plays a role in the production of an enzyme called DNA methyltransferase 1, which is involved in DNA methylation. This enzyme is essential for the regulation of neuron maturation, differentiation, migration, and most importantly, survival. The mutations involved in ADCAN alter a certain region in the enzyme produced by the gene which helps DNA methylation, which ends up distorting said process. This affects the expression of various genes. This also disrupts neuron maintenance, leading to the characteristic psychiatric and cognitive symptoms of this condition. [17] [4]
This condition can be diagnosed by using methods such as whole exome sequencing and examination of the patient's symptoms. [10] [13] [12]
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More than 80 cases from families around the world have been described in medical literature. [8] [2]
The following list comprises all countries of origin (according to OrphaNet): [2]
This condition was first discovered in 1995 by Melberg et al. when they described 5 members of a 4-generation Swedish family where cerebellar ataxia and sensorineural deafness presented as an autosomal dominant trait, 4 of them had narcolepsy and 2 had diabetes mellitus. The oldest members had psychiatric symptoms, neurological anomalies, and optic atrophy, showing the progressive nature of the condition. [18]
Tietz syndrome, also called Tietz albinism-deafness syndrome or albinism and deafness of Tietz, is an autosomal dominant congenital disorder characterized by deafness and leucism. It is caused by a mutation in the microphthalmia-associated transcription factor (MITF) gene. Tietz syndrome was first described in 1963 by Walter Tietz (1927–2003) a German Physician working in California.
Wolfram syndrome, also called DIDMOAD, is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders including neurodegeneration. Symptoms can start to appear as early as childhood to adult years. There is a 25% recurrence risk in children.
Spinocerebellar ataxia (SCA) is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a neurological condition in its own right. An estimated 150,000 people in the United States have a diagnosis of spinocerebellar ataxia at any given time. SCA is hereditary, progressive, degenerative, and often fatal. There is no known effective treatment or cure. SCA can affect anyone of any age. The disease is caused by either a recessive or dominant gene. In many cases people are not aware that they carry a relevant gene until they have children who begin to show signs of having the disorder. Currently, research is being conducted at Universities, such as the University of Minnesota, to elucidate many of the unknown characteristics of the disease.
Cerebellar abiotrophy (CA), also called cerebellar cortical abiotrophy (CCA), is a genetic neurological disease in animals, best known to affect certain breeds of horses, dogs and cats. It can also develop in humans. It develops when the neurons known as Purkinje cells, located in the cerebellum of the brain, begin to die off. These cells affect balance and coordination. They have a critical role to play in the brain. The Purkinje layer allows communication between the granular and molecular cortical layers in the cerebellum. Put simply, without Purkinje cells, an animal loses its sense of space and distance, making balance and coordination difficult. People with damage to the cerebellum can experience symptoms like unsteady gait, poor muscle control, and trouble speaking or swallowing.
Spinocerebellar ataxia type 6 (SCA6) is a rare, late-onset, autosomal dominant disorder, which, like other types of SCA, is characterized by dysarthria, oculomotor disorders, peripheral neuropathy, and ataxia of the gait, stance, and limbs due to cerebellar dysfunction. Unlike other types, SCA 6 is not fatal. This cerebellar function is permanent and progressive, differentiating it from episodic ataxia type 2 (EA2) where said dysfunction is episodic. In some SCA6 families, some members show these classic signs of SCA6 while others show signs more similar to EA2, suggesting that there is some phenotypic overlap between the two disorders. SCA6 is caused by mutations in CACNA1A, a gene encoding a calcium channel α subunit. These mutations tend to be trinucleotide repeats of CAG, leading to the production of mutant proteins containing stretches of 20 or more consecutive glutamine residues; these proteins have an increased tendency to form intracellular agglomerations. Unlike many other polyglutamine expansion disorders expansion length is not a determining factor for the age that symptoms present.
Spinocerebellar ataxia type 13 (SCA13) is a rare autosomal dominant disorder, which, like other types of SCA, is characterized by dysarthria, nystagmus, and ataxia of gait, stance and the limbs due to cerebellar dysfunction. Patients with SCA13 also tend to present with epilepsy, an inability to run, and increased reflexes. This cerebellar dysfunction is permanent and progressive. SCA13 is caused by mutations in KCNC3, a gene encoding a voltage-gated potassium channel KV3.3. There are two known mutations in this gene causative for SCA13. Unlike many other types of SCA, these are not polyglutamine expansions but, rather, point mutations resulting in channels with no current or altered kinetics.
