Clinical characteristics.

Spinocerebellar ataxia type 4 (SCA4) is a progressive neurologic disease characterized by cerebellar involvement (gait ataxia, balance disturbances, eye movement abnormalities), brain stem involvement (dysarthria, dysphagia), sensory neuropathy, motor neuron involvement (muscle wasting and spasticity), autonomic dysfunction (especially orthostatic hypotension), and cognition and/or behavior manifestations. Age of onset ranges from 12 to 65 years. In the approximately 10% of individuals whose onset is before age 25 years disease manifestations are more severe and often different from those with later-onset disease. As the disease progresses, particularly in those with early-onset disease, eye movement abnormalities, dysarthria, dysphagia, sensory neuropathy, upper and lower motor neuron involvement, and orthostatic hypotension can further aggravate balance and gait problems. Most individuals eventually require a walker or wheelchair. Reduced life expectancy in individuals with earlier-onset severe SCA4 is associated with weight loss, infections, and cardiac arrhythmia. Life expectancy is normal or near normal in individuals with later-onset SCA4.

Diagnosis/testing.

The diagnosis of SCA4 is established in a proband with suggestive findings by the identification of a heterozygous abnormal trinucleotide GGC repeat expansion in the terminal exon of ZFHX3 by molecular genetic testing.

Management.

Treatment of manifestations: Multidisciplinary care by neurologists (possible pharmacologic treatment of ataxia); physical therapists (maintain mobility and function); occupational therapists (optimize activities of daily living); speech-language therapists (optimize communication, including augmentative and alternative communication as needed); neuro-ophthalmologists (counsel to minimize impact of eye movement abnormalities); nutritionists and occupational therapists (manage dietary needs and consider need for gastrostomy tube placement); neurologists and neurorehabilitation specialist (manage autonomic dysfunction); and mental health specialists (manage mood disorders and changes in cognition and/or behavior).

Surveillance: Monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations via routine evaluations as recommended by the treating clinicians.

Agents/circumstances to avoid: Medications that (1) further reduce cerebellar function, including drinking alcohol and use of sedating drugs; and (2) exacerbate orthostatic hypotension such as large carbohydrate-rich meals and dehydration.

Genetic counseling.

SCA4 is inherited in an autosomal dominant manner. Most individuals diagnosed with SCA4 have an affected parent. As anticipation is common in SCA4, the affected parent frequently has milder disease with a later age of onset than their affected offspring. Each child of an individual with SCA4 has a 50% chance of inheriting an abnormal GGC repeat expansion in ZFHX3. Once a pathogenic ZFHX3 GGC repeat expansion has been identified in an affected family member, predictive testing for at-risk family members and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

Spinocerebellar ataxia type 4 (SCA4) should be considered in probands with the following clinical and imaging findings and family history [Maschke et al 2005, Wictorin et al 2014, Chen et al 2024, Figueroa et al 2024, Paucar et al 2024, Wallenius et al 2024a].

Establishing the Diagnosis

The diagnosis of SCA4 is established in a proband with suggestive findings by the identification of a heterozygous abnormal exonic trinucleotide GGC repeat expansion in the terminal exon (exon 10 of 10 in MANE transcript NM_006885.4) of ZFHX3 by molecular genetic testing (see Table 1 and Table 6). (For more information on MANE transcripts, see www.ncbi.nlm.nih.gov/refseq/MANE.)

Note: Pathogenic GGC repeat expansions in ZFHX3 are not reliably detected by standard sequence-based multigene panels, exome sequencing, or genome sequencing and may require specific bioinformatic methods for their detection (see Molecular Genetics, ZFHX3 technical considerations).

Repeat sizes. To date, ZFHX3 GGC repeat lengths have been reliably characterized by long-read sequencing in 35 persons with SCA4 [Chen et al 2024, Figueroa et al 2024, Paucar et al 2024, Wallenius et al 2024a, Wallenius et al 2024b] and by PCR fragment analysis in nine unrelated individuals with SCA4 [Dalski et al 2024]; thus, the repeat ranges provided here will likely be modified as molecular tools and detection methods evolve.

