The full article

What are Rare Disorders?

According to the National Center for Advancing Translational Sciences (NCATS), a rare disorder or disease is a condition that affects fewer than 200,000 people in the United States. Rare diseases are also known as orphan diseases because drug companies were uninterested in developing treatments for these (1).

Hence, the U.S. Congress created the Orphan Drug Act of 1983 to provide financial incentives for pharmaceutical companies to develop a treatment for these rare diseases (2).

NCATS says that there may be around 7,000 rare diseases, with 25 to 30 million Americans afflicted with these. When someone is diagnosed, only a few types of rare diseases are tracked, making it difficult to determine the exact number of rare diseases and sufferers in the U.S.

One of these rare diseases is corticobasal degeneration.

What is Corticobasal Degeneration?

Corticobasal degeneration is a rare, progressive disorder that causes nerve cell 

loss and degeneration of several parts of the brain. 

Causes of corticobasal degeneration have yet to be determined, but researchers have observed that people suffering from the disease have accumulated abnormal levels of tau, a protein that is found in the brain(3)

Too much tau in the brain cells could lead to the deterioration of these cells and cause symptoms of corticobasal degeneration. Tau protein is also associated with neurodegenerative diseases. These include Alzheimer’s, progressive supranuclear palsy (PSP), and frontotemporal dementia. (4)

The symptoms usually appear in people around 60 years old. Initially, only one side of the body is affected, but eventually, the symptoms will affect both sides.

Symptoms include (5):

    • Poor coordination and rigidity (similar to Parkinson’s)
    • Memory loss
    • Dementia
    • Visual-spatial problems
    • Apraxia (inability to make familiar and purposeful movements)
    • Hesitant and halting speech
    • Myoclonus (involuntary muscular jerks)
    • Dysphagia (difficulty swallowing)

People who are suffering from other degenerative diseases like Alzheimer’s, Lewy body disease, and PSP experience the same corticobasal degeneration symptoms. Because of this, these symptoms have been dubbed as “corticobasal syndrome.” (6)

In the advanced stages, patients experience dementia, loss of inhibition, and behavioral changes like lack of empathy. They also experience an inability to communicate and ambulate as well as difficulty walking and balancing. (7)

Over six to eight years, the disease progresses gradually and could lead to death. The usual causes are pneumonia, a severe infection of the blood (sepsis), or a blood clot in the lungs (pulmonary embolism). (8)

Some medications like clonazepam can help with the involuntary muscle jerks. Likewise, Botox and therapy (occupational, physical, and speech therapy) can help manage corticobasal degeneration symptoms; however, there is no specific treatment for the disease (9)

CBD and Corticobasal Degeneration

A study in 2005 (10) reveals that cannabidiol (CBD), the non-psychoactive component of cannabis plants, inhibits Tau.

Tau is the protein that accumulates in the brain cells of people suffering from corticobasal degeneration. It is also associated with several neurodegenerative diseases. 

The researchers conclude that CBD is a possible pharmacological tool in treating these diseases, especially since it has “extremely low toxicity in humans.” (11)

Another study in 2017 reports that CBD has beneficial effects on patients who have Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. The study discusses CBD’s therapeutic properties, like its neuroprotective effects on several pathological conditions (12).

According to the researchers of the 2017 study, CBD’s antioxidant and anti-inflammatory properties benefit parts of the brain responsible for the development and maintenance of neurodegenerative diseases (13)

Some of the diseases in the 2017 study have symptoms shared by patients suffering from corticobasal degeneration. Hence, CBD use may be an alternative that can be explored.

CBD comes in various forms like gummies, tinctures (drops), patches, balms, and even gelcaps. 

The use of CBD has not been approved by the U.S. Food and Drug Administration, so there is no standard dosage. It is recommended that patients begin with small doses and, if there are no adverse effects, gradually increase the dosage.

Before adding CBD products to a patient’s medication regimen, it is recommended to consult with a doctor first.

Conclusion

Several rare diseases have no treatment yet. One of these is corticobasal degeneration. 

Upon the symptoms’ appearance in patients, it only takes six to eight years before the disease becomes life-threatening. 

There are no known treatments for corticobasal degeneration. A study (14), however, has found that CBD may inhibit Tau, the protein that may be one of the causes of corticobasal degeneration. 

Another study on neurodegenerative diseases also reports CBD’s neuroprotective benefits on pathological conditions (15).

CBD may be an alternative that can help treat corticobasal degeneration. It is essential to consult with a doctor first before taking CBD.


