NEUROGENETIC DISEASES

  • A wide spectrum of genetic tests, for both common and rare neurogenetic disorders
  • Comprehensive testing, through a combination of modern analytical techniques, aiming at the highest possible detection rate for pathogenic mutations

Genetic investigations of neurogenetic diseases, which constitute a large group of relatively frequent genetic diseases involving hundreds of diseases (muscular dystrophies, myopathies, neurological diseases, etc.), has always been a primary area of research and diagnostic activity of InterGenetics.

Historically, starting from genetic testing for spinal muscular atrophy – SMA and muscular dystrophy Duchenne/Becker, we gradually developed genetic tests for a range of neurogenetic diseases, becoming a reference center in Greece and internationally.

During its ~30 years of operation, InterGenetics has examined more than 800 clinical cases involving all kinds of neurogenetic diseases.

Recently, we added new genomic testis for uncovering the underlying genetic cause in several neurogenetic-neuromuscular disorders, such as the genomic analysis of all human genes (whole exome sequencing – WES) and various specific multi-gene panels, having already completed and successfully diagnosed a large number of complex patient cases.

It is also worth noting that InterGenetics, recognizing the importance of the prevention of these diseases, pioneered in 2012 the incorporation of genetic testing for spinal muscular atrophy – SMA in all routine prenatal chromosomal diagnosis tests, affording the diagnosis of affected fetuses (not healthy carriers).

In this context, we have tested more than 3.000 embryos and have already prevented the birth of affected children, from parents who did not know they were carriers of the disease.

InterGenetics provides the most up to date and comprehensive approach to the genetic investigation of patients and the safe guidance of families burdened with such problems.

General Information

In general, neurological and neuromuscular disorders affect the nerves that control voluntary function of our muscles, such as motor control of the hands and feet. Nerve cells called neurons, send signals that control these muscles, and when neurons are damaged, then the communication between the nervous system and muscles breaks down, causing the muscle to weaken and deteriorate.

This weakness can lead to convulsions, cramps, aches and of course motor disabilities. Sometimes these diseases can even affect heart function and our breath.

The majority of neuromuscular disorders are progressive, some evident at birth, some in childhood and others occur in adults. Life expectancy varies depending on the disease and its severity, ranging from death at a very young age up to normal life. Heart and respiratory problems are the most frequent cause of death.

Timely diagnosis is important in the first stages of disease expression

For many years, neuroscience and the classification of neurological diseases has been based mainly on clinical symptoms (phenotype), and later, with our increased understanding afforded through developments in neurophysiology and neuroimaging, there was a more accurate classification of these diseases.

The grouping of disorders based on the mode of inheritance is not particularly helpful in the classification, since different diseases, such as certain ataxias and neuropathies, are manifested in a similar mode of inheritance.

Nowadays, we know that mutations in hundreds of different genes can cause different types of neurogenetic diseases, i.e. diseases that cause damage to the nervous and neuromuscular system and have a genetic basis.

It is perhaps easy to realize that this large group of diseases includes genetic disorders exhibiting characteristic symptoms, but also with a great phenotypic overlap. Overall, neurogenetic diseases are quite common, as for example more than 1 million people in the US are affected with some form of neuromuscular disease and about 40% of these patients under 18 years old.

In a more simplified way we can say that a class of neurogenetic diseases is associated mainly with neurological abnormalities, such as Huntington’s disease, Friedreich’s ataxia, spinocerebellar ataxias (SCA), etc..

Another category concerns neuromuscular disorders also affecting the muscular system, such as spinal muscular atrophy (SMA), myotonic dystrophy (DM), spastic paraplegias (HSP), etc..

Finally, there is a third category, which concerns a large group of muscular dystrophies and myopathies, such as Duchenne/Becker muscular dystrophy, the limb-girdle muscular dystrophies (LGMDs), etc., affecting almost exclusively the muscle tissues.

The above distinctions are of course simplified in order to provide a better understanding of these complex diseases, included in this broad category of genetic disorders.

