Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY (original) (raw)

Summary

NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.

Clinical characteristics.

Infantile-onset spinocerebellar ataxia (IOSCA) is a severe, progressive neurodegenerative disorder characterized by normal development until age one year, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis. Ophthalmoplegia and sensorineural deafness develop by age seven years. By adolescence, affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident. Epilepsy can develop into a serious and often fatal encephalopathy: myoclonic jerks or focal clonic seizures that progress to epilepsia partialis continua followed by status epilepticus with loss of consciousness.

Management.

Treatment of manifestations: Hearing loss, sensory axonal neuropathy, ataxia, psychotic behavior, and severe depression are treated in the usual manner. Conventional antiepileptic drugs (phenytoin and phenobarbital) are ineffective in most affected individuals.

Surveillance: Small children: neurologic, audiologic, and ophthalmologic evaluations every six to 12 months; neurophysiologic studies when indicated; brain MRI every three to five years. Adolescents and adults: neurologic examination yearly; audiologic and ophthalmologic examinations every one to two years; EEG and brain MRI at least during status epilepticus.

Agents/circumstances to avoid: Valproate, which can cause significant elevation of serum concentration of bilirubin and liver enzymes.

Genetic counseling.

IOSCA is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family are known.

Diagnosis

Infantile-onset spinocerebellar ataxia (IOSCA) is a clinical spectrum that was originally described in individuals of Finnish descent; however, the phenotype has been expanded by the identification of affected individuals of non-Finnish descent whose features may deviate from the originally described "classic" phenotype

Clinical diagnostic criteria for IOSCA were published by Koskinen et al [1994a] and Koskinen et al [1994b].

Suggestive Findings

Infantile-onset spinocerebellar ataxia (IOSCA) should be suspected in individuals with the following clinical features and supportive laboratory findings.

Clinical features. After normal early development, children with IOSCA typically display the following clinical features, often in successive order (although the time and order of presentation of clinical symptoms can vary in those who are not of Finnish ancestry) starting in the second year of life:

Supportive laboratory findings

Note: Muscle biopsy with histology and respiratory chain enzyme analysis are not required for the diagnosis of IOSCA.

Establishing the Diagnosis

The diagnosis of IOSCA is established in a proband with typical clinical findings and the identification of biallelic pathogenic (or likely pathogenic) variants in TWNK by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2)

Identification of biallelic TWNK variants of uncertain significance (or of one known TWNK pathogenic variant and one TWNK variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Single-gene testing

A multigene panel that includes TWNK and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Infantile-Onset Spinocerebellar Ataxia

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Gene 1 Method Proportion of Pathogenic Variants 2 Identified by Method
TWNK Sequence analysis 3 100% 4, 5
Gene-targeted deletion/duplication analysis 6 None reported 7

1.

2.

See Molecular Genetics for information on variants detected in this gene.

3.

4.

In the exon / flanking intron regions sequenced; pathogenic variants in non-sequenced intron and regulatory regions are not detected.

5.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

Clinical Characteristics

Clinical Description

Infantile-onset spinocerebellar ataxia (IOSCA) was originally described in individuals of Finnish descent who had biallelic pathogenic founder variants in TWINK. Individuals with this genotype were described as having the classic features on which clinical diagnostic criteria are based. However, affected individuals from multiple ethnicities who have pathogenic variants in TWINK that are different from the original founder variant have now been described. Clinical features in these individuals have expanded the phenotype of IOSCA. These affected individuals are sometimes referred to as having "atypical IOSCA." However, IOSCA represents a continuum in which the clinical differences between affected individuals are due to the underlying pathogenic variants in TWINK (see Genotype-Phenotype Correlations).

Classic infantile-onset spinocerebellar ataxia (IOSCA) is a severe, progressive neurodegenerative disorder [Koskinen et al 1994b]. Affected children are born after an uneventful pregnancy and develop normally until age one year, when the first clinical symptoms of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis appear. Ophthalmoplegia and sensorineural deafness develop by school age (age 7 years). By adolescence sensory axonal neuropathy, optic atrophy, and hypergonadotropic hypogonadism in females become evident. Migraine, psychiatric symptoms, and epilepsy are late manifestations.

By adolescence affected individuals are no longer ambulatory, being dependent on either a walker or wheelchair. The hearing deficit is severe (>100 dB) and communication relies on sign language. Progressive pes cavus foot deformity and neurogenic scoliosis are common, as well as autonomic nervous system dysfunction, which manifests as increased perspiration, difficulty with urination and/or urinary incontinence, and obstipation.