  1. “FAQs About Rare Diseases.” Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases.
  2. Ibid.
  3. “Corticobasal Degeneration.” Stanford Health Care (SHC) – Stanford Medical Center, stanfordhealthcare.org/medical-conditions/brain-and-nerves/corticobasal-degeneration.html.
  4. U.S. Department of Health and Human Services. op. cit. 
  5. Stanford Health Care. op. cit. 
  6. Ibid. 
  7. “Corticobasal Syndrome (CBS).” Baylor College of Medicine, www.bcm.edu/healthcare/care-centers/parkinsons/conditions/corticobasal-syndrome.
  8. Stanford Health Care. op. cit. 
  9. Ibid. 
  10. Esposito, Giuseppe, et al. “The Marijuana Component Cannabidiol Inhibits Beta-Amyloid-Induced Tau Protein Hyperphosphorylation through Wnt/Beta-Catenin Pathway Rescue in PC12 Cells.” Journal of Molecular Medicine (Berlin, Germany), U.S. National Library of Medicine, Mar. 2006, www.ncbi.nlm.nih.gov/pubmed/16389547.
  11. Ibid.
  12. Mannucci, Carmen, et al. “Neurological Aspects of Medical Use of Cannabidiol.” CNS & Neurological Disorders Drug Targets, U.S. National Library of Medicine, 2017, www.ncbi.nlm.nih.gov/pubmed/28412918.
  13. Ibid. 
  14. Esposito, G. (2006 Mar). op. cit. 
  15. Mannucci, C. (2017) op. cit.

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March 2015

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Taste Perception and Sensory Sensitivity: Relationship to Feeding Problems in Boys with Barth Syndrome

Stacey Reynolds, PhD, OTR/L; Consuelo M. Kreider, PhD, OTR/L; Lauren E. Meeley, MS, OTR/L and Roxanna M. Bendixen, PhD, OTR/L

Whistling Seizures – A Unique Case Report of a Rare Automatism

Anuradha Singh, MD, Daniel Torres, MD, and Kaitlyn Lillemoe, MD

Eisenmenger Syndrome: Pulmonary Hypertension Resulting
in a Right-To-Left Cardiac Shunt

Oliver De Neini, BSc

Clinical Natal and Neonatal Teeth: A Report of Four Cases

Assistant Prof. Dr. Eda Haznedaroglu, Prof. Dr. Ali Mentes,

Oocytes Derived by Mild IVF-IVM After Repeated Empty Follicle Syndrome: A Case Report

Oocytes Derived by Mild IVF-IVM After Repeated Empty Follicle Syndrome: A Case Report

Hatirnaz Safak, MD, and Hatirnaz Ebru, MD

Table of Contents

Taste Perception and Sensory Sensitivity: Relationship to Feeding Problems in Boys with Barth Syndrome

Whistling Seizures – A Unique Case Report of a Rare Automatism

Eisenmenger Syndrome: Pulmonary Hypertension Resulting
in a Right-To-Left Cardiac Shunt

Clinical Natal and Neonatal Teeth: A Report of Four Cases

Oocytes Derived by Mild IVF-IVM After Repeated Empty Follicle Syndrome: A Case Report

An Open Access Journal

July 2017

Table of Contents

Recurrent Hyponatremia in a 16 Year Old Female with Acute Intermittent Porphyria

Swaminathan Sundaresan, BA, Devona Martin, MD, Luke Hamilton, MS, and Don P. Wilson, MD

A Prospective Study of Neurological Abnormalities in
Phelan-Mcdermid Syndrome

Yitzchak Frank MD, Jesslyn M. Jamison BA, M. Pilar Trelles MD, et al.

The Future of Castleman Disease Research: Proceedings From 2015 and 2016 Annual Meetings

The Future of Castleman disease Research: Proceedings from 2016 and 2016 Annual Meetings

Michael P. Croglio, BS, Raj K. Jayanthan, MD, and Hayley Williamson et al

Newborn Screening for Lysosomal Storage Diseases:Current Landscape and State-Wide Perspectives in the US

Lokhande S,Joshi M, Castelli J, and Gershkowitz J

This issue:

July 2017

Table of Contents

Recurrent Hyponatremia in a 16 Year Old Female with Acute Intermittent Porphyria

A Prospective Study of Neurological Abnormalities in
Phelan-Mcdermid Syndrome

The Future of Castleman Disease Research: Proceedings From 2015 and 2016 Annual Meetings

Newborn Screening for Lysosomal Storage Diseases:Current Landscape and State-Wide Perspectives in the US

—-

An Open Access Journal

April 2013

Table of Contents

Letter from the Editors

Letter from the Editors

Ian Phillips, PhD, DSc, FAHA and Tim Coté, MD, MPH

Welcome to the first issue of the Journal of Rare Disorders.

Rare and Orphan Diseases Challenges: Clinical Development and Clinical Practice

Rare and Orphan Diseases Challenges: Clinical Development and Clinical Practice

Cara Cassino, MD; May Orfali, MD; and Robert J. Charnigo; Deborah L. Marsden, MD

Although rare diseases individually affect small populations, the 7000 identified rare diseases collectively affect more than 50 million people in the United States and Europe combined.1 Most rare diseases have a genetic basis, 85% are serious or life threatening, and >50% affect children. Approved treatments are available for <5% of rare diseases, and for many, the outcome is fatal.2 Drug developers and practitioners share challenges in delivering effective treatments to patients with rare diseases.

Skin Findings Reveal Deeper Issues: A Case of Birt Hogg Dubé Syndrome

Skin Findings Reveal Deeper Issues: A Case of Birt Hogg Dubé Syndrome 

Jodi D.Hoffman, MD, Neeta Vora, MD, Gary Strauss, MD, Alireza Sepehr, MD, and Ben Solky, MD

Birt-Hogg-Dubé syndrome is a rare, multi-system genetic disorder. The diagnosis consists of a triad of findings; dermatologic, pulmonary, and renal. This article aims to increase awareness of this rare syndrome and the need to consider Birt-Hogg-Dubé syndrome in patients with fibrofolliculomas or tricodiscomas, pneumothorax or lung cysts, and renal tumors. Early diagnosis allows for management and screening of the associated lung and renal findings, which benefits patients with this autosomal dominant condition as well as their families.

