Fnip1 regulates skeletal muscle fibre type specification, fatigue resistance, and suspectibility to muscular dystrophy

Folliculin (FLCN) and the associated folliculin-interacting proteins FNIP1 and FNIP2 have been shown to play a role in cell metabolism through regulation of the AMPK-mTOR pathways. Previously Hasumi et al. (2012) reported that selective deletion of Flcn in mouse skeletal muscle resulted in an increase in mitochondrial biogenesis and muscle fibre specification (discussed in this blog post).

Reyes et al. (2014) have now contributed more to the understanding of muscle fibre specification using a Fnip1-/- mouse (described in Park et al. 2012) which also shows altered muscle fibre specification from type IIb (fast twitch) to type I (slow twitch). Usually Fnip1 protein is expressed in type IIb muscle fibres but not in type I fibres. However in theFnip1 null mice there was an increased proportion of type I fibres indicated by an increase in mitochondrial gene transcripts, an increase in oxygen consumption indicative of an increase of functional mitochondria, and type I fibre specific physiology.

FLCN and FNIP1/2 interact with each other but also directly interact with the metabolicAMPK – a key regulator in energy homeostasis and mitochondrial biogenesis but also skeletal muscle fibre specification in response to exercise (Hardie, 2011). AMPK activation results in activation of the transcriptional regulators PGC1α and PGC1β and subsequent downstream programmes for mitochondrial biogenesis and oxidative metabolism. Within skeletal muscle activation of AMPK and PGC1 α, often associated with endurance exercise, also increases type I fibre specification (Hambrecht et al., 1997).

Fnip1 interaction inhibits AMPK activity and subsequently, as seen in this paper, a loss of Fnip1 results in increased phosphorylation of AMPK and increased levels of downstream pathway components, such as PGC1α, as detected by qPCR and western blot. This suggests that perturbed Fnip1 activity, as seen with FLCN loss, results in an increase in basal AMPK activity which in turn leads to changes in PGC1α expression and activity.

Fnip1-/- PGC1a-/- double null mice show a reduction in aberrant muscle specification, suggesting that the muscle fibre specification changes seen in the Fnip1-/- mice are dependent on PGC1α induction and as such the authors conclude that PGC1α is an essential mediator of fibre specification. Although the exact connection between Fnip1 loss and an increase in PGC1α activity is not fully understood it is likely to be mediated by AMPK activity. The authors suggest that under normal conditions Flcn and Fnip1 work as a complex to inhibit AMPK thereby reducing PGC1α expression and oxidative metabolism.

Although AMPK activation has been reported, via activation of TSC, which inhibits mTOR activity, thereby minimising ATP consumption and cell growth (Gowans et al. 2014), the Fnip1-/- muscle showed an increase in mTOR activity. The changes in mTOR activity were determined not to play a role in muscle fibre specification but may indicate a novel role for Fnip1 in coupling AMPK to mTOR. It is also possible that the increase in intracellular ATP has, through a negative feedback loop, resulted in AMPK inactivation thereby disrupting mTOR regulation as suggested previously in cardiac hypertrophy associated with a loss of FLCN (Hasumi et al 2014).

The loss of FLCN resulting in hyperactivity of AMPK and PGC1α, increased mitochondrial biogenesis and changes to energy levels has been previously reported (Yan et al. 2014). In BHD an increase in mitochondrial respiration has been linked to increased activation of the HIF pathway known to increase tumourigenic potential with increased expression of PGC1α and HIF1 having been identified in BHD renal carcinoma samples (Klomp et al. 2010, Preston et al. 2011). Whilst disruptions to the AMPK-mTOR regulatory pathways are of great importance in BHD research, the exact role played FNIP1 is not entirely understood. What Reyes et al. indicate however, based on the loss of Fnip1 being sufficient to induce an increase in AMPK activity and mitochondrial biogenesis, is that FNIP1 does play an important role that requires further investigation.

Interestingly the group also report a reduction in muscle damage in the Dmdmdx-4CV mouse model of Duchenne Muscular Dystrophy (DMD) when Fnip1 is absent. As the specific overexpression of PGC1α in skeletal muscle has a similarly protective effect (Chan et al. 2014) it suggests that the reduction in muscle loss seen with the inhibition of Fnip1 may, in part, be through induction of PGC1α.