• Normal: Fewer than 31 GGC repeats (most common length: 21 repeats, including non-GGC interruptions)
• Intermediate: Range from 31 to 41 GGC repeats. Note: To date, there is insufficient evidence that intermediate repeats are pathogenic.
• Pathogenic (high penetrance): 42 or more GGC repeats (no interruptions). Note: To date, the smallest number of GGC repeats that is pathogenic has not been well defined.

Note: (1) Normal alleles always contain interruptions in the regularly repeated GGC sequence that encodes glycine. The most common normal allele includes one AGT triplet (encoding serine, or a "serine interruption") and two GAC triplets (also encoding glycine); however, many different variations have been observed in normal alleles [Wallenius et al 2024a, Table S5]. Together, these interruptions are referred to as "non-GGC interruptions." (2) Intermediate alleles have been observed in only a few individuals to date; thus, no conclusions about their composition can be drawn. (3) Pathogenic alleles are composed of pure GGC repeats and do not contain non-GGC interruptions to date.

Molecular genetic testing relies on specific tools to characterize the size and purity of ZFHX3 GGC repeat expansions. Based on current knowledge and molecular methods, the authors propose a two-tiered testing approach:

1.

Short-read whole-genome sequencing. Short-read whole-genome sequencing-based tools developed for the detection of nucleotide repeat expansions have led to the identification of exonic GGC repeats in the terminal exon of ZFHX3 [Ibañez et al 2022, Chen et al 2024, Figueroa et al 2024, Paucar et al 2024, Wallenius et al 2024a].

2.

Long-read sequencing or PCR fragment analysis. Long-read sequencing is likely the most reliable method for the detection of ZFHX3 GGC repeat expansions [Figueroa et al 2024, Wallenius et al 2024b], especially if SCA4 cannot be ruled out by analysis of short-read data or if the exact number of expanded repeats needs to be determined. Recently, PCR fragment analysis was described as an orthogonal method to detect pathogenic repeat expansions in ZFHX3 and determine their length [Dalski et al 2024].

For further information, see Molecular Genetics, ZFHX3 technical considerations.

Clinical Description

Spinocerebellar ataxia type 4 (SCA4) is a progressive neurologic disease characterized over time by cerebellar / brain stem involvement, sensory neuropathy, upper and lower motor neuron involvement, and autonomic dysfunction as well as less common signs and symptoms including weight loss.

To date, more than 200 affected individuals have been identified in families with SCA4. For many reports only historical information is available; however, several publications have provided information on modern genetic studies and more detailed clinical information on individuals and kindreds described previously [Flanigan et al 1996, Hellenbroich et al 2003, Maschke et al 2005, Hellenbroich et al 2006, Wictorin et al 2014]. Recently, clinical assessments on more than 50 individuals have been reported [Chen et al 2024, Dalski et al 2024, Figueroa et al 2024, Paucar et al 2024, Wallenius et al 2024a]. Among these reports, the extent of the assessments and descriptions of disease signs and symptoms differ. The following description of the phenotypic features of SCA4 is based on these reports.

Age of onset of initial manifestations of SCA4 reported to date ranges from 12 to 65 years. Compared to individuals with milder, later-onset disease, those with early-onset disease (i.e., before age 25 years) develop more severe and often different manifestations.

Genotype-Phenotype Correlations

Genotype-phenotype correlations to date are preliminary as data are only available on 35 individuals with SCA4 whose repeat sizes have been studied by long-read sequencing [Chen et al 2024, Figueroa et al 2024, Paucar et al 2024, Wallenius et al 2024a, Wallenius et al 2024b] and 26 individuals studied with PCR fragment analysis [Dalski et al 2024].

Age of onset correlates inversely with the GGC repeat size; however, the correlation is not perfect, suggesting that unidentified additional genetic or non-genetic factors may also affect the age of onset.

• The longest pathogenic repeat, 74 GGC repeats, was observed in an individual whose balance disturbances started at age 15 years.
• The shortest pathogenic repeat, 44 GGC repeats, was observed in an individual whose disease onset was at age 60 years.