Prenatal Findings in Cases of Familial and Sporadic 22q11.2 Deletion Syndrome

Prenatal Findings in Cases of Familial and Sporadic 22q11.2 Deletion Syndrome

Atena Asiaii, Jodi Hoffman, Sally Harris, Laurie Demmer, Neeta Vora

To date, published information is lacking regarding the prenatal natural history of DiGeorge syndrome/velocardiofacial syndrome. Caused by the deletion of chromosome 22q11.2 in most cases, this syndrome is increasingly detected prenatally with the use of microarrays.

The authors hypothesized that current prenatal screening methods (such as nuchal translucency, maternal serum markers, and ultrasonography) may be useful as prenatal indicators for the early diagnosis of the 22q11.2 deletion syndrome (DS). The goal of this study was to identify characteristic findings, including sonographic abnormalities, in 22q11.2 DS to improve prenatal detection

Brain Vascular Malformation Consortium: Overview, Progress and Future Directions

Brain Vascular Malformation Consortium: Overview, Progress and Future Directions

Amy L. Akers, PhD; Karen L. Ball, BS; Marianne Clancy, BS; Anne M. Comi, MD; Marie E. Faughnan, MD; Rashmi Gopal-Srivastava, PhD; Thomas P. Jacobs, PhD; Helen Kim, PhD; Jeffrey Krischer, PhD;

Brain vascular malformations are resource-intensive to manage effectively, are associated with serious neurologic morbidity, lack specific medical therapies, and have no validated biomarkers for disease severity and progression. Investigators have tended to work in “research silos” with suboptimal cross-communication. We present here a paradigm for interdisciplinary collaboration to facilitate rare disease research. The Brain Vascular Malformation Consortium (BVMC) is a multidisciplinary, interinstitutional group of investigators, 1 of 17 consortia in the Office of Rare Diseases Research of the Rare Diseases Clinical Research Network (RDCRN).

The Cochrane Report-Enzyme Replacement Therapy For Anderson-Fabry Disease

The Cochrane Report

Regina P. El Dib, PhD; Paulo Nascimento, MD, PhD; and Gregory M. Pastores, MD

This review highlights the need for continued research on the use of enzyme replacement therapy for

Anderson-Fabry disease.

This issue:

2325-6222

 

Premier Issue

Co-Editors: M. Ian Phillips, PhD, DSc, FAHA and Tim Cote, MD, MPH

Table of Contents

Letter from the Editors

Rare and Orphan Diseases Challenges: Clinical Development and Clinical Practice

Skin Findings Reveal Deeper Issues: A Case of Birt Hogg Dubé Syndrome

Prenatal Findings in Cases of Familial and Sporadic 22q11.2 Deletion Syndrome

Brain Vascular Malformation Consortium: Overview, Progress and Future Directions

The Cochrane Report-Enzyme Replacement Therapy For Anderson-Fabry Disease

—-

OOCYTES DERIVED BY MILD IVF‐IVM AFTER REPEATED EMPTY FOLLICLE

SYNDROME: A CASE REPORT  

Hatırnaz Şafak, MD, and Hatırnaz Ebru, MD

Clinart IVF and Women’s Health Center, Trabzon, Turkey

ABSTRACT

Empty follicle syndrome (EFS) is one of the most disappointing events in assisted reproductive technology that cannot be predicted before retrieval of the oocytes. The case presented here is of a 27‐year‐old woman with polycystic ovary syndrome whose husband had azospermia. She had experienced EFS in previous in vitro fertilization attempts and came to our clinic for a new approach. Microsurgical testicular sperm extracƟon with sperm freezing was offered to her husband first, and then the patient underwent an antagonist cycle with good follicular growth. However, neither oocytes nor cumulus cells in the follicular fluid were collected. Repeated genuine EFS was diagnosed and in vitro maturation (IVM) with follicle‐stimulating hormone priming was planned for the next cycle. Six germinal‐vesicle oocytes were collected; 4 matured and were injected with thawed sperm. A single embryo was transferred, but the beta‐human chorionic gonadotropin (beta‐hCG) test was negative. To our knowledge, this is the first case to obtain oocytes by IVM, and this treatment could be a promising choice in repeated genuine EFS cases.

INTRODUCTION

Empty follicle syndrome (EFS) is an uncommon complication of in vitro fertilization (IVF) treatment, with a prevalence ranging from 0.045% to 7%.1‐4 The existence of EFS is sƟll under debate, and whether it is a cause or a result of inferƟlity is as yet unclear. Most cases of EFS are due to insufficiency of human chorionic gonadotropin (hCG) for triggering, with fewer cases considered to be genuine EFS. The case presented here is one of genuine EFS—the patient experienced recurrent EFS in stimulated IVF cycles. With the decision to aƩempt in vitro maturation (IVM) and the couple’s consent, a mild IVF‐IVM program was planned and 6 germinal‐vesicle (GV) oocytes were collected, 4 of which were injected with thawed sperm by intracytoplasmic sperm injection (ICSI) performed 30 hours atier oocyte pickup (OPU) following IVM. One 4‐ cell embryo with grade 1 morphology was transferred, but the pregnancy test was negaƟve on the 12th day.