  • Chan MC, Rowe GC, Raghuram S, Patten IS, Farrell C, Arany Z. Post-natal induction of PGC-1α protects against severe muscle dystrophy independently of utrophin. Skelet Muscle. 2014 Jan 22;4(1):2. doi: 10.1186/2044-5040-4-2. PubMed PMID: 24447845.
  • Gowans GJ, Hardie DG. AMPK: a cellular energy sensor primarily regulated by AMP. Biochem Soc Trans. 2014 Feb;42(1):71-5. doi: 10.1042/BST20130244. PubMed PMID: 24450630
  • Hambrecht R, Fiehn E, Yu J, Niebauer J, Weigl C, Hilbrich L, Adams V, Riede U, Schuler G. Effects of endurance training on mitochondrial ultrastructure and fiber type distribution in skeletal muscle of patients with stable chronic heart failure. J Am Coll Cardiol. 1997 Apr;29(5):1067-73. PubMed PMID: 9120161
  • Hardie DG. Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism. Proc Nutr Soc. 2011 Feb;70(1):92-9. doi: 10.1017/S0029665110003915. Epub 2010 Nov 11. Review. PubMed PMID:21067629
  • Hasumi H, Baba M, Hasumi Y, Huang Y, Oh H, Hughes RM, Klein ME, Takikita S, Nagashima K, Schmidt LS, Linehan WM. Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN. J Natl Cancer Inst. 2012 Nov 21;104(22):1750-64. doi: 10.1093/jnci/djs418. Epub 2012 Nov 12. PubMed PMID: 23150719
  • Hasumi Y, Baba M, Hasumi H, Huang Y, Lang M, Reindorf R, Oh HB, Sciarretta S, Nagashima K, Haines DC, Schneider MD, Adelstein RS, Schmidt LS, Sadoshima J, Marston Linehan W. Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation. Hum Mol Genet. 2014 Nov 1;23(21):5706-19. doi: 10.1093/hmg/ddu286. Epub 2014 Jun 6. PubMed PMID: 24908670
  • Klomp JA, Petillo D, Niemi NM, Dykema KJ, Chen J, Yang XJ, Sääf A, Zickert P, Aly M, Bergerheim U, Nordenskjöld M, Gad S, Giraud S, Denoux Y, Yonneau L, Méjean A, Vasiliu V, Richard S, MacKeigan JP, Teh BT, Furge KA. Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression. BMC Med Genomics. 2010 Dec 16;3:59. doi: 10.1186/1755-8794-3-59. PubMed PMID: 24908670
  • Reyes NL, Banks GB, Tsang M, Margineantu D, Gu H, Djukovic D, Chan J, Torres M, Liggitt HD, Hirenallur-S DK, Hockenbery DM, Raftery D, & Iritani BM (2015). Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy. Proceedings of the National Academy of Sciences of the United States of America, 112 (2), 424-9 PMID: 25548157
  • Park H, Staehling K, Tsang M, Appleby MW, Brunkow ME, Margineantu D, Hockenbery DM, Habib T, Liggitt HD, Carlson G, Iritani BM. Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development. Immunity. 2012 May 25;36(5):769-81. doi: 10.1016/j.immuni.2012.02.019. Epub 2012 May 17. PubMed PMID: 22608497
  • Yan M, Gingras MC, Dunlop EA, Nouët Y, Dupuy F, Jalali Z, Possik E, Coull BJ, Kharitidi D, Dydensborg AB, Faubert B, Kamps M, Sabourin S, Preston RS, Davies DM, Roughead T, Chotard L, van Steensel MA, Jones R, Tee AR, Pause A. The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. J Clin Invest. 2014 Jun 2;124(6):2640-50. doi: 10.1172/JCI71749. Epub 2014 Apr 24. PubMed PMID: 24762438
Print Friendly

BHD Research Blog: 2014 Annual Review

With the New Year upon us, we thought we would use this week’s blog to review the studies we’ve particularly enjoyed writing about, and to revisit emerging themes.

During the summer-autumn period, there were a number of interesting studies that shed light on the molecular function of FLCN. Firstly, Goncharova et al. reported that FLCN activates AMPK signaling via LKB1 and E-cadherin, in Alveolar Type II (ATII) cells. Conversely, both Yan et al. and Possik et al. showed that FLCN inhibits AMPK signaling in MEFs and C.elegans nematodes, and that loss of FLCN leads to tumorigenic metabolic changes consistent with the Warburg Effect. These conflicting findings were resolved in August, when Khabibullin et al. published data showing that FLCN function is highly cell-specific.

FLCN’s role in autophagy was further elucidated by Dunlop et al. who reported that FLCN modulates autophagy through its interactions with ULK1 and GABARAP; FLCN was shown to be important for cardiomyocyte development (Hasumi et al., 2014); and a hitherto unknown role for FNIP1 in iNKT cell development was reported by Park et al.

