MIM

310200 (Duchenne type)

300376 (Becker type)

Clinical features

Contractures of tendo-Achilles, muscle pseudohypertrophy (see Figure 29), and weakness, predominantly proximal, with delay in walking. This has a slow, relentless progression so that the patient will be wheelchair-bound by their early teens (or by mid to late adulthood in Becker type). Treatment by regular physiotherapy, or by Achilles tenotomy in late childhood, may help with walking.

Figure 29

Calf hypertrophy in a boy with Duchenne muscular dystrophy.

Gene

DMD (dystrophin)

Chromosomal location

Xp21.2

Prevalence

1 in 5,000 males (Duchenne); 1 in 18,500 males (Becker)

Inheritance

Sex-linked recessive. "Manifesting" female carriers occasionally occur (females who carry one copy of the gene and have mild symptoms or weakness).

History

Following a description by Meryon in 1852, Guillaume Duchenne described this disorder in 1861. In 1879, Gower described the pseudohypertrophy and the classic maneuver of rolling over and rising from the floor from lying flat by using the hands to help with leverage. The milder type was described by Becker in 1957.

Age at onset

Childhood. Usually between 3–5 years of age, although onset of the Becker type is later (starting around 5 years, but may be as late as 50 years).

Diagnosis

Raised serum creatine phosphokinase (levels >10,000 U/L are almost diagnostic). Muscle biopsy confirms dystrophic change and absence of dystrophin in Duchenne type (see Figure 30). Reduced dystrophin staining in the Becker type.

Figure 30

Dystrophic muscle showing the absence of a dystrophin stain.

Genetic testing

Available for mutations in DMD. Around 70% of boys have deletions, 5% have duplications, and the remainder have point mutations (which are difficult to detect).

Screening

Perform genetic tests and measure the creatine phosphokinase level in at-risk males. Conduct carrier testing in at-risk females.

Counseling issues

Prenatal diagnosis is available. Carrier testing should be offered in all families. Around a third of mutations are de novo in boys, but a third can be de novo in the mother and give rise to germline mosaicism risks. The average life expectancy in the Duchenne type is 15–25 years. Life expectancy is variable in Becker type, but ranges from 40 to 60 years.

MIM

118220 (CMT1 type 1A [CMT1A])

118200 (CMT type 1B [CMT1B])

302800 (CMT X-linked [CMTX])

Clinical features

Wasting of the intrinsic muscles of the hand, especially thenar and hypothenar eminences, with wasting and atrophy of the peroneal muscles.

Genes

PMP22 (peripheral myelin protein 22), P0 , CX32 (connexin-32; also known as GAP junction protein, β-1 [GJB1]), various others

Chromosomal location

17p11 (CMT1A), 1q32 (CMT1B), Xq13 (CMTX)

Prevalence

1 in 2,500

Inheritance

Autosomal dominant (several types, including CMT1A and CMT1B). Autosomal recessive and sex-linked (CMTX).

History

Described by Jean Charcot, the French neurologist (who created the famous neurologic clinic at the Salpêtrière clinic in Paris), along with his pupil, Pierre Marie, in 1886. Howard Tooth, an English neurologist, described the condition the same year, indicating that it was a peripheral neuropathy.

Age at onset

Variable, from early childhood to middle age. The average is 12 years of age.

Diagnosis

Neurophysiologic testing will confirm the muscle wasting and weakness.

Genetic testing

Available for the common dominant types CMT1A and CMT1B and the X-linked dominant type CMTX ( CX32 ).

Screening

Genetic testing will help to clarify the exact subtype. Around 60%–80% of cases are CMT1A. Several rare dominant and recessive types exist.

Mutational spectrum

Heterogeneity exists, with genes for several of the dominant and recessive types still to be identified.

Counseling issues

This is complex. Most centers will test for CMT1A, CTM1B, CMTX, and CMT2, but other types need careful counseling. A related disorder, hereditary neuropathy with pressure palsies (MIM 162500), is caused by a deletion of the region duplicated on chromosome 17p in CMT1A.

MIM

143100

Clinical features

Triad of movement disorder (including choreiform movements), psychiatric dysfunction (including mood swings, irritability, inertia, and depression), and cognitive dysfunction. There is often shrinkage of the basal ganglia and, in particular, atrophy of the caudate nucleus occurs before atrophy of other parts of the brain (see Figure 31).

Figure 31

Caudate nucleus shrinkage shown on computed tomography.

Gene

A CAG expansion (see Glossary) in the huntingtin gene.