CASE

A 27‐year‐old woman whose husband had male infertility due to nonobstructive azospermia (NOA) came to our clinic because she had previously experienced EFS. Microsurgical testicular sperm extraction (microTESE) with sperm freezing was offered to her husband before we attempted IVF. Atier sperm cryopreservation, an antagonist IVF cycle was administered but neither oocytes nor cumulus cell mass was retrieved. The couple was informed about the EFS outcome. Mild IVF‐IVM was recommended as an alternative to the sƟmulated cycle, and this treatment modality was accepted. The patient had no history of health problems, but her husband had a history of type 2 diabetes mellitus together with NOA. Laboratory and blood analyses of the couple were normal. It was unfortunate that her husband had azospermia and that the microTESE‐derived frozen sperms used for ICSI were found to have poor morphology and motility, which may impact clinical outcome. The patient was evaluated on day 3 by transvaginal ultrasound, and a follicle‐sƟmulaƟng hormone priming cycle was started with follitropin alfa for injecƟon (Gonalf, EMD Serono, Geneva, Switzerland) 75 IU subcutaneously for 3 days together with estrogen on day 3 for endometrial thickening. On day 8, she was evaluated by ultrasound, which revealed endometrial thickness of 9.2 mm with follicles less than 12 mm in size. hCG priming with choriogonadotropin alfa (Ovitrelle, EMD Serono) 250 μg subcutaneously was given on day 8, and 36 hours later, OPU was performed. One oocyte from the left  ovary and 5 oocytes from the right ovary were collected and placed into the IVM medium for 28 to 30 hours; 4 of 6 GV oocytes (66% maturation) were found to be mature. Thawed sperms were injected by ICSI at 30 hours, and only 1 fertilized oocyte and 2 pronuclear oocytes (25% fertilization rate) were observed the next morning. On day 12, the 4‐cell, grade 1 embryo was transferred. The IVM protocol is well accepted and used widely in indicated cases. Although the beta‐hCG test was negative, the couple was hopeful and decided to repeat the treatment because they still had frozen sperm in the laboratory.

DISCUSSION 

EFS is a condition in which no oocytes can be obtained from the follicular fluid of properly sƟmulated IVF paƟents. It is quite rare, and the etiology is unknown. Two types have been defined according to hCG levels, genuine and false, and the existence of the genuine type is a maƩer of debate. No single treatment option is available, but the improper administration of hCG, which may cause EFS, can be corrected. EFS needs to be further researched in regard to oocyte maturation and ovarian biology. EFS was first described by Coulam et al, as a condiƟon of no oocytes in apparently normal growing follicles of stimulated ovaries with meticulous follicular aspiration.5 The genuine type has been defined as failed retrieval in case of appropriate hCG levels, whereas the false type has been defined as a low level of hCG (<40 IU/L) due to misadministration or low bioavailability of medicaƟon.6

EFS is a rare complication of IVF that cannot be anticipated before the OPU procedure. Occurrence has been estimated to be 0.0045% to 7% of paƟents undergoing OPU.3 Aktas et al found 25 cases among 3060 cycles, with a prevalence of 0.81%.1 Reichman et al estimated false group incidence at 0.045%.2 Mesen et al evaluated the genuine and false types of EFS separately and found 0.016% to be genuine and 0.072% to be false among a total of 18,294 cycles.4 Castillo et al reported an incidence of EFS of 3.5% among 2034 oocyte donor cycles and 3.1% among 1433 IVF cycles performed between years 2009 and 2010 was retrospectively analyzed to identify cases of EFS in each group.7 That study also reported that the triggering method does not significantly change the outcome.   In a case report by Vutyavanich et al, follicular fluids were filtrated at the stimulated cycle aŌer EFS, and immature oocytes were collected and matured in vitro.8 The most common underlying mechanism in the false group has been shown to be inefficient hCG blood levels. Defects in manufacturing, rapid plasma clearance of hCG, and misuse by the patient also have been suggested as causes 3,6 as well as early oocyte atresia in conƟnued follicular growth.4,7  Inan et al analyzed whole gene expression of granulosa cells from a 22‐year‐old patient with recurrent EFS and found a total of 160 differently expressed genes.9 According to the investigators, the absence of oocytes may have been due to “the increased apoptoƨc gene expression and the reduction of transcripts whose products are responsible for healthy follicular growth.” In another case, the presence of oocytes and their apoptosis was proposed to be due to the presence of thin zona pellucida of 200 preantral follicles in the follicular aspirates.10 Ovarian aging has also been suggested to have a significant role in genuine EFS.9 Other investigators have considered low ovarian reserve as the cause.11 In addition, geneƟc causes of EFS have also been proposed. Onalan et al reported on a possible inherited condiƟon of EFS with moderate sensorineural deafness affecting 2 sisters.12 Any alteration that changes the transient and sequenƟal expression of epidermal growth factor in family members might affect the oocyte growth in follicles, owing to impaired cumulus expansion and oocyte release. Although some believe there is no recurrence of EFS in subsequent treatments, it has been shown that  among paƟents with EFS, recurrent EFSs occurred in 15.8% of subsequent cycles.13

CONCLUSIONS

In light of the literature, this case appears to be the first to attempt to manage EFS with a mild IVF‐IVM modality. Selection of this mode of treatment is compatible with the etiopathogenesis of EFS. If the oocytes were present but failed to mature in the follicles during stimulation, it may be more effective to remove the immature oocytes and apply the maturation process in vitro. Although the beta‐hCG was negative, this case could lead to an alternative approach to genuine EFS and may encourage investigation of the underlying reasons for this condition.

