Journal of Neuromuscular Diseases

Generally, neuropathies of peripheral nerves are a frequent condition (prevalence 2–3%) and most frequently due to alcoholism, diabetes, renal insufficiency, malignancy, toxins, or drugs. However, the vast majority of neuropathies has orphan status. This review focuses on the etiology, frequency, diagnosis, and treatment of orphan neuropathies.

Literature review

Rareness of diseases is not uniformly defined but in the US an orphan disease is diagnosed if the prevalence is <1:200000, in Europe if <5:10000. Most acquired and hereditary neuropathies are orphan diseases. Often the causative variant has been reported only in a single patient or family, particularly the ones that are newly detected (e.g. SEPT9, SORD). Among the complex neuropathies (hereditary multisystem disorders with concomitant neuropathies) orphan forms have been reported among mitochondrial disorders (e.g. NARP, MNGIE, SANDO), spinocerebellar ataxias (e.g. TMEM240), hereditary spastic paraplegias (e.g UBAP1), lysosomal storage disease (e.g. Schindler disease), peroxisomal disorders, porphyrias, and other types (e.g. giant axonal neuropathy, Tangier disease). Orphan acquired neuropathies include the metabolic neuropathies (e.g. vitamin-B1, folic acid), toxic neuropathies (e.g. copper, lithium, lead, arsenic, thallium, mercury), infectious neuropathies, immune-mediated (e.g. Bruns-Garland syndrome), and neoplastic/paraneoplastic neuropathies.

Though orphan neuropathies are rare per definition they constitute the majority of neuropathies and should be considered as some of them are easy to identify and potentially treatable, as clarification of the underlying cause may contribute to the knowledge about etiology and pathophysiology of these conditions, and as the true prevalence may become obvious only if all ever diagnosed cases are reported.

Photovoice is a qualitative research tool increasingly utilized in the healthcare field to understand the illness experience from the patient and caregiver perspective. This is the first study to evaluate photovoice in the context of amyotrophic lateral sclerosis (ALS).

A patient and caregiver centered research tool was utilized to gain a greater understanding of challenges faced when living with ALS.

Eight patients and three corresponding caregivers participating by taking photographs, writing descriptive text, and participating in individual and group interviews. Inductive thematic analysis was employed to uncover recurring themes.

Five main themes were identified; 1) facing the diagnosis, 2) loss of function, 3) isolation, 4) health system challenges, and 5) hope. Despite the devasting impact of ALS, the majority of participants reported a surprising amount of positivity in the face of receiving this difficult diagnosis, and demonstrated incredible creativity and adaptability to meet the ensuing loss of function. However, patients and caregivers discussed feelings of isolation and health care system challenges. The importance of hope was a strong and recurring theme.

The photovoice research tool demonstrates the profound resilience of these participants, and challenges the medical community to find ways of fostering positivity and hope throughout the ALS disease course. Further clinic and community resources, education, and supports are needed to combat the sense of isolation and health care system challenges experienced by patients and their caregivers.

Spinal muscular atrophy (SMA) is a motor neuron disease associated with progressive muscle weakness and motor disability.

This study aims to report the evaluation of nusinersen, an antisense oligonucleotide, on motor function in patients with SMA types 2 and 3.

This single-center retrospective observational study assessed nusinersen therapy outcomes, measured by HSMFSE or CHOP-INTEND scales, in patients with SMA types 2 and 3, compared to untreated patients, for at least 24 months.

A total of 41 patients with SMA types 2 and 3 under nusinersen treatment were included. In 30 treated patients (mean age: 10.6 years; 14 with SMA type 2), the mean change in HFMSE scores was +1.47 points (SD = 0.4) and +1.60 points (SD = 0.6) after 12 and 24 months of treatment, respectively. In contrast, the control group (N = 37) (mean age: 10.2 years; 20 with SMA type 2) presented a mean change of −1.71 points (SD = 0.02) and −3.93 points (SD = 0.55) after 12 and 24 months of follow-up, respectively. The most severe patients under nusinersen treatment (N = 11) showed a change of +2.37 (SD = 1.13) on the CHOP-INTEND scale after 12 months of follow-up. Disease duration at the beginning of treatment was the main predictor of functional improvement. Despite functional gain and motor stabilization, treatment with nusinersen did not prevent the progression of scoliosis.

Our data provide evidence for the long-term safety and efficacy of nusinersen use in the treatment of later-onset SMA, and patients with shorter disease duration showed better response to treatment.

Cure SMA maintains the largest patient-reported database for people affected with spinal muscular atrophy (SMA). In 2017, Cure SMA initiated annual surveys with their membership to collect demographic and disease characteristics, healthcare, and burden of disease information from patients and caregivers.

To summarize results from two large-scale Cure SMA surveys in 2017 and 2018.

Cure SMA database members were invited to complete surveys; these were completed by caregivers for living or deceased individuals with SMA and/or affected adults.

