Clinical Features

The usual pattern of disease is characterized by a slowly progressive movement disorder and insidious impairment of intellectual function with psychiatric disturbance and eventual dementia. The mean duration of the illness is approximately 15 to 20 years and chorea is the most common movement abnormality. This takes the form of subtle involuntary movements such as facial grimacing, twitching of the face and limbs, folding of the arms, and crossing of the legs. As the disease progresses the gait becomes very unsteady and speech unclear.

Intellectual changes in the early stages of HD include memory impairment and poor concentration span. Anxiety and panic attacks, mood changes and depression, aggressive behavior, paranoia, irrationality, increased libido, and alcohol abuse can also occur. There is a gradual deterioration in intellectual function, leading eventually to total incapacitation and dementia.

Genetics

Traditionally HD has been said to show autosomal dominant inheritance with a variable age of onset, close to complete penetrance, and a very low mutation rate. In addition, it has been noted that the disorder often shows anticipation, whereby the onset is at a younger age in succeeding generations, particularly when transmitted by a male. The discovery of the HD gene in 1993 provided an explanation for some of these observations.

Clinical Features

In contrast to most forms of muscular dystrophy, clinical features in MD are not limited exclusively to the neuromuscular system. Individuals with MD usually present in adult life with slowly progressive weakness and myotonia. This latter term refers to tonic muscle spasm with prolonged relaxation, which can manifest as a delay in releasing the grip on shaking hands. Other clinical features include cataracts (Figure 19.1), cardiac conduction defects, disturbed gastrointestinal peristalsis (dysphagia, constipation, diarrhea), weak sphincters, increased risk of diabetes mellitus and gallstones, somnolence, frontal balding, and testicular atrophy. The age of onset is very variable and in its mildest form usually runs a relatively benign course. However, as the age of onset becomes earlier, so the clinical symptoms increase in severity and more body systems are involved. In the ‘congenital’ form, affected babies present at birth with hypotonia, talipes, and respiratory distress that can prove life threatening (see Figure 7.19). Children who survive tend to show a lack of facial expression (‘myopathic facies’) with delayed motor development and learning difficulties (Figure 19.2).

FIGURE 19.1 Refractile lens opacities in an asymptomatic person with myotonic dystrophy.

(Courtesy Mr. R. Doran and Mr. M. Geall, Department of Ophthalmology, General Infirmary, Leeds, UK.)

FIGURE 19.2 A mother and child with myotonic dystrophy. The child has clear features of facial myopathy and suffers from the congenital form; the mother has only mild facial myopathy. The marked generational difference in the severity of disease illustrates the phenomenon of anticipation.

The diagnosis of MD used to be based on the myotonic discharges seen on electromyography but mutation analysis is more reliable and much less painful.

Genetics

It follows autosomal dominant inheritance with increasing severity in succeeding generations—anticipation (p. 120). It used to be thought that this reflected ascertainment bias, caused by the greater likelihood of detecting a mildly affected parent with a severely affected child, rather than the other way round. However, studies in the 1980s confirmed that anticipation is a real phenomenon.

Genotype–Phenotype Correlation in Myotonic Dystrophy

In unaffected persons the CTG sequence lying 3′ to the DMPK gene consists of up to 37 repeats (see Table 19.1). Affected individuals have an expansion of at least 50 copies of the CTG sequence. There is a close correlation between disease severity and the size of the expansion, which can exceed 2000 repeats. The severe congenital cases show the largest repeat copy number, with almost invariable inheritance from the mother. Thus, meiotic or germline instability is greater in the female for alleles containing large sequences. Curiously, expansion of a relatively small number of repeats appears to occur more commonly in the male, and most MD mutations are thought to have occurred originally during meiosis in the male. One possible explanation for these observations is that mature spermatozoa can carry only small expansions, whereas ova can accommodate much larger expansions.

Another puzzling feature of MD is the reported tendency for healthy individuals who are heterozygous for MD alleles in the normal size range to preferentially transmit alleles greater than 19 CTG repeats in size. This possible example of meiotic drive (p. 135) could explain the relatively high frequency of MD with constant replenishment of a reservoir of potential MD mutations.

The MD Protein Kinase

Perhaps surprisingly, it may be that DMPK is not directly responsible for muscle symptoms—mice with both overexpression and underexpression of Dmpk show neither myotonia nor other typical clinical features of MD. It is now appears that the RNA produced by expanded DMPK alleles interferes with the cellular processing of RNA produced by a variety of other genes. Expanded DMPK transcripts accumulate in the cell nuclei, and this is believed to have a gain-of-function effect through its binding with a CUG RNA-binding protein (CUG-BP) that has been identified. Excess CUG-BP has been shown to interfere with a number of genes relevant to MD; this is not surprising because CUG repeats are known to exist in various alternately spliced muscle-specific enzymes.

Clinical Applications and Future Prospects

Presymptomatic genetic testing and prenatal diagnosis can be offered to those families for whom it is appropriate and acceptable. This is particularly relevant for couples who have had a child with the severe congenital form, for whom the risk of recurrence is relatively high. As in HD, presymptomatic testing should not be undertaken without an offer of long-term support and medical care, and a discussion about possible difficulty in obtaining life and health insurance (p. 366).

Important components of the management of MD include regular surveillance for cardiac conduction defects and the provision of information about risks associated with general anesthesia. Logical approaches to gene therapy will almost certainly have to await a better understanding of the mechanism whereby expansion of the repeat sequence in the 3′ untranslated region of the DMPK gene causes such diverse and variable clinical abnormalities.