 

REFERENCES

  1. Aktaş M, Beckers NG, van Inzen WG, et al. Oocytes in the empty follicle: a controversial syndrome. Fertil Steril.2005;84:1643‐1648.
  2. Reichman DE, Hornstein MD, Jackson KV, Racowsky C. Empty follicle syndrome—does repeated administration of hCG really work? Fertil Steril. 2010;94:375‐377.  
  3. Coşkun S, Madan S, Bukhari I, et al. Poor prognosis in cycles following ‘’genuine’’ empty follicle syndrome. Eur J Obstet Gynecol Reprod Biol. 2010;150:157‐159.
  4. Mesen TB, Yu B, Richter KS, et al. The prevalence of genuine empty follicle syndrome. Fertil Steril. 2011;96:1375‐1377.
  5. Kim JH, Jee BC. Empty follicle syndrome. Clin Exp Reprod Med. 2012;39:132‐137.
  6. Stevenson TL, Lashen H. Empty follicle syndrome: the reality of controversial syndrome, a systemaƟc review. Fertil Steril. 2008;90:691‐698.
  7. CasƟllo JC, Garcia‐Velasco J, Humaidan P. Empty follicle syndrome atier GnRHa triggering versus hCG triggering in COS. J Assist Reprod Genet. 2012;29:249‐ 253.
  8. Vutyavanich T, Piromlertamorn W, Ellis J. Immature oocytes in “apparent empty follicle syndrome”: a case report. Case Report Med. 2010;2010:367505
  9. Inan MS, Al‐Hassan S, Ozand P, Coskun S. Transcriptional profiling of granulosa cells from a paƟent with recurrent empty follicle syndrome. Reprod Biomed Online. 2006;13:481‐491.
  10. Desai N, Austin C, AbdelHafez F, et al. Evidence of ‘genuine empty follicles’ in follicular aspirate: a case report. Hum Reprod. 2009;24:1171‐1175.
  11. Younis JS, Skournik A, Radin O, et al. Poor oocyte retrieval is a manifestation of low ovarian reserve. Fertil Steril. 2005;83:504‐507.
  12. Onalan G, Pabuçcu R, Onalan R, et al. Empty follicle syndrome in two sisters with three cycles: case report. Hum Reprod. 2003;18:1864‐1867.  
  13. Baum M, Machtinger R, Yerushalmi GM, et al. Recurrence of empty follicle syndrome with sƟmulated IVF cycles. Gynecol Endocrinol. 2012;28:293‐295

 

CLINICAL CHARACTERIZATION OF MYOPATHY IN A RARE AUTOSOMAL DISEASE:

HEREDITARY BONE DYSPLASIA/OSTEOSARCOMA AND LIMB GIRDLE MYOPATHY

IN A UNIQUE FAMILY

Katrina J. Llewellyn, Ph.D.1, Angèle Nalbandian, Ph.D.1, Olga Camacho‐Vanegas, Ph.D.2, Marie Wencel, B.S.1 ,Robert Chilcote, M.D.2, John A. MarTIgneƫ, M.D., Ph.D.3, Virginia E. Kimonis, M.D.1

Division of Genetics and Metabolism, Department of Pediatrics, University of California‐Irvine, Irvine, CA 92697   2 Division of Hematology/Oncology, Department of Pediatrics, University of California‐Irvine, Irvine, CA 92697 3 Departments of Genetics and Genomic Sciences, Pediatrics and Oncological Sciences, Icahn School of Medicine at Mount Sinai,  New York, NY 10029 

 ABSTRACT

Autosomal‐dominant myopathic disorder associated with diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS‐MFH) is characterized by myopathy, bone fragility, and osteosarcoma. DMS‐MFH was recently associated with mutations in the methylthioadenosine phosphorylase gene  (MTAP). MTAP is a ubiquitously expressed enzyme crucial for polyamine biosynthesis. Two disease‐causing mutations have been identified in MTAP: c.813‐2A>G and c.885A>G, both of which result in dysregulated alternative splicing of MTAP isoforms. Here, we report on myopathy in two cousins with the c.813‐2A>G mutation. Both developed a progressive limb‐girdle type myopathy at age 30 years. To our knowledge, we are the first group to characterize the myopathy associated with DMS‐MFH, discovering varied muscle fiber size, degeneration, and increased centralized nuclei. In this report, expression levels of transactive response DNA‐binding protein (TDP)‐43, light chain (LC)3‐I/II, and p62/sequestome 1 (SQSTM1) in the muscle fibers were increased, suggesting a possible dysregulaTIon of autophagy. Elucidation of the pathologic mechanism(s) in DMS‐MFH offers the potential to uncover key molecular signaling pathways and the promise of novel future treatments.

