Autosomal recessive, X-linked, autosomal dominant
Cerebellar ataxias are a highly heterogeneous group of genetic disorders distinguished by abnormal wide-based gait, irregular eye and hand movements, speech difficulties, and morphologically characterized by cerebellar atrophy. Ataxia is a neurological feature of abnormal gait due to the lack of appropriate muscle coordination and it is a common clinical symptom in hundreds of different diseases. Hereditary ataxias are caused by changes in more than 50 genes1, 2 and can be inherited in autosomal dominant, recessive, X-linked or mitochondrial fashion.
The prevalence of hereditary ataxias is estimated at 1–9/100,000 people 1, 2, 3. Prevalence of autosomal dominant cerebellar ataxias is estimated at 1-5/100,000 1, 2, while autosomal recessive types of hereditary ataxia account for approximately 3/100,000 1, 2. The prevalence of genetic early-onset/childhood ataxia is estimated at 0.1-10/100,000 1, 3.
Clinical features of hereditary cerebellar ataxia are poor coordination of movement and abnormal, dysfunctional, wide-based uncoordinated and unsteady gait. In a vast majority of cases cerebellar ataxia may result from one or any of the following:
- Cerebellar dysfunction and/or abnormalities in associated brain areas
- Spinal cord lesions
- Peripheral sensory loss Hereditary ataxias exhibit a wide variety of clinical phenotypes.
Commonly ataxias are presented as “pure cerebellar” phenotypes, characterized by ataxic gait and movements, nystagmus, dysarthria and hypotonia. Magnetic resonance imaging demonstrates cerebellar atrophy, as a pathological sign of the disease. Other forms of ataxias can present with additional neurological symptoms, including tremor, epilepsy, spasticity, dementia, and/or neuropathy, and some patients demonstrate deafness and intellectual disability. The age of onset in affected individuals is also variable, with symptoms presenting from birth through late decades of life. Congenital ataxias display symptoms within the first year of life and are often non-progressive, while the late onset ataxias are more commonly progressive and result in patients rapidly becoming wheelchair bound.
The classification and nomenclature of the hereditary ataxias is an ongoing process; however to date more than 40 different forms of hereditary cerebellar ataxias have been identified, including spinocerebellar ataxia type 1 (SCA1)-SCA42 1, 4. Spinocerebellar ataxia (SCA) is a historical term, first used for autosomal dominant hereditary ataxias. The numbers of SCA subtypes are assigned in the order of disease discovery.
Hereditary cerebellar ataxias are classified mainly according to the inheritance pattern as follows:
- Autosomal dominant cerebellar ataxias are classified as “ADCA”
- Autosomal recessive SCAS are referred as “SCAR”
- X-linked ataxias are labeled as “SCAX
- Episodic ataxias are labeled as “EA”
- SPAX refers to ataxia subtypes that have a prominent component of spasticity 1, 5.
Typical clinical signs and symptoms of autosomal dominant ataxias (ADCA) include the following:
- Limb and truncal ataxia
- Hyperreflexia and spasticity (pyramidal signs) are commonly found in patients with SCA1 and SCA3
- Cognitive impairment has been reported in association with SCA2, SCA12, SCA13, and SCA17
- Chorea may manifest in patients with dentatorubral-pallidoluysian atrophy (DRPLA) or SCA17
- Common findings include dysarthria, dysphagia, and neuropathy
- SCA2 shows Parkinsonian signs.
ADCAs are usually slowly progressive and have an age of onset from childhood to adulthood. They cannot be differentiated by clinical or neuroimaging studies, however, they are associated with cerebellar atrophy.
The most common forms of autosomal dominant ataxias are caused by an expansion of trinucleotide repeats in one of the ataxin-related genes (ATXN1, ATXN2 etc.). The most common repeat expansions are CAG expansions, polyglutamine or polyQ repeats (CAG encodes glutamine, amino acid “Q”). There are currently seven known autosomal dominant ataxias caused by CAG polyglutamine expansions: SCA1, SCA2, SCA3 (Machado Joseph disease/MJD), SCA6, SCA7, SCA17, and DRPLA. Repeat expansions could be localized outside the coding region, in untranslated regions of the gene or introns, where they interfere with the gene regulation. Examples of these mutations are the following: CTG repeats in SCA8, ATTCT in SCA10, CAG in SCA12, TGGAA in SCA31 and GGCCTG in SCA36. Other subtypes of autosomal dominant ataxia are caused by conventional mutations including insertions, SNVs and deletions, such as SCA28 (AFG3L2), SCA29/SCA16 (ITPR1) or SCA14 (PRKCG).
