PERSONALIZED MEDICINE VS GOOGLE

It is of public domain that Larry Page, the ambitious CEO of Google, has engaged in the exciting challenge of solving the biggest problems of medicine. The guys at Google are in fact betting on nanotechnology applications to win everlasting enemies like cancer. Page started this new adventure by opening a top-secret lab on Google's campus and by buying companies like Calico.

DM1 AND DM2 ARE THE ONLY DEFINITE CAUSES OF MYOTONIC DYSTROPHY

Myotonic dystrophy is a genetic disease crucially characterized by myotonia (described as the difficulty in releasing musculature; typically these patients may find difficult to release the grip after shaking hands). The only known causes of myotonic dystrophy to date are either DMPK or ZNF9 repeat expansions (associated with DM1, also known as Steinert disease, and DM2 respectively).

LYMPHEDEMA FOLLOWING BREAST CANCER TREATMENT: SURGICAL APPROACH

Breast cancer-related upper extremity lymphedema can be a complication with a reported incidence of about 1 in 5 (but almost 1 in 2 when complete axillary lymph node dissection was done).

Lymphedema may rise immediately after surgery but most often occurs after a latent period. The causes are still not full understood, but obesity and radiotherapy are risk factors. Increased volume and weight of the affected limb and  are the main signs. Although physically not much disabling, the condition may be an emetional and psychological burden, as the patient may develop sensations of funtional handicap as well as aesthetical concerns.

D4Z4 ANALYSIS IS NO LONGER USEFUL FOR FSHD TESTING

Traditionally, “normal” D4Z4 alleles were considered those ones having 11-100 repeat units, whereas those associated with facioscapulohumeral muscular dystrophy (FSHD) were thought to have between one and ten repeat units. However, because there are individuals with reduced D4Z4 alleles that do not have clinical signs of FSHD, it had been proposed that the genetic signature of the disease must result from the combination of:

(1) a reduction in the number of D4Z4 elements

(2) the presence of the 4qA allele

(3) the PAS in the pLAM sequence

However, this model does not apply to all FSHD cases. For example, nonpenetrant carriers have been reported in FSHD families, and there are FSHD patients carrying full-length D4Z4 alleles (≥11 repeats) that are clinically indistinguishable from patients carrying D4Z4 alleles of reduced size (≤8 repeats).

Indeed, Isabella Scionti et al found that 2.7% of cases in the Italian National Registry for FSHD (which contains over 1,100 unrelated FSHD patients) were compound heterozygotes carrying two D4Z4-reduced alleles (0.5% were homozygotes for the 4A161 haplotype). Based on this finding, they estimated that the population frequency of the 4A161PAS haplotype associated with a D4Z4-reduced allele could be higher than 1%.

Even more recently Isabella Scionti (2012; PMID: 22482803) analyzed a large cohort of normal controls and patients and established that the 4APAS structure is a frequent genetic polymorphism that is neither sufficient nor necessary for the development of FSHD.

Summarizing, recent evidence seems to demonstrate that  D4Z4/4qA/PAS testing is not specific enough to assess a genetic diagnosis of FSHD.

BOOK REVIEW: APPLIED GENETICS IN HEALTHCARE

Written by H. Skirton, C. Patch and J. Williams, "Applied Genetics in Healthcare - a handbook for specialist practitioners" is an easy introduction to medical genetics and its practice, with some helpful hints for all professionals. Starting from the basics of genetic biology, the authors discuss some different aspects of the approach to patients and their families. The trained geneticist will find himself already familiar with these, yet he might be surprised by some interesting curiosities. For instance, did you know that, according to what reported by Strachan and Read, it is believed that some paternally derived genes may be imprinted to protect the mother from the aggressive demands for nutrients from the foetus while, conversely, some maternal genes are imprinted to allow the foetus to grow adequately? Or, did you know that the mitochondrial disorders are mainly affecting the neuromuscualr system just because neuron cells have more mitochondria than other types of cells? And definitively a must-read is the chapter on Bayesian risk calculations: don't miss it!

If you are interested, Applied Genetics in Healthcare - a handbook for specialist practitioners is available at Amazon:

Reference: 
H. Skirton, C. Patch and J. Williams, Applied Genetics in Healthcare - a handbook for specialist practioners; Taylor & Francis, 2005.