The results from the trial of Rapamycin as a treatment for fibrofolliculomas were published this year, and reported that Rapamycin was not effective (Gijezen et al., 2014).

A cohort study of 33 BHD patients with kidney cancer showed that the majority of tumours were of oncocytic, choromophobe or mixed histology, and that the median age at the diagnosis of the first tumour was 46 (Benusiglio et al., 2014). This corresponds well with a study by Schuch et al. which found that patients with a genetic predisposition to kidney cancer developed tumours nearly 25 years earlier than patients with sporadic tumours. Thus, Schuch et al. recommend that doctors should consider germline genetic testing in kidney cancer patients under the age of 46.

A number of papers regarding the lung symptoms of BHD have been published this year. In July, it was reported that BHD can cause pneumothoraces in children in rare cases (Johannesma et al., 2014a), and in September, 1 in 16 BHD patients were found to be at risk of developing a pneumothorax within 30 days of taking a commercial flight (Postmus et al. 2014). Two separate groups hypothesized that defective cell-cell adhesion made cyst walls more likely to burst under mechanical stress, leading to an accumulation of air in the pleural space and potentially causing a pneumothorax (Johannesma et al., 2014b, Kumasaka et al., 2014).

Finally, two case studies have reported that somatic FLCN mutations contributed to the development of sporadic tumours (Sirintrapun et al., 2014, Wagle et al., 2014). These studies indicate that FLCN mutations may play a wider role in disease than just causing BHD Syndrome, suggesting that BHD is a fundamental disease.

These papers are just a selection of those published in 2014, and we at the BHD Foundation are very much looking forward to seeing how the field develops in 2015. We wish all our readers a very Happy New Year.


