Novel Titin Gene Mutation Causing Autosomal Dominant Limb-Girdle Muscular Dystrophy.

We report a genotype-phenotype analysis of a family in which a titinopathy is transmitted in an autosomal dominant pattern. In this family, following neurological history and examination, electromyogram, and muscle biopsy, the diagnosis of limb-girdle muscular dystrophy with contractures was made in an affected mother and son. Genetic testing employing the whole exome was performed and revealed two variants in the TTN gene, c.712G>C, p. Glu238Gln and c.1397A>C, p.Gln466Arg, which segregated with the disease in the affected mother-son duo but not in an unaffected sibling. Although protein modeling suggests that the c.712G>C, p. Glu238Gln polymorphism is damaging, it has been reported in the Genome Aggregation Database which includes exome and genome sequence data of unrelated individuals sequenced as part of various disease-specific and population genetic studies. In contrast, the c.1397A>C, p.Gln466Arg variant is novel and has not been reported in any public genetic databases or our internal laboratory database. Protein modeling analysis indicates that p.Gln466Arg is damaging and we hypothesize that it is the disease-producing mutation resulting in muscular dystrophy. Our research report expands the spectrum of mutations causing titinopathy.

Bruton's Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures.

Clinical development of BTK kinase inhibitors for treating autoimmune diseases has lagged behind development of these drugs for treating cancers, due in part from concerns over the lack of selectivity and associated toxicity profiles of first generation drug candidates when used in the long term treatment of immune mediated diseases. Second generation BTK inhibitors have made great strides in limiting off-target activities for distantly related kinases, though they have had variable success at limiting cross-reactivity within the more closely related TEC family of kinases. We investigated the BTK specificity and toxicity profiles, drug properties, disease associated signaling pathways, clinical indications, and trial successes and failures for the 13 BTK inhibitor drug candidates tested in phase 2 or higher clinical trials representing 7 autoimmune and 2 inflammatory immune-mediated diseases. We focused on rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE) where the majority of BTK nonclinical and clinical studies have been reported, with additional information for pemphigus vulgaris (PV), Sjogren's disease (SJ), chronic spontaneous urticaria (CSU), graft versus host disease (GVHD), and asthma included where available. While improved BTK selectivity versus kinases outside the TEC family improved clinical toxicity profiles, less profile distinction was evident within the TEC family. Analysis of genetic associations of RA, MS, and SLE biomarkers with TEC family members revealed that BTK and TEC family members may not be drivers of disease. They are, however, mediators of signaling pathways associated with the pathophysiology of autoimmune diseases. BTK in particular may be associated with B cell and myeloid differentiation as well as autoantibody development implicated in immune mediated diseases. Successes in the clinic for treating RA, MS, PV, ITP, and GVHD, but not for SLE and SJ support the concept that BTK plays an important role in mediating pathogenic processes amenable to therapeutic intervention, depending on the disease. Based on the data collected in this study, we propose that current compound characteristics of BTK inhibitor drug candidates for the treatment of autoimmune diseases have achieved the selectivity, safety, and coverage requirements necessary to deliver therapeutic benefit.

A Novel Duplication Mutation in the Myelin Protein Zero Gene Causing Mild, Nonprogressive Demyelinating Neuropathy.

Mutations in the myelin protein zero (MPZ) gene can cause a variety of clinical and electrophysiological forms of genetic neuropathies including Charcot-Marie-Tooth (CMT) type 1B disease which is characterized by demyelinating features. We present a father and daughter with neuropathy carrying a novel 31 base pair duplication mutation in the 5' untranslated region of the MPZ gene, c.-23_8dup31. Genetic analysis and protein modeling indicated that this is a frameshift mutation resulting in premature truncation of the encoded protein. The daughter underwent repeat neurological examination and electromyography testing over an 11-year time span demonstrating no clinical or electrophysiological change. Our study expands the clinical and genetic spectrum of mutations that can cause CMT type 1B disease and demonstrates the value of sequence analysis of noncoding portions of a gene that are not intronic.

Complicated SPG4 presenting with recurrent urinary tract infection.

We present a 62-year-old woman who developed recurrent urinary tract infections in her early fifties and, after an evaluation by an infectious disease physician, was referred for a neurological consultation. Her history and neurological examination were consistent with spastic paraparesis and there was significant family history of a variety of neurological diagnoses suggesting a genetic disorder. Whole exome genetic testing revealed a novel change, a c.508 C > T variant in the SPAST gene. Our genetic and protein modeling analysis suggest that this is a disease-producing mutation confirming the diagnosis of hereditary spastic paraplegia type 4 (SPG4). This patient expands the spectrum of mutations that can cause this disorder and demonstrate the importance of recognizing the role of neurological disorders in causing neurogenic bladder and recurrent urinary tract infections.

Adult Diagnosis of Type 1 Fiber Predominance Myopathy Caused by Novel Mutations in the RYR1 Gene.

We describe a 57-year-old patient with mild diffuse weakness that was incidentally detected when he was evaluated for restless leg syndrome. An electromyography confirmed the presence of a myopathy without suggestion of inflammatory myopathy. A muscle biopsy demonstrated type 1 fiber predominance with minimal inflammatory features suggesting a genetic myopathy. Exome sequencing revealed c.10648C > T variant (p.R3550W), and a novel variant, c.10749_10753delGGAGG (E3584Rfs*3), in the ryanodine receptor 1 (RYR1) gene transmitted through his asymptomatic father indicating these mutations are in trans. Prompted by these results, a 47-year-old sister presented for evaluation. Her examination showed mild proximal muscle weakness, and an electromyography confirmed a noninflammatory myopathy. Her genotype was identical to her affected brother confirming that in these siblings, the RYR1 mutations, transmitted in an autosomal recessive pattern, are the cause of their myopathy. The adult age at diagnosis of these affected siblings likely reflects the mild and minimally progressive nature of the myopathy.