INTRODUCTION

Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS‐MFH) (MIM 112250) is an autosomal‐dominant syndrome characterized by myopathy, bone fragility, and osteosarcoma.1–5 Patients with this disorder experience limb‐girdle myopathy, fractures, defective healing of long bones, cortical growth abnormalities, presenile cataracts, potential coronary artery disease, and osteosarcoma.1–8 The bone pathology begins in childhood and affects ~90% of DMS‐MFH individuals.7,8 It has a unique bone‐dysplasia phenotype and is characterized by cortical growth abnormalities, including diffuse diaphyseal medullary stenosis with overlying endosteal cortical thickening and metaphyseal striations, and scattered bone infarcTIons.8 Osteosarcomas/ malignant fibrous histiocytomas develop in ~35% of individuals with DMS.1,3–5 Progressive muscle weakness affects ~70% of members of families with DMS‐MFH, with onset in the 20s or 30s.7,8 The myopathic phenotype affects a significant portion of the DMS‐MFH population and is characterized in this report. The cause of this disorder was mapped, by MarTIgneƫ et al1 in 1999, to chromosomal region 9p21–22, establishing a disease gene 2.9‐Mb critical region between markers D9S736 and D9S171.3 A number of DMS‐MFH candidate genes were originally screened, including the methylthioadenosine phosphorylase gene (MTAP; MIM 156540). IniTIally, MTAP had been thought to consist of eight exons and seven introns9 ; however, Camacho‐ Vanegas et al in 2012 identified mutations in the previously unknown terminal exons of the MTAP gene. 10 They found that all affected members of five unrelated DMS‐MFH families possessed one of two synonymous mutations, one located within exon 9, c.885A>G, and the other upstream of exon 9 in the intron splicing boundary, c.813‐2A>G. These mutations result in exon skipping and subsequent loss of exon 9 in alternatively spliced, biologically active isoforms.10 MTAP is a ubiquitously expressed enzyme that plays a crucial role in the salvage pathway for adenine and methionine in all  Tissues.11,12 This dysregulated expression of the MTAP splice variants has an effect on overall MTAP enzymaTIc acTIvity because increased levels of MTA have been found in the serum of affected DMS‐MFH paTIents10 ; however, how this dysregulaTIon affects the pathophysiology remains unclear. In this report, we examine myopathy, MTAP splice variant expression, and pathologic mechanism(s) in two cousins with a c.813‐2A>G mutaTIon affected by limb‐girdle myopathy caused by DMS‐MFH.

CASE REPORT

Clinical History: Case A, V:7

We report a 45‐year‐old white  man with a deteriorating course of muscle strength, bone fragility, and osteosarcoma, leading to early death (Figure 1, individual V:7). The paTIent had had 22 fractures throughout his life, including in the tibia, fibula , wrists, hands, shoulder, and femur. He experienced chronic pain disorder largely due to these fractures. At the age of 31 years, he was found to have myopathy, with weakness and atrophy in his biceps, brachioradialis, wrist extensors, and facial muscles. His motor strength, as graded using the Medical Research Council (MRC) scale, was 4 or 4+/5 in most muscle groups: neck flexors, deltoids, triceps, wrist extensors, hip flexors, knee extensors, and ankle dorsiflexors. His reflexes were graded as 1 to 2+ in the knees and upper extremities, and he had normal coordination. His creatine phosphokinase concentration was 498 U/L (normal, 20–220 U/L), and nerve conduction studies were normal. Also at 31 years, needle electrode examination in several muscle groups revealed fibrillation potentials and short‐ duration small‐amplitude polyphasic motor unit potentials in the biceps and brachioradialis on the left  side. Subtle changes were noted in the triceps and deltoid, consistent with a myopathic process. These findings are not suggestive of amyotrophic lateral sclerosis or any neurogenic process, and nerve conduction studies were normal bilaterally. A muscle biopsy specimen showed no abnormal muscle fiber type grouping, atrophy, regenerating, or “ragged” red fibers. No increase in fat or connecTIve TIssue and no structural abnormality of the fibers were seen. Staining for glycogen, periodic acid Schiff (PAS), desmin, nicotinamide adenine dinucleoTIde + hydrogen (NADH), adenosine triphosphatase (ATPase), and Gomori trichrome were all normal. However, myopathy was confirmed on electromyography and clinical examinaTIon despite the muscle biopsy specimen showing no pathology. It is likely that the biopsy specimen was taken too early in the onset of myopathy. The myopathy was concluded to have been most likely facioscapulohumeral dystrophy, or limb‐girdle muscular dystrophy. At the age of 44 years, the patient’s MRC scale grades of strength of his neck flexors were 4/5; deltoids were graded at 4–/5; he had very liTTle strength in his biceps, which were graded at 2/5; and his triceps were graded at 4+/5. His cardiovascular examinations by chocardiography and electrocardiography were normal. Also at age 44 years, the patient developed acute pain in his right tibia, which was incorrectly attributed to his fractures; magnetic resonance imaging revealed a large lesion present in his right proximal TIbia that measured 11 cm by up to 6 cm (Figure 2A). A biopsy revealed a high‐grade Stage III osteosarcoma. The patient underwent three cycles of chemotherapy with cisplatin and doxorubucin. The osteosarcomal mass in the proximal right tibia, however, progressed despite chemotherapy. Subsequently, follow‐up imaging showed a new lesion on the thoracic spine at T8. The paTIent’s right leg was amputated just above the knee, and a biopsy specimen of the T8 lesion revealed that it was a metastatic osteosarcoma. The patient died a year later, at the age of 45 years, from complicaTIons due to the metastasis of this osteosarcoma.

