Sensory neuropathy in patients with Pompe disease: a case series in Iran.

Background

Pompe disease, known as acid maltase deficiency is a rare autosomal recessive disorder caused by Acid Alpha-1,4-Glucosidase (GAA) lysosomal enzyme deficiency. Depending on the age of onset and the type of symptoms, it is categorized into Infantile Onset Pompe Disease (IOPD) and Late-Onset Pompe Disease (LOPD) phenotypes [ 1 ]. Cardiac, respiratory, and limb muscles are commonly the most severely impacted, exerting significant influence on clinical outcomes. The administration of enzyme replacement therapy (ERT) has been associated with a shift in the disease phenotype. As patients with longer lifespans experience the natural progression of the condition, novel signs and symptoms may emerge that were not previously observed. These may encompass the involvement of both the central and peripheral nervous systems [ 1 , 2 ].

Previous studies have indicated a reduction in skin innervation in the distal lower limbs of patients with LOPD, along with the presence of numerous small glycogen deposits surrounding both myelinated and non-myelinated axons in mice [ 2 – 4 ]. Despite these findings, there has been limited exploration into both small and large fiber neuropathy in individuals with Pompe disease [ 5 , 6 ]. Small fiber neuropathy affects smaller nerve fibers, causing pain, tingling, and sensitivity. Large fiber neuropathy affects larger nerve fibers, leading to weakness, clumsiness, and balance issues ( Fig. 1 ) [ 3 , 7 ].

With the advent of ERT and an increase in life expectancy, attention to less common symptoms such as neuropathy has grown [ 5 ]. Therefore, this study aimed to assess the presence of concomitant sensory neuropathy of undetermined etiology in IOPD and LOPD patients using the Small Fiber Neuropathy Screening List (SFNSL), SUDOSCAN R , Sympathetic Skin Response (SSR) and sensory Nerve Conduction Study (NCS).

Methods

Study design

This case series recruited patients diagnosed with Pompe disease who underwent Enzyme Replacement Therapy (ERT) at a teaching hospital in Tehran, Iran, from March 2021 to December 2021. Inclusion criteria consisted of: (A) meeting at least two of the following criteria: (1) presence of myopathic changes in muscle biopsy with evidence of glycogen deposition, (2) identification of two pathogenic mutations on the GAA gene via PCR sequencing, and (3) abnormal low GAA enzyme activity measured in at least one tissue [ 5 ], and (B) voluntary participation in the study among patients with Pompe disease referred to the Physical Medicine and Rehabilitation Department. Among the 31 living patients with Pompe disease registered for treatment in Iran, nine patients were ultimately included in the study following evaluation for exclusion criteria, including a medical history of polyneuropathy risk factors (Table 1 ).

Measures

The SFNSL was employed to subjectively assess patients for the presence of Small Fiber Neuropathy (SFN). All documents had been completed by investigator. This questionnaire is often used as a screening tool and can help to identify individuals who may be at risk for or experiencing SFN, and it comprises 21 items, with a total score exceeding 11 indicating a positive screening [ 6 , 8 ]. It typically includes questions about various symptoms associated with SFN, such as pain, numbness, weakness and autonomic dysfunction. Subsequently, NCS were conducted to evaluate large fiber neuropathy based on international clinical and electrodiagnostic criteria. Participants were age-matched to control for potential age-related variations in electrodiagnostic parameters too. Based on the previous research, we have considered the normal range for Sural SNAP latency < 4ms, Sural SNAP amplitude > 10µV, Median SNAP latency < 4.1ms, Median SNAP amplitude > 20µV [ 9 – 13 ]. SSR is defined as the electrical conductivity caused by sweating, showing sympathetic cholinergic function. In this test, a small electrical current is applied to the hand or foot and the nerves response of the sweat glands is measured. This stimulates the sympathetic nervous system, with the normal range in hand between 1.39 and 1.65 s [ 9 ], alongside SUDOSCAN R examinations to evaluate both the peripheral sympathetic autonomic system and SFN [ 14 ]. SUDOSCAN R serves as a non-invasive method for assessing C-fibers function, offering quick and straightforward usability in detecting sweat gland activity in the palms of the hands and feet. During the procedure, participants were instructed to maintain continuous contact with the metal plates of the device for approximately 2 min, refraining from additional movement or vibration [ 15 ].