Progressive Myoclonic Epilepsies (PME) are a rare group of inherited neurodegenerative diseases characterized by myoclonus, resistance to treatment, and neurological deterioration. The cause of PME depends largely on the type of PME. Most PMEs are caused by autosomal dominant or recessive and mitochondrial mutations. The location of the mutation also affects the inheritance and treatment of PME. Diagnosing PME is difficult due to their genetic heterogeneity and the lack of a genetic mutation identified in some patients. The prognosis depends largely on the worsening symptoms and failure to respond to treatment. There is no current cure for PME and treatment focuses on managing myoclonus and seizures through antiepileptic medication (AED).
Mitochondrially encoded tRNA histidine, also known as MT-TH, is a transfer RNA which, in humans, is encoded by the mitochondrial MT-TH gene.
Gillespie syndrome, also called aniridia, cerebellar ataxia and mental deficiency, is a rare genetic disorder. The disorder is characterized by partial aniridia, ataxia, and, in most cases, intellectual disability. It is heterogeneous, inherited in either an autosomal dominant or autosomal recessive manner. Gillespie syndrome was first described by American ophthalmologist Fredrick Gillespie in 1965.
EAST syndrome is a syndrome consisting of epilepsy, ataxia, sensorineural deafness and salt-wasting renal tubulopathy. The tubulopathy in this condition predispose to hypokalemic metabolic alkalosis with normal blood pressure. Hypomagnesemia may also be present.
Vestibulocerebellar syndrome, also known as vestibulocerebellar ataxia, is a progressive neurological disorder that causes a variety of medical problems. Initially symptoms present as periodic attacks of abnormal eye movements but may intensify to longer-lasting motor incapacity. The disorder has been localized to the vestibulocerebellum, specifically the flocculonodular lobe. Symptoms of vestibulocerebellar syndrome may appear in early childhood but the full onset of neurological symptoms including nystagmus, ataxia, and tinnitus does not occur until early adulthood. To date, vestibulocerebellar syndrome has only been identified in three families but has affected multiple generations within them. Based on the familial pedigrees it has been characterized as an autosomal dominant disorder, although the exact genetic locus has not been identified. It has been found to be genetically distinct from other seemingly similar forms of neurological syndromes such as episodic ataxia types 1 and 2. Due to its rarity, however, little is known about specific details of the pathology or long-term treatment options. There is currently no cure for vestibulocerebellar syndrome, although some drug therapies have been effective in alleviating particular symptoms of the disorder.
Emmanuel Mignot is a sleep researcher and director of the Stanford Center for Sleep Sciences and Medicine, at Stanford University. Dr. Mignot is an authority on sleep research and medicine, and is mostly known for his work on narcolepsy. He is the Craig Reynolds Professor of Sleep Medicine at Stanford Medical School, Stanford University.
Autosomal recessive cerebellar ataxia type 1 (ARCA1) is a condition characterized by progressive problems with movement. Signs and symptoms of the disorder first appear in early to mid-adulthood. People with this condition initially experience impaired speech (dysarthria), problems with coordination and balance (ataxia), or both. They may also have difficulty with movements that involve judging distance or scale (dysmetria). Other features of ARCA1 include abnormal eye movements (nystagmus) and problems following the movements of objects with their eyes. The movement problems are slowly progressive, often resulting in the need for a cane, walker, or wheelchair.
Autosomal dominant cerebellar ataxia (ADCA) is a form of spinocerebellar ataxia inherited in an autosomal dominant manner. ADCA is a genetically inherited condition that causes deterioration of the nervous system leading to disorder and a decrease or loss of function to regions of the body.
Arts syndrome is a rare metabolic disorder that causes serious neurological problems in males due to a malfunction of the PRPP synthetase 1 enzyme. Arts Syndrome is part of a spectrum of PRPS-1 related disorders with reduced activity of the enzyme that includes Charcot–Marie–Tooth disease and X-linked non-syndromic sensorineural deafness.
PRICKLE1-related progressive myoclonus epilepsy with ataxia is a very rare genetic disorder which is characterized by myoclonic epilepsy and ataxia.
Palmoplantar keratoderma with deafness, also known as Palmoplantar keratoderma-deafness syndrome is a rare genetic disorder which is characterized by either focal or diffuse early-onset palmoplantar keratoderma and sensorineural deafness. Transmission is autosomal dominant with incomplete penetrance.
CAPOS syndrome is a rare genetic neurological disorder which is characterized by abnormalities of the feet, eyes and brain which affect their normal function. These symptoms occur episodically when a fever-related infection is present within the body. The name is an acronym for "cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss".
Autosomal dominant leukodystrophy with autonomic disease is a rare neurological condition of genetic origin which is characterized by gradual demyelination of the central nervous system which results in various impairments, including ataxia, mild cognitive disability and autonomic dysfunction. It is part of a group of disorders called "leukodystrophies".
Wolfram-like syndrome is a rare autosomal dominant genetic disorder that shares some of the features shown by those affected with the autosomal recessive Wolfram syndrome. It is a type of WFS1-related disorder.