Autosomal dominant cerebellar ataxia

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. Degeneration occurs at the cellular level and in certain subtypes results in cellular death. Cellular death or dysfunction causes a break or faulty signal in the line of communication from the central nervous system to target muscles in the body. When there is impaired communication or a lack of communication entirely, the muscles in the body do not function correctly. Muscle control complications can be observed in multiple balance, speech, and motor or movement impairment symptoms. ADCA is divided into three types and further subdivided into subtypes known as SCAs (spinocerebellar ataxias).^[1]

Autosomal Dominant Hereditary Tree

ADCA types

Type 1

Type 1 ADCA is characterized by different symptoms of ataxia as well as other conditions that are dependent on the subtype. Type 1 ADCA is divided into 3 subclasses based on pathogenesis of the subtypes each contain.^[1]

Subtype 1

Subtypes in the first subclass are caused by CAG nucleotide repeats in the DNA, which code for the amino acid glutamine.^[1] This glutamine is toxic to the cell on the level of proteins and has degenerative effects.^[1] Within the first subclass of Type 1 are SCA1, SCA2, SCA3, SCA17, and DRPLA. This first subclass is the most common of Type 1 ADCAs with SCA3 being the most common subtype of all of Type 1. SCA3, Machado-Joseph disease, is the most common because the mutation repeats more than 56 times while the regular length is around 13 to 31.^[1]

Subtype 2

The second subclass of Type 1 ADCA is also caused by the same nucleotide repeats but instead in RNA and in a region that does not code for proteins. Gene expression is affected instead of proteins in subtype two SCAs because of this. Subtype 2 contains SCA8, SCA10, and SCA12.^[1]

Subtype 3

The third subclass of Type 1 ADCA is caused by different mutations and deletions in genes. It comprises SCA13, SCA14, SCA15, SCA16, SCA27, and SCA28.^[1]

Spinocerebellar ataxia

The designated loci, SCA, portrays the involvement of two systems: the cerebellum and the spinal cord. 11 to 18 known genes are mutated within this region. All other SCAs are caused by conventional mutations or rearrangement in genes with different functions, such as: calcium signaling (SCA15/16), glutamate signaling (SCA5/SPTBN2), channel functioning (SCA13/KCNC3, SCA27), tau regulation (SCA11/TTBK2), mitochondrial activity (SCA28) and RNA alteration (SCA 31).

Type 2/3

Type II ADCA is composed of SCA7 and syndromes associated with pigmentary maculopathies^[1] (see Retinitis pigmentosa). SCA7 is a disease that specifically displays retinal degeneration, along with the common degeneration of the cerebellum. Moving further into SCA7's pathology, a similar genetic process is described. The function of ATXN7 (an ataxin gene) is much like a component of the SAGA complex. The SAGA complex uses two histone-modifying techniques to regulate transcription. These activities are the Gcn5 histone acetyltransferase and the Usp22 deubiquitinase. Mutant ATXN7 in HAT activity causes an increase in activity, which was reported from an in-vivo analysis in the retina. There are also studies that show a loss in activity when human ATXN7 in yeast was used. The SCA7 autosomal-dominant inheritance pattern is similar to a mutant ATXN5-induced gain in Gcn5 HAT.^[2]

Spinocerebellar ataxia type 15 has been classified as an ADCA Type 3 as it has been noted to have postural and action tremor in addition to cerebellar ataxia.^[1] Additionally, spinocerebellar ataxia type 20 (SCA20) is organized in ADCA III that often exhibits disease-like symptoms at an earlier age, sometime starting at fourteen years old.^[1] Classifying these ataxia syndromes into three major categories allows clinicians to better treat patients presented with defined SCA phenotypes and focus in on potential diagnostic possibilities.^[1]

Frequency

SCA3, MJD, is the most frequent with 57.8% of affected families, followed by DRPLA with 11.2%, and those patients were characterized by prominent anticipation and a variable combination of epilepsy, extra-pyramidal symptoms and dementia.Patients with SCA1 and SCA7 had African ancestry.^[3]

Genetics

11 of 18 known genes are caused by repeated expansions in corresponding proteins, sharing the same mutational mechanism. SCAs can be caused by conventional mutations or large rearrangements in genes that make glutamate and calcium signaling, channel function, tau regulation and mitochondrial activity or RNA alteration.^[4]

Symptoms

Symptoms typically are onset between the ages of twenty-five to forty-five years, although, childhood cases have also been observed. Common symptoms include a loss of coordination which is often seen in walking, and slurred speech.^[5] ADCA primarily affects the cerebellum, as well as, the spinal cord. There are several kinds of ataxias which are grouped depending on how the specific disorder partners with cerebellar ataxia. Type I ataxia, the most common disorder displays the symptoms of motor impairment, optic atrophy, oculomotor paralysis, and intelligence disorders.^[5] Equilibrium disorders also indicate the presence of the disease. Speech production disorders are also another sign of cerebellar damage. Impairment of proprioreception resulting in the inability for a patient to perceive the position and orientation of their limbs is also observed.^[5] Certain eye muscles can also become paralyzed, along with some swallowing disorders, and impairment of the sphincter function. These symptoms vary from different individuals and usually develop over a long period of time, around 20 to 30 years.^[5] Individuals with dominant cerebellar ataxia have a late onset of narcolepsy and deafness around the age of 30 to 40 years old.

Diagnosis

Three main approaches of diagnosing the condition are the patients clinical history or their past health examinations, a current physical examination to check for any physical abnormalities, and a genetic screening of the patients genes and the genealogy of the family.^[6] The large category of cerebellar ataxia is caused by a deterioration of neurons in the cerebellum. Magnetic Resonance Imaging (MRI) is used to detect any structural abnormality such as lesions and tumors which are the primary cause of the ataxia. Computed tomography (CT) scans can also be used to view neuronal deterioration, but the MRI provides a more accurate and detailed picture.

Treatments and management

There is not a lot of information about treatments or therapies at this time. There are some ideas that give hope for future treatments. For the disease to manifest itself, these diseases require mutant protein expression.^[2] Manipulating the use of protein homoestasis regulators can be therapuetic agents. Also, a treatment to try and correct an altered function that makes up the pathology is one current idea.^[2] There is evidence that for SCA1 and two other polyQ disorders that the pathology can be reversed after the disease is underway.^[2] There no effective treatments that could alter the progression of this disease. Therefore care is given, like occupational and physical therapy for gait dysfunction and speech therapy for impaired articulatory ability.

References