The supratentorial brain (i.e., cerebral cortex, cerebral white matter, basal ganglia, and other deep brain nuclei) is well preserved until the onset of epilepsy. In 15 children, epilepsy developed into a serious encephalopathy, beginning at ages two and four years in those who were compound heterozygotes for the Finnish founder variant and another pathogenic variant, and between ages 15 and 34 years (mean age 24 years) in homozygotes for the Finnish founder variant. The seizures were myoclonic jerks or focal clonic seizures that progressed to epilepsia partialis continua and further to status epilepticus with loss of consciousness and tonic-clonic seizures. Death of nine of these 15 individuals was directly or indirectly related to epilepsy. The oldest individual (without epilepsy) who is homozygous for the Finnish founder variant is alive at age 50 years.

Atypical IOSCA. The clinical course is more rapid and severe in individuals with certain genotypes (see Genotype-Phenotype Correlations) and is characterized by severe early-onset encephalopathy and signs of liver involvement. The clinical manifestations include hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, intractable epilepsy, and elevation of serum transaminases. The liver may show mtDNA depletion, whereas the muscle mtDNA is only slightly affected.

Neuroimaging. The supratentorial findings of cortical edema and later cortical and central atrophy appear at the time of and after the onset of epilepsy. The cortical edema is of a nonvascular distribution. The area of swollen cortex varied from multiple small lesions to the involvement of the whole hemisphere, thalamus, and caudate nucleus. In diffusion-weighted imaging (DWI), the lesions showed restricted diffusion, thus behaving like early ischemic changes. Some of these lesions were reversible, but a T1-weighted hyperintense cortical signal compatible with cortical laminar necrosis developed in individuals with recurrent status epilepticus. Supratentorial cortical and central atrophy was seen in all individuals with intractable status epilepticus, but not in children or adults without refractory epilepsy. Epileptic encephalopathy in IOSCA is similar to that seen in other mitochondrial disorders, including MELAS.

Spinocerebellar degeneration progresses gradually with increasing age. Serial brain MRI imaging reveals cerebellar, cortical, and brain stem atrophy with increased signal intensity in the cerebellar white matter on T2-weighted images [Koskinen et al 1995b].

Neuropathology. Postmortem studies show moderate brain stem and cerebellar atrophy and severe atrophic changes in the dorsal roots, posterior columns, and posterior spinocerebellar tracts of the spinal cord [Koskinen et al 1994a, Lönnqvist et al 1998].

Genotype-Phenotype Correlations

Classic IOSCA. Within and between families, individuals with IOSCA who are homozygous for the c.1523A>G founder variant show similar early-onset symptoms and clinical course, except for the onset of epilepsy [Koskinen et al 1994b].

Atypical IOSCA. Individuals who are not homozygous for the pathogenic Finnish founder variant may have signs and symptoms that develop and progress differently from the "classic" clinical course described above. For example:

Nomenclature

IOSCA was originally known as OHAHA (_o_phthalmoplegia, _h_ypoacusis, _a_taxia, _h_ypotonia, _a_thetosis) syndrome [Kallio & Jauhiainen 1985].

Prevalence

The carrier frequency of the c.1523A>G founder variant varies between 0.44% (1:230) in all of Finland and 2.0%-2.4% (1:50-1:40) in selected sub-isolates in Ostrobothnia and Savo.

Differential Diagnosis

Differential diagnosis for infantile-onset spinocerebellar ataxia (IOSCA) should include all early-onset cerebellar ataxias with sensory axonal neuropathy and epileptic encephalopathy.

The spinocerebellar degeneration in IOSCA is similar to that in Friedreich ataxia and other mitochondrial disorders with axonal neuropathy.

_POLG-_related disorders. POLG, a nuclear gene that encodes mitochondrial DNA polymerase subunit gamma-1, is a functional partner of twinkle in the mtDNA replication fork [Hakonen et al 2007]. This close biologic relationship explains the phenotypic overlap of the disorders caused by TWNK pathogenic variants and those caused by POLG pathogenic variants. Of note, disorders caused by POLG pathogenic variants are more common than disorders caused by TWNK pathogenic variants.

The syndromes associated with biallelic POLG pathogenic variants range from an infantile hepatoencephalopathy (Alpers-Huttenlocher syndrome) to ataxia neuropathy spectrum (ANS) disorders.

Ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, frequent infections, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation.

Diagnosis of A-T relies on clinical findings including slurred speech, truncal ataxia, and oculomotor apraxia; family history; and neuroimaging. Testing that supports the diagnosis includes serum alphafetoprotein concentration (elevated in >95% of individuals with A-T), identification of a 7;14 chromosome translocation on routine karyotype of peripheral blood, the presence of immunodeficiency, and in vitro radiosensitivity assay. A-T is caused by biallelic pathogenic variants in ATM.

