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GNE myopathy is a rare autosomal recessive distal myopathy characterized by early adult-onset, slowly to moderately progressive distal muscle weakness that preferentially affects the tibialis anterior muscle and that usually spares the quadriceps femoris. Muscle biopsy reveals presence of rimmed vacuoles.

Epidemiology Worldwide prevalence is estimated at 1/1,000,000, however it is more frequent in populations of Persian Jewish and Japanese ethnicity. Clinical description The disease usually starts during the third decade of life (but the onset may range from the early teens to the 5th decade). Typically, distal weakness in the legs with foot drop is the first sign, followed by (usually) slow progression to the proximal muscles (thigh) and the upper limbs (hand muscles). Shoulder girdle muscles are subsequently involved, with relative sparing of the triceps. Neck flexor muscles are also commonly affected. A unique clinical pattern of this myopathy is sparing of quadriceps in spite of major involvement of other thigh muscles. Unusual patterns of onset in proximal lower limb musculature and even in the upper limbs have been observed. Ocular, pharyngeal, and cardiac muscles are usually spared. Respiratory muscles are generally not affected until the very late stages in wheelchair-bound patients. Occasionally, affected individuals may present facial weakness.

Etiology GNE myopathy is caused by biallelic mutations in the GNE gene (9p13.3) which encodes a bi-functional enzyme involved in the sialic acid biosynthetic pathway. Mutations in this gene result in a 30-60% decrease in enzyme activity leading to a decreased sialylation of glycoproteins and glycolipids. Hyposialylation appears to be involved in disease pathogenesis, but the process by which a defect in GNEleads to muscle disease is still elusive. With increasing number of patients, genotype-phenotype correlations are currently emerging. Detailed Description GNE Myopathy is a recessive disease, that is, it is caused when both copies of chromosome 9 in the patients carry a mutated version of GNE. The activity of GNE leading to sialic acid production is reduced and is low enough to manifest as myopathy in adult life. Sialic acid is a sugar that attaches itself to many proteins in each cell. This process is called sialylation and is necessary for these proteins to perform their designated functions. Reduced sialylation is probably a major cause of GNE Myopathy as administration of sialic acid or its precursor ManNAc, could arrest the development of disease in the mouse models. However, the picture may not be that simple. Functions of GNE protein other than sialic acid synthesis could also be involved. It has been found that GNE protein interacts with many other proteins of the cell including those from cytoskeleton and mitochondria. Expression of mutant GNE proteins can lead to enhanced apoptosis, mis-localization of proteins within the cellular compartments and defect in signalling and interaction with other cells. All these can explain observed phenotype seen in patients. We need to understand the nature of molecular mechanisms underlying pathobiology of the disease in order to develop proper therapies for GNE Myopathy. Preliminary results obtained from clinical trials based on sialic acid and ManNac supplementation indicate lack of significant improvement or even complete arrest of progression of the disease, suggesting that the phenotype seen may be due to defects in pathways other than that of sialic acid. Clinical signs and symptoms

Very Frequent

Fatty replacement of skeletal muscle

Foot dorsiflexor weakness

Lower limb muscle weakness

Mildly elevated creatine phosphokinase

Muscle fiber inclusion bodies

Rimmed vacuoles

Tibialis muscle weakness

Frequent

Absent Achilles reflex

EMG: myopathic abnormalities

EMG: myotonic discharges

EMG: positive sharp waves

Hip flexor weakness

Hypothyroidism

Increased variability in muscle fiber diameter

Limited shoulder movement

Limited wrist extension

Shoulder girdle muscle weakness

Steppage gait

Occasional

Abnormality of the foot musculature

Abnormality of the right hemidiaphragm

Facial palsy

Lower limb amyotrophy

Muscle weakness

Scapular winging

Shoulder girdle muscle atrophy

Rare

Cardiomyopathy

Weakness of long finger extensor muscles

Diagnostic methods Diagnosis is suspected in individuals with early-onset foot drop, negative dominant family history, sustained quadriceps sparing despite marked weakness of all other thigh muscles, modest elevation of serum creatine kinase (2-5x), muscle biopsy showing fiber size variation (with atrophy) and presence of rimmed vacuoles and congophilic protein aggregates. MRI reveals a characteristic pattern of muscle involvement with (from the early stages of the disease) severe fatty-fibrous replacement of the biceps femoris short head muscles, accompanied by less severe involvement of the gluteus minimus, tibialis anterior, extensor hallucis and digitorum longus, soleus and gastrocnemius medialis muscles. Genetic screening revealing pathogenic variants in GNE confirms the diagnosis. Differential diagnosis Differential diagnosis includes other adult-onset distal myopathies with rimmed vacuolar pathology (i.e. distal myopathy, Welander type; tibial muscular dystrophy; adult-onset distal myopathy due to VCP mutation; and vocal cord and pharyngeal distal myopathy), myofibrillar myopathies, and Laing early-onset distal myopathy. Genetic counseling Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% chance of having an affected child.

Prognosis Most patients become wheelchair-bound after 15-20 years of disease onset. About 5% of patients have atypical early involvement of the quadriceps muscle resulting in earlier non-ambulation.