Type 2 MD

Some families with a variable presentation of similar features to MD, but without the (CTG)_n expansion of DMPK, have been shown to link to 3q21. Originally referred to as proximal myotonic myopathy (PROMM), these cases are designated type 2 MD to distinguish them from the more common type 1 MD. The molecular defect has been shown to be a (CCTG)_n expansion mutation in intron 1 of a gene called ZNF9 and its protein is thought to bind RNA. Most families are of German descent, and haplotype studies suggest a single founder mutation occurring between 200 and 500 generations ago.

Clinical Features

In autosomal dominant HMSN-I—the most common form—there is onset of slowly progressive distal muscle weakness and wasting in the lower limbs between the ages of 10 and 30 years, followed later by the upper limbs in many patients, and associated ataxia and tremor. The appearance of the lower limbs has been likened to that of an ‘inverted champagne bottle’ (Figure 19.3). With age, locomotion becomes more difficult and the feet tend to show exaggeration of their normal arch, known as ‘pes cavus’. Despite these quite striking changes, many patients retain reasonable muscle strength and are not too seriously disabled. Other faculties such as vision, hearing, and intellect are not impaired. Palpable thickening of peripheral nerves can sometimes be detected.

FIGURE 19.3 Lower limbs of a male with hereditary motor and sensory neuropathy (HMSN) showing severe muscle wasting below the knees.

The clinical features in other forms of HMSN are similar but differ in the age of onset, rate of progression, and presence of other neurological involvement. For example, in HMSN-II onset is usually later than in HMSN-I, and the disease course is milder to the extent that some affected individuals are asymptomatic. By contrast, in HMSN-III, which is very rare, onset is in early childhood and there is severe delay in achieving motor milestones.

Genetics

HMSN can show autosomal dominant, autosomal recessive or X-linked inheritance, although autosomal dominant forms are by far the most common. More than 70% of cases of HMSN-I are due to a DNA duplication of 1.5 Mb chromosome 17p that encompasses the peripheral myelin protein-22 (PMP22) gene. The glycoprotein product is present in the myelin membranes of peripheral nerves, where it helps to arrest Schwann cell division. HMSN-I in humans is therefore thought to be the result of a PMP22 dosage effect, though point mutations can be found some patients. The duplication is generated by misalignment and subsequent recombination between homologous sequences that flank the PMP22 gene (Figure 19.4); this event usually occurs in male gametogenesis (rather than in the female, which is the case in Duchenne muscular dystrophy [p. 307]). The reciprocal deletion product of this misaligned recombination event, giving rise to haploinsufficiency, causes a relatively mild disorder known as hereditary neuropathy with liability to pressure palsies. Minor nerve trauma, such as pressure from prolonged sitting on a long-haul flight, causes focal numbness and weakness. The same misalignment recombination mechanism occurs in Hb Lepore and anti-Lepore (see Figure 10.3; p. 157), congenital adrenal hyperplasia (p. 174), and deletion 22q11 syndrome (p. 282), to name but a few.

FIGURE 19.4 Mechanism by which misalignment and recombination with unequal crossing over lead to formation of the duplication and deletion that cause hereditary motor and sensory neuropathy type I (HMSN-I) and hereditary neuropathy with liability to pressure palsies (HNPP). X and Y represent homologous sequences flanking the PMP22 gene.

Future Prospects

Genetic testing in HMSN has greatly improved diagnostic precision, though there is still a place for nerve conduction studies in clinical assessment, especially when genetic testing fails to yield a positive result. Treatment remains elusive but in HMSN-Ia efforts at gene therapy may be directed at trying to achieve a reduction in gene dosage by switching off, or ‘downregulating’, PMP22 expression.

Clinical Features

The most notable features of NF1 are small pigmented skin lesions, known as café-au-lait (CAL) spots, and small soft fleshy growths known as neurofibromata (Figure 19.5). CAL spots first appear in early childhood and continue to increase in both size and number until puberty. A minimum of six CAL spots at least 5 mm in diameter is required to support the diagnosis in childhood, and axillary and/or inguinal freckling should be present. Neurofibromata are benign tumors that arise most commonly in the skin, usually appearing in adolescence or adult life, and increasing in number with age.

FIGURE 19.5 A patient with neurofibromatosis type I showing truncal freckling, café-au-lait spots, and multiple neurofibromata.

Other clinical findings include relative macrocephaly (large head) and Lisch nodules. These are small harmless raised pigmented hamartomata of the iris (Figure 19.6). The most common complication, occurring in a third of childhood cases, is mild developmental delay characterized by a non-verbal learning disorder. For many, significant improvement is seen through the school years. Most individuals with NF1 enjoy a normal life and are not unduly inconvenienced by their condition. However, a small number of patients develop one or more major complications, such as epilepsy, a central nervous system tumor, or scoliosis.

FIGURE 19.6 Lisch nodules seen in neurofibromatosis type I.

(Courtesy Mr. R. Doran, Department of Ophthalmology, General Infirmary, Leeds, UK.)

Genetics

NF1 shows autosomal dominant inheritance with virtually 100% penetrance by the age of 5 years. The effects are very variable and affected members of the same family can show striking differences in disease severity. The features in affected MZ twins are usually very similar, so the variability in family members with the same mutation may be due to modifying genes at other loci. Approximately 50% of cases of NF1 are due to new mutations, with the estimated mutation rate being approximately 1 per 10,000 gametes. This is around 100 times greater than the average mutation rate per generation per locus in humans.

There are a few reports of more than one affected child born to unaffected parents—the result of gonadal mosaicism (p. 121), usually paternal in origin. Somatic mosaicism in NF1 can manifest with features limited to a particular part of the body. This is referred to as segmental NF.