IOSCA is distinguished from A-T by: normal chromosome studies, normal immune function, loss of deep-tendon reflexes, early ophthalmoplegia, deafness, and absence of telangiectasias.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with infantile-onset spinocerebellar ataxia (IOSCA), the following are recommended (if not already been completed as part of the evaluation that led to the diagnosis):

Treatment of Manifestations

Treatment is symptomatic:

Surveillance

Small children

Adolescents and adults

Agents/Circumstances to Avoid

Valproate is contraindicated in those with IOSCA, as it is in other disorders that potentially affect mitochondrial function in liver. Valproate caused significant elevation of liver enzymes (alanine aminotransferase: 232 units/L [normal: 10-35 U/L]; gamma-GT: 160 U/L [normal: 5-50 U/L]) and icterus with elevated bilirubin levels (total: 224 μmol/L [normal: 5-25 μmol/L]; conjugated: 160 μmol/L [normal:1-8 μmol/L]) in one affected individual, and similar elevation of liver transaminases in another. When valproate was discontinued, icterus resolved and liver enzymes normalized.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Infantile-onset spinocerebellar ataxia (IOSCA) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

Offspring of a proband. Individuals with IOSCA do not reproduce.

Other family members. Each sib of the proband's parents is at 50% risk of being a carrier of a TWNK pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the TWNK pathogenic variants in the family.

Prenatal Testing and Preimplantation Genetic Testing

Once the TWNK pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

_Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —_ED.

Table A.

Infantile-Onset Spinocerebellar Ataxia: Genes and Databases

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Data are compiled from the following standard references: gene fromHGNC;chromosome locus fromOMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, clickhere.

Molecular Pathogenesis

Infantile-onset spinocerebellar ataxia (IOSCA) is caused by pathogenic variants in TWNK (previously known as C10orf2), a ubiquitously expressed nuclear gene encoding mitochondrial protein isoforms twinkle and twinky [Nikali et al 2005].

Gene structure. The longest TWNK transcript and major splice variant (NM_021830.4) comprises five exons and encodes the protein isoform twinkle (also known as isoform A).

Transcript variant NM_001163812.1 is a minor splice variant that encodes the distinct protein isoform known as twinky (also known as isoform B). This cDNA results from the use of a downstream exon 4 splice-donor site and leads to a 43-base-pair (bp) insertion between the regular exon 4 - exon 5 sequence, which causes a premature stop codon [Spelbrink et al 2001].

For a detailed summary of gene, transcript, and protein isoforms, see Table A, Gene.

Pathogenic variants. All pathogenic variants underlying IOSCA have been observed only in the genetically isolated Finnish population. See Table 3.

To date, 24 individuals with IOSCA have been identified [Nikali et al 2005, Hakonen et al 2007]:

Table 3.

TWNK Pathogenic Variants Discussed in This GeneReview

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DNA Nucleotide Change Predicted Protein Change Reference Sequences
c.1287C>T p.Ala429= 1 NM_021830​.4 NP_068602​.2
c.952G>A p.Ala318Thr
c.1370C>T p.Thr457Ile
c.1523A>G p.Tyr508Cys

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Designates that no variant that changes (or is predicted to change) the protein sequence was found; see Abnormal gene product.

Normal gene product. TWNK was originally cloned and the proteins resulting from the variant splicing of the gene, twinkle and twinky, were characterized by Spelbrink et al [2001]. Twinkle and twinky are nuclear-encoded evolutionarily conserved mitochondrial proteins, twinkle being essentially involved in the maintenance of mtDNA.

Abnormal gene product. The cellular pathogenesis of IOSCA originally remained largely unresolved, and current research has focused mainly on the major splice variant twinkle and the founder variant p.Tyr508Cys, even though the pathogenic variant is also present in the twinky protein.

The following describes the behavior and function of the twinkle protein isoform with the p.Tyr508Cys pathogenic variant.

Small amounts of normal TWNK transcripts are not sufficient to rescue the IOSCA phenotype caused by the c.1523A>G pathogenic variant, whereas a full amount of mRNAs expressed from at least one normal allele is required to preserve the development of a healthy individual [Nikali et al 2005].

Chapter Notes

Author History

Tuula Lönnqvist, MD, PhD (2009-present)
Kaisu Nikali, MD, PhD; University College London (2009-2018)

Revision History

References

Literature Cited