Genotype-phenotype correlation and natural history study of dysferlinopathy: a single-centre experience from India.

Dysferlinopathies are a group of limb-girdle muscular dystrophies causing significant disability in the young population. There is a need for studies on large cohorts to describe the clinical, genotypic and natural history in our subcontinent. To describe and correlate the clinical, genetic profile and natural history of genetically confirmed dysferlinopathies. We analysed a retrospective cohort of patients with dysferlinopathy from a single quaternary care centre in India. A total of 124 patients with dysferlinopathy were included (40 females). Median age at onset and duration of illness were 21 years (range, 13-50) and 48 months (range, 8-288), respectively. The average follow-up period was 60 months (range, 12-288). Fifty-one percent had LGMD pattern of weakness at onset; 23.4% each had Miyoshi and proximo-distal type while isolated hyperCKemia was noted in 1.6%. About 60% were born to consanguineous parents and 26.6% had family history of similar illness. Twenty-three patients (18.6%) lost ambulation at follow-up; the median time to loss of independent ambulation was 120 months (range, 72-264). Single-nucleotide variants (SNVs) constituted 78.2% of patients; INDELs 14.5% and 7.3% had both SNVs and INDELs. Earlier age at onset was noted with SNVs. There was no correlation between the other clinical parameters and ambulatory status with the genotype. Thirty-seven (45.7%) novel pathogenic/likely pathogenic (P/LP) variants were identified out of a total of 81 variations. The c.3191G > A variant was the most recurrent mutation. Our cohort constitutes a clinically and genetically heterogeneous group of dysferlinopathies. There is no significant correlation between the clinico-genetic profile and the ambulatory status.

Atypical presentations of inclusion body myositis: Clinical characteristics and long-term outcomes.

INTRODUCTIONS/AIMS: Inclusion body myositis (IBM) typically presents with progressive weakness preferentially involving finger flexors and quadriceps. Atypical presentations have been less commonly reported. Here, we aim to describe the clinical characteristics and long-term outcomes of IBM patients with atypical presentations. METHODS: We retrospectively searched the Mayo Clinic medical records to identify IBM patients with atypical disease onset, seen between 2015 and 2020. RESULTS: We identified 357 IBM patients, of whom 50 (14%) had an atypical presentation. Thirty-eight patients were diagnosed with IBM because they fulfilled one of the European Neuromuscular Center diagnostic categories at a later stage, 10 had all IBM histopathological features, and 2 were diagnosed on the basis of clinical and laboratory data. The most common presentation was dysphagia (50%), followed by asymptomatic hyperCKemia (24%; CK, creatine kinase), then foot drop (12%). 6% of patients presented with proximal arm weakness, 4% with axial weakness and 4% with facial diplegia. Median time from symptom onset to diagnosis was 9 y. Median age at diagnosis was 70.5 y. 16% of patients needed a walking aid. When tested, 86.5% of patients had impaired swallowing and 56% had elevated cytosolic nucleotidase-1A antibodies. Only 1/26 patients who received immunotherapy had minimal improvement. Upon follow-up, most patients had generalization of their weakness with a decline in their strength summated score of 0.082/mo. DISCUSSION: A significant proportion of IBM patients may have an atypical presentation. Recognition of such heterogeneity could improve early diagnosis, prevent unnecessary immunotherapy, and provide insight for future diagnostic criteria development and clinical trials.

The clinical, myopathological, and molecular characteristics of 26 Chinese patients with dysferlinopathy: a high proportion of misdiagnosis and novel variants.

