Jessica Jackson

Case report: 5 year follow-up of adult late-onset mitochondrial encephalomyopathy with lactic acid and stroke-like episodes (MELAS)

Mitochondrial encephalomyopathy with lactic acid and stroke-like episodes (MELAS) is a multisystem mitochondrial disorder that typically presents in childhood. We describe the follow-up of a patient who was diagnosed with late-onset MELAS at the age of 49. Her clinical course includes sensorineural hearing loss, seizures, and multiple episodes of stroke-like metabolic crises. Molecular genetic testing on whole blood revealed 31% heteroplasmy of a m.3243A > G variant in the mtDNA, the causative variant in approximately 80% of MELAS cases. The original diagnostic criteria for MELAS required the onset of stroke-like episodes prior to 40 years of age but this case and others demonstrate that onset may be delayed in certain individuals. Therefore, MELAS should be included in the differential diagnosis of stroke-like episodes in patients of any age.

Whole exome sequencing of a patient with suspected mitochondrial myopathy reveals novel compound heterozygous variants in RYR1

Pathogenic variants in ryanodine receptor 1 (RYR1, MIM# 180901) are the cause of congenital myopathy with fiber‐type disproportion, malignant hyperthermia susceptibility type 1, central core disease of muscle, multiminicore disease and other congenital myopathies.

Physician interpretation of variants of uncertain significance

A growing number of physicians will interact with genetic test results as testing becomes more commonplace. While variants of uncertain significance can complicate results, it is equally important that physicians understand how to incorporate these results into clinical care. An online survey was created to assess physician self-reported comfort level with genetics and variants of uncertain significance. Physicians were asked to respond to three case examples involving genetic test results. The survey was sent to 488 physicians at Mayo Clinic FL on 8/16/2017. Physicians from all specialties were invited to participate. A total of 92 physicians responded to the survey. Only 13/84 (14.6%) responded to all three case examples with the answer deemed “most correct” by review of literature. Physicians that specialized in cancer were more likely to answer questions appropriately (P = .02). Around half (39/84) of the physicians incorrectly defined a variant of uncertain significance (VUS). Over 75% made a recommendation for genetic testing that was not warranted. Many physicians have never received formal genetics training; however, they will be expected to provide an accurate explanation of the genetic test results and subsequent evidence-based medical management recommendations. These results demonstrate that a substantial proportion of physicians lack a true understanding of the implications a VUS. Utilization of supplemental genetics training programs coupled with increase awareness of genetic services may help to improve patient care.

Early-onset limb-girdle muscular dystrophy-2L in a female athlete.

The limb-girdle muscular dystrophies (LGMD) are a diverse group of childhood and adult-onset muscle diseases that are distinct from the X-linked muscular dystrophies. The worldwide prevalence of LGMD is estimated to be between 1 in 14,500 and 1 in 45,000. Several genes have been implicated in the LGMD phenotypic spectrum including pathogenic variants in anoctamin-5 (ANO5), the cause of autosomal recessive limb-girdle muscular dystrophy-2L (LGMD2L, MIM #611307). LGMD2L is typically associated with elevated serum creatine kinase (CK) levels, exerciseinduced myalgia, proximal or distal muscle weakness, and onset of symptoms beginning at an average age of 35 years. However, the range of onset is 15 to 70 years, and some individuals have elevated CK without other symptoms. The spectrum of anoctaminopathies also includes pathogenic variants in ANO5 that are less commonly associated with autosomal recessive Miyoshi-like disease or Miyoshi muscular dystrophy 3 (MIM #613319) that is characterized by early onset calf weakness between ages 20 and 25 years. The presenting symptoms may include walking difficulties, reduced exercise tolerance, difficulty standing on the toes, and nonspecific exertional myalgia or fatigue. Patients may have asymmetric muscle weakness and atrophy, and the progression of disease is slow. The ANO5 gene encodes anoctamin-5, a member of the anoctamin/TMEM16 family of proteins that function as Ca dependent ion channels and plasma membrane phospholipid scramblases, which transport phospholipids bidirectionally in response to Ca. ANO5 is predicted to have 8 membrane-spanning helices and a hydrophilic cavity that is exposed to the lipid bilayer that likely represents the site of catalysis. ANO5 is primarily localized to skeletal muscle and thyroid and is localized intracellularly within the endoplasmic reticulum. The function of ANO5 is not well known, but high sequence similarity to ANO6 suggests that it may behave as a scramblase. A recent study by Griffin et al. in which they investigated normal ANO5 function, revealed that the protein may be involved in repair of muscle membranes following injury, similar to dysferlin. They showed that Ano5 deficient mice have dysfunctional sarcolemmal repair following laser-induced damage, show delayed regeneration after cardiotoxin injury, and have myoblast fusion defects that lead to improper regeneration and repair of multinucleated myotubes. The ANO5-related myopathies have phenotypic overlap with autosomal recessive dysferlinopathies, including Miyoshi muscular dystrophy 1 (MIM #254130), limb-girdle muscular dystrophy type 2B (MIM #253601), and distal myopathy with anterior tibial onset (MIM #606768). Women affected with LGMD2L typically have less severe symptoms and later onset of disease than men. In this report, we describe an athlete with progressive muscle weakness and rhabdomyolysis beginning in her late teens who was diagnosed with LGMD2L after a protracted diagnostic odyssey.

