Ataxia with Ocular Apraxia Type 1 (AOA1) (APTX, W279* Mutation): Neurological, Neuropsychological, and Molecular Outlining of a Heterogenous Phenotype in Four Colombian Siblings

Hereditary ataxias are a group of devastating neurological disorders that affect coordination of gait and are often associated with poor coordination of hands, speech, and eye movements. Ataxia with Ocular Apraxia type 1 (AOA1) (OMIM: 606350.0006) is characterized by slowly progressive symptoms of childhood-onset and pathogenic mutations in APTX; the only known cause underpinning AOA1. APTX encodes the protein Aprataxin, composed of three domains sharing homology with proteins involved in DNA damage, signaling, and repair. We present four siblings from an endogamic family in a rural, isolated town of Colombia with ataxia and ocular apraxia of childhood-onset and confirmed molecular diagnosis of AOA1, homozygous for the W279* p.Trp279Ter mutation. We predicted the mutated APTX with Alpha Fold to demonstrate the effects of this stop-gain mutation that deletes three beta helices encoded by amino acid 270 to 339 rescinding the C2H2-type zinc fingers (Znf) (C2H2 Znf) DNA-binding and DNA-repair domain and the whole tridimensional structure of the APTX. All siblings exhibited different ages of onset (4, 6, 8, and 11 y/o) and heterogeneous patterns of dysarthria (ranging from absence to mild-moderate dysarthria). Neuropsychological evaluation showed no neurocognitive impairment in three siblings, but one sibling showed temporospatial disorientation, semantic and phonologic fluency impairment, episodic memory affection, constructional apraxia, moderate anomia, low executive function, and symptoms of depression. This heterogeneous phenotype suggests genetic interactions can shape the natural history of AOA1. To our knowledge, this report represents the most extensive series of siblings affected with AOA1 in Latin America, and the genetic analysis completed adds important knowledge to outline this family’s disease and general complex phenotype of hereditary ataxias.

Application of a custom NGS Gene Panel revealed a high diagnostic utility for molecular testing of hereditary ataxias.

Background Hereditary ataxias (HA) are a rare group of heterogeneous disorders. Here, we present results of molecular testing a group of ataxia patients using custom-designed Next Generation Sequencing (NGS) panel. Due to genetic and clinical overlapping of hereditary ataxias and spastic paraplegias (HSP), designed panel encompassing together HA and HSP genes. Methods The NGS libraries comprising coding sequence for 152 genes were performed using KAPA HyperPlus and HyperCap Target Enrichment Kit and sequenced on the MiSeq instrument. Obtained results were analyzed using BaseSpace Variant Interpreter and Integrative Genomics Viewer. All pathogenic and likely pathogenic variants were confirmed using the Sanger sequencing. Results A total of 29 patients with hereditary ataxias were enrolled to the NGS testing, and 16 patients had a confirmed molecular diagnosis with diagnostic efficiency of 55.2%. Pathogenic or likely pathogenic mutations were identified in 10 different genes: POLG (PEOA1, n=3; SCAE, n=2), CACNA1A (EA2, n=2), SACS (ARSACS, n=2), SLC33A1 (SPG42, n=2), STUB1 (SCA48, n=1), SPTBN2 (SCA5, n=1), TGM6 (SCA35, n=1), SETX (AOA2, n=1), ANO10 (SCAR10, n=1), SPAST (SPG4, n=1). Conclusions We demonstrated that approach based on targeted NGS panel can be highly effective and useful tool in the molecular diagnosis of ataxia patients. Furthermore, we highlight that sequencing panel targeted to ataxias together with HSP genes increase the diagnostic success.

