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Chapter 14: Patterns of inheritance 519

Table 14.4 Mitochondrial inherited conditions
Disease Gene
Kearns–Sayre syndrome MTTL1 Mutations in mitochondrial tRNA (leucine)-1-gene or deletions of
multiple genes. Ophthalmoplegia, ptosis, retinal degeneration,
diabetes, ataxia, cardiomyopathy.
Leber optic atrophy Multiple loci Sudden onset adult blindness, cardiomyopathy, cardiac conduction
defects.
Myoclonic epilepsy and ragged MTTK1, MTTL1 Can be produced by mutations in more than one mitochondrial gene.
red fibre (MERRF) Causes myoclonus, optic atrophy, retinopathy, deafness and ataxia.
Mitochondrial MTTL1, MTND6, MTTQ Can be produced by mutations in more than one mitochondrial gene.
encephalomyopathy, lactic Causes headaches, seizures, hemiparesis, stroke like episodes,
acidosis and stroke like deafness, dementia, short stature, lactic acidosis.
episodes (MELAS)

Clinical features sibling (recurrence risk is 1% overall, higher if a bal-
Neonatal features include hypotonia, poor Moro re- anced translocation).

flex, joint hyperflexibility, excess skin at the nape of Postnatal chromosome analysis is diagnostic.
the neck and flat facies.
Characteristic facies with a small midface, low bridged Prognosis

upturned nose, oblique palpebral fissures, epicanthal 15–20% die before age 5, usually as a result of severe
folds and enlarged protruding tongue. inoperative heart disease. The remainder survive well
Short stature (long bones of limbs are short). Short into adult life, but by 40 almost all have Alzheimer’s

middle phalynx of little finger, single horizontal pal- disease.
mar crease in broad hands, increased space between
the fist and second toe. Lax joints with risk of at-
lantoaxial dislocation. Klinefelter syndrome
Congenitalheartdiseasein30%,mostcommonlyatri-

Definition
oventricular septal defects.
Chromosomal abnormality with a genotype 47XXY.
Tracheo-oesophageal fistula, duodenal atresia, annu-

lar pancreas, Hirschsprung’s disease.
Mental retardation, hypotonia, Alzheimer’s disease by
Incidence
age 40 (cortical atrophy, ventricular dilation, neuro- 1in 1000 males.
fibrillary tangles).
Age
Complications Congenital.
Fifteenfold increased risk in developing leukaemia (ALL
and AML), hypothyroidism.
Sex
Phenotypically males.
Investigations
Prenatal: Reduced maternal serum α feto protein and

oestriol, and increased maternal serum βHCG in- Aetiology/pathophysiology
dicates an increased risk of Down syndrome (triple In 80–90% there is a 47XXY karyotype, the extra X com-
test). Increased nuchal fold thickness on ultrasound at ingfromthemother.48XXXYand49XXXXYkaryotypes
12–14 weeks has been shown to be as sensitive and are usually associated with mental retardation, i.e. the
specific a test. Definitive diagnosis is made by chori- more X chromosomes the more severe the phenotype.
onic villus sampling at 10–11 weeks or amniocentesis Many cases go undetected as patients are generally nor-
early in the second trimester (15–16 weeks). Indica- mal. All appear normal until puberty when hypogo-
tions for testing include maternal age and a Down nadism becomes prominent.