Chromosomal location

4p16.3

Prevalence

1 in 10,000

Inheritance

Autosomal dominant

History

Described by George Huntington, a general practitioner in Ohio, in 1872.

Age at onset

Classically early middle life (35–50 years of age), but about 10% of cases have onset before 20 years and around 25% of cases have onset after 50 years.

Diagnosis

Autosomal dominant choreiform disease with relentless progression is classic. Few therapies are available. Fetal neural transplantation, in which fetal cells are injected into the caudate and putamen, looks promising in early trials, but is controversial.

Genetic testing

Available for triplet expansion of CAG repeats within the huntingtin gene.

Screening

Presymptomatic genetic testing is available for those at risk.

Counseling issues

Complex testing protocol because of the ethical implications of testing for a late-onset disorder with no treatment.

MIM

309550

Clinical features

Mental retardation, long face, large testicles, and behavioral difficulties.

Gene

FMR1 (fragile site mental retardation 1)

Chromosomal location

Xq28

Prevalence

1 in 4,000 males. This is the most common cause of mental retardation in males.

Inheritance

X-linked (female gene carriers may have mild expression of features).

Age at onset

Childhood, with behavioral problems and developmental delay.

Diagnosis

Testing by molecular genetics for FMR1 is widely available. Variable-sized CCG expansion within the gene is diagnostic. Generally, the larger the expansion, the worse the condition. The chance of a premutation (around 55–200 repeats) expanding to a full mutation is positively associated with the size of the repeat (~95% by 90 repeats).

Screening

At-risk family members may have genetic testing. National screening in the neonatal period is under consideration in some countries, including the UK.

Mutational spectrum

Heterogeneity exists. Other causes of mental handicap are common, but genetic testing is not usually available. In FMR1 mutation-negative cases, a routine chromosome analysis should be carried out to exclude chromosomal anomaly. Referral for specialist genetic assessment is appropriate.

Counseling issues

Females may be gene carriers and show mild expression. Males with a small expansion (a "premutation") may be normal, but transmit the premutation to all daughters, who will be unaffected by overt learning difficulties. Women with premutations have an increased chance (16%) of menopause before 40 years of age.

MIM

158900

Clinical features

Progressive weakness, particularly of the scapula (with winging), face, upper arm, and hip girdle. Affected individuals have a normal life expectancy, but often require a stick to assist with walking and a small proportion (10%–20%) will require a wheelchair.

Gene

Unknown, but FSHD can be identified by a rearrangement of DNA repeat sequence at 4q35.

Chromosomal location

4q35

Prevalence

5–10 per 100,000

Inheritance

Autosomal dominant. Around 10%–30% of cases are new mutations. Penetrance is approximately 95% by 20 years of age.

History

Described by Joseph Landouzy, a French physician, and Joseph Dejerine, a French neurologist, in a paper in 1886.

Age at onset

Childhood weakness of scapulae and difficulty with reaching up to high shelves.

Diagnosis

Clinical, with support from electromyography. Genetic testing is routinely possible and confirms the clinical diagnosis in over 95% of cases.

Screening

Genetic testing for rearrangement in families will help clarify the diagnosis and potential age of onset.

Counseling issues

Surgery with scapular fixation will repair and help the shoulder weakness and allow the patient to reach their arms up (to high shelves, to change light bulbs, etc). However, surgery is only used in a small number of cases, mostly for occupational reasons (eg, electricians), as it requires a plaster cast for some weeks with resulting inconvenience, particularly if a bilateral operation is carried out.

MIM

126900

Clinical features

Thickening and contraction of the palmar fascia causing flexion contractures of the fingers, particularly the fourth and fifth. It is also associated with Peyronie's disease of the penis (MIM 171000) in 20% of cases and popliteal fasciitis. Sporadic forms are associated with diabetes, alcoholism, and liver disease.

Gene

Unknown

Chromosomal location

Unknown

Prevalence

Very common – occurs in around 20%–30% of the Caucasian population over 65 years of age.

Inheritance

Autosomal dominant (males more than females)

History

Guillaume Dupuytren, the leading French surgeon of the early 19th century, described this in 1832, realizing that the defect lay in the palmar fascia. Ling suggested a dominant inheritance in 1963. A suggestion of Viking ancestry has been made.

Age at onset

Middle age

Diagnosis

Clinical

Counseling issues

Surgical release of the contracture is possible. The risk for first-degree relatives is approximately 70%.

MIM

142700

Clinical features

Dislocation of the hip noted at birth on neonatal examination. Figure 32 shows an X-ray of the pelvis of an adult man whose CDH was missed as a child.