Larger GGC repeat sizes are associated with more severe disease manifestations, faster disease progression, poorer outcome, and shorter life expectancy. Exact cutoffs for large GGC repeat size causing severe manifestations has not been determined; however, it is likely that a gradual increase in disease severity is observed with increasing repeat sizes.

Some disease manifestations have only been observed in individuals with younger-onset disease who have longer repeat expansions, including very severe orthostatic hypotension that make erect or seated positions impossible, clinically relevant cognitive or behavioral changes that may remain mild or might include autism spectrum disorder [Wallenius et al 2024a], and reduced life expectancy.

Penetrance

To date, ZFHX3 repeats with 42 or more GGC triplets have only been found in individuals with SCA4, whereas more than 46,000 alleles from individuals without SCA4 had at the most 30 GGC triplets, suggesting high, possibly complete, penetrance of expanded repeats with 42 triplets or more.

Penetrance is age dependent, with onset between ages 12 and 65 years in all individuals with SCA4 reported to date.

Intergenerational Instability

Anticipation (earlier disease onset in successive generations) has been observed in many families; however, some children developed disease manifestations at a later age than their affected parents [Chen et al 2024, Dalski et al 2024, Figueroa et al 2024, Paucar et al 2024, Wallenius et al 2024a].

In five families for which individual-level data on age at onset was published, affected children developed manifestations of SCA4 one to 30 years earlier (mean: 10.1 years; standard deviation: 7.5 years) than their affected parents; two children developed manifestations seven and nine years later than their affected parent [Wallenius et al 2024a]. In other reports, affected children developed manifestations of SCA4 an average of 5.2 years [Flanigan et al 1996], 11 years [Dalski et al 2024, Paucar et al 2024], or 21.6 years earlier than their affected parents. Ascertainment or reporting biases may have affected these observations.

No difference in anticipation between maternal and paternal transmission was observed.

Increasing repeat length with parent-to-child transmission has been described in several instances [Dalski et al 2024, Figueroa et al 2024, Wallenius et al 2024b] and likely explains the tendency of the disease to manifest at a younger age in children of affected parents (anticipation). Future studies may be able to determine the degree of intergenerational instability more accurately (see Molecular Genetics).

Nomenclature

SCA4 was previously referred to as "spinocerebellar ataxia, autosomal dominant, with sensory axonal neuropathy" or "autosomal dominant cerebellar ataxia with slow ocular saccades, neuropathy and orthostatism." These terms are no longer in use.

Prevalence

To date, ZFHX3 repeat expansions have been described in more than 200 affected individuals from 26 families or kindreds [Chen et al 2024, Dalski et al 2024, Figueroa et al 2024, Paucar et al 2024, Wallenius et al 2024a]. While these studies included evaluation of several large and previously described pedigrees, at least 18 probands or smaller families were identified in a relatively short time after the disease-causing genetic variants became known.

To date, all reported families with ZFHX3 GGC repeat expansions have originated from Sweden (many from the limited geographic area of Skåne, the southernmost region of Sweden) or Germany (particularly northern Germany), suggesting a founder event [Chen et al 2024, Dalski et al 2024, Figueroa et al 2024, Wallenius et al 2024a]. Likely, the founder event is the (successive) loss of the non-GGC interruptions by spontaneous mutational events over many generations [Wallenius et al 2024a]. This is compatible with the inability to establish genealogical links between the families described despite intense attempts [A Puschmann, personal observations] and the fact that members in the oldest generations of several known pedigrees remained clinically unaffected.

No pathogenic ZFHX3 GGC repeats were found in 76 persons with undiagnosed ataxia from Brazil or in 258 persons with unexplained ataxia and 411 persons with multiple system atrophy from Hokkaido, Japan [Matsushima et al 2024, Novis et al 2024, Shirai et al 2024], indicating that SCA4 is rare in these populations.