Treatment(Undergoing Research)

Gene Editing Gene editing means changing the DNA sequence of an organism (such as human) in situ, that is, within a living organism. This technology has the potential to change any sequence (like a mutation) in a patient’s DNA and convert it back into the normal sequence . Several types of gene editing methods have been developed in the last decade. However, a major discovery made public three years back by Profs Jennifer Doudna of University of California, Berkeley and Emmanuelle Charpentier, now at the Helmholtz Centre for Infection Research in Germany, changed this field, opening up the possibility of successfully carrying out gene editing in whole animals. They discovered a cheap and efficient new system for editing DNA. Known as CRISPR-Cas9 it has been adopted by scientists around the world. CRISPRs (clustered regularly interspaced short palindromic repeats) are short segments of DNA, while Cas9 (Crispr-associated protein 9) is an enzyme. They are found in bacteria as a defence system against attacks from viruses. CRISPR sequences code for short RNAs called guide RNAs which scan the genome looking for their matching sequences and then use the Cas9 protein as molecular scissors to snip through the DNA. The faulty DNA is cut out and may be replaced with a piece of normal DNA. The technique is cheap and highly precise, a major advantage for use in human system.

Stem Cell Therapy

Each organ of our body is made up of cells that are designed to carry out their own specialized function. Thus, cells of bone are different from those of muscle or blood and so on. But all of these different cell types were originally derived from very similar cells during our development in the womb right up to adulthood. These cells are called stem cells. A stem cell is a cell that can multiply by division, and in response to some stimulus can differentiate (convert) into a specialized cell-type of a particular tissue/organ. Stem cell numbers are very high in the fetus but drop in the adult as development is complete and no more differentiation is required. However some stem cells are present in the adult to help in replacement of dead cells and regeneration of damaged tissue. These cells can be an attractive source for therapy as they are derived from the same individual. DEVELOPMENT OF STEM CELL TECHNOLOGY Ever since it became clear that stem cells could be used to replace damaged tissues in patients there have been concerted efforts world-wide to develop appropriate technologies to harvest the potential power of stem cells. The field has seen monumental advances in the last two decades. Basically the need is to have stem cells in sufficiently large numbers, which would differentiate into the organ of one’s choice, would not be rejected by the host, and would not show adverse effects (like tendency to form tumors). It is therefore important to have definitive clinical studies to demonstrate efficacy of each stem cell therapy before it can be tried with patients. Embryonic stem cells (obtained from embryos) are one of the best sources of pluripotent stem cells (that is, they can differentiate into any tissue); however it is not always possible to get these due to various issues, including ethical ones. They could also sometimes lead to tumors. Adults also contain stem cells in their tissues- although their numbers are low. Bone marrow is used as a source of adult Mesenchymal stem cells. These can differentiate into a variety of tissues like bone, muscle, nerves, cartilage, ligament, tendon, fat, blood cells. A limitation in their use is their typically low numbers. Induced pluripotent stem cells (iPSC) can be generated in the lab. As their name suggests, they can be induced to form, by coaxing a small amount of skin tissue from an adult to form stem cells. These can further be converted into specialized cells like nerve and muscle cells. Due to the potentially vast application of this technology to convert any cell into a stem cell it fetched the Nobel prize to its inventor (Shinya Yamanaka from Japan).

Case Study of Tara(How she dealt with this disease is a ray of hope):

The moment when my doctor told me I had GNE Myopathy, my first sense was one of relief. An unusual reaction, maybe, but his words were an answer to a decades-long family mystery. Forty years since my oldest sister started walking with a mysterious waddling gait, the disease that would become our constant, nameless companion finally had a name. That was a turning point, the beginning of a new path lined with courage and hope. Growing up in a large family with six siblings, our lives began to change the year we watched my sister’s gait worsen and her strength wane. She was diagnosed with Limb-Girdle Muscular Dystrophy (LGMD). In the years that followed I began to experience similar symptoms, as did three of my siblings. Our entire family was then observed as part of a LGMD study in the 90s. Sadly, the team of doctors and researchers were originally focused on the wrong condition.

Navigating Bumpy Terrain By the year 2000, my symptoms were severe enough to interfere with my life. I began to fall and have other mobility-related accidents. I started wearing a leg brace, hidden under long pants so that my children wouldn’t worry. What I found to be most frustrating was that I could not be physically spontaneous anymore. At times I felt defeated because my disease was preventing me from doing the things I once loved, like dancing or playing with my children. I also stepped down from a job I loved as a Dietary Director at a nursing facility. It wasn’t until 2010, after numerous tests and studies by many doctors, that I was finally diagnosed with GNEM – a rare, muscle-wasting condition. A correct diagnosis made a world of difference. I could therefore conduct my own research; I could get answers; I could get the support I need. The Destination Lies Ahead I’ve seen the devastation that this disease can wreak, and I’m motivated to help others get speedier testing and diagnosis by connecting them with the right support groups and resources. I focus my efforts on expanding awareness of GNEM, the importance of genetic testing and latest research. I have been fortunate to meet with others living with GNEM face-to-face, as well as through my blog, social media and the global online community at GNE-Myopathy.org. Through it all, I am touched and inspired by the grace with which they handle their challenges. It’s what keeps me going. If I had to give advice to others with this condition, or any other rare disease, it would be to not let your disease stop you. Whatever your dreams and motivations in life are, continue with them even if you need to modify and adapt them to fit your unique life circumstances. “I remind myself often that on this journey of living with GNEM, I must undergo some remarkable personal challenges and push myself to clear these recurrent physical and emotional hurdles. I must come to a place of acceptance within myself as I witness my physical decline. I have learned that acceptance is not failure, for it frees me up intellectually and emotionally to continue the battle until it is won.”

Refreences

https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=8729&Disease_Disease_Search_diseaseGroup=gne-myopathy&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=GNE-myopathy&title=GNE%20myopathy&search=Disease_Search_Simple http://gne-myopathy.org/ http://ultrarareadvocacy.com/patient-story/gne-myopathy/.