Ethical considerations

This study was conducted in accordance with the principles outlined in the Declaration of Helsinki and was approved by the Research Ethics Committee of Shahid Beheshti University of Medical Sciences (approval number: IR.SBMU.MSP.REC.1400.068). Informed consent was obtained from all parents, and the patient’s privacy and confidentiality were strictly maintained throughout the study.

Results

The case series included 9 patients (6 males, 3 females) with late-onset Pompe disease (LOPD, n = 5) and infantile-onset Pompe disease (IOPD, n = 4). The patients ranged in age from 2 years to 48 years at the time of study. All patients had initiation of ERT with recombinant human acid α-glucosidase (rhGAA) and most showed subsequent improvement in fatigue and weakness, though the extent of improvement varied.

Genetic analysis revealed pathogenic GAA mutations in 8 of 9 patients, including both previously reported mutations and novel variants. Specific genotypes are detailed in Table 2 .

Seven patients had abnormal small fiber neuropathy screening list (SFNSL) scores indicating possible small fiber involvement. From these patient, one patient had abnormal SSR (patient#1), one patient had abnormal SUDOSCAN R (patient#2) and One patient had sensory axonal neuropathy (patient#5). More comprehensive clinical and genetic data for each patient is provided in Tables 2 and 3 .

Discussion

In this case series study, nine patients with Pompe disease, representing approximately 30% of the total 31 registered patients with Pompe disease in Iran, were examined for sensory neuropathy. Among them, seven patients exhibited positive SFNSL scores, while three patients (3/9, approximately 30%) tested positive on at least one electrophysiological test, including SSR, SUDOSCAN R or NCS. Notably, these three patients also had positive SFNSL scores.

Given the significance of deafness as a symptom in Pompe disease patients, comprehensive evaluations of both the peripheral and central nervous systems are warranted [ 16 , 17 ]. Postmortem histopathological studies in patients with Pompe disease have revealed glycogen accumulation in both the central and peripheral nervous systems, including in dorsal root ganglia, anterior horn cells and peripheral nerves [ 18 , 19 ]. Furthermore, studies in mouse models have shown progressive glycogen accumulation within axons and Schwann cells of peripheral nerves starting at an early presymptomatic stage [ 20 , 21 ]. These postmortem and animal model findings provide evidence of underlying peripheral neuropathy pathology in Pompe disease.

In a study by Monteiro et al. in 2019, three out of six LOPD patients, aged 39, 45, and 52 years, were found to have axonal sensory neuropathy [ 5 ]. Additionally, Enax-Krumova et al. in 2022 identified pain as a common symptom of SFN among LOPD patients, with a high frequency of small nerve fiber pathology observed regardless of pain presence, symptom onset, or duration of ERT therapy, necessitating further investigation into the underlying mechanisms [ 2 ]. These findings align with our study, in which three of seven patients exhibited at least one positive electrophysiological test. However, no distinct commonalities were observed among patients with positive electrophysiological tests or between those with positive questionnaires and negative electrophysiological results. Consequently, the complementary test results were incongruent. Given that the SFNSL questionnaire is heavily reliant on pain symptoms and that myopathic pain may not always correlate with small fiber involvement, this could be a contributing factor to the discrepancies.

In contrast to the Monteiro and Enax-Krumova studies, which exclusively evaluated LOPD, our study considered both LOPD and IOPD. Despite this, no significant disparity in neuropathy prevalence was observed between the LOPD and IOPD groups. Given the high prevalence of positive subjective evaluations (SFNSL scores) in approximately 70% of patients and objective electrophysiological findings in approximately 30%, consistent with previous research [ 2 , 5 , 6 ], comprehensive neuropathy screening and evaluation should be a priority for Pompe disease patients.

Given that patients with positive electrophysiological test results also had higher scores on the SFNSL, it appears that this questionnaire demonstrates good validity and screening value for neuropathies. However, it’s worth noting that this questionnaire is primarily designed for SFN screening [ 8 ]. Further investigation into this relationship is warranted, ideally through studies with larger sample sizes. Additionally, it seems that, in the sample of this study, SUDOSCAN R may not have been ideal due to the physical particularities of patients with Pompe disease.

Since all patients exhibit less than 1% enzyme activity, there appears to be no association between enzyme activity levels and neuropathy. Furthermore, it was noted that Iranian patients with Pompe disease exhibit a wide variety of mutations, making it challenging to evaluate neuropathy and determine prevalence based on specific genetic mutations. Consequently, broader studies focusing on enzyme activity and genetic mutations are strongly recommended.