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HINTS ON THE TREATMENT OF DYSPLASIA EPIPHYSEALIS HEMIMELICA

Dysplasia epiphysealis hemimelica (DEH, also known as Trevor disease) is a rare developmental disorder characterized by a benign overgrowth of the epyphisealis joint cartilage. The distal femur, proximal tibia, talus, navicular and medial cuneiform bones are most commonly involved. One single limb is usually affected, showing multiple sites of overgrowth (the bilateral involvement is exceptional). The disease mostly appears in the first decade of life (but onset has been described even in the elderly). DEH is thought to have an incidence of 1 in one million and it isn't hereditary, being its cause still unknown. Symptoms mainly consist in firm swelling or lump, usually (but not always) without pain. Malignant transformation has not been reported. For asymptomatic patients an invasive treatment may not be indicated, whereas simple periodic visits are suggested. Nevertheless, a major issue may arise from the lenght discrepancy of the lower limbs, which may not be easily addresses by the surgeon. In the extra-articular forms presenting a clear cleavage plan the lesion total exerisis is usually enough to relieve the pain, while in intra-articular forms an osteotomy may be needed to correct the deformity. Some cases of ankle localization at the talus have been reported to need an arthrodesis (a joint fixation).
Click here for DEH X-ray images at http://emedicine.medscape.com.

References

Acquaviva A, Municchi G, Marconcini S, Mazzarella F, Occhini R, Toti P, Mazzei MA, Volterrani L. Dysplasia epiphysealis hemimelica in a young girl: role of MRI in the diagnosis and follow-up. Joint Bone Spine. 2005 Mar;72(2):183-6.

Connor JM, Horan FT, Beighton P. Dysplasia epiphysialis hemimelica. A clinical and genetic study. J Bone Joint Surg Br. 1983 May;65(3):350-4.

Freihaut RB, O'Keane JC, Stephens MM. Dysplasia epiphysealis hemimelica with associated osteochondral lesion of the talus: a case report and review of the literature. Foot Ankle Int. 2007 Jun;28(6):727-30.

Glick R, Khaldi L, Ptaszynski K, Steiner GC. Dysplasia epiphysealis hemimelica (Trevor disease): a rare developmental disorder of bone mimicking osteochondroma of long bones. Hum Pathol. 2007 Aug;38(8):1265-72. Epub 2007 May 8.

Golli M, Jellali MA, Hmida B, Jazaerli N, Younes M, Salem R, Hafsa C, Zrig A, Bergaoui N. [Dysplasia epiphysealis hemimelica: a rare cause of ankle pain in children].Arch Pediatr. 2009 Oct;16(10):1374-7. Epub 2009 Aug 15.

Karam AR, Birjawi GA, Saghieh S, Tawil A, Khoury NJ. Generalized dysplasia epiphysealis hemimelica with contralateral sacro-iliac joint involvement. Skeletal Radiol. 2008 Dec;37(12):1147-52. Epub 2008 Sep 23.

Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: 127800 (last edited 25 Jun 1994)

UPDATING REFERENCES ON ARNOLD-CHIARI SYNDROME AND CHIARI MALFORMATIONS

References of our post on the Chiari and Arnold-Chiari malformations nomenclature has been updated: check out below and here to read the full story!

References

OMIM (Online Mendielian Inheritance in Man) database, MIM numbers 118420 (at http://www.ncbi.nlm.nih.gov/omim/118420) and 207950 (at http://www.ncbi.nlm.nih.gov/omim/207950

Peyman Pakzaban. Chiari Malformation  (updated 17 Jun 2010) at  http://emedicine.medscape.com/article/1483583-overview

Stevenson KL. Chiari Type II malformation: past, present, and future. Neurosurg Focus. 2004 Feb 15;16(2):E5. PMID: 15209488

Speer CM, Enterline DS, Lorraine Mehltretter, Hammock P, Joseph J, Dickerson M, Ellenbogen RG, Milhorat TH, Hauser MA, George TM. Chiari type I malformation with or without syringomyelia: prevalence and genetics. Journal of Genetic Couseling. 2003, 12(4), 297-311.

