Genetic Disorders

INTRODUCTION

Genetic testing is now available for many common hereditary disorders, such as the HFE genes for haemochromatosis. Presymptomatic DNA tests are available for the hereditary neurological disorders, such as Huntington disease, and predictive DNA testing is available for some forms of hereditary cancer, such as breast and colon cancer, and in the future for cardiovascular disease and diabetes.

Carrier screening The presence of common mutations in severe recessive (autosomal and X-linked) disorders means that carrier screening in a community can be performed.

The disorders for which this commonly occurs are: thalassaemia, Tay–Sachs disease, cystic fibrosis

• The reproductive triple carrier screening test is for cystic fibrosis, fragile X syndrome and spinal muscular atrophy

• The non-invasive prenatal test on pregnant mothers is an aneuploidy test for 21 Down syndrome, 18 Edward syndrome and 13 Patau syndrome

• Newborn screening can test for 25 or more conditions including phenylketonuria, galactosaemia, hypothyroidism

SPECIFIC IMPORTANT GENETIC DISORDERS

• Haemochromatosis: an autosomal recessive (AR) disorder ( 277)

• Thalassaemia: AR ( 29)

• Cystic fibrosis: AR ( 181)

• Congenital adrenal hyperplasia (AR)

• Neurofibromatosis: AD two types:

  • – NF2—peripheral type (von Recklinghausen disorder) light-brown skin patches + skin tumours + axillary freckles

  • – NF2—central type, bilateral acoustic neuromas

  • – No specific treatment: refer to a neurofibroma clinic

• Duchenne muscular dystrophy:

  • – X-linked recessive condition

  • – DxT: male child + gait disorder + bulky calves

  • – most are wheelchair bound by 10–12 yrs

  • – most die of respiratory problems by age 20

• Glucose-6-phosphate dehydrogenase deficiency (favism)

  • – neonatal jaundice (check those at risk)

  • – most symptomless

  • – episodic acute haemolytic anaemia triggered by antioxidants, infections, some drugs and fava bean

• Galactosaemia

  • – autosomal recessive disorder (1/60 000 births)

  • – inability to metabolise galactose to glucose

  • – infants become anorexic and jaundiced with milk

  • – management is lactose-free formula, e.g. soy

• Familial hyperlipoproteinaemia

  • – familial hypercholesterolaemia

  • – familial combined hyperlipidaemia

  • – homozygous patients → atherosclerotic disease in childhood

  • – heterozygous patients manifest in 30s or 40s

• Spinal muscular atrophy

  • – autosomal recessive disorder (1 in 6000 births) : carriers 1 in 40

  • – at least 4 types with SMAI rarely living >2 years

  • – affects motor neurones causing atrophy of muscles

  • – no cure at present and treatment is supportive

  • – claimed to be the leading cause of infant death

INHERITED ADULT-ONSET NEUROLOGICAL DISORDERS

• Huntington disease: autosomal dominant (AD)

  • – DxT: chorea + abnormal behaviour + dementia + family history

  • – onset usually 35–55 yrs

  • – usually fatal outcome 15–20 yrs

  • – offspring have 1 in 2 risk

  • – no current cure or specific treatment

• Creutzfeldt–Jakob disease and other prion diseases

• Familial Alzheimer disease: 2 forms—early-onset <65 yrs and late

• Familial epilepsy

• Familial motor neurone disease

• Muscular dystrophies and myotonic dystrophy

• Friedreich ataxia

• Mitochondrial disorders: includes MELAS syndrome (encephalopathy, lactic acidosis, stroke)

• Others

MENTAL HEALTH ...