  • Benusiglio, P., Giraud, S., Deveaux, S., Méjean, A., Correas, J., Joly, D., Timsit, M., Ferlicot, S., Verkarre, V., Abadie, C., Chauveau, D., Leroux, D., Avril, M., Cordier, J., & Richard, S. (2014). Renal cell tumour characteristics in patients with the Birt-Hogg-Dubé cancer susceptibility syndrome: a retrospective, multicentre study Orphanet Journal of Rare Diseases, 9 (1) DOI: 10.1186/s13023-014-0163-z
  • Dunlop EA, Seifan S, Claessens T, Behrends C, Kamps MA, Rozycka E, Kemp AJ, Nookala RK, Blenis J, Coull BJ, Murray JT, van Steensel MA, Wilkinson S, & Tee AR (2014). FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy, 10 (10) PMID: 25126726
  • Gijezen LM, Vernooij M, Martens H, Oduber CE, Henquet CJ, Starink TM, Prins MH, Menko FH, Nelemans PJ, & van Steensel MA (2014). Topical rapamycin as a treatment for fibrofolliculomas in birt-hogg-dubé syndrome: a double-blind placebo-controlled randomized split-face trial. PloS one, 9 (6) PMID: 24910976
  • Goncharova EA, Goncharov DA, James ML, Atochina-Vasserman EN, Stepanova V, Hong SB, Li H, Gonzales L, Baba M, Linehan WM, Gow AJ, Margulies S, Guttentag S, Schmidt LS, & Krymskaya VP (2014). Folliculin Controls Lung Alveolar Enlargement and Epithelial Cell Survival through E-Cadherin, LKB1, and AMPK. Cell reports, 7 (2), 412-23 PMID: 24726356
  • Hasumi Y, Baba M, Hasumi H, Huang Y, Lang M, Reindorf R, Oh HB, Sciarretta S, Nagashima K, Haines DC, Schneider MD, Adelstein RS, Schmidt LS, Sadoshima J, & Marston Linehan W (2014). Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation. Human molecular genetics PMID: 24908670
  • Johannesma PC, van den Borne BE, Gille JJ, Nagelkerke AF, van Waesberghe JT, Paul MA, van Moorselaar RJ, Menko FH, & Postmus PE (2014a). Spontaneous pneumothorax as indicator for Birt-Hogg-Dubé syndrome in paediatric patients. BMC pediatrics, 14 PMID: 24994497
  • Johannesma PC, Houweling AC, van Waesberghe JH, van Moorselaar RJ, Starink TM, Menko FH, & Postmus PE (2014b). The pathogenesis of pneumothorax in Birt-Hogg-Dubé syndrome: A hypothesis. Respirology (Carlton, Vic.), 19 (8), 1248-50 PMID: 25302759
  • Khabibullin D, Medvetz DA, Pinilla M, Hariharan V, Li C, Hergrueter A, Laucho Contreras M, Zhang E, Parkhitko A, Yu JJ, Owen CA, Huang H, Baron RM, & Henske EP (2014). Folliculin regulates cell-cell adhesion, AMPK, and mTORC1 in a cell-type-specific manner in lung-derived cells. Physiological reports, 2 (8) PMID: 25121506
  • Kumasaka T, Hayashi T, Mitani K, Kataoka H, Kikkawa M, Tobino K, Kobayashi E, Gunji Y, Kunogi M, Kurihara M, & Seyama K (2014). Characterization of pulmonary cysts in Birt-Hogg-Dubé syndrome: histopathologic and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology PMID: 24393238
  • Park H, Tsang M, Iritani BM, & Bevan MJ (2014). Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development. Proceedings of the National Academy of Sciences of the United States of America, 111 (19), 7066-71 PMID: 24785297
  • Possik E, Jalali Z, Nouët Y, Yan M, Gingras MC, Schmeisser K, Panaite L, Dupuy F, Kharitidi D, Chotard L, Jones RG, Hall DH, & Pause A (2014). Folliculin regulates ampk-dependent autophagy and metabolic stress survival. PLoS genetics, 10 (4) PMID: 24763318
  • Postmus PE, Johannesma PC, Menko FH, & Paul MA (2014). In-Flight Pneumothorax: Diagnosis May Be Missed because of Symptom Delay. American journal of respiratory and critical care medicine, 190 (6), 704-5 PMID: 25221882
  • Shuch B, Vourganti S, Ricketts CJ, Middleton L, Peterson J, Merino MJ, Metwalli AR, Srinivasan R, & Linehan WM (2014). Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 32 (5), 431-7 PMID: 24378414
  • Sirintrapun SJ, Geisinger KR, Cimic A, Snow A, Hagenkord J, Monzon F, Legendre BL Jr, Ghazalpour A, Bender RP, & Gatalica Z (2014). Oncocytoma-like renal tumor with transformation toward high-grade oncocytic carcinoma: a unique case with morphologic, immunohistochemical, and genomic characterization. Medicine, 93 (15) PMID: 25275525
  • Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, Gray N, Barletta JA, Guo Y, Swanson SJ, Ruan DT, Hanna GJ, Haddad RI, Getz G, Kwiatkowski DJ, Carter SL, Sabatini DM, Jänne PA, Garraway LA, & Lorch JH (2014). Response and acquired resistance to everolimus in anaplastic thyroid cancer. The New England journal of medicine, 371 (15), 1426-33 PMID: 25295501
  • Yan M, Gingras MC, Dunlop EA, Nouët Y, Dupuy F, Jalali Z, Possik E, Coull BJ, Kharitidi D, Dydensborg AB, Faubert B, Kamps M, Sabourin S, Preston RS, Davies DM, Roughead T, Chotard L, van Steensel MA, Jones R, Tee AR, & Pause A (2014). The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. The Journal of clinical investigation PMID: 24762438

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

Print Friendly

A shower of second hit mutations causes bilateral, multifocal kidney cancer in TSC patients

Tuberous sclerosis complex (TSC) is caused by autosomal dominant inactivating mutations in either the TSC1 or TSC2 genes, and patients are predisposed to developing tumours in the brain, eyes, heart, skin, lungs and kidneys throughout their lifetime. While more than 80% of TSC patients develop benign renal angiomyolipoma, only 3% of TSC patients develop renal cell carcinoma (Yang et al., 2014).

Tyburczy et al., (2014) describe two TSC patients who presented with bilateral multifocal renal cell carcinoma.

The first patient received a left nephrectomy to remove 12 tumours at the age of 24. Three years later, a right nephrectomy was required to remove three tumours. Histological analysis showed all tumours to be of TSC-associated papillary renal cell carcinoma (RCC) (Yang et al., 2014).

Fresh frozen tissue was available from four left and one right kidney tumour. Direct sequencing and microsatellite marker analysis showed loss of heterozygosity (LOH) at the TSC2 allele in one tumour sample, but not in the other four tumours. Targeted next generation sequencing found different second hit somatic TSC2 mutations in each of the other four tumours: two nonsense, one frameshift and one missense mutation. Whole exome sequencing of DNA from all five tumours showed an average of four somatic mutations in other genes in each tumour, and no gene was mutated in more than one sample. Furthermore, no copy number changes were observed in any tumour. This suggests that biallelic inactivation of TSC2 is the driving tumorigenic mutation in all five tumours.