BACKGROUND: Dysferlinopathy is an autosomal recessive muscular dystrophy caused by pathogenic variants in the dysferlin (DYSF) gene. This disease shows heterogeneous clinical phenotypes and genetic characteristics. METHODS: We reviewed the clinical and pathological data as well as the molecular characteristics of 26 Chinese patients with dysferlinopathy screened by immunohistochemistry staining and pathogenic variants in DYSF genes. RESULTS: Among 26 patients with dysferlinopathy, 18 patients (69.2%) presented as Limb-girdle Muscular Dystrophy Type R2 (LGMD R2), 4 (15.4%) had a phenotype of Miyoshi myopathy (MM), and 4 (15.4%) presented as asymptomatic hyperCKemia. Fifteen patients (57.7%) were originally misdiagnosed as inflammatory myopathy or other diseases. Fifteen novel variants were identified among the 40 variant sites identified in this cohort. CONCLUSION: Dysferlinopathy is a clinically and genetically heterogeneous group of disorders with various phenotypes, a high proportion of novel variants, and a high rate of misdiagnosis before immunohistochemistry staining and genetic analysis.

Recurrent, non-traumatic, non-exertional rhabdomyolysis after immunologic stimuli in a healthy adolescent female: a case report.

BACKGROUND: Dysferlinopathy refers to a heterogenous group of autosomal recessive disorders that affect a skeletal muscle protein called dysferlin. These mutations are associated with limb-girdle muscular dystrophy type 2B, Miyoshi myopathy, asymptomatic hyperCKemia, and distal myopathy with anterior tibial onset. CASE PRESENTATION: A 16 year old female presented with myalgia, weakness and dark urine one week after her second BNT162b2 mRNA (Pfizer) vaccine. Initial serum creatine kinase (CK) was measured at 153,000 IU/L, eventually up-trending to over 200,000 IU/L. However, stable renal function precluded hemodialysis allowing discharge after 10 days of intravenous (IV) hydration and alkaline diuresis. Just two years prior to the current presentation, the patient was hospitalized following Group A Streptococcal pharyngitis infection complicated by rhabdomyolysis. She presented with fatigue, lower extremity weakness, and dark oliguria with CK measuring 984,800 IU/L. IV hydration was attempted however hemodialysis was ultimately required throughout her 24-day hospital stay. Her episode was presumed to be idiopathic and no further work-up was performed at that time. During the patient's current hospitalization, she reported similar symptomology (myalgias and weakness) following her first quadrivalent Gardasil vaccine at age 11. No hospitalization was required at that time. A comprehensive workup was now initiated while the patient was being treated for her suspected second or third non-exertional, non-traumatic rhabdomyolysis. Rheumatologic, metabolic, infectious, and endocrinologic workup were all unremarkable. Patient eventually had whole exome sequencing performed which revealed a heterozygous pathogenic variant in the DYSF gene (DYSF c.2643 + 1G > A) encoding dysferlin. No clinically significant sequelae occurred thus far. CONCLUSIONS: While there have been reports of symptomatic heterozygote carriers of dysferlinopathies, to our knowledge none have been associated with recurrent rhabdomyolysis after immunogenic stimuli. This unique case presentation highlights the importance of a multi-disciplinary care team, the utility of modern whole-exome gene sequencing, and the future challenges of balancing vaccine risk vs benefit.

Anoctamin 5 (ANO5) muscular dystrophy-three different phenotypes and a new histological pattern.

OBJECTIVE: Anoctamin 5 (ANO5) is a putative intracellular calcium-activated chloride channel. Recessive mutations in ANO5 may present from asymptomatic hyperCKemia and exercise-induced myalgia to proximal and/or distal muscle weakness. Here we describe the clinical, pathological, and molecular findings of three unrelated patients with ANO5-related muscular dystrophy. METHODS: In this retrospective study, we analyzed our database which includes 1700 muscle biopsies performed for diagnostic purposes from October 2004 to February 2019. Patients were attended by two myology experts, who performed and analyzed the muscle biopsies. Muscle biopsies were frozen in cooled isopenthane, cryostat sectioned, and routinely stained and reacted (minimum 16 stainings). A custom panel, including 115 genes (Nextera Rapid Capture, Illumina) and whole-exome sequencing analysis, was used for next-generation sequencing in cases without a definite pathological diagnosis. RESULTS: Three patients were diagnosed with ANO5-related muscular dystrophy, with all presenting the common exon 5 mutation c.191dup plus a compound heterozygous missense mutation. They showed three different phenotypes (distal myopathy, LGMD2L, and asymptomatic hyperCKemia). Curiously, all three muscle biopsies showed different patterns, but numerous ragged-red fibers with little endomysial inflammation and partial invasion cell by T lymphocytes were observed in one. CONCLUSION: ANO5-related muscular dystrophy is a heterogeneous disease with different clinical phenotypes as well as different histological patterns, which may even mimic a mitochondrial myopathy. The results of this study provide further knowledge of the clinical, histological, and pathological features related to ANO5 mutations.