Increased risk of recurrence in a family with an already affected member

The group of muscular dystrophies comprises a variety of neuromuscular genetic diseases in which there is damage and subsequent loss of muscle fibers (without damage to the nerve cells), resulting in the damaged muscles becoming progressively weaker.

Although loss of muscle mass in itself is not painful, muscle weakness can cause cramps, stiffness, deformities, chronic pain and sometimes contractions. Classic examples of muscular dystrophies are the relatively frequent Duchenne/Becker muscular dystrophy, limb-girdle muscular dystrophies (LGMDs), Emery-Dreifuss muscular dystrophy (EDMD), but there are also tens of other, individually rare, types of muscular dystrophies with several overlapping clinical symptoms .

Neurogenetic/neuromuscular diseases are inherited in all possible modes of inheritance, i.e. autosomal recessive (parents healthy carriers), autosomal dominant (usually with an affected parent or through a de novo mutation in the patient without a family history) but also X-linked (affected males only).

Furthermore, the same type or class of disease may be due to mutations in several different genes, such as the Charcot-Marie-Tooth (CMT) group of neuropathies, limb-girdle muscular dystrophies (LGMDs), Emery-Dreifuss muscular dystrophies (EDMD) etc. and the mode of inheritance depends on the gene involved.

A more detailed understanding and grouping of neurogenetic disorders, as to their underlying genetic causes, has been made possible by the rapid development of genetic techniques in recent years, and today we know of more than 300 genes that cause or contribute to the expression of these diseases.

A special contribution to the discovery of new genes has come from the application of the new genomic technologies of massive parallel sequencing (Next Generation Sequencing – NGS) of human genes, allowing the simultaneous detection of possible mutations in hundreds of genes in one step.

This latter approach has become today a valuable clinical diagnostic tool for the successful diagnosis of the genetic causes associated with this highly complex group of diseases.

Diagnostic strategies

Genetic testing for neuromuscular disorders is applied differently for each disease, always depending on the mode of inheritance, family history and the clinical features of the disease. Especially for dominant neurogenetic diseases (e.g. Huntington, Charcot-Marie-Tooth CMT1A), molecular genetic testing is typically performed:

  • as a diagnostic test, in affected individuals exhibiting symptoms consistent with the disease
  • as a predictive/presymptomatic test, in a family with affected relatives who wish to know if they are at risk of being affected. In this case genetic tesing must be preceded by genetic counseling
  • as prenatal diagnosis in a the fetus, in cases where a parent is affected and the genetic cause has already been identified (a prerequisite), to determine whether the fetus is at risk of being affected later in life. Note that in some cases there is a possibility to reveal also the risk for one of the parents, who probably did not know or did not want to know their risk. In this case, prenatal diagnosis must be preceded by genetic counseling.

For recessive nuerogenetic disorders, such as Friedreich ataxia, spinal muscular atrophy- SMA, etc., molecular genetic testing is applied:

  • as a diagnostic test, in affected individuals exhibiting symptoms consistent with the disease
  • for identifying carriers of the disease in the population or in family members with an affected relative, before starting a pregnancy or very early in pregnancy
  • very early in pregnancy, as prenatal diagnosis the fetus, in cases where both parents rare carriers of the disease and the genetic cause has already been identified in both (a prerequisite), to determine whether the fetus is at risk of being affected

Finally, in the case of X-linked neuromuscular diseases, for example Duchenne/Becker muscular dystrophy, Charcot-Marie-Tooth CMTX1, Kennedy disease and Rett syndrome, molecular genetic testing is applied:

  • as a diagnostic test, in affected individuals exhibiting symptoms consistent with the disease
  • for identifying female carriers of the disease in a family with an affected male relative (e.g. brother), before starting a pregnancy or very early in pregnancy
  • very early in pregnancy, as prenatal diagnosis the fetus, in cases where the mother is a known carrier of the disease and the genetic cause has already been identified (a prerequisite), to determine whether the fetus is at risk of being affected

Description of selected cases

Tests included in the group