In 2017, 726 surveys were completed for 695 individuals with SMA; in 2018, 796 surveys were completed for 760 individuals with SMA. Data from both survey years are available for 313 affected individuals. Age at symptom onset, distribution of SMN2 gene copy number, and representation of each SMA type in the surveys were consistent with that expected in the SMA population. In the 2018 survey, the average age at diagnosis was 5.2 months for SMA type I and the reported mean age at death for this subgroup was 27.8 months. Between survey years, there was consistency in responses for factors that should not change within individuals over time (e.g., reported age at diagnosis).

Results from the Cure SMA surveys advance the understanding of SMA and facilitate advocacy efforts and healthcare services planning. Longitudinal surveys are important for evaluating the impact of effective treatments on changing phenotypes, and burden of disease and care in individuals with SMA.

Limb girdle muscular dystrophy recessive type 1 (LGMDR1, Previously LGMD2A) is characterized by inactivating mutations in CAPN3. Despite the significant burden of muscular dystrophy in India, and particularly of LGMDR1, its genetic characterization and possible phenotypic manifestations are yet unidentified.

We performed bidirectional CAPN3 sequencing in 95 LGMDR1 patient samples characterized by calpain-3 protein analysis, and these findings were correlated with clinical, biochemical and histopathological features.

We identified 84 (88.4%) cases of LGMDR1 harboring 103 CAPN3 mutations (71 novel and 32 known). At least two mutant alleles were identified in 79 (94.2%) of patients. Notably, 76% exonic variations were enriched in nine CAPN3 exons and overall, 41 variations (40%) correspond to only eight exonic and intronic mutations. Patients with two nonsense/out of frame/splice-site mutations showed significant loss of calpain-3 protein as compared to those with two missense/inframe mutations (P = 0.04). We observed a slow progression of disease and less severity in our patients compared to European population. Rarely, presenting clinical features were atypical, and mimicked other muscle diseases like FSHMD, distal myopathy and metabolic myopathies.

This is first systematic study to characterize the genetic framework of LGMDR1 in the Indian population. Preliminary calpain-3 immunoblot screening serves well to direct genetic testing. Our findings prioritized nine CAPN3 exons for LGMDR1 diagnosis in our population; therefore, a targeted-sequencing panel of nine exons could serve well for genetic diagnosis, carrier testing, counseling and clinical trial feasibility study in LGMDR1 patients in India.

Muscle weakness is a cardinal sign of myotonic dystrophy type 1, causing important functional mobility limitations and increasing the risk of falling. As a non-pharmacological, accessible and safe treatment for this population, strength training is an intervention of choice.

To document the effects and acceptability of an individualized semi-supervised home-based exercise program on functional mobility, balance and lower limb strength, and to determine if an assistive training device has a significant impact on outcomes.

This study used a pre-post test design and men with the adult form of DM1 were randomly assigned to the control or device group. The training program was performed three times a week for 10 weeks and included three exercises (sit-to-stand, squat, and alternated lunges). Outcome measures included maximal isometric muscle strength, 10-Meter Walk Test, Mini-BESTest, 30-Second Chair Stand Test and 6-minute walk test.

No outcome measures showed a significant difference, except for the strength of the knee flexors muscle group between the two assessments. All participants improved beyond the standard error of measurement in at least two outcome measures. The program and the device were well accepted and all participants reported many perceived improvements at the end of the program.

Our results provide encouraging data on the effects and acceptability of a home-based training program for men with the adult form of DM1. These programs would reduce the financial burden on the health system while improving the clinical services offered to this population.

Vasculitic peripheral neuropathy (VPN) is caused by vessel inflammation leading to peripheral nerve injury of acute-to-subacute onset. When VPN occurs in the context of systemic disease it is classified as Systemic Vasculitic Neuropathy (SVN) and as Non-Systemic Vasculitic Neuropathy (NSVN) when restricted to the nerves.

This study aimed to compare the clinical characteristics, biopsy findings and disease outcome in patients with VPN.

Clinical records of adult patients with VPN diagnosed at our institution between June-2002 and June-2019 were retrospectively reviewed. Demographic characteristics, clinical manifestations, nerve conduction studies, nerve biopsies, treatment and clinical evolution were analyzed in all patients with at least 6 months follow-up.

Twenty-five patients with VPN were included (SVN, n = 10; NSVN, n = 15). No significant differences in demographic or clinical features were found between groups. The median delay between symptom onset and nerve biopsy was significantly longer in NSVN patients (10 vs 5.5 months, p = 0.009). Erythrocyte sedimentation rate (ESR) values over 20 mm/h were significantly more common in SVN patients (100% vs. 60%, p = 0.024). Nerve biopsies showed active lesions more frequently in treatment-naive patients compared to those who had received at least 2 weeks of corticosteroids (92% vs 38%; p = 0.03), with a higher proportion of definite VPN cases (92 vs 46%; p = 0.04).

Although the clinical manifestations are similar, ESR is an important tool to help distinguish between both conditions. Early nerve biopsy in untreated patients increases diagnostic accuracy, avoiding misdiagnosis.