Figure 32

X-ray of congenital dislocation of the hip in an adult man with a missed diagnosis at birth. Note the failure of the acetabulum to develop.

Gene

Unknown

Chromosomal location

Unknown

Prevalence

Around 1 in 1,000 in the Caucasian population. More common in females.

Inheritance

Autosomal dominant and autosomal recessive forms are suspected.

Age at onset

Birth

Diagnosis

Clinical examination, with ultrasound or magnetic resonance imaging for accurate diagnosis.

Screening

A hip examination before discharge from hospital in the neonatal period is routine in several countries.

Counseling issues

May be part of joint laxity syndromes, including Ehlers–Danlos and Larsen syndromes. Common in breech deliveries and Caesarean sections. A recurrence risk of 5% for siblings is usually quoted.

MIM

182940

Clinical features

Any partial formation of the neural tube, ranging from spina bifida occulta (see Figure 33), through spinal lipoma to open or closed meningomyelocele (see Figure 34) or anencephaly.

Figure 33

Spina bifida occulta.

Figure 34

Meningomyelocele.

Gene

Unknown

Chromosomal location

Unknown

Prevalence

1 in 500–800 in high-risk areas such as the northwest of the British Isles, or on the Indian subcontinent, where the role of genetic and environmental factors (research is still unsure which) is much higher than elsewhere; 1 in 3,000 in the rest of Europe and the USA.

Inheritance

Multifactorial, including some rare autosomal recessive and X-linked families.

Age at onset

Congenital. Prenatal diagnosis is available by ultrasound and serum screening.

Diagnosis

By prenatal ultrasound: elevated serum or amniotic fluid α-fetoprotein. Clinical diagnosis at birth or by ultrasound or X-ray of the spine.

Genetic testing

Available for the MTHFR (methylene tetrahydrofolate reductase) gene, as reduced folate is a risk factor for neural tube defects, but no gene has yet been identified for pure neural tube defects.

Screening

Advice to avoid recurrence is high-dose folic acid (4–5 mg) periconceptually (2–3 months before conception to around 3 months after conception).

Mutational spectrum

Heterogeneity exists, and several syndromic causes need to be excluded.

Counseling issues

In the majority of cases, advising the mother about diet and taking folic acid should reduce the risk of recurrence. The risk of recurrence is around 1 in 100 if there is just one case in the family. If there are two affected members in a family, the risk increases to around 1 in 10; if there are three affected family members, the risk of recurrence is around 1 in 4, as there is a strong genetic component.

MIM

307000 (X-linked hydrocephalus)

Clinical features

The X-linked type typically affects males, with early onset of prenatal hydrocephalus and adducted thumbs. Most cases of hydrocephalus are due to congenital causes, acquired infection, or trauma.

Gene

L1CAM (L1 cell adhesion molecule)

Chromosomal location

Xq28

Prevalence

Present in around 1 in 30,000 male births.

Inheritance

Sporadic, X-linked, autosomal dominant (rare).

Age at onset

Congenital, some rare later onset types.

Diagnosis

Cranial imaging – ultrasound in the neonatal period or magnetic resonance imaging after 2–3 months of age.

Genetic testing

Available for L1CAM in specialist centers on a research basis.

Screening

Possible during pregnancy by serial ultrasonography.

Counseling issues

Genetic types should be suspected in males with prenatal onset with adducted thumbs and gene testing considered for L1CAM . Rare autosomal dominant types occur. Screening for congenital infections is useful.

MIM

115650 (autosomal dominant)

302200 (X-linked)

Clinical features

Lens opacities

Gene

Various

Chromosomal location

14q24 (autosomal dominant), Xp (X-linked)

Prevalence

A very common condition. The incidence increases with age and with illnesses such as diabetes.

Inheritance

Autosomal dominant, autosomal recessive, and X-linked recessive.

Age at onset

Recessive cataracts generally have an early onset (from birth to early childhood). Dominant cataracts may commence from early adulthood into later life.

Diagnosis

Ocular examination combined with slit-lamp examination by an ophthalmologist.

Genetic testing

Available in research laboratories for some types.

Screening

Regular ophthalmic examination

Mutational spectrum

Heterogeneity exists

Counseling issues

Genetic counseling to exclude a syndromic form, especially in infancy- or childhood-onset types. Exclude other causes of cataracts that may also run in families, including diabetes. Occasionally, cataracts are the result of rare mitochondrial defects. These cataracts are asssociated with retinopathy and muscle weakness.