Volume 32, Issue 3

Inherited peripheral neuropathy is the most common hereditary neuromuscular disease with a prevalence of about 1:2,500. The most frequent form is Charcot-Marie-Tooth disease (CMT, or hereditary motor and sensory neuropathy [HMSN]). Other clinical entities are hereditary neuropathy with liability to pressure palsies (HNPP), distal hereditary motor neuropathies (dHMN), and hereditary sensory and autonomic neuropathies (HSAN). With the exception of HNPP, which is almost always caused by defects of the PMP22 gene, all other forms show genetic heterogeneity with altogether more than 100 genes involved. Mutation detection rates vary considerably, reaching up to 80 % in demyelinating CMT (CMT1) but are still as low as 10–30 % in axonal CMT (CMT2), dHMN, and HSAN. Based on current information, analysis of only four genes ( PMP22 , GJB1 , MPZ , MFN2 ) identifies 80–90 % of CMT-causing mutations that can be detected in all known disease genes. For the remaining patients, parallel analysis of multiple neuropathy genes using next-generation sequencing is now replacing phenotype-oriented multistep gene-by-gene sequencing. Such approaches tend to generate a wealth of genetic information that requires comprehensive evaluation of the pathogenic relevance of identified variants. In this review, we present current classification systems, specific phenotypic clues, and diagnostic yields in the different subgroups of hereditary CMT and motor neuropathies.

Background: Charcot-Marie-Tooth (CMT) neuropathies represent an important group of neuromuscular disorders and are mostly autosomal dominantly inherited. The question, if there is a higher complication rate in pregnancy and delivery in CMT neuropathy and if there is a possible influence of pregnancy on muscles and nerves themselves, is important for medical care and prepregnancy counselling of affected women. Objectives: In this review we first address general issues of the clinical picture of CMT disease and physiological adaptations in pregnancy. In the second part of this paper we summarise specific results of two comparable studies on the obstetric history of women with CMT neuropathy in order to address the obstetric complication rate, newborn vitality, possible deterioration of CMT in or after pregnancy and personal attitudes. The results are based on two combined cohort studies with 21 and 54 participants. Results: We documented 148 pregnancies (129 deliveries), resulting in 131 infants. There were no increased complication rates in the recorded pregnancies. Miscarriage rate was 12.8 % and thus as high as in unaffected women. Deliveries were not associated with specific risks; there were no increased preterm deliveries, vaginal operations or caesarean sections, and no increased postpartum haemorrhages. Newborn vitality was normal and birth measurements were within the normal range. A deterioration of CMT related symptoms was reported in about one-third of the pregnancies and after delivery, however, the functional impact on everyday life was rather low in classical CMT. Most women expressed a positive attitude towards having own children and family life but those with a larger handicap would recommend medical advice and assistance in caring for the family. Discussion and conclusion: Pregnancy can be safely undertaken in women with classical CMT, despite the fact that a negative influence on the disease course appears possible. The data of a Norwegian study which found higher rates of presentation anomalies and operative deliveries and a higher risk of postpartum haemorrhage have not been confirmed in our study.

Whole genome sequencing (WGS) is regarded by many as the pinnacle of contemporary molecular genetic testing, and has only been possible because of the rapid development and roll-out of next-generation sequencing technologies. It provides a phenotype-agnostic analysis of the genome and has important advantages compared to other techniques including a consistent coverage across the coding and non-coding genome, the application of high resolution homozygosity mapping and the ability to detect and highlight structural variation. Realising this potential and with a bid to sequence 100,000 genomes, the UK rolled out the 100,000 Genomes Project as a proof of concept of integrating genomics in the national health service. Participants with cancer and rare diseases enrolled in the project whose infrastructure comprises of a central national biorepository and 13 regional genomic medicine centres where clinicians, geneticists and other scientists work as part of a multidisciplinary team. Amongst participants are also patients with genetically unclassified Charcot-Marie-Tooth disease who have benefited substantially from improved diagnostic rates and many more stand to benefit as the analysis of genomic data is ongoing. WGS is an important tool as we head towards more personalised medicine and in our quest to improve public health and treat and where possible prevent disease.

Peripheral sensory neurons are afferent neurons that innervate the skin, joints, bones, muscles, and mucosal tissues. By converting different stimuli into action potentials, they transmit signals for the sensing of temperature, touch, pressure, or pain. This review discusses the known Mendelian disorders which affect pain sensing in humans. For painlessness, these disorders can be classified as developmental, neurodegenerative, or functional, where pain-sensing neurons (nociceptors) are present but cannot be activated or produce action potentials. Affected patients suffer from numbness with recurrent injuries, burns, and poorly healing wounds. For Mendelian disorders of excess pain, aberrant overactivity of nociceptors is a hallmark and leads to paroxysmal or continuous pain states. Again, the effect can be functional or, as in small fiber neuropathies, can be accompanied by degeneration of small unmyelinated nerve fibers in the skin. About 20 different genes are known to cause Mendelian pain disorders and the molecules involved are of general interest for human pain research and as analgesic targets. Comprehensive genetic testing is the key to early diagnosis and adaptation of clinical management.

Neuropathy might be the presenting or accompanying sign in many neurogenetic and metabolic disorders apart from the classical-peripheral neuropathies or motor-neuron diseases. This causes a diagnostic challenge which is of particular relevance since a number of the underlying diseases could be treated. Thus, we attempt to give a clinical overview on the most common genetic diseases with clinically manifesting neuropathy.

Proximal spinal muscular atrophy (SMA) is an autosomal-recessive inherited neuromuscular disorder caused by the degeneration of alpha motor neurons in the anterior horn of the spinal cord. Patients show hypotonia, muscular atrophy and weakness of voluntary proximal muscles. SMA is one of the most common genetic diseases, with a frequency of about 1 in 7,000 newborns in Germany. The vast majority of patients carry a homozygous deletion of exons 7 and 8 of the survival motor neuron ( SMN ) 1 gene on chromosome 5q13.2; only about 3–4 % of patients are compound heterozygous for this common mutation and an additional subtle mutation in SMN1 . The severity of the disease is mainly influenced by the copy number of the highly homologous SMN2 . Since the discovery of the underlying genetic defect 25 years ago, both the diagnostics of SMA and its treatment have undergone constant and in recent times rapid improvements. SMA has become one of the first neuromuscular disorders with effective therapies based on gene targeted strategies such as splice correction of SMN2 via antisense oligonucleotides or small molecules or gene replacement therapy with a self-complementary adeno-associated virus 9 expressing the SMN1 -cDNA. With the availability of treatment options, which are most effective when therapy starts at a pre-symptomatic stage, a newborn screening is indispensable and about to be introduced in Germany. New challenges for diagnostic labs as well as for genetic counsellors are inevitable. This article aims at summarising the current state of SMA diagnostics, treatment and perspectives for this disorder and offering best practice testing guidelines to diagnostic labs.

Zusammenfassung Die Vereinigung der beiden deutschen Staaten vor dreißig Jahren am 3. Oktober 1990 ermöglichte auch eine Vereinigung der getrennt existierenden Gesellschaft für Humangenetik (GfH) der Bundesrepublik Deutschland und der Gesellschaft für Humangenetik der DDR. Dieser Beitrag beschreibt auf Basis des eigenen Erlebens, wie im Fach Humangenetik die Trennung in Ost und West überwunden wurde. Innerhalb eines Jahres konnte die Einheit herbeigeführt werden. Dabei waren Schwierigkeiten zu überwinden, da eine einfache Fusion aus vereinsrechtlichen Gründen nicht möglich war. Dennoch war im Jahr 1991 die Zusammenführung vollendet.