Genetic Disorders
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Direct answer
Genetic disorders arise from single-gene defects, chromosomal aneuploidies, trinucleotide repeat expansions, imprinting abnormalities or mitochondrial mutations. FMGE rewards pattern recognition: Down syndrome's facies and cardiac defects, Turner versus Klinefelter cytogenetics, the repeat-expansion diseases and the lysosomal storage disorders with their missing enzymes and hallmark cells. Autosomal dominant traits usually involve structural proteins, recessive traits enzymes, and X-linked recessive traits classically affect boys.
What you must remember
- Trisomy 21: flat nasal bridge, epicanthic folds, Brushfield spots, single palmar crease, endocardial cushion defects, duodenal atresia and leukaemia risk. Trisomy 18 shows clenched overlapping fingers and rocker-bottom feet; trisomy 13 shows cleft palate, polydactyly and holoprosencephaly.
- Sex chromosomes: Klinefelter (47,XXY) — tall eunuchoid male, gynaecomastia, small testes, Barr body positive; Turner (45,X) — short female, webbed neck, aortic coarctation, streak gonades, Barr body negative.
- Autosomal dominant: Marfan (fibrillin-1, lens subluxation upward, aortic root dilatation), achondroplasia (FGFR3), neurofibromatosis type 1 (chromosome 17), adult polycystic kidney disease.
- X-linked recessive: Duchenne muscular dystrophy (dystrophin, calf pseudohypertrophy, high creatine kinase), haemophilia, G6PD deficiency. Mitochondrial (maternal): MELAS, Leber optic neuropathy.
- Repeat expansions: fragile X (CGG, FMR1 — most common inherited intellectual disability in boys, large ears, macro-orchidism), Huntington (CAG), myotonic dystrophy (CTG), Friedreich ataxia (GAA).
- Storage diseases: Gaucher (glucocerebrosidase, crumpled tissue-paper macrophages), Niemann-Pick (sphingomyelinase, foam cells), Tay-Sachs (hexosaminidase A, cherry-red spot without organomegaly), Fabry (alpha-galactosidase A). Hurler (MPS I) clouds corneas; Hunter (MPS II) is X-linked with clear corneas.
- Imprinting at 15q11-13: paternal deletion gives Prader-Willi (hypotonia, hyperphagia, obesity); maternal deletion gives Angelman (happy puppet, seizures).
Common confusion
Prader-Willi versus Angelman is the top imprinting pair — one deletion, opposite parental origin, opposite syndromes. Niemann-Pick versus Tay-Sachs: both have cherry-red spots, but Tay-Sachs spares liver and spleen while Niemann-Pick causes hepatosplenomegaly. Also keep von Gierke (glucose-6-phosphatase, fasting hypoglycaemia with hepatomegaly) apart from McArdle (muscle phosphorylase, exercise cramps).
Exam-focused takeaway
FMGE gives a buzzword or karyotype and expects the syndrome: Brushfield spots, an adolescent with eunuchoid features and 47,XXY, a boy with macro-orchidism and a fragile site. Learn each disorder as inheritance pattern plus defective protein plus one hallmark; read cytogenetic notation in seconds.
Frequently asked questions
What distinguishes Prader-Willi from Angelman syndrome?
Loss of the paternal 15q11-13 segment causes Prader-Willi with hypotonia and hyperphagia; loss of the maternal segment causes Angelman with seizures and puppet-like laughter. Both illustrate genomic imprinting.
Which syndrome shows Brushfield spots?
Down syndrome, with epicanthic folds and a single palmar crease; atrioventricular septal defects and duodenal atresia are the classic associations.
Which enzyme is deficient in Tay-Sachs disease?
Hexosaminidase A, causing GM2 ganglioside accumulation, a cherry-red macular spot and neurodegeneration without hepatosplenomegaly. It is commoner in Ashkenazi populations.
Why is Duchenne dystrophy X-linked recessive?
The dystrophin gene lies on the X chromosome, so boys lack dystrophin, giving calf pseudohypertrophy, proximal weakness and grossly raised creatine kinase. Carrier mothers may show mild enzyme rises.
Name a mitochondrial inheritance disorder.
MELAS — mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes — passes from mothers to all children through mitochondrial DNA.
What is defective in Hurler syndrome?
Alpha-L-iduronidase (MPS I), causing coarse facies, corneal clouding, intellectual disability and hepatosplenomegaly. Hunter syndrome is X-linked and spares the cornea.