Genetic analysis revealed pathogenic GAA mutations in the majority of patients, including both previously reported mutations and novel variants. For example, patient 2 harbored two heterozygous mutations, with the c.-32-13T > G mutation previously identified in 36–90% of adult-onset GSDII patients [ 22 , 23 ] and the c.2560 C > T nonsense mutation commonly seen in both GSDII and infantile-onset Pompe disease [ 24 – 26 ]. Patient 3 carried the common c.-32-13T > G mutation along with c.258dup , a frameshift variant classified as pathogenic in multiple reports [ 25 , 27 , 28 ]. Patient 4 had homozygous c.2015G > A , described as pathogenic in prior studies [ 29 , 30 ]. Patient 6 possessed homozygous c.896T > C , a known pathogenic variant associated with < 10% of normal GAA activity [ 31 – 33 ]. Lastly, patient 7 had the novel c.2078dup variant, which was recently reported to segregate with disease in a GSDII patient [ 34 ] and is predicted to cause loss of function according to ACMG criteria. Overall, these genetic findings demonstrate the diversity of mutations underlying our cohort of patients with Pompe disease as well as the presence of both common and rare pathogenic variants. Further genotype-phenotype analyses in larger patient samples are needed.

Our study represents a pioneering investigation into sensory neuropathy in both infantile and late-onset Pompe disease, encompassing a broad range of patient ages. However, certain limitations were encountered. Due to logistical constraints and patient refusal, skin biopsies for intraepidermal fiber density quantification and quantitative sensory testing (QST) were not obtained. These procedures are integral components of SFN diagnosis [ 35 ]. Consequently, our conclusions primarily relied mostly on the pain scale and tests that may not fully capture the characteristic features of SFN and neuropathy was indicated by a limited number of laboratory findings. Future studies could address these shortcomings by incorporating intraepidermal small fiber quantification and quantitative sudomotor axon reflex test (QSART) [ 36 ]. Additionally, a small sample size resulted from patient physical limitations, geographic distance, the COVID-19 pandemic, and infection concerns. To mitigate these limitations, multicenter studies conducted across various geographical regions are recommended by considering genotype and other relevant factors. Such studies can facilitate a more accurate diagnosis of SFN through a combination of questionnaire assessments and electrodiagnostic studies in the management of patients with Pompe disease (Fig. 1 ). Once SFN is identified, implementing appropriate treatment strategies can greatly enhance patient’s quality of life. Figure 2 summarizes various treatment options that have been proposed for SFN to effectively manage symptoms [ 37 ].

Conclusion

Our findings underscore the importance of recognizing sensory fiber neuropathy as a comorbid condition in patients with Pompe disease. Given the advent of Enzyme Replacement Therapy (ERT) and the consequent increase in life expectancy, timely screening using available methods such as questionnaires, physical exams, or electrodiagnostic studies is crucial for preventing potential debilitating conditions.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

Not applicable.

Abbreviations

Creatine kinase

Enzyme replacement therapy

Acid alpha-1,4-glucosidase

Infantile-onset pompe disease

Late-onset pompe disease

Recombinant human acid alpha-glucosidase

Small fiber neuropathy

Small fiber neuropathy screening list

Sympathetic skin response

Author contributions

M.B., S.M.R., H.L. and M.B. contributed to the research design. M.R. and M.B. collected clinical samples and performed the experiments. V.Z. analyzed the data. M.R., M.B. and S.D. wrote the manuscript. M.R., M.B. and H.L. gave final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All the authors reviewed and approved the final version of the manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study was conducted in accordance with the principles outlined in the Declaration of Helsinki and was approved by the Research Ethics Committee of Shahid Beheshti University of Medical Sciences (approval number: IR.SBMU.MSP.REC.1400.068). Informed consent was obtained from parents and patients, and the patient’s privacy and confidentiality were strictly maintained throughout the study.

Consent for publication

We did not use any identifying images or other personal or clinical details of participants that could compromise their anonymity. Therefore, this item is not applicable to this study. We confirm that all authors listed in the manuscript are aware of the submission and have agreed to submit the paper to this journal.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Supplementary Materials

Supplementary Material 1

Data Availability Statement

No datasets were generated or analysed during the current study.