Clinical AreaNeurology

Here you will find the disease-related gene panels available for the clinical area specified above.

If you cannot find the disease you are looking for, please use a known synonym in the search (also in English).

By means of neurogenetic diagnostics, the hereditary causes of neurological and psychiatric diseases are clarified. The aim here is to detect deviations from the reference genome ("wild type") and then, if necessary, to differentiate between neutral variants and pathogenic mutations that are important for the physiological development and undisturbed functioning of the nervous system. The inheritance patterns of neurogenetic diseases are the basis of genetic counselling for patients, persons at risk and affected families.

In the last 30 years, several hundred genes have been characterised which cause neurogenetic diseases or contribute to the development of neurological/psychiatric disorders. Current results of neurogenetic research have a direct impact on the diagnostic procedure in the laboratory and in genetic counselling. For example, mutations in independent genes on different chromosomes can cause clinically indistinguishable, hereditary motor-sensitive forms of neuropathy. On the other hand, different mutations in one and the same gene, which codes for a subunit of a calcium channel, lead to clinically apparently separated disease entities (hemiplegic migraine vs. episodic ataxia vs. spinocerebellar ataxia type 6).

Formal genetically and etiologically the following groups of neurogenetic diseases can be distinguished:

• monogenic diseases (autosomal or X-chromosomal inheritance)
• mitochondrial diseases (maternal or autosomal inheritance)
• multifactorial diseases (interaction of several to many genes plus environmental factors)

Congenital malformations of the nervous system often appear sporadically - is there a genetic (co-)cause? Several hundred inherited neurological/psychiatric disorders are proven to be based on genetic changes and lead to disorders in the proteins that build up the central nervous system and peripheral nerves. DNA diagnostics therefore often involves a step-by-step procedure in which the most frequent mutations are first tested before the very rare genetic causes are also identified in parallel approaches using extensive and cost-intensive panel procedures. Mutations found or all variants with unclear significance (VUS) are verified by DNA sequence analysis using the Sanger technique. Some of the more common groups of diseases are listed below.

In the majority of neuropaediatric diseases one or more genetic factors are causally involved in the causal pathogenesis of developmental disorder. Often numerical and structural chromosomal defects are detectable, and sometimes gene mutations that cause monogenic syndromes (e.g. the relatively common Fragile X syndrome). Diagnostic gene panels for developmental disorders comprise up to several hundred genes, which are sequenced in parallel. Initially, only those genes that appear associated with the clinical picture are analysed. The individual gene panels can be used separately or in combination for diagnostic purposes.

Neuromuscular diseases affect the muscles, the anterior horn cells of the spinal cord or the motor end plates and lead to the prime symptom of muscle weakness. The differential diagnosis of neuromuscular diseases requires not only thorough clinical examinations in the muscle centre but also a detailed family tree, electrophysiology and muscle biopsy with specialised (immune) histology. In many cases, however, only molecular genetic analysis allows the exact diagnosis to be determined. Examples of neuromuscular diseases are dystrophinopathies (Duchenne / Becker disease), numerous forms of limb girdle muscular dystrophies, myotonic dystrophies, muscle atrophies (spinal muscular atrophy, SMA) and spinobulbar muscular atrophy (type Kennedy; SBMA). For the abovementioned and many other diseases of this type, the heredity patterns are precisely known and the genetic defects are directly detectable. If the clinical diagnosis remains less specific, several gene panels are available depending on the disease group.

Most polyneuropathies are not of direct genetic origin. Nevertheless, often only comprehensive molecular genetic diagnostics allows a clear determination of the diagnosis or causal pathogenesis. Hereditary polyneuropathies are caused by metabolic and structural defects. Several dozens of genes (>60) are known to be mutated, and without clinical examination including laboratory tests differential diagnosis is virtually impossible. Hereditary motor sensitive neuropathies (HMSN / CMT abbreviated for heredity motor-sensory neuropathy / Charcot-Marie-Tooth disease) are divided into up to seven groups according to clinical appearance and the inheritance mode. Depending on the clinical findings, different comprehensive gene panels are used.

Epileptic seizures are caused by episodic dysfunctions of nerve cells, which are triggered by excessive neural discharges as a result of increased excitability. Epilepsy is a common, clinically and genetically very heterogeneous disease affecting up to 1% of the population. Approximately one third of cases are due to exogenous factors (trauma, tumours, infections, toxins, etc.). In almost two thirds of epilepsies, the etiology remains largely cryptogenic or idiopathic and is probably mostly to be called multifactorial. Increasingly, more and more forms of epilepsy that are obviously monogenic, such as frontal lobe epilepsies or progressive myoclonic epilepsies, can be clarified by molecular genetics. Diagnostic gene panels for epilepsy comprise up to several hundred genes which are sequenced in parallel. The first genes to be analysed are those which appear to be associated best with the clinical picture. The individual gene panels can be used separately or in combination for diagnostic purposes.

Neurodegenerative diseases are sometimes monogenic disorders of children up to adulthood, which lead to corresponding neurological symptoms due to premature degeneration of certain cells and structures of the nervous system. These include the model disease Huntington disease, the autosomal dominant inherited spinocerebellar ataxias and also Friedreich's ataxia (autosomal recessive inheritance). In addition, Alzheimer's disease (half of all cases of dementia; 4th most frequent cause of death in industrialised countries) in its rare hereditary forms can be confirmed by mutations in several genes, unless it is multifactorially caused. Furthermore, Mendelian forms of Parkinson disease are inherited monogenetically as well as several amyotrophic lateral sclerosis phenotypes. Due to a central distal axonopathy in the spinal cord (tractus corticospinalis, posterior strands), multiple forms of hereditary spastic spinal paralysis develop, which are passed on according to different inheritance patterns. Due to the extreme genetic heterogeneity of this clinical picture, increasingly larger gene panels are used for differential diagnosis in DNA sequence analysis after initial exclusion of the most common types. Trinucleotide block expansion diseases (Huntington disease, spinocerebellar ataxias, FRAX syndrome etc.) are clarified by determining the length of the expanded block.

The skin and nervous system each develop from the ectoderm. Neurocutaneous syndromes are by definition characterized by combinations of symptoms with different skin findings involving the peripheral and/or central nervous system. More common conditions of these rare monogenic diseases are neurofibromatosis with its subtypes and tuberous sclerosis.

Epplen JT, Hoffjan S: Klinische Neurogenetik in Klinische Neurologie, Berlit P, Springer-Verlag, Heidelberg 2012; new edition in print