Autosomal recessive cerebellar ataxias may present with additional extra–central nervous system signs and symptoms, including the following:
- Slowly progressive early onset ataxia
- Oculomotor apraxia
- Common findings include deafness, seizures, optic atrophy, myopathy, nystagmus etc.
Common forms of autosomal recessive ataxias (reported in more than 5 families1, 5) include the following:
- Friedrich ataxia, caused by CAG trinucleotide expansion in FXN
- Ataxia with oculomotor apraxia, caused by mutations in APTX or SETX
- Ataxia-telangiectasia caused by mutations in ATM
- Ataxia with vitamin E deficiency (AVED), caused by mutations in TTPA
- Ataxia with oculomotor apraxia type 1 (AOA1) caused by mutations in APTX
- Ataxia with oculomotor apraxia type 2 (AOA2) caused by mutations in SETX
- POLG (polymerase γ1)-associated hereditary ataxias, mitochondrial recessive ataxic syndrome and SANDO (sensory ataxia, neuropathy, dysarthria, and ophthalmoplegia).
- Autosomal recessive spastic ataxia of Charlevoix-Saguenay, caused by mutations in SACS.
- Refsum disease, associated with mutations in PHYH and PEX7.
- Coenzyme Q10 (CoQ10) deficiency, associated with mutations in COQ2, COQ8A, COQ9, PDSS1 or PDSS2.
Numerous conditions with autosomal recessive inheritance are accompanied by ataxia and/or cerebellar atrophy, such as Joubert syndrome, congenital disorders of glycosylation, peroxisomal biogenesis disorders, Zellweger spectrum disorders, and others.
X-linked inheritance of cerebellar ataxia is uncommon except for the Fragile X tremor ataxia syndrome (FXTAS), caused by mutations in FMR1. Also, some rare ataxia forms are associated with mutations in mitochondrial DNA, including MERRF (myoclonic epilepsy with ragged red fibers), NARP (neuropathy, ataxia, and retinitis pigmentosa), and Kearns-Sayre syndrome5.
Table 1. Overview of genes included in Cerebellar ataxia panel
|Gene||OMIM (Gene)||Associated diseases (OMIM)||Inheritance||CentoMD® exclusive variant numbers (++)|
|APTX||606350||Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia||AR||31|
|COQ2||609825||Multiple system atrophy, susceptibility to; Coenzyme Q10 deficiency, primary, 1||AD, AR||16|
|COQ8A||606980||autosomal recessive spinocerebellar ataxia 9||AR||38|
|COQ9||612837||Coenzyme Q10 deficiency, primary, 5||AR||11|
|DNMT1||126375||cerebellar ataxia, deafness and narcolepsy; Neuropathy, hereditary sensory, type IE||AD||49|
|PDSS1||607429||Coenzyme Q10 deficiency, primary, 2||AR||28|
|PDSS2||610564||Coenzyme Q10 deficiency, primary, 3||AR||10|
|POLG||174763||progressive external ophthalmoplegia; mitochondrial DNA depletion syndrome type 4A; autosomal recessive progressive external ophthalmoplegia; sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; mitochondrial DNA depletion syndrome type 4B||AD, AR||55|
|SACS||604490||spastic ataxia of Charlevoix-Saguenay||AR||25|
|SETX||608465||amyotrophic lateral sclerosis 4; autosomal recessive spinocerebellar ataxia 1||AD, AR||78|
|SLC2A1||138140||Dystonia-9; GLUT1 deficiency syndrome; dystonia 18; Epilepsy, idiopathic generalized, suscpetibility to, 12||AD, AR||37|
|SPG7||602783||spastic paraplegia 7||AD, AR||49|
|SYNE1||608441||autosomal recessive spinocerebellar ataxia 8; Emery-Dreifuss muscular dystrophy 4||AD, AR||96|
|TTPA||600415||ataxia with vitamin E deficiency||AR||9|
|VLDLR||192977||Cerebellar ataxia, mental retardation, and dysequilibrium syndrome||AR||17|
Abbreviations: SCAR-Spinocerebellar ataxia; AOA-Ataxia oculomotor apraxia; EAOH-Early onset ataxia with oculomotor apraxia and hypoalbuminemia; CoQ10D-Coenzyme Q10 deficiency; HSN-Hereditary sensory neuropathy; ADCADN-Cerebellar ataxia deafness and narcolepsy autosomal dominant; FRDA-Fridreich ataxia; MTDPS-mitochondrial DANN depletion syndrome; SANDO-Sensory ataxic neuropathy dysarthria and ophtalmoparesis; PEOA-Progressive external ophtalmoplegia with mitochondrial DANN deletions; SACS-Spastic ataxia Charlevoix-Saguenay type; SPAX-Spastic ataxia autosomal recessive; ALS-Amyotrophic lateral sclerosis; EDMD-Emery-Dreifuss muscular dystrophy; AVED-Ataxia Freidreich-like with selective vitamin E deficiency; CAMRQ-Cerebellar ataxia mental retardation and disequilibrium syndrome.