McLendon RE, Crain BJ, Oakes WJ, Burger PC. Cerebral polygyria in the Chiari Type II (Arnold-Chiari) malformation. Clin Neuropathol. 1985 Sep-Oct;4(5):200-5. PMID: 4064385.

NOMENCLATURE ISSUES: THE TRUTH ABOUT ARNOLD-CHIARI SYNDROME AND CHIARI MALFORMATION

It is largely assumed that Arnold-Chiari syndrome and Chiari malformations are the same thing and that "Chiari" and "Arnold-Chiari" are just synonyms, but the two conditions are quite different indeed. Not few arguments have arisen among professionals, since confusion in the nomenclature may lead to misundestandings and errors in the patient management, especially from a legally point of view.

The huge importance gained by the rare diseases national systems and the creation in many countries of dedicated welfare programs for rare diseases affected patients primary imply issues of correctness in the diagnosis, which often gives access to expensive aids and treatments. For example, it happens in Italy that Arnold-Chiari syndrome but not Chiari malformation is included as a rare disease in the Ministerial List of Rare Diseases.

The original nomenclature, based on the revision of large amounts of literature and the consultation of the major databases (i.e. OMIM, ICD-10, etc) is in accordance with the following classification:

Chiari Malformation type I (CM1)

Chiari Malformation type II (CM2, a.k.a. Arnold-Chiari syndrome or Arnold-Chiari malformation)

Chiari Malformation type III (CM3)

Chiari Malformation type IV (CM4, not universally recognized)

Let's immediately say that Arnold-Chiari syndrome (a.k.a. CM2) IS a rare disease (i.e. with a prevalence < 1:2.000/2.500), while CM1 IS NOT a rare disease, having an estimated prevalence of 0.1-0.5% with a slight female predominance. It is of consequence that while Arnold-Chiari syndrome patients are entitled to access facilitations in the context of rare diseases systems, CM1 patients do not have the same right. CM1 patients can suffer from even severe symptoms, but Arnold-Chiari syndrome is undoubtely a more serious condition, being unvariably associated with spina bifida. 

The partial overlap between the two conditions is surely the cause of their eponyms misuse. Indeed the literature is very clear: Chiari first described the protrusion of the cerebellar tonsils through the foramen magnum (CM1), while Arnold described the variant in which there is the descent of the cerebellar tonsils, cerebellar inferior vermis, and portions of the cerebellar hemispheres into the spinal canal along with displacement of the brainstem and fourth ventricle in association to spina bifida and hydrocephalus. As for CM3 (caudal displacement of the medulla and herniation of part of the cerebellum in an occipital or cervical meningocele) and CM4 (not universally recognized, according to some it is the hypoplasia or aplasia of the cerebellar hemispheres and alterations of the pons with marked dilatation of the fourth ventricle, cisterna magna, and basal cisterns) they're extremely rare.

To greater highlight of the differences, it is of note that while CM2, CM3 and CM4 are considered to be primarily neural in origin resulting from neuroectodermal anomalies, CM1 is considered to result from a mesodermal defect.

References

OMIM (Online Mendielian Inheritance in Man) database, MIM numbers 118420 (at http://www.ncbi.nlm.nih.gov/omim/118420) and 207950 (at http://www.ncbi.nlm.nih.gov/omim/207950

Peyman Pakzaban. Chiari Malformation  (updated 17 Jun 2010) at  http://emedicine.medscape.com/article/1483583-overview

Stevenson KL. Chiari Type II malformation: past, present, and future. Neurosurg Focus. 2004 Feb 15;16(2):E5. PMID: 15209488

Speer CM, Enterline DS, Lorraine Mehltretter, Hammock P, Joseph J, Dickerson M, Ellenbogen RG, Milhorat TH, Hauser MA, George TM. Chiari type I malformation with or without syringomyelia: prevalence and genetics. Journal of Genetic Couseling. 2003, 12(4), 297-311.

McLendon RE, Crain BJ, Oakes WJ, Burger PC. Cerebral polygyria in the Chiari Type II (Arnold-Chiari) malformation. Clin Neuropathol. 1985 Sep-Oct;4(5):200-5. PMID: 4064385.