To date, no pathogenic ZFHX3 GGC repeats have been identified in datasets of individuals with ataxia in other populations; however, information is lacking on the exact population background of these individuals.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SCA4, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for SCA4. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Agents/Circumstances to Avoid

Persons with SCA4 can be advised to avoid the following:

• Drinking alcohol, which can further reduce cerebellar function, especially if excessive
• Sedating drugs, which may reduce cerebellar function
• Any other agents that may impair balance or lower blood pressure
• Large carbohydrate-rich meals, as they may cause postprandial hypotension and exacerbate orthostatic decreases in blood pressure
• Dehydration, especially in high ambient temperatures, as it may exacerbate hypotension

The benefit of the use of diuretics or antihypertensive agents needs to be balanced against the risk of increasing orthostatic hypotension [Wieling et al 2022].

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 access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Spinocerebellar ataxia type 4 (SCA4) is inherited in an autosomal dominant manner.

Anticipation (earlier disease onset in successive generations) has been observed in many families and is an important issue to address when counseling family members of individuals with SCA4 (see Intergenerational Instability).

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with SCA4 have an affected parent. As anticipation is common in SCA4, the affected parent frequently has milder disease with a later age of onset than their affected offspring.
• To date, only one individual diagnosed with SCA4 represents a simplex case (i.e., the only affected family member) [Figueroa et al 2024]. Based on data available to date, it is possible that an unaffected parent of a proband with SCA4 may have lost non-GGC interruptions in the regularly repeated ZFHX3 GGC sequence resulting in GGC repeat instability and expansion; however, this not been observed empirically (see Establishing the Diagnosis).
• A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, de novo occurrence of an abnormal GGC repeat expansion in ZFHX3 in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has an abnormal GGC repeat expansion in ZFHX3.

Sibs of a proband. Risk to sibs of a proband depends on the clinical/genetic status of the proband's parents:

• If a parent has an abnormal GGC repeat expansion in ZFHX3, the risk to each sib of inheriting an allele with an expanded GGC repeat is 50%. Because anticipation and intergenerational instability have been reported in SCA4, a sib may inherit a ZFHX3 allele with more GGC repeats than the transmitting parent. Longer repeat expansions are associated with earlier age of onset and a more severe phenotype; however, these correlations are not perfect and additional factors also play a role (see Genotype-Phenotype Correlations).
• If a parent has an intermediate number of repeats (i.e., approximately 31-41 GGC repeats), the parent is not likely to display manifestations of SCA4; however, the repeat size may expand on transmission to offspring and the risk to each sib is increased (see Intergenerational Instability). Note that to date clinical descriptions of individuals with intermediate repeats are not available.
• If the genetic status of the parents is unknown and:
  • There is more than one affected family member, the risk to each sib is presumed to be 50%.
  • The proband represents a simplex case (rare in SCA4 and most likely observed in individuals who develop SCA4 late in their lives), the risk to sibs cannot be quantified but is presumed to be increased.

Offspring of a proband

• Each child of an individual with SCA4 has a 50% chance of inheriting an abnormal GGC repeat expansion in ZFHX3.
• The likelihood that an abnormal ZFHX3 GGC repeat will expand further on transmission from a proband to offspring (resulting in an earlier age at onset in offspring compared with the proband) is much greater than the likelihood of later disease onset in offspring. Differences in repeat sizes between probands and offspring appear to be independent of the affected parent's sex (see Intergenerational Instability).

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent lacks non-GGC interruptions in the repetitive GGC DNA sequence or has a GGC repeat size in the pathogenic range, the parent's family members may be at risk.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once an abnormal ZFHX3 GGC repeat size has been identified in an affected family member.
• Such testing should be performed in the context of formal genetic counseling and is not useful in reliably predicting age of onset, severity, type of manifestations, or rate of progression in asymptomatic individuals.
• Potential consequences of such testing (including, but not limited to, psychological consequences and the perceived need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. Such counseling needs to take into account that there may be wide individual, societal, and legislative differences with regard to which consequences might arise after genetic testing of asymptomatic individuals.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years) for typically adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality should be discussed in the context of formal genetic counseling. The autonomy of the minor is a primary concern and consideration should be given to delay of predictive genetic testing until the at-risk individual is capable of informed decision making.

In a family with an established diagnosis of SCA4, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once a pathogenic ZFHX3 GGC repeat expansion has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: Age of onset, severity, and progression of SCA4 are variable and cannot be reliably predicted by the family history or prenatal molecular genetic testing results.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate.