Some forms of hereditary ataxia can be successfully treated, such as ataxia with selective loss of vitamin E, AVED (treatment with vitamin E), Refsum disease (dietary restriction of phytanic acid intake), cerebrotendinous xanthomatosis, CTX (chenodeoxycholic acid), and CoQ10 deficiency (CoQ10). Management for other ataxias is usually directed to rehabilitation medicine and occupational and physical therapy.
CENTOGENE offers the following panels designed for molecular diagnostics of different subtypes of ataxias:
- Cerebellar ataxia panel (genes: COQ8A, APTX, COQ2, COQ9, DNMT1, FXN, PDSS1, PDSS2, POLG, SACS, SETX, SYNE1, TTPA, VLDLR). All genes, except FXN, are sequenced and analyzed, while for FXN we offer repeat expansion test.
- SCA repeat expansion panel selectively designed for repeat expansion analysis causing SCAs (genes: ATN1, ATXN1, ATXN10, ATXN2, ATXN3, ATXN7, ATXN8OS, BEAN1, CACNA1A, FXN, NOP56, PPP2R2B, TBP)
- SCA comprehensive panel (genes: ABCB7, ABHD12, ABHD5, ACADVL, COQ8A, AFG3L2, ANO10, APTX, ATCAY, ATM, ATP2B3, C10orf2, CA8, CACNA1A, CCDC88C, CWF19L1, DNMT1, EEF2, ELOVL4, ELOVL5, FGF14, FXN, GRID2, GRM1, ITPR1, KCNC3, KCND3, PDYN, PRKCG, RUBCN, SACS, SETX, SIL1, SLC1A3, SPTBN2, STUB1, SYNE1, SYT14, TDP1, TGM6, TPP1, TTBK2, TTPA, VAMP1, WWOX, ZNF592)
The differential diagnosis of cerebellar ataxia-related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Acquired, non-genetic causes of ataxia:
- Vitamin deficiencies
- Multiple sclerosis
- Vascular disease
- Primary or metastatic tumors or paraneoplastic diseases associated with occult carcinoma of the ovary, breast, or lung
- Disorders of mitochondrial oxidative metabolism
- Hyperammonemias caused by deficiencies of urea cycle enzymes
- Aminoacidurias, including Hartnup disease.
CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for episodic ataxia using NGS Panel Genomic targeted towards this specific cerebellar ataxia phenotype:
Step 1: Repeat expansions analysis is offered for FXN.
Step 2: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Cerebellar ataxia panel. Copy Number Variants analysis derived from NGS data is also included.
Step 3: If no mutation is identified after analysis of the Cerebellar ataxia panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.
The following individuals are candidates for cerebellar ataxia panel testing:
- Individuals with a family history of cerebellar ataxia and presentation of the most common symptoms
- Individuals without a positive family history of cerebellar ataxia, but with resembling symptoms
- Individuals with a negative but suspected family history of cerebellar ataxia, in order to perform proper genetic counseling.
Sequencing, deletion/duplication of the panel genes should be performed in all individuals suspected of having episodic ataxia and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the cerebellar ataxia and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.