and thus assist genetic advice. One example is Tay–Sachs disease.
X‐Linked Inheritance
Transmission is via an unaffected female carrier. Examples are Duchenne muscular dystrophy and Kennedy’s disease. If the disease does not affect fertility because it allows survival into the reproductive period, such as in Fabry’s disease and Becker‐type muscular dystrophy transmission can be via female carriers and affected males. X‐linked adrenoleucodystrophy, ataxia syndromes and forms of Charcot–Marie–Tooth disease are other examples.
Mitochondrial Disorders
More than 70 different polypeptides interact to form the mitochondrial respiratory chain. Thirteen essential subunits are encoded by the 16.5 kb mitochondrial genomic DNA (mtDNA).
Mitochondrial diseases caused either by mutations in mtDNA or in mitochondrial genes are transmitted via maternal inheritance.
Examples are disorders such as myoclonic epilepsy and ragged red fibres (MERRF), mitochondrial myopathy, encephalopathy, lactic acidosis and stroke (MELAS) and Leber’s hereditary optic neuropathy (LHON). Chronic progressive external ophthalmoplegia (CPEO) is usually the result of a large deletion. A single mitochondrial disorder can present with variable features. For instance, the m.3243A>G point mutation may cause either MELAS, CPEO, diabetes mellitus or deafness.
Expanded Repeat Disorders
The majority of simple nucleotide repeats that occur frequently throughout the genome are not associated with disease. However, some are of great importance.
In 1991, an expansion in a trinucleotide (CAG) repeat in the androgen receptor gene was identified in X‐linked spinal and bulbar muscular atrophy a.k.a. Kennedy’s disease. The repeat normally 13–30 CAGs, lengthens to 40 or more CAGs in this condition.
Huntington’s disease (see Chapter 7 for detail) and spinocerebellar ataxias – SCA1‐3, Friedreich’s ataxia are others. An expanded hexanucleotide repeat occurs in familial amyotrophic lateral sclerosis with fronto‐temporal dementia.
Disorders can exhibit anticipation – severity worsens in successive generations. This correlates with the increased number of repeats.
Practical and Ethical Considerations
When considering genetic testing it is important to understand the practicalities, cost and the advertising pressures placed upon patients and their families.
A three‐tier approach is usual:
Initial low cost screening for common defects
Screening of rarer genes using a gene panel approach
Diagnostic exome sequencing.
Predictive genetic testing is frequently offered to individuals at risk, such as in late‐onset autosomal dominant inherited conditions. Most experience of predictive testing comes from Huntington’s disease.
Important considerations:
Do all involved understand the implications – work, insurance, plans, disclosure and confidentiality issues? In the past there has been a tendency to suggest that those potentially at risk have a duty to be tested. This pressure is now less common ‐ and there are situations where individuals prefer not to be tested.
Does the individual – rather than another family member – really wish to be tested and give informed consent?
Immune Mechanisms: Concepts and Components
The immune system is dynamic and reactive. It is a system that distinguishes self from non‐self and deletes, inactivates or supresses foreign invaders and distinguishes irreparable or altered tissue from normal, to maintain homeostasis. Where effective surveillance fails, infection or neoplasia can develop. Where active components become misdirected, autoimmune disease can follow. It is assumed that the reader has a basic understanding of the immune system and its components, the cytokine network and their interactions.
Blood–Brain and Blood–Nerve Barriers
The blood–brain barrier (BBB) is a concept – that divides the systemic compartment from the CNS and across which fluids, solutes and cells can pass selectively. This gives CNS machinery relative resistance to immune attack but it also provides an environment in which unique autoimmune processes can occur, that either limit or cause damage. The blood–nerve barrier (BNB) is less well understood – the endoneurial space of the peripheral nerve. The BNB is more permeable than the BBB, but it undoubtedly modifies immune responses that would occur if nerves were not shielded. See Chapter 10.
Cerebrospinal Fluid
The invasive nature of lumbar puncture and the normal CSF label of ‘gin clear’ tended to diminish its diagnostic value. Advances have shown that CSF is a useful fluid in which biomarkers can be identified.
CSF Solutes
In health, the CSF is maintained as a protein‐poor solvent in which are dissolved proteins derived mainly from brain tissue. The normal levels of CSF antibodies, amyloid beta, tau and phosphotau proteins are a baseline from which change indicates disease.
When there is a dysfunctional BBB, CSF total protein contains contributions from both CNS and systemic compartments, but this is non‐specific. Analysis of specific proteins is more useful.
Albumin: no albumin is produced in the normal CNS. Any CSF albumin is present either via direct transport or leakage through a dysfunctional BBB.
IgG: in health, all the CSF IgG is actively transported across the BBB. A raised CSF IgG in comparison to the serum (raised CSFIgG : serumIgG) or the IgG quotient (QIgG) can indicate disease.
Other solutes such as a‐beta amyloid proteins, tau, neurofilament proteins, S‐100 β and 14‐3‐3 protein can also be measured. Their profiles can provide biomarker support for the diagnosis of Alzheimer’s disease versus frontotemporal dementia and other degenerative diseases (Chapter 5).
CSF Cells and Other Constituents
CSF is essentially acellular. Few cells are found in normal CSF: most laboratories quote <5 white cells/mm3 as normal, but any cells should provoke suspicion. Cells are typically lymphocytes: macrophages or neutrophils are almost certainly disease‐related. Red blood cells are always abnormal, though the commonest cause is a traumatic tap. Cytology/flow cytometry may be needed, for example in malignant meningitis and haematological malignancy.
Bacteria and fungi can be isolated by culture and seen on microscopy. Viruses: PCRs are specific but variably sensitive. Whole genome and next generation sequencing techniques are available. Oligoclonal banding pattern can identify the relative production of monoclonal or oligoclonal responses, useful in inflammatory diseases. The antigenic target in MS of oligoclonal bands remains a mystery.
Immune Nervous System Diseases
While immunology, like genetics and ion channels, is a part of every chapter in this book, it is often difficult to make dogmatic statements. Here are examples where immune pathogenesis is truly relevant.
Antibody‐Mediated Diseases