Persistent asymptomatic or mild symptomatic hyperCKemia due to mutations in ANO5: the mildest end of the anoctaminopathies spectrum.

BACKGROUND: The ANO5 gene encodes for anoctamin-5, a chloride channel involved in muscle cell membrane repair. Recessive mutations in ANO5 are associated with muscular diseases termed anoctaminopathies, which are characterized by proximal or distal weakness, or isolated hyperCKemia. We present the largest series of patients with asymptomatic/paucisymptomatic anoctaminopathy reported so far, highlighting their clinical and radiological characteristics. METHODS: Twenty subjects were recruited retrospectively from the Neuromuscular Disorders Units database of two national reference centers. All had a confirmed genetic diagnosis (mean age of diagnosis was 48 years) established between 2015 and 2019. Clinical and complementary data were evaluated through clinical records. RESULTS: None of the patients complained about weakness or showed abnormal muscular balance. Among paucisymptomatic patients, the main complaints or findings were generalized myalgia, exercise intolerance and calf hypertrophy, occasionally associated with calf pain. All patients showed persistent hyperCKemia, ranging from mild-moderate to severe. Muscle biopsy revealed inflammatory changes in three cases. Muscle magnetic resonance imaging revealed typical signs (preferential involvement of adductor and gastrocnemius muscles) in all but one patient. In two cases, abnormal findings were detectable only in STIR sequences (not in T1). Three patients showed radiological progression despite remaining asymptomatic. Twelve different mutations in ANO5 were detected, of which seven are novel. CONCLUSIONS: Recessive mutations in ANO5 are a frequent cause of undiagnosed asymptomatic/paucisymptomatic hyperCKemia. Patients with an apparent indolent phenotype may show muscle involvement in complementary tests (muscle biopsy and imaging), which may progress over time. Awareness of anoctaminopathy as the cause of nonspecific muscular complaints or of isolated hyperCKemia is essential to correctly diagnose affected patients.

HiperCKemia asintomática benigna. A propósito de dos casos / Benign asymptomatic hyperCKemia. With regard to two cases

La hiperCKemia asintomática es definida como una elevación persistente de niveles séricos de Creatin Fosfoquinasa (CPK), sin manifestaciones clínicas, electromiográficas o histológicas. Su curso es benigno a largo plazo y en muchos casos no es necesario un seguimiento continuo. Si la hiperCKemia es un hallazgo incidental en unos exámenes de laboratorio de rutina, no se justifican estudios extensivos más aun si los pacientes no presentan alteraciones al exámen físico y si los estudios electromiográficos son normales. En este artículo, presentamos dos casos con hiperCKemia asintomática, que son los primeros informados en Hispanoamérica.

Asymptomatic hyperCKemia is defined as a persistent elevation of serum CPK levels, without clinical manifestation abnormal electrodiagnostic, or histologic findings. It has a long-term benign course and in many cases it is not necessary a continuous follow-up. If hyperCKemia is an incidental finding during a routine laboratory check-up, extensive studies are not justified still more if the patients do not present alterations in the physical exam and if the electrodiagnostic studies are normal. In this paper we present two cases of asymptomatic hyperCKemia, that are the first reported in Hispano-America.