Discussion

SCAs are genetically heterogeneous group of neurodegenerative diseases, and there are over 40 distinct subtypes of the disease. They are usually characterized by progressive gait disturbance, limb incoordination, and cerebellar dysarthria with a wide variability in the constellation of symptoms according to the underlying gene defect. Autosomal recessive spinocerebellar ataxias (SCARs), which are lower than the autosomal dominant forms, are increasingly recognized with the advent of next-generation sequencing technologies. Among them, spinocerebellar ataxia type 27 (SCAR27) is linked to a pair of mutations (doublets) in the gene GDAP2, which was relatively recently described and which is a bit of a gene that just started to make physiological sense [6,19].

Patients with GDAP2-associated ataxia typically start experiencing symptoms in adolescence or early adulthood and include symptoms such as instability with walking, dysarthria, and other signs seen in cerebellar dysfunction. In several cases, clinical worsening is accompanied by spasticity, cognitive impairment, and structural cerebellar atrophy on MRI. However, there is an important phenotypic variability. The case here is interesting in that it shows the predominance of progressive dysarthria over several years, with subtler cerebellar ataxia and normal neuroimaging during earlier stages of the disease.

Such a presentation is not the usual course of the hereditary ataxias. Often, the gait disturbance is the earliest and most disability-causing feature. The predominance of GDAP2 mutations points to the heterogeneous nature of the expression of the GDAP2 mutation and indicates a predisposition of definite cerebellar circuits to disease in certain genetic backgrounds, especially those connected with motor speech coordination.

Comparison with the reported literature

Since it was first described, the phenotypic spectrum of GDAP2-associated spinocerebellar ataxia has been reported in very few instances. Breza et al. (2020) studied homozygous GDAP2 mutations, which were found to cause juvenile-onset cerebellar ataxia, characterized by prominent gait instability and dysarthria, and the disease mechanism was determined to be a loss of function [20]. They made multiple points about variable presentations that manifest between adolescent and adult onset, which were often characterized by cerebellar atrophy on MRI and, in some cases, cognitive impairment [21]. GDAP2-related ataxia has been reported with variable clinical presentations, including adult-onset cerebellar ataxia [20].

The common idea in these reports is that gait ataxia and limb incoordination are usually the first and most debilitating manifestations, and dysarthria, albeit frequently, is often comorbid but not overriding. Conversely, the current case has shown a phenotype of dysarthria being more prominent and dominant over a span of several years before gait disturbance, which highlights the heterogeneity of the GDAP2-related disease expression. The outcomes of neuroimaging are also dissimilar. In the majority of the reported cases, cerebellar atrophies were severe. Still, MRI was confirmed as normal in this patient, even after years of symptom experience had passed, which indicated any structural change might be delayed by impaired relative functionalization, and even absent in some [21]. Furthermore, it did not have the extra-cerebellar manifestation (i.e., spasticity or cognitive impairment) as described in other cohorts and was not evident in this instance, which suggests a milder clinical outcome.

The frequency of all these comparisons demonstrates that GDAP2 mutations can lie in the range of the extreme clinical phenotypes, including intractable early-onset ataxia and neuroimaging abnormalities, as well as milder phenotypes with isolated dysarthria. This underlines the need to document the atypical cases so as to concentrate on the genotype-phenotype relationship and also to identify SCAR27 in other clinical locations.

Diagnostic challenges

Middle-aged progressive dysarthria is typically attributed to more common conditions such as cerebrovascular disease, motor neuron disease, or demyelinating disorders. The first impression, once created by routine imaging and neurophysiological tests in the given case, was indicative of a hereditary ataxia.

Usually, the family members carry similar findings and course progression, which is not found in this case. Despite such indications, genetic testing should also be an earlier diagnostic tool for clinicians, particularly in the case of people who develop neurological disease with a previous history in their family [22].

Genotype-phenotype correlation

The range of the clinical manifestations of GDAP2 mutations leads to significant concerns about how the phenotypes and the genes are related [23]. Patients have shown evident variations in the age of onset and in the distribution of clinical manifestations, even though the protein activity of GDAP2 is always compromised [24]. In cases where mutations are confirmed as loss-of-function, such mutations consistently initiate the disease process and drive its progression. In some individuals, cerebellar atrophy appears on MRI, with juvenile-onset cerebellar ataxia and a fast course, and in other individuals in middle adulthood with partially isolated dysarthria or gradually progressive gait instability [25]. This broad range implies that other genetic, epigenetic, or environmental factors contribute to the development of the illness, rather than being determined by the presence of the mutation [2].

The modification of mitochondrial activity, oxidative stress response, or synaptic communication can elevate or mitigate the role of GDAP2 malfunction using modifier genes. Although environmental exposures (such as lifestyle, pollutants, or co-morbid medical conditions) may influence the course of disease progression, epigenetic factors, including DNA methylation and histone modification, may further determine neuronal susceptibility [26]. However, the current situation emphasizes the need to carefully record new variants and related phenotypes to improve the associations between the phenotype and the genotype. Such information may help doctors to forecast the most likely clinical outcome and improve the predictive power of genetic counseling. Moreover, a new set of presentations to the collection offers meaningful new information on selective cerebellar vulnerability and helps to guide customized treatment provisions. Therefore, the sensitivity of the diversity of SCAR27 is not only important in diagnosing it appropriately, but also in the direction of future research and family therapy [10].

Clinical implications

There are several practical implications associated with the identification of a new GDAP2 mutation. First, it extends the phenotypic range of SCAR27 to include phenotypes where progressive dysarthria may be the onset of gait ataxia. This is why clinicians should never overlook the possibility of hereditary ataxia among patients with progressive speech disorders. Second, the exclusion criterion is not restricted to the imaging abnormalities, in terms of considering a genetic diagnosis. Third, the case highlights the importance of family history: the discovery of an affected sibling was also important to begin the diagnostic process.

Genetic confirmation also has implications for patient care, and the same applies to family counseling. Even though there is no curative prophylaxis, due to appropriate diagnosis, it provides psychological closure, prognosis, and helps one decide concerning reproduction. Moreover, patients with a genetic diagnosis will be able to join clinical trials or such research opportunities that explore the specific background for ataxia therapies.

Broader research and therapeutic perspectives

In research terms, further studies where GDAP2 variants are reported help maintain a more extensive picture of the role of the gene in cerebellar functioning and neurodegeneration. The role of GDAP2 in adaptation to stress and mitochondrial homeostasis is rather clear; however, the specific mechanism of stress adaptation remains unclear. Additional functional investigations would also be required to interpret the causes of the listed mutations to produce selective weakness of cerebellar neurons.

Clinically, an understanding of the involvement of stress-response mechanisms in GDAP2-related ataxia creates the possibility of an intervention to improve neuronal tolerance to oxidative stress. Although the present management approach is favorable, potential future therapeutic approaches involve gene replacement, RNA-based therapies to overcome nonsense mutations, or pharmacological compounds to enhance mitochondrial performance and stress adaptation mechanisms.

Limitations of the case

Like all case reports, there are some limitations. Genetic testing was confined to the proband, and there was no segregation testing of other family members. There were no functional studies that directly tested the nature of the effect of the identified mutation on protein expression. However, the clinical picture, positive genetic mutation in two symptomatic siblings, and classification of the variant as potentially pathogenic are strong reasons to assert its role in the occurrence of the disease.