Limb Girdle Muscular Dystrophy due to Digenic Inheritance of DES and CAPN3 Mutations.

We report the clinical and genetic analysis of a 63-year-old man with progressive weakness developing over more than 20 years. Prior to his initial visit, he underwent multiple neurological and rheumatological evaluations and was treated for possible inflammatory myopathy. He did not respond to any treatment that was prescribed and was referred to our center for another opinion. He underwent a neurological evaluation, electromyography, magnetic resonance imaging of his legs, and a muscle biopsy. All testing indicated a chronic myopathy without inflammatory features suggesting a genetic myopathy. Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), RYR1 (rs143445685), CAPN3 (rs138172448), and DES (rs144901249) genes. We hypothesized that the inheritance pattern could follow a digenic pattern of inheritance. Screening for these polymorphisms in an unaffected sister revealed the presence of all these same variants except for that in the CAPN3 gene. All variants were studied to determine their frequency and if they had been previously reported as mutations. They were also subjected to protein modeling programs, including SIFT, PolyPhen, and MutationTaster. This analysis indicated that the CAPN3 variant c.1663G>A (rs138172448), which results in a p.Val555Ile change, and the DES gene variant c.656C>T (rs144901249), which results in a p.Thr219Ile change, are both predicted to be damaging. These 2 variants were further investigated employing the STRING program that analyzes protein networks and pathways. This analysis provided further support for our hypothesis that these mutations in the CAPN3 and DES genes, through digenic inheritance, are the cause of the myopathy in this patient.

Novel Mutation in Anoctamin 5 Gene Causing Limb-Girdle Muscular Dystrophy 2L.

We report a 49-year-old man who presented with a history of asymmetric weakness. His neurological examination and electromyogram testing suggested the presence of a myopathy. A muscle biopsy confirmed the presence of a myopathy with several lobulated, whorled and ring fibers, and it showed no evidence of inflammation. Genetic testing of more than 50 genes known to cause myopathy was performed and demonstrates the presence of the common founder mutation in ANO5 gene c.191dupA, which he inherited from his unaffected father. In addition, he inherited a novel mutation, c.1063C>T (p.L355F) in exon 11 of ANO5 gene from his unaffected mother. The founder mutation is a known pathogenic variant and, based on our protein modeling analysis, the novel c.1063C>T (p.L355F) variant is likely pathogenic. This indicates that he is a compound heterozygote, providing strong support for the diagnosis of limb-girdle muscular dystrophy 2L.

Clinical and Genetic Analysis of an Asian Indian Family with Charcot-Marie-Tooth Disease Type 4C.

Charcot-Marie-Tooth disease type 4C, an autosomal recessive genetic neuropathy, is caused by mutations in the SH3TC2 (SH3 domain and tetratricopeptide repeats 2) gene. Interestingly, although mutations in this gene have been observed in European gypsies, a population that originated in India, there are few publications describing Indian patients. We report our analysis of a 50-year-old woman of Asian Indian descent with onset of progressive distal weakness and sensory loss in childhood. A clinical examination revealed the presence of a neuropathy with pes cavus without spinal abnormalities. Electrophysiological testing confirmed a sensorimotor length-dependent neuropathy with demyelinating features. A genetic analysis revealed she carries 2 novel mutations, c.2488G>T variant (rs879254317) and c.731+5G>A variant (rs879254316), in the SH3TC2 gene. Further genetic testing demonstrated that her son is a carrier of the c.731+5G>A mutation. Our analysis confirms that this patient is a compound heterozygote inheriting these mutations, which are in trans, in an autosomal recessive pattern. Her son developed an episode of sciatic neuropathy with complete resolution. We hypothesize that in his case, haploinsufficiency caused by c.731+5G>A mutation may have predisposed him to the development of this focal neuropathy.

Factors Affecting Phenotype Variability in a Family with CMT2B: Gender and LRSAM1 Genotype.

Charcot-Marie-Tooth disease type 2 (CMT2) is an autosomal dominant axonal neuropathy caused by mutations in various genes. The subtype CMT2B results from missense mutations in RAB7A, member RAS oncogene family gene, whereas missense mutations in the Leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) gene cause CMT2P. We describe the genotype/phenotype analysis of a family in which a previously described mutation in the RAB7A gene and a novel mutation in the LRSAM1 gene were identified. In this family, none of the individuals had ulceromutilating features, and there was a marked variability in the age of onset. We discuss the possible etiology of the observed phenotypic variability including the role of gender and possible RAB7A/LRSAM1 gene interactions.

Congenital insensitivity to pain: a case report and review of the literature.

Congenital insensitivity to pain (CIP) is a rare autosomal recessive genetic disease caused by mutations in the SCN9A gene. We report a patient with the clinical features consistent with CIP in whom we detected a novel homozygous G2755T mutation in exon 15 of this gene. Routine electrophysiological studies are typically normal in patients with CIP. In our patient, these studies were abnormal and could represent the consequences of secondary complications of cervical and lumbosacral spine disease and associated severe Charcot's joints.