Whole Exome Sequencing Identifies Atypical Welander Distal Myopathy in Patient

Abstract Welander distal myopathy is a rare autosomal dominant disorder characterized by muscle weakness in the hands and feet. Exome sequencing of affected families discovered a segregating p.Glu384Lys pathogenic variant in TIA-1 as the main genetic cause of Welander distal myopathy. TIA-1 encodes an RNA-binding protein which serves as a key component of stress granules. This protein also regulates splicing and translation of mRNA. Our patient developed progressive weakness in his hands and feet during his late 40s that was misdiagnosed as a neuropathy that caused muscle atrophy. Follow-up genetic testing revealed a p.Glu384Lys pathogenic variant in TIA-1, and he was then diagnosed with Welander distal myopathy. Our case report underlines the importance of electrodiagnostic and genetic testing of patients.

A case of contralateral breast cancer and skin cancer associated with NBN heterozygous pathogenic variant c.698_701delAACA

Approximately 39.6% of people will be diagnosed with cancer during their lifetime. Several factors including, lifestyle, environment and genetics may play a role in its development. Understanding these causes will greatly improve treatment methods, prevention, and survival rates of these patients. Our patient, who has a positive family history of cancer, presented with contralateral breast cancer and multiple skin malignancies. Genetic testing revealed a frameshift variant in NBN. This gene encodes the protein, nibrin, which is involved in maintaining genomic stability. Several reports have identified heterozygous NBN frameshift (c.2028delT, c.2097dupT, c.657-661delACAAA) and splice site variants (c.1397+delG) in patients with breast cancer. However, our report is the first to describe a heterozygous c.698_701delAACA NBN variant in a patient with breast cancer. Since NBN is involved in DNA integrity, loss of functional protein due to pathogenic variants significantly increases the risk of various cancers. Given the family and personal history of our patient, in connection with previous reports of NBN pathogenic variants predisposition to cancer, this variant is predicted to be pathogenic and clinically significant.

Personalized molecular modeling for pinpointing associations of protein dysfunction and variants associated with hereditary cancer syndromes

Although the process of reclassification of a variant of uncertain significance can be complex, they are commonly detected through molecular testing. It often takes years before enough clinical data are acquired, and it can be costly and time‐consuming to perform functional analysis of a single variant. It is important that other tools are developed to aid in clarifying how a specific genetic variant impacts a proteins function, and ultimately the health of the patient.

Novel Gfap Variant in Adult-onset Alexander Disease With Progressive Ataxia and Palatal Tremor

Introduction: Alexander disease is a rare neurodegenerative disease caused by variants in the glial fibrillary acidic protein gene (GFAP). This disorder can develop as an infantile, juvenile or adult-onset form and is characterized by several clinical features, including macrocephaly, seizures, ataxia, and bulbar/pseudobulbar signs. While the majority of these patients have the more progressive infantile form which causes severe leukodystrophy and early death; the less common adult form is more variable (ie, onset age, symptoms), with bulbar dysfunction as the primary feature. Case Report: In our investigation, we describe a patient with progressive neuromuscular issues including dyspnea, dysphagia, dysarthria and progressive ataxia with palatal tremor. Conclusions: Through genetic testing, we determined that our patient has a novel variant in GFAP typical of Alexander disease.

Expanded phenotype in a patient with spastic paraplegia 7

Hereditary spastic paraplegia is a group of clinically and genetically heterogeneous neurodegenerative disorders, often characterized by weakness and spasticity in the lower limbs. In our study, we describe a spastic paraplegia type 7 patient with an expanded phenotype who was diagnosed after the discovery of pathogenic variants in SPG7.