Short summary

Today we know that around 20 % of all multiple sclerosis patients have relatives with the same diagnosis and the aetiology of multiple sclerosis is expected to involve a genetic component. Despite many attempts, little is known about the genetic contribution. There are several clinical assembles between multiple sclerosis and the diseases hereditary spastic paraplegia and mitochondria illness, which are both inherited diseases. In this study we will establish a cohort of familial multiple sclerosis cases and attempt to characterize/analyse them to establish, if there among familial multiple sclerosis patients are patients, who have hereditary spastic paraplegia or mitochondria illness as the primary reason for the symptoms, which have led to the multiple sclerosis diagnosis. 

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Rationale

Aims:

The aims of the study are to investigate whether some of the familiar multiple sclerosis cases have a monogenic disorder causing the symptoms, which have led to the multiple sclerosis diagnosis. The monogenic disorders suspected are hereditary spastic paraplegia and mitochondria illness. Based on information of co-morbidities among multiple sclerosis patients and their closest relatives and the multiple sclerosis subtype, a cohort of patients will be selected with the purpose of clinical and molecular genetic investigations and further characterization using registries. Furthermore, the subtype of the familial multiple sclerosis cases will be characterized.

Background:

Multiple sclerosis is a heterogenic disorder and the disease is characterized by three different subtypes; primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis. The aetiology behind multiple sclerosis is not fully understood. In around 20 % of the multiple sclerosis cases other family members also have a multiple sclerosis diagnosis.

Hereditary spastic paraplegia is characterized by a slowly progressive spasticity in the lower limbs, the same clinical feature as seen in primary progressive multiple sclerosis patients. Hereditary spastic paraplegia is related to mutations in a number of different genes.

Mitochondria disorder has clinical features in common with relaps-remitting and secondary progressive multiple sclerosis. Mitochondria have their own DNA (mtDNA) containing 37 genes. In addition to the genes in mtDNA, there are also genes encoding mitochondrial proteins in the nuclear DNA. Genetic changes in mtDNA or genes encoding mitochondrial proteins in nuclear DNA, are assumed to be related to the development of symptoms consistent with multiple sclerosis.

Hypotheses:

1. As a reflection of the differences in aetiology, the frequency of familial occurrence of multiple sclerosis is different among the different multiple sclerosis subtypes.
2. The cause of apparently familial occurrence of multiple sclerosis can be an unrecognized monogenic inherited disorder
3. Among familial cases of primary progressive multiple sclerosis, hereditary spastic paraplegia is underestimated.
4. Among familial cases of secondary progressive multiple sclerosis and relapsing-remitting multiple sclerosis, mitochondrial disease is underestimated.

Method:

Hypotheses 1: By using the CPR registry, the Danish Sclerosis registry and the National Patient registry we will select a cohort of familial multiple sclerosis patient and subdivid them on the basis of multiple sclerosis subtype.

Hypotheses 2 and 3: Familial multiple sclerosis patients with the subtype primary progressive will participate in a clinical interview a genetic testing for genes associated with hereditary spastic paraplegia.

Hypothesis 2 and 4: Familial multiple sclerosis patient with the subtypes secondary progressive and relaps-remitting will be further characterized on the basis of information on co-morbidity from the National Patient registry.

Perspective:

The project is expected to contribute to the understanding of the genetic aetiology as the cause of development of familial multiple sclerosis. Register study of the cohort with suspected mitochondria disorder could form the basis for future clinical projects.

The project is expected to have implications for patients with suspected multiple sclerosis. Revision of the diagnosis means altering the prognosis and treatment and opportunity for family for risk assessment. 

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Description of the cohort

The individuals involved in this study are multiple sclerosis patients from families with multiple cases of multiple sclerosis (familial multiple sclerosis patients). The cohort has been established using data from tree Danish registries (The Danish Sclerosis registry, The CPR registry and The National Patient Registry (Landspatientregisteret) 

Using registry data the cohort has been subdivided on behalf of the multiple sclerosis sub-types.

Familial multiple sclerosis cases with the sub-type primary progressive living in the Region of Southern Denmark will be invited to participate in clinical interviews and gene test for genes associated with hereditary spastic paraplegia.

Familial multiple sclerosis patient with the sub-type relapse-remitting and secondary progressive will be further characterized on behalf of data from the National Patient registry. The characterization will consist of information on co-morbidity in relation to mitochondria illness. 

Data and biological material

The registry part involves information from the following registries: the CPR registry, the National Patient Registry (Landspatientregisteret) and the Danish Sclerosis registry. By using the registries we will be able to find familial cases of multiple sclerosis living in Denmark. Familial cases are defined as families with first-degree relatives with a multiple sclerosis diagnosis.  We will characterize this group of patients further to find out if they have other symptoms or diagnoses that could confirm, that a mitochondrial disease could be the real reason to the symptoms that lead to the multiple sclerosis diagnoses. We will collect the same information on non-familial multiple sclerosis cases and from a cohort from the background population matched on age, sex and family structure for comparison.

The clinical part includes familial multiple sclerosis cases with the subtype primary progressive living in the Region of Southern Denmark. On this group of patients we collect clinical interviews regarding the multiple sclerosis diagnose, their current symptoms and family history. On this group we will also do genetic testing for genes associated with the disease hereditary spastic paraplegia. To do the genetics tests we will use Next Generation Sequencing. 

Collaborating researchers and departments

Department of Clinical Genetics, Odense University Hospital and Department of Neurology, Hospital of Southern Jutland

• PhD-student Maria Steenhof, MD

Department of Clinical Genetics, Odense University Hospital, and Research Unit of Human Genetic, Clinical Institute, University of Southern Denmark

• Professor and Consultant Jens Michael Hertz, MD, DMSc
• Molecular biologist Klaus Brusgaard, PhD

Department of Neurology, Hospital of Southern Jutland

• Professor Egon Stenager

Department of Clinical Research, University of Southern Denmark

• Professor and Head of Institute Kirsten Ohm Kyvik, MD, PhD, MPM