Clinical History: Case B, V:1

We report a 53‐year‐old white female paTIent (Figure 1, individual V:1), the cousin of case A with the familial disease. As a child, she had had bruising but seemed to have no problems with the healing of superficial cuts. Atage 18 years, invesTIgaTIon of her bruising led to a diagnosis of type 1 von Willebrand disease, based on a low von Willebrand anTIgen level of 0.26 U (normal, >0.50 U). By age 30 years, the paTIent had developed graying hair and was experiencing proximal muscle weakness, back pain, and numbness in her hands. At age 35 years, she found climbing stairs to be difficult from the muscle weakness. A physical examination demonstrated bilateral muscle weakness in her legs; however, she demonstrated no weakness in her shoulder girdle or arms. She had asymmetric weakness in the hip flexors, with an MRC grade of 2 on the right and 4 on the left, and most of the other muscle groups demonstrated an MRC grade of 4– or her reflexes were all normal. The patient’s creatinephosphokinase concentraTIon was 75 U/L (normal, 20–220 U/L). At this  TIme, the paTIent was also diagnosed with type 2 diabetes mellitus. Due to the conTInued muscle weakness, at age 36 years, the paTIent had a muscle biopsy specimen obtained from her right quadriceps, and histology revealed normal variability in muscle fiber size and shape, with no muscle fiber type grouping, atrophy, or ragged red fibers seen, and normal staining for glycogen, ATPase, and Gomori trichrome. There was prominent lipid staining in many muscle fibers, which was dismissed as possibly related to the diabetes. Immunohistochemical studies for dystrophin showed normal sarcolemmal localization of the three dystrophin domains. At age 40 years, the patient continued to experience progressive muscle weakness and had stopped all exercise activities. At the age of 44 years, a second muscle biopsy specimen obtained from the right quadriceps revealed extensive areas of fat replacement of muscle and groups of atrophic fibers. Staining for glycogen, PAS, desmin, NADH, ATPase, and Gomori trichrome were all normal. At age 47 years, the paTIent had developed chronic osteomyeliTIs of the right femur due to methicillin‐sensitive Staphylococcus aureus infecTIon. Her progressive muscle weakness was exacerbated by her inactivity related to the fracture. At this point, she was at 40% weight‐bearing with a walker and crutches. At age 51 years, she experienced another subtrochanteric fracture of her right femur, and during surgery a muscle biopsy specimen from her right quadriceps was obtained (Figure2). Characterization of Muscle Pathology In case B, muscle pathology was characterized by histopathology, and in case A, by biochemical analysis (western blot). The muscle biopsy was obtained from the right quadriceps in case B at age 51 years, at the time of the right subtrochanteric fracture. H&E staining of the muscle demonstrated fiber size variability, increased centrally located nuclei, degeneration and regeneration of muscle fibers, large‐scale atrophy, and extensive areas of fat replacement. No areas of inflammation were observed (Figure 2, B and C). Trichrome staining analysis did not reveal any evidence of ragged red fibers (data not shown). A muscle biopsy specimen revealed normal glycogen staining, normal checkerboard‐type distribuTIon with ATPase staining, and normal sarcolemmal immunolocalizaTIon of the three dystrophin domains (data not shown). To further explore disease mechanisms, we examined the ubiquiTIn proteasome and autophagy pathways, as these pathways have been shown to be dysregulated in valosin‐containing protein–associated diseases (eg, inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia [IBMPFD]) with several similariTIes to DMS‐MFH.10,11 Immunohistochemistry of the quadriceps muscles in case B revealed increased autophagy marker expression levels of p62/SQSTM1, TDP‐43, and LC3‐I/II compared with those in healthy control muscle (Figure 2, D–F). This was also shown in case A by western blot analysis and was confirmed by densitometry (Figure 2G). DisrupTIon of MTAP Splice Variants in Two Cousins with DMS‐MFH To analyze the expression patterns of the MTAP splice variants in these two DMS‐MFH–affected cousins, we quantified the mRNA levels in muscle and tumor  Tissue samples. ANOVA revealed the muscle TIssue sample from case A with unaffected levels of wild‐type MTAP, whereas MTAP_v2 was significantly downregulated in both muscle (P = 0.002) and osteosarcoma (P = 0.001), and MTAP_v3 was significantly upregulated in the muscle sample (P =0.012); however, MTAP_v3 was not upregulated in the osteosarcoma (Figure 2H). The difference in MTAP_v3 levels in case A quadriceps and osteosarcoma could possibly be explained by a loss of heterozygosity, with the MTAP gene being deleted in one allele in the osteosarcoma—a common occurrence with tumor suppressor genes in several types of malignant tumors.