The second patient was found to have bilateral, multifocal tumours, and received partial nephrectomy of both kidneys at the age of 36. All tumours showed the same TSC-associated papillary RCC histology. Analysis of three tumours showed no evidence of LOH at the TSC2 allele. Only one tumour sample yielded sufficient DNA for sequencing analysis, and showed a somatic splicing mutation in TSC2, again suggesting that somatic second hits in TSC2 are driving tumorigenesis in this patient.

Both patients carried the same missense R905Q TSC2 mutation, which is associated with a milder presentation of TSC (Jansen et al., 2006). As this mutation is present in fewer than 1% of TSC patients, and only 3% of TSC patients develop RCC, it seems likely this this mutation may predispose patients to developing RCC. Indeed, in a cohort of 19 TSC patients who developed RCC, germline sequencing data was available for three patients who also developed TSC-associated papillary RCC. While none carried the R905Q mutation, all three had non-truncating TSC2 mutations – two missense and one in-frame deletion. This suggests that patients with non-truncating mutations may be at a higher risk of developing RCC (Yang et al., 2014).

Tyburczy et al. calculate the likelikhood of the first patient developing 15 tumours through 15 independent second hit events to be 1 in 3.6 trillion. This suggests that all tumours arose following a single event, which led to a shower of second hit TSC2 mutations occuring in these patients’ kidney tissue. However, the disease mechanism that leads to multiple second hit mutations in in a single gene is currently unknown.


  • Jansen AC, Sancak O, D’Agostino MD, Badhwar A, Roberts P, Gobbi G, Wilkinson R, Melanson D, Tampieri D, Koenekoop R, Gans M, Maat-Kievit A, Goedbloed M, van den Ouweland AM, Nellist M, Pandolfo M, McQueen M, Sims K, Thiele EA, Dubeau F, Andermann F, Kwiatkowski DJ, Halley DJ, & Andermann E (2006). Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation. Ann Neurol, 60 (5), 528-39 PMID: 17120248
  • Tyburczy ME, Jozwiak S, Malinowska IA, Chekaluk Y, Pugh TJ, Wu CL, Nussbaum RL, Seepo S, Dzik T, Kotulska K, & Kwiatkowski DJ (2014). A shower of second hit events as the cause of multifocal renal cell carcinoma in Tuberous Sclerosis Complex. Hum Mol Genet PMID: 25432535
  • Yang P, Cornejo KM, Sadow PM, Cheng L, Wang M, Xiao Y, Jiang Z, Oliva E, Jozwiak S, Nussbaum RL, Feldman AS, Paul E, Thiele EA, Yu JJ, Henske EP, Kwiatkowski DJ, Young RH, & Wu CL (2014). Renal cell carcinoma in tuberous sclerosis complex. Am J Surg Pathol, 38 (7), 895-909. PMID: 24832166

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

Print Friendly

Providing written information significantly improves parents’ understanding of TSC

Last week, we launched the new patient information pages on the BHD Foundation website. The information has been rewritten with the principles of health literacy in mind, and we hope these will be of greater use to patients and their families. This week’s blog discusses a study which demonstrates the value of providing well-written patient information.

Tuberous Sclerosis Complex (TSC) is a paediatric genetic syndrome which causes tumours to form in the brain, eyes, heart, skin, lungs and kidneys. There is no cure for TSC, but correct management of the individual symptoms can greatly improve health outcomes. Thus, educating care givers – usually the child’s parents – can improve patients’ quality of life.

Samia et al. (2014) tested whether providing parents with written information in addition to the information given in person at the TSC clinic in Cape Town, South Africa, improved parents’ understanding of TSC. 21 parents took part in the study, their baseline understanding of TSC was determined, and parents were split into two groups at random. The first group received a written leaflet about TSC to take home after their child’s appointment, while the second group did not. Parents’ knowledge of TSC was assessed 3 months later at their child’s next clinic appointment. Leaflets were based on information available on the TS Alliance website, and translated into both Xhosa and Afrikaans.

The study found that parents’ understanding of TSC increased by 20% in the group who received the written leaflet, compared with only 3% in the group who did not. The difference in knowledge was particularly striking in those parents who had completed between 8 and 11 years of education. The level of knowledge improved less in those parents who had over 11 years of education, suggesting that their baseline level of understanding was already high.

However, the study also found that written information was not useful to those parents who had not completed at least 8 years of education, and should be supplemented with verbal counseling. These appointments should be in a more relaxed setting, as previous studies have shown that in the formal setting of a doctor’s appointment, patient retention of information is low.

