Genetics Flashcards
A one-year-old child presents with seizures and a history of developmental regression. Post mortem examination reveals bilateral symmetrical necrotising lesions in the brain.
Leigh syndrome. Also known as subacute necrotizing encephalomyelopathy. Children have developmental delay or regression with seizures, ataxia, weakness and dystonia. Lactic acidosis is a feature. Post mortem reveals bilateral symmetrical necrotising lesions in the basal ganglia, thalamus, brainstem and spinal cord.
An 11-year-old child with developmental regression is diagnosed with an autosomal recessive lysosomal storage disease.
Metachromic leukodystrophy. Caused by arylsulfatase A gene mutation. Can be infantile, juvenile or late onset. There is no curative treatment. Hunter and Hurler syndrome are also lysosomal storage disorders. However, Hunter syndrome is X linked and children with Hurler syndrome do not usually survive beyond 10 years of age – most children pass away by six years.
A child with loss of language, stereotypical hand movements and MCEP2 mutation
Rett syndrome. Affects girls. Typically, development is normal initially but then there is loss of language. Girls have microcephaly and develop stereotypical movements.
Tay Sachs disease
Tay-Sachs’s disease is an autosomal recessive condition caused by disruption of enzyme β-hexosaminidase A. GM2 ganglioside build up to toxic levels in neurons leading to progressive neurodegenerative symptoms. The infantile form is the most common; presenting around six months of age, characterised by hyperekplexia (enhanced startle response) especially to sound, macrocephaly, hypertonia and hyperreflexia with gradual loss of skills and seizures by the age of two, and early death usually by the age of five. >90% can have bilateral macular cherry-red spot present.
Metachromatic leukodystrophy
Metachromatic leukodystrophy results from white matter accumulation of sphingolipid that leads to demyelination and neurodegeneration. The infantile form is the most common presenting with developmental delay, seizures, ataxia and mixed upper and lower motor neuron signs due to peripheral neuropathy resulting in reduced/absent deep tendon reflexes. MRI changes are seen later on with frontal and periventricular confluent white matter T2 hyperintensity.
Fabry disease
Fabry disease is an X-linked recessive condition due to deficiency in α- galactosidase A. Disease onset by 10 years of age is often seen with initial manifestations including neuropathic pain, hyophydrosis, reduced exercise tolerance and fever of unknown cause. Angiokeratomas often develop in the second decade of life. By third decade of life, ischaemic cardiovascular and renal complications can be seen.
Achondroplasia
Achondroplasia is the most common skeletal dysplasia resulting in disproportionate small stature. Affected individuals have short arms and legs, a large head, and characteristic facial features with frontal bossing and midface retrusion.
The long bones usually are of normal length in the second trimester and usually don’t appear disproportionately short until the third trimester. Therefore, the routine morphology ultrasound in the second trimester does not exclude this diagnosis
The c.1138G>A (p.Gly380Arg) variant in the FGFR3 gene is the cause in ~98% of individuals. However, genetic testing is not indicated without a radiological diagnosis and is likely to take several weeks for a result. It is not the first investigation to arrange at this stage.
Approximately 80% of individuals with achondroplasia have normal statured parents and it is a de novo (new) event.
A skeletal survey is characteristic and diagnostic and is the first investigation indicated in confirming a diagnosis.
Specific management concerns in a neonate with achondroplasia, including protection of the newborn cervical spine due to increased risks c-spine instability and stenosis. It is not wise to wait for further investigations until follow-up in 6 weeks.
An infant with renal hypoplasia and ocular abnormality is found to have mutation of the CHD7 gene.
CHARGE = Coloboma, Heart defects, choanal Atresia, Retarded growth, GU defects, Ear anomalies – caused by mutations of CHD7 on chromosome 8q12. The combination of renal hypoplasia and coloboma could be caused by CHARGE or Renal-coloboma. You need to know that CHARGE is caused by CHD7 mutation
A 16-year-old girl presents with primary amenorrhoea. On examination, she appears normal. An USS reveals renal agenesis and vaginal agenesis
Turner syndrome can present with primary amenorrhoea and renal abnormalities are common. However, you would expect the patient to be short and you would not expect vaginal agenesis. This scenario describes Mayer-Rokitansky-Kuster-Hauser syndrome – also known as vaginal agenesis or Mullerian agenesis. The cause is unknown and up to 50% will have associated renal abnormalities.
An infant with joint laxity, ocular abnormality and renal hypoplasia is found to have mutations in the PAX2 gene.
Renal-coloboma syndrome is associated with mutations in the PAX2 gene. It is an autosomal disorder associated with coloboma, renal abnormalities, SNHL, seizures and joint laxity. Marfan syndrome is associated with joint laxity and ocular abnormalities – specifically ectopia lentis – but is not usually associated with renal abnormalities
What is the most common cause of Prader-Willi syndrome?
Prader-Willi syndrome is caused by loss/abnormal methylation of the paternal allele of chromosome 15q11.2q13.
A deletion of the paternal allele accounts for 65-75% of cases. Maternal UPD 20-30%, imprinting defect 5%, gene mutation 0.1% and balanced translocation 0.1%.
Lesch-Nyhan disease
a rare X-linked disorder of purine metabolism that results from hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, resulting in excess uric acid production. This enzyme is normally present in each cell in the body, but its highest concentration is in the brain, especially in the basal ganglia.
Manifestations include hyperuricemia, mental retardation, cerebral palsy with early choreoathetosis and later spasticity and dystonia, dysarthric speech, and compulsive self-biting, usually beginning with the eruption of teeth. Classic LNS corresponds to low or undetectable levels of the HPRT enzyme.
At birth, infants with LNS have no apparent neurologic dysfunction. After several months, developmental retardation and neurologic signs become apparent. Hypotonia, recurrent vomiting, and difficulty with secretions may be noted. By 8-12 months, extrapyramidal signs appear, including chorea and dystonia.. By 12 months, pyramidal tract signs may become evident with hyperreflexia, sustained ankle clonus, positive Babinski sign, and scissoring. Spasticity may become apparent at this time or, in some instances, later in life. Up to this point children have often been diagnosed as having choreoathetoid CP. Cognitive function is usually reported to be in the mild-to-moderate range of delay.
Self-injury may occur as early as 1 year. The self-injurious behavior usually begins with self-biting, although other patterns of self-injurious behavior emerge with time. Most characteristically, the fingers, mouth, and buccal mucosa are mutilated.