 Figure 1. Pedigree of a diaphyseal medullary stenosis with malignant fibrous hisTIocytoma (DMS‐MFH)‐affected family. A DMS‐MFH–affected family with hereditary bone dysplasia/osteosarcoma and limb girdle muscular dystro‐phy. All affected family members have mutaTIon c.813‐2A>G located in the intron region on a splicing boundary region resulting in the dysregulation of methylthioadenosine phosphorylase (MTAP) splice variants. The mutation analysis was performed, with informed consent from all patients and unaffected family members, at the laboratory at Icahn School of Medicine at Mount Sinai, New York, New York.

 Figure 2. Analysis of quadriceps and osteosarcoma TIssues in two diaphyseal medullary stenosis with malignant fi‐ brous hisTIocytoma (DMS‐MFH)‐affected cousins. A, Magnetic resonance image of a large (11 × 6‐cm) osteosar‐ coma (arrow) in the right proximal TIbia (case A). B and C, Quadriceps muscles from case B (V:1), stained with H&E. Scale bars = 250 µm (B) and 100 µm (C). Control and case B (V:1) were stained with autophagy markers anTI‐p62/ sequestome 1 (SQSTM1) (D), transacTIve response DNA‐binding protein (TDP)‐43 (E), and light chain (LC)3‐I/II‐ specific anTIbodies (F). Scale bar = 10 µm. G, Upper panel, Densitometry confirming Western blot levels in case A (V:7); lower panel , western blot analysis of p62/SQSTM1, TDP‐43, and LC3‐I/II in case A (V:7) were increased com‐ pared with those in the healthy control. H, MTAP splice variant expression of MTAP, MTAP_v2, MTAP_v3, and MTAP_v4 in quadriceps and osteosarcoma tissues from case A (V:7). Data are mean (SE). *P < 0.05; **P < 0.005

DISCUSSION

DMS‐MFH is an autosomal‐dominant syndrome characterized by myopathy, bone fragility, and osteosarcoma, caused by mutations in the MTAP gene. Affected family members were first clinically described by Henry et al2 in 1958 as having histologic evidence of an irregular osteoporotic process with coarse trabeculation with osteosarcoma, a rare complication of Paget disease of bone. The human MTAP locus on chromosome 9p21 is one of the most frequently somatic, hypermethylated, translocated, and/or deleted regions in human cancer. Several types of human tumors are deficient somaTIcally in MTAP, including non–small‐cell lung cancers13 ; hepatocellular carcinomas14; and, highlyrelevant to this disease, osteosarcomas.15,16In this case study, we investigated the expression of the MTAP splice variants within this family with the c.813‐2A>G mutation and found upregulation of MTAP_v3. Wedid not find a difference in expression with MTAP_v6, aswas previously reported in a family with the c.885A>G mutaTIon.10 We characterized the myopathy of DMS‐ MFH, finding variability in fiber size, increased centrally located nuclei, degeneration of muscle fibers, and fatty replacement of muscle. Due to the crucial role of MTAP in cancer suppression, the relationship between cancer growth and autophagy inhibition,17 and the pathologic similarities between DMS ‐MFH and IBMPFD,10 we decided to investigate the autophagy pathway in DMS‐MFH. We discovered increased expression of several autophagy markers in the two affected individuals in this case study, making it plausible that the autophagy cascade is crucial in the pathophysiology of tissue damage seen in this disease. Several papers have been published demonstrating that there were changes in levels of polyamines and amino acids, which may influence autophagy in normal cells, and that a disruption in the autophagy cascade may cause damage to these cells.18–20 Autophagy has been postulated as a pathogenic event in several muscle disorders.21–25 potential therapies for patients with MTAP

related disease may also include carbamazepine, tamoxifen, and rapamycin compounds, which have been demonstrated to influence autophagy in experimental systems.26–28 Future translational metabolomics studies using in vitro disease modeling of DMS‐MFH disease and investigation of the genomic regulation of the splice variants of MTAP will determine their association with myopathy, bone dysplasia, and osteosarcoma.

CONCLUSIONS

Autosomal‐dominant myopathic disorder associated with DMS‐MFH is characterized by myopathy, bone fragility, and osteosarcoma associated with mutations in the MTAP gene. Here, we report on the myopathy in two cousins with DMS‐MFH. They developed a progressive limb‐girdle type myopathy at age 30 years. We characterized the myopathy associated with DMS‐MFH, discovering varied muscle fiber size, degeneration, and increased centralized nuclei. The expression levels of LC3 ‐I/II and p62/SQSTM1 in the muscle fibers were increased, suggesting a possible dysregulation of autophagy. Elucidation of the pathologic mechanism(s) of DMS‐MFH offers the potential to uncover key molecular signaling pathways and the promise of novel future treatments.

 ACKNOWLEDGMENTS

This study was funded by grants from the National Institutes of Health (AR050236), the Muscular Dystrophy Association (V.E.K.), and The Liddy Shriver Sarcoma Initiative (O.C.V. and J.A.M.). The authors have indicated that they have no conflicts of interest with regard to the content of this article. We thank the family of cases A and B and their physicians for their help in this research.

 

REFERENCES

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Address Correspondence To:

Virginia E. Kimonis, MD

Division of GeneTIcs and Genomic Medicine, Dept. of Pediatrics

University of California

101 The City Drive South, ZC4482 Orange, CA 92868, USA

 

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