In this study, the majority of caregivers who took part in the study were female (18/21), and for most the clinic was their primary source of information about TSC. However, there are countries where women do not receive the same level of education as men, but are still likely to be the main caregiver of a disabled child. In these cases, health information providers will need to predominantly cater for a low literacy audience.

Additionally, in the UK, the internet is the primary source of health information for 87% of people, meaning that information providers should predominantly produce online content, and concentrate less on developing hard copy pamphlets to distribute at clinics. Thus, information providers need to understand their audience and have a flexible approach. This is especially important for those writing rare disease information, where fewer information resources are available and information providers are more likely to be generating information that is used internationally.

The link between improved health literacy and health outcomes is well-documented (Berkman et al., 2011): greater understanding of a disease leads people to seek diagnosis earlier and to greater compliance to treatment regimens. In turn this leads to improved health outcomes and reduced healthcare costs. Therefore, providing patients and caregivers with the right information, at the right time, and in the right format is an issue of public health.


  • Berkman ND, Sheridan SL, Donahue KE, Halpern DJ, & Crotty K (2011). Low health literacy and health outcomes: an updated systematic review. Ann Intern Med, 155 (2), 97-107. PMID: 21768583
  • Samia P, Donald KA, Schlegel B, & Wilmshurst JM (2014). Parental Understanding of Tuberous Sclerosis Complex. J Child Neurol. PMID: 25414235

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

Print Friendly

Introducing the new BHD patient information pages

Like many rare diseases, there is no cure for BHD. However, appropriate management of symptoms – particularly kidney cancer – can vastly reduce the likelihood of early death due to the disease (Menko et al., 2009, Stamatakis et al., 2013). Therefore, providing BHD patients with clear, easy to understand information can help patients manage their condition and improve their quality of life.

Last year we wrote about how learning about health literacy helped us develop our Introductory Pamphlets for newly diagnosed patients. Whilst doing this project, we realised that some of the patient information on the website was quite technical and could be improved. Today we are pleased to launch the new patient information pages. These have been updated to include new information, and rewritten with the principles of health literacy in mind.

The new patient pages are split into ten sections: What is BHD; a Genetics overview; information about the skin, lung, kidney and other symptoms of BHD; practical considerations; the Science of BHD; FAQs; and Glossary.

What is BHD, simply provides a brief overview of BHD. The “Genetics overview” describes the genetics of BHD; suggests who should be tested for BHD, and why you should consider genetic testing; provides information about the genetic test itself and getting the results; and discusses the next steps are if you do have BHD, including information about how to find a doctor.

Previously, medical information about BHD was split into two sections: symptoms, and treatment & diagnosis. Now, this information is split into the different organs affected by BHD: skin, lung, kidney and other symptoms. For the skin, lung and kidney sections, each has its own introduction, followed by information about the symptoms, diagnosis, treatment options and differential diagnosis.

The “Practical considerations” section has remained largely the same. However, we have added three new resources to “Telling others about BHD”. The Medical Education Kit links to three important papers written by BHD experts, describing the best treatment regimens for patients (Gupta et al., 2013, Menko et al., 2009, Stamatakis et al., 2013). We recommend that patients print out copies of these papers to give to their doctors. This allows patients to educate their doctors about BHD and the best methods of treating patients. We have also written a lay summary of each paper so that patients are aware of the results and recommendations outlined in each.

To help patients tell their families about BHD, we have written a BHD Family Letter, which can be personalised to fit each patient’s circumstances. We have also reinstated the BHD Medicard, which can be folded into the size of a credit card, meaning that patients can easily carry round a handy list of their symptoms and treatments at all times.

There are three brand new sections. Firstly, we have added an FAQs section, which lists the answers to questions we are often asked about BHD. We have also added a glossary of terms, which spells out the more difficult or unfamiliar terms phonetically. And finally, we have written a brief description of the science of BHD specifically for patients. This section does not provide information that is directly relevant to patients’ health or care, but provides an insight into the underlying biology of the disease.

We hope that patients find the new pages informative and are better able to understand and manage their condition as a result. If you would like give any feedback on the new pages, you can email us at contact@BHDSyndrome.org, or fill out our online feedback form.