A Brief Review on Spinocerebellar Ataxia and its Treatment

Ataxia is defined as a neurological sign including the lack of muscle movement coordination particularly of gait abnormality, talking changes, and also abnormality in eye actions. In ataxia, a part of nervous system is dysfunction which is also coordinate movement such as the cerebellum. In adults, ataxia can be acquired or genetic disorder. The Spinocerebellar ataxia is hereditary, progressive, degenerative, genetic disease or often fatel. There are no effective treatment and cure for Spinocerebellar ataxia (SCA). Spinocerebellar ataxia is a progressive disorders in which the cerebellum slowly degenerates. An average results estimated that 150,000 peoples in the United States have a diagnosis of Spinocerebellar ataxia (SCA) at any given time periods. Spinocerebellar ataxia (SCA) can affects anybody persons of at all ages. A current systemic review shows that the global prevalence of Spinocerebellar ataxia (SCA) is 3 in 100,000 people. However, a wide regional variation exists. SCA3 is common subtype around the world, SCA2 is additional prevalent in Cuba than SCA3 whilst SCA7 is the most frequent subtype in Venezuela due to strong founder’s effect. SCA6 is 1 of the most general ADCA in the North of England, with a global prevalence of 5.2/100,000.There are many different types of spinocerebellar ataxia (SCA) and each may have unique signs and symptoms. And these includes: Problems with coordination and balance (ataxia), Uncoordinated walk, poor hand eye coordination, Abnormal speech, Involuntary eye movement, Vision problems, Difficulty processing, Learning and remembering information. The hereditary ataxias are categorized by mode of inheritance and causative gene or chromosomal locus. The hereditary ataxias can be inherited in an autosomal dominant, autosomal recessive,or X-linked manner. Some types of SCA inherited in an autosomal dominant manner are caused by trinucleotide repeat expansions. A trinucleotide repeat is a segment of DNA that is repeated a number of times. It is normal for these repeats to exist and they typically do not cause any problems. Some Spinocerebellar ataxia SCAs remain unspecified and cannot be precisely diagnosed, but in the previous decades genetic testing has permissible precise identification of dozens of different SCAs and extra tests are being added each year. The spinocerebellar ataxia are classified SCA1 to SCA35for the treatment of SCA. There are no effective and cure treatment available for the spinocerebellar ataxia (SCA). But there are some methods; therapies and treatment are available which will be fruitful for the SCA. And these included the following: Meditation, Zolpidem, N-acetyl leucine, Rehabilitation

Clinical and Neuroradiological Features of Hereditary Ataxia Patients: Hospital Based Study

Background Ataxia (GK Taxis mean lack of orders) is defined by imbalance in coordination in gait, limbs and speech. It usually results from disorders in cerebellum or its connections. It is disorder of rate, range, direction and force of movements. Aim of the Work to investigate and identify the prevalence of hereditary ataxias regarding clinical and radiological. Subjects and Methods our study is composed of 23 patients, (their age range from 15 years old to 40 years old).We study the effect of positive family history and consanguinity on the prevalence of hereditary ataxias. We assess patients functionally using SARA score. Results there was positive relationship between positive family history and consanguinity and appearance of disease in cases so, it is important to ask about family history, similar condition and do family pedigree to know mode of inheritance if possible. Also, we found positive correlation between duration of disease and SARA score. There was positive correlation between MRI brain finding (cerebellar atrophy or brain stem atrophy), neurophysiological studies (axonal neuropathy) and disease. Conclusion positive family history and consanguinity are risk factors for hereditary ataxias. SARA score is a useful tool to assess hereditary ataxias functionally. MRI brain and neurophysiological studies are useful tools to diagnose hereditary ataxias.

Treating Hereditary Ataxias—Where Can We Help?

Hereditary ataxias comprise a group of neurological disorders which affect different levels of the neurological axis including the cerebellum, peripheral nerves, cognition, and the extrapyramidal system. These are categorized by the mode of inheritance as autosomal recessive, autosomal dominant, X-linked, and mitochondrial cerebellar ataxia. Definitive curative therapy is not available for these disorders. However, a wide array of emerging treatment options, especially in terms of symptomatic therapy, rescues this group from therapeutic nihilism. Several drugs have been assessed including riluzole, valproate, lithium, etc., as well as rehabilitative, and neuromodulatory strategies. In addition, symptomatic therapies for ancillary symptoms, such as seizures, movement disorders, spasticity, dystonia, etc., should also be targeted. Lastly, molecular therapeutic possibilities are also being explored in animal studies. In this review, we elucidate on the current treatment options available for hereditary ataxias.