Molecular Pathogenesis

ZFHX3 encodes zinc finger homeobox protein 3 (ZFHX3; previously called ATBF1), a transcription factor that is moderately to highly expressed in the brain, spine, and endocrine tissue (thyroid) and variably expressed in many other tissues. In the nervous system, it has known roles in neuronal differentiation as well as protecting cerebellar neurons from oxidative stress [Ishii et al 2003, Jung et al 2005, Kim et al 2010]. RNA expression is highest in arteries and low in the adult brain; however, prenatally it reaches high expression in several regions in the developing brain [Pérez Baca et al 2024].

ZFHX3 comprises four homeodomains and 23 zinc finger motifs. In its terminal exon (exon 10 of 10 in MANE transcript NM_006885.4), ZFHX3 has a variable GGC repeat that encodes polyglycine; expansion of this repeat is associated with disease. (For more information on MANE transcripts, see www.ncbi.nlm.nih.gov/refseq/MANE.)

Neuropathologic findings and possible cellular pathomechanisms. Neuropathologic findings, reported in five persons with spinocerebellar ataxia type 4 (SCA4), include cell loss in the cerebellum (particularly of Purkinje cells), brain stem, and spinal alpha motor neurons. Volume loss has also been observed in the posterior columns of the spinal cord and/or spinocerebellar tracts [Hellenbroich et al 2006, Figueroa et al 2024, Paucar et al 2024, Wallenius et al 2024a]. Sensory impairment corresponds to the degeneration of the posterior columns and/or spinocerebellar tracts of the spinal cord observed in nerve conduction studies, MRI, and neuropathology.

Many affected neurons have p62-positive inclusions, mostly in the nucleus but also in the cytoplasm [Figueroa et al 2024, Paucar et al 2024, Wallenius et al 2024a]. Similar p62-positive inclusions containing polyglycine-rich protein have been found in the other known polyglycine disorders (such as neuronal intranuclear inclusion disease [OMIM 603472], fragile X tremor/ataxia syndrome, or oculopharyngodistal myopathies) [Liufu et al 2022, Zhang et al 2024]. Thus, the polyglycine domains of mutated ZFHX3 may increase aggregation of ZFHX3. In cell models, GGC expansions increase ZFHX3 protein levels and cause abnormalities in autophagy [Figueroa et al 2024].

Mechanism of disease causation. Gain of function

ZFHX3 technical considerations

• Sequence of repeat. GGC trinucleotide repeat expansion in ZFHX3 encoding a polyglycine
• Intergenerational instability. Non-expanded alleles typically consist of 18 GGC repeats, two synonymous GGT repeats, and a single non-synonymous AGT interruption. The GGT repeats also encode glycine but interrupt the repetitive GGC DNA sequence. Normal alleles therefore result in a protein with 20 glycine residues interrupted by a single serine at position 7 [Wallenius et al 2024a]. Loss of these interruptions within this region is hypothesized to predispose to allele expansion from generation to generation.
  Note: Some of the oldest generations in SCA4 families were not known to have neurologic manifestations (molecular data are not available for these individuals). However, these families are known to share a common founder, suggesting that the founder event may have been the elimination of non-GGC interruptions in ZFHX3 [Chen et al 2024, Dalski et al 2024, Figueroa et al 2024, Wallenius et al 2024a].

Methods to characterize ZFHX3 GGC repeats. Due to the technical challenges of detecting and sizing the ZFHX3 GGC repeat expansions, multiple methods may be needed to rule out SCA4 or to detect and accurately size an expanded ZFHX3 GGC allele.

• Repeats in the normal range (below 31 GGC repeats) can often be detected in short-read exome and genome data.
• Methods to detect and approximate the size of expanded repeats (42 or more GGC repeats) include the following methods [Chen et al 2024, Dalski et al 2024, Figueroa et al 2024, Paucar et al 2024, Wallenius et al 2024a, Wallenius et al 2024b]:
  • Whole-genome sequencing (short-read sequencing with customized analytic tools)
  • Exome sequencing or sequencing-based multigene panels including ZFHX3, if read lengths are sufficient (150 bp) and if appropriate or customized analytic tools are used
  • Long-read sequencing has been shown to reliably detect the presence of a pathogenic repeat expansion and accurately quantify repeat length for all repeat expansions identified to date.
  • PCR fragment analysis has recently been shown to accurately determine repeat lengths [Dalski et al 2024].