  • Gupta N, Seyama K, & McCormack FX (2013). Pulmonary manifestations of Birt-Hogg-Dubé syndrome. Familial cancer, 12 (3), 387-96 PMID: 23715758
  • Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER, & European BHD Consortium (2009). Birt-Hogg-Dubé syndrome: diagnosis and management. The Lancet. Oncology, 10 (12), 1199-206 PMID: 19959076
  • Stamatakis L, Metwalli AR, Middelton LA, & Marston Linehan W (2013). Diagnosis and management of BHD-associated kidney cancer. Familial cancer, 12 (3), 397-402 PMID: 23703644

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

Print Friendly

The natural history of angiomyolipoma in cases of sporadic LAM

Lymphangioleiomyomatosis (LAM) is a cystic lung disease that predominantly affects women. Roughly 90% of cases are sporadic and are caused by somatic mutation of the TSC2 gene, but some patients develop LAM as part of the syndrome Tuberous Sclerosis Complex (TSC), which is caused by germline mutations either TSC1 or TSC2.

Angiomyolipoma (AML) is a type of kidney tumour that develops in nearly 100% of patients with TSC, and 50% of patients with sporadic LAM. AML are typically benign, but if untreated, larger tumours can haemorrhage and require the patient to undergo a nephrectomy. While the natural history of AML is known for TSC patients, it has not been systematically studied in LAM patients, and there are no official clinical recommendations of how to monitor and treat AML in sporadic LAM patients.

Yeoh et al. (2014) recently published a natural history study on a cohort of 107 sporadic LAM patients recruited via the National Centre for LAM in Nottingham, UK. Of these patients, 53 (50%) had had at least 1 AML in their lifetime and the average age of AML diagnosis was 39.1. Ten patients were diagnosed with AML up to 11 years before they were diagnosed with LAM, ten patients were diagnosed with both at the same time, and the remaining patients were diagnosed with AML up to 38 years after their LAM diagnosis. This suggests that sporadic LAM patients are at risk of developing AML throughout their entire lifetime.

Presence of AML was not linked to the severity of the pulmonary symptoms of LAM in these patients. AMLs in sporadic LAM patients were generally smaller, less likely to be bilateral, and the time from diagnosis to renal event – such as haemorrhage or surgical intervention – was 34 years, compared with 25 years in TSC patients. However, there was no difference in the incidence of haemorrhage or the need for medical intervention between this cohort and TSC patients. This suggests that AML in sporadic LAM patients should be managed in a similar fashion to AML in TSC patients.

The authors recommend that abdominal MRI should be performed every 1 to 3 years throughout the lifetime of sporadic LAM patients, and surgical intervention should occur when tumours reach 3 cm, as patients with larger tumours are at significant risk of haemorrhaging. All patients should have an abdominal MRI scan when they are diagnosed with LAM to assess whether they have any AMLs. Patients with tumours smaller than 1 cm in diameter should have follow up scans every two years, patients with tumours between 1-2cm in diameter should be screened annually, and patients with tumours over 3 cm should either have follow up scans after 6 months, or should be referred for intervention.

The authors note that this study only takes tumour size into account and suggest that contrast CT or MRI could be used to detect the vasculature of AML tumours, which may allow patients to be stratified into high risk and low risk groups that are managed differently. Indeed, there were 11 patients in this cohort who underwent nephrectomy to treat AML haemorrhage, and the average age of these patients at the time of surgery was 23. This is significantly younger than the average age of AML diagnosis of the cohort as a whole, which was 39.1, and suggests that these 11 patients did have a more aggressive form of AML.

  • Yeoh ZW, Navaratnam V, Bhatt R, McCafferty I, Hubbard RB, & Johnson SR (2014). Natural history of angiomyolipoma in lymphangioleiomyomatosis: implications for screening and surveillance. Orphanet journal of rare diseases, 9 PMID: 25277108

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

Print Friendly

Computational approaches may expedite drug repurposing for rare diseases

Drug repurposing is predicated on the fact that many diseases are caused by the dysregulation of similar signaling pathways, or that drugs may affect several biological targets at once, meaning that a single drug may be able to treat multiple diseases. Repurposing an existing drug is easier, cheaper and faster than developing a brand new drug, as there are comparatively few research and development costs, and the drug is already known to be effective and safe for use in patients.

Currently, the vast majority of additional indications for existing drugs have been found by chance (Liu et al., 2013). However, as technology improves, researchers have developed high throughput in silico methods to analyse the structures and biological activities of existing drugs to identify new indications (Ekins et al., 2011, Liu et al., 2013). A recent study by Gramatica et al. (2014) report an alternative approach, using computational linguistics and graph theory to identify previously unknown links between drugs and diseases.

Gramatica et al. analysed three million publication abstracts relating to 300 rare diseases from the PubMed literature database. Analysing the language in the abstracts allowed the researchers to build visual networks linking different types of node, such as disease, protein, biological process, or drug. To show how these networks were built, the researchers used an example from a paper describing the pathogenesis of lymphangioleimyomatosis (LAM).

