Genome profile in multiple sclerosis

article and editorial
Hafler DA et al. Risk alleles for multiple sclerosis identified by genomewide study. NEJM 2007; 357:851-862.Peltonen L. Old suspects found guilty-- the first genome profile of multiple sclerosis. NEJM; 2007; 357: 927-929.

Editorial comments on use of SNP's (single nucleotide polymorphisms) to define genetic diseases. The technique has localized diseases (DM, Crohn's) to unsuspected pathways, genese without a known function, or to noncoding regions of genes. Identical twins have a 30 % concordance of developing MS; dizygotic twins, 2 %, general population, 0.1 %. Since 1972, there has been an association with HLA-DRB1 gene on chromosome 6p21. Minor loci are seen on 5p, 17q, and 19q. The above study of NS Genetics Consortium supports the prediction of multiple risk alleles.

The test analyzed more than 330,000 SNP's in 931 trios (affected patient and both parents)by monitoring the overtransmission of any SNP to the affected child with transmission dysequilibrium testing. The data support the HLA locus but also 2 interesting genes, IL2RA which encodes the alpha subunit of the IL-2 receptor (also known as CD 21) on chromosome 10p15, and IL7RA which encodes the alpha subunit of the IL-7 receptor on chromosome 5p13. IL2 receptor is critical for the regulation of T Cell responses, and IL-7 for the homeostasis of the memory T cell pool and generation of the autoreactive T cells in MS. These two genes together, though explain only a small portion of the variance (0.2%) in risk of MS.

Author suggests the potential high risk alleles in large study samples should be sequenced, to encounter, probably, rare high impact alleles with critical importance for disease risk in some families or patients (analagous to BRCA1,2 testing). Author believes other genome variants should be sought, terms finding somewhat disappointing.

Vaccines in multiple sclerosis

Guidelines for Administration of Human Papillomavirus (HPV) Vaccine (Gardasil®) to Multiple Sclerosis Patients
(Developed by the Executive Committee of the National Clinical Advisory Board, National MS Society USA)

November 30, 2007—Gardasil® (Merck) is available as a prophylactic vaccine, designed to prevent the following conditions in girls and women 9 to 26 years of age:

HPV 6, 11, 16 and /or 18-related cervical cancer
cervical dysplasias
vulvar and vaginal dysplasias
condyloma acuminata
Gardasil is a vaccine prepared from noninfectious purified virus-like particles of recombinant major capsid (L 1) protein of HPV types 6, 11, 16, and 18. The product information states that individuals with impaired immune responsiveness may have reduced antibody response to active immunization due to:
immunosuppressive therapy
genetic defect
HIV infection
Immune response to vaccines may be reduced due to immunosuppressive therapy, including:
irradiation
antimetabolites
alkylating agents
cytotoxic drugs
corticosteroids (used in greater than physiologic doses)
This vaccine has been tested exclusively in 9 to 26-year-old healthy females (it has not been tested in an MS population):
Safety and efficacy information is available only for healthy girls/women of that age group.
Studies of the vaccine are now being done in boys/men and women older than 26 years of age.
FDA consideration for licensing the vaccine for other groups will take place when there are data to show that it is safe and effective for them.
It is important for girls and women to get HPV vaccine before they become sexually active.
Immunizations and Multiple Sclerosis*, a clinical practice guideline published by the Multiple Sclerosis Council for Clinical Practice Guidelines in 2001, presents conclusions based upon available research data. The expert panel used the recommendations of the Centers for Disease Control and Prevention (CDC) as a foundation for the development of its guideline. The consensus of the panel, based on available research data, was that:

People with MS should not be denied access to health-preserving and potentially-life saving vaccines because of their MS.
Vaccinations that do not contain live viruses can be given to MS patients unless they are currently experiencing an exacerbation.
The immune modulators approved by the FDA for use in MS are not believed to contraindicate vaccination with Gardasil:
Glatiramer acetate (Copaxone® )
Interferon beta1a (Avonex® and Rebif®)
Interferon beta1b (Betaseron®)
Natalizumab (Tysabri®) also should not contraindicate vaccination with Gardasil. Mitoxantrone (Novantrone®), like other immunosuppressive agents, would be likely to interfere with effective immunization by Gardasil.
*Available from the ProfessionalResource Center by calling our toll free number 866-MS-TREAT (866-678-7328) or by emailing: MD_info@nmss.org or healthprof_info@nmss.org.


--The Executive Committee of the National Clinical Advisory Board

Narcolepsy caused by ADEM

Gledhill RF, et al. Arch Neurol 2004; 61: 758-760.

Narcolepsy/cataplexy usually occurs sporadically in patients positive foo HLA DQB1*0602 with a loss of hypocretin/orexin in CSF, and is presumed autoimmune. However, it can also occur secondary to a lesion, in this case due to ADEM and partly responsive to steroids. In this case the lesion surrounded the third ventricle and hypothalamus and extended to the basal forebrain. The patient had sleep onset rem periods (SOREM) and cataplectic attacks.

injection reactions with morning injection

TIMING OF INJECTIONS COULD MINIMIZE SIDE EFFECTS
Individuals on interferon therapy often do their injections at night so that they can sleep through side effects, such as flu-like symptoms. However, a recent study suggests that injecting in the morning may minimize side effects.

German researchers conducted a study with 16 people who were just starting interferon therapy. Half were given injections at 8 a.m. and the other half at 6 p.m. Those who injected in the evening experienced more intense side effects than those who injected in the morning. The evening injectors also had a greater increase of cytokines (a protein involved in the immune response) like IL-6. After six months of treatment, however, all side effects and most of the blood chemistry changes ceased.

Investigators believe that natural fluctuations of hormones and cytokines over the course of the day and night affect the body's response to interferon injections. They suggest that anyone having a problem with side effects consider trying morning injections to see if that proves helpful.

Toxocariasis of CNS simulating ADEM

Marx et al. Toxocariasis of the CNS Simulating ADEM. Neurolgy 2007; 69: 806-807. General notes about the disease: there are two forms, visceral larval migrans (systemic) and disease focused on optic nerves. The hosts are dogs and ADin which adults live in intestine. Humans ingest embryonated eggs fromsoil (geophagia, pica) or through exposure to dirty hands, raw vegetables, larva from undercooked giblets. Case was a 2 year old girl with fever and cough, leukocytosiswith MRI of brain and spinal cord extensively involved mimicking ADEM.

Diagnosis is made by high titers of T. canis with ELISA or Western blot, eosinophils in blood or CSF, demonstration of intrathecal synthesis of anti T Canis antibodies and close contact with dogs. Clinicalnormalization with treatment supports the diagnossi.

Daclizumab in MS

Rose JW, Burns JB et al. Daclizumab phase II trial in relapsing and remitting multiple sclerossi.MRI and clinical results. Neurology 2007; 69:785-789.

Daclizumab binds to the alpha chain (CD25) of interleukin 2 receptor (IL2R) which is involved in activation of T and B cells. Currently its approved for renal allograft rejection.

Subjects had RRMS with EDSS 1-6.5, withone relapse in previous year and failed IFN therapy with at least 2 GD+ lesions on one or more of the baseline scans. 11 patients were studied. AE's included severe UTI's severe relapse at time of infusion, transient thrombocytopenia (while also receiving Bactrim). Study shows promise of daclizumab as monotherapy for MS.