Normal-length alleles can be confirmed in whole-genome, exome, and sequence-based multigene panels that include ZFHX3 (e.g., to rule out SCA4). Pathogenic ZFHX3 GGC repeat expansions have been identified using short-read exome or genome sequencing when specific analytic tools for the detection of repeat expansions were used [Ibañez et al 2022, Figueroa et al 2024, Wallenius et al 2024a]. The ability of these methods to correctly determine read length depends on the specific methods and analytic tools used by the genetic testing laboratory, and on the length of the individual's GGC repeat. Bioinformatic methods have been developed that either use a sequence with the most common non-GGC interruptions as reference or look for sequences with pure GGC repeats, as in pathologically expanded alleles; these methods can complement each other. Furthermore, visual inspection by a bioinformatician for the presence or absence of non-GGC interruptions can aid in diagnosis [Wallenius et al 2024a].

By contrast, automated analytic pipelines can be insufficient to analyze for ZFHX3 repeats in short-read data. Pre-test inquiry with the genetic laboratory is recommended when use of short-read (conventional) exome or whole-genome sequencing, or reanalysis of short-read exome or genome data, is considered.

A crucial factor in the detection ability of standard sequencing-based methods is a read length of at least 100 bp or more to ensure accurate mapping of expanded alleles. Although such testing can detect an expanded GGC repeat, it is typically unable to accurately determine the number of repeats. To date, sequencing methods with read lengths below 150 bp have not been able to reliably detect an expansion, although the loss of non-GGC interruptions is reliably detected.

The detection of non-GGC interruptions can probably exclude the diagnosis of SCA4 even when the exact number of repeat units has not been accurately determined. Conversely, lack of non-GGC interruptions may indicate a possible diagnosis of SCA4 and may prompt validation with additional methods.

Detailed evaluation of all available data from single-molecule long-read sequencing suggests that the exact length of expanded repeats may differ slightly between blood cells of an individual with SCA4 (due to either mosaicism or technical reasons). This can make it impossible to define one single repeat length for an individual; rather, one individual may have a range of repeat lengths in a blood sample. However, this range is relatively narrow, and in all 35 individuals with SCA4 analyzed by long-read sequencing to date, it was possible to determine clearly if repeats were pathogenically expanded or not [Chen et al 2024, Figueroa et al 2024, Wallenius et al 2024a, Wallenius et al 2024b].

Author Notes

The authors work within the Clinical Neurogenetics Research group at Lund University and Skåne University Hospital in Lund, Skåne, Sweden, where they have identified several families with spinocerebellar ataxia type 4 (SCA4) and continue to follow them clinically and perform genetic analyses. Drs Sorina Gorcenco, Andreas Puschmann, and Klas Wictorin are neurologists, Dr Sigurd Dobloug is a resident in neurology, and Joel Wallenius, MSc, is a bioinformatician.

Dr Andreas Puschmann ([email protected]) is actively involved in clinical research regarding individuals with SCA4. He would be happy to communicate with persons who have any questions regarding diagnosis of SCA4 or other considerations.

Contact Dr Andreas Puschmann to discuss any findings of intermediate ZFHX3 GGC repeat expansions, or individuals with other types of ZFHX3 variants (missense, nonsense, copy number variants) who have ataxia, neuropathy, or dysautonomia.

Acknowledgments

We are grateful to the families with SCA4 from Skåne, Sweden, who have participated in our research studies. Many neurologists at our center have through the years contributed valuable clinical information on the phenotype of SCA4 in these individuals. Bioinformatician and medical geneticist Efthymia Kafantari has contributed to many bioinformatic analyses that ruled out alternative causes for the disorder in our SCA4 families. We thank Region Skåne, Lund University, and MultiPark, a strategic research area at Lund University, as well as others, for financial and institutional support.

Revision History

• 12 December 2024 (bp) Review posted live
• 18 June 2024 (ap) Original submission

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