Each sentence was analysed independently, the nodes highlighted, and arranged into a network with each node linked pairwise, like so:


Each separate network was then rearranged to form a single, larger network representing the whole paper:


Where multiple links occur between nodes – such as LAM and Lung in this example – these nodes were considered to be more closely linked. Networks were then combined to cover multiple papers, and multiple diseases, building a large network of rare diseases, genes, biological processes, and drugs.


By arranging the results of a large number of studies – in this case three million – into a single network, links between drugs and diseases that were not previously recognized can be identified. Pathways with fewer steps linking a drug and a disease, and where multiple different pathways linked a drug and a disease, were considered to be particularly plausible candidates for drug repurposing.

To test whether this method led to the identification of new drug-disease pairs, the researchers used the network to identify new therapies for the rare lung disease Sarcoidosis, and new disease targets for the cancer drug Imatinib. They found that the peptides Aviptadil, ɑ-Melanocyte Stimulating Hormone (ɑ-MSH) and C-type Natriuretic Peptide (CNP) were possible candidates to treat Sarcoidosis. Indeed, a Phase II clinical trial in 20 patients reports that Aviptadil is an effective treatment for Sarcoidosis (Prasse et al., 2010), suggesting that ɑ-MSH and CNP may also be effective.

The network also predicted that Imatinib may be an effective treatment for spongiform encephalopathies, such as Creutzfeldt-Jakob disease. Imatinib inhibits the c-Abl tyrosine kinase, which has shown to be dysregulated and lead to neuronal cell death in multiple neurodegenerative disorders (Schlatterer et al., 2011) and Imatinib has been shown to clear mis-folded proteins from prion infected cells (Ertmer et al., 2004).

Together, these results suggest that combined computational linguistics and graph theory is able to identify previously unrecognized drug-disease pairs, which will expedite the repurposing of drugs for new indications.

Drug repurposing is a particularly valuable approach for identifying new treatments for rare and neglected diseases, where there is a high unmet medical need, and a number of rare disease organisations such as Findacure, Cures Within Reach and IRDiRC are actively funding and promoting this research. Indeed, there have been a number of successes in this area, for example Rapamycin has been repurposed as a treatment for Autoimmune Lymphoproliferative Syndrome and thalidomide is now an approved treatment for leprosy, multiple myeloma and bone marrow cancer (Teo et al., 2005).

The number of new therapies being approved for rare diseases is at an all-time high, but with only 133 new therapies approved since 2010, at this rate it will still take around 200 years to develop treatments for all rare diseases. Thus, although computational approaches to drug repurposing are in their infancy, the continued refinement of these approaches to expedite the discovery of drug-disease pairs will be of immense value to the field of rare diseases.


  • Ekins S, Williams AJ, Krasowski MD, & Freundlich JS (2011). In silico repositioning of approved drugs for rare and neglected diseases. Drug discovery today, 16 (7-8), 298-310 PMID: 21376136
  • Ertmer A, Gilch S, Yun SW, Flechsig E, Klebl B, Stein-Gerlach M, Klein MA, & Schätzl HM (2004). The tyrosine kinase inhibitor STI571 induces cellular clearance of PrPSc in prion-infected cells. The Journal of biological chemistry, 279 (40), 41918-27 PMID:15247213
  • Gramatica R, Di Matteo T, Giorgetti S, Barbiani M, Bevec D, & Aste T (2014). Graph theory enables drug repurposing–how a mathematical model can drive the discovery of hidden mechanisms of action. PloS one, 9 (1) PMID: 24416311
  • Liu Z, Fang H, Reagan K, Xu X, Mendrick DL, Slikker W Jr, & Tong W (2013). In silico drug repositioning: what we need to know.Drug discovery today, 18 (3-4), 110-5 PMID: 22935104
  • Prasse A, Zissel G, Lützen N, Schupp J, Schmiedlin R, Gonzalez-Rey E, Rensing-Ehl A, Bacher G, Cavalli V, Bevec D, Delgado M, & Müller-Quernheim J (2010). Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. American journal of respiratory and critical care medicine, 182 (4), 540-8 PMID: 20442436
  • Schlatterer SD, Acker CM, & Davies P (2011). c-Abl in neurodegenerative disease. Journal of molecular neuroscience : MN, 45(3), 445-52 PMID: 21728062
  • Teo SK, Stirling DI, & Zeldis JB (2005). Thalidomide as a novel therapeutic agent: new uses for an old product. Drug discovery today, 10 (2), 107-14 PMID: 15718159

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

Print Friendly