Chromosome and genetic disease

Mnemonics
Marfan's syndrome : chromosome 15 (15 alphabates)
APKD 1 (Polycystic kidney) : chromosome 16 (16 alphabates)
Neurofibromatosis 1 / Von Recklinghausen : chromosome 17 (17 alphabates)

Note: The above are all autosomal dominant

PKD 2 : chromosome 4
NF type 2 : chromosome 22
Cystic fibrosis : chromosome 7
Haemochromatosis : chromosome 6
Huntington's disease : chromosome 4
Wilson's disease : chromosome 13

Ethnic group and genetic disease

Chinese : G6PD deficiency
Northern Europeans : cystic fibrosis
Ashkenazi Jews : Tay Sachs disease, Gaucher disease
Africans : sickle cell disease, thalassemia
Sephardic Jews and Armenians : Familial Mediterranean fever
Scandinavians : AAT, LCAT deficiency
Eskimos : CAH, pseudocholinesterase deficiency
Mediterranean race : thalassemia. G6PD deficency, FMF

Mitochondrial myopathies

- mitochondrial diseases are maternally inherited

Chronic progressive external ophthalmoplegia (CPEO)
- slowly progressive paralysis of extraocular muscles
- bilateral, symmetrical, progressive ptosis followed by ophthalmoparesis months to years later

Leber's hereditary optic neuropathy (LHON)
- characterised by blindness, ataxia, peipheral neuropathy and cardiac arrhythmias
- usually affects men, most commonly in the late twenties or early thirties
- commonest cause of blindness in young men

MELAS (myopathy, encephalopathy, lactic acidosis and stroke like episodes)
- lactic acidosis: high lactate to pyruvate ratio
- proximal myopathy, hypotonia, seizure and sttoke like episodes

MERRF (myoclonic epilepsy, ragged red fibres)
- myoclonic seizure that are usually sudden, brief, jerking spasm that can affect the limbs or the entire body
- short stature, deafness, ataxia, dysarthria, optic atrophy, dementia and nystagmus can occur

Kearns-Sayre syndrome
- ophthalmoplegia, heart block, cerebellar ataxia, deafness and mental deficiency

Pearson syndrome
- lactic acidosis, pancreatic insufficiency and pancytopenia

Wolfram syndrome

- DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deafness)
- autosomal recessive
- mutation in transmembrane gene, WFS1

Kallman's syndrome

- isolated GnRH deficiency
- X-linked, resulting from mutation of KAL1 gene which encodes anosmin-1
- occurs in 1:10,000 males
- results form disordered migration of gonadotrophin releasing hormone (GnRH) producing neurones into hypothalamus
- associated with anosmia, cleft palate, colour blindness, obesity, hypogonadotrophic hypogonadism
- treatment: male - hCG or testosterone restore pubertal development and secondary sexual characteristic. pulsed GnRH restore fertility ; female - cyclic estrogen and progesterone

Marfan's syndrome

- autosomal dominant
- mutation in fibrillin gene (FBN-1) on chromosome 15 (15 alphabates in Marfan's syndrome)
- abnormal fibrillin-1 interfere with normal microfibril formation, results in defects in ligament of lens, as well as abnormalities in structural integrity of aortic wall, lens zonules, ligaments, lung airways and spinal dura
- clinical features: tall stature, ectopia lentis, MVP, aortic root dilatation, aortic dissection, scoliosis, high arched palate, pectus excavatum, upward and temporal lens dislocation (downward in homocystinuria)
- treatment: beta-blocker (slow rate of dilatation of aortic root), lifestyle alteration, yearly echocardiogram

Mitochondrial inheritance

- maternal in origin
- both sexes can be affected

Examples
- Leber's optic atrophy
- MELAS (mitochondrial encephalopathy + lactic acidosis + stroke)
- MERRF (myoclonic epilepsy with ragged red fibre)
- Kearns-Sayre syndrome (oculocraniosomatic disease)
- progressive external ophthalmoplegia
- Pearson syndrome (lactic acidosis + pancreatic insufficiency + pancytopenia)
- some deafness
- some familial diabetes mellitus

von Hippel Lindau disease

- autosomal dominant
- mutation in VHL gene (chromosome 3)
- features
   - cerebellar, brainstem and spinal hemangioblastoma
   - retinal angioma
   - phaeochromocytoma / paraganglioma
   - clear cell renal cell carcinoma (most common cause of death)
- genetic testing (VHL gene analysis) in affected families should take place around 5 years of age
- affected individual requires yearly urinalysis, catecholamine screening, fluorescein angiography and 3 yearly brain MRI screening

Klinefelter syndrome

- 47 XXY
- most common chromosomal disorder associated with male hypogonadism and infertility
- poor sexual development, small or undescended testes, scanty pubic hair, gynaecomastia and infertility
- testes are firm due to fibrosis and hyalinisation of seminiferous tubules
- involves loss of Leydig cell and seminiferous tubular dysgenesis
- associated with increased risk of male breast cancer
- low serum testosterone, high serum FSH & LH (primary hypogonadism)
- diagnosis: chromosomal analysis

Fragile X syndrome

- a.k.a Martin-Bell syndrome
- X-linked recessive
- trinucleotide repeat disorder (in FMR 1 gene)   - genetic anticipation
- most common cause of inherited intellectual disability
- second most common known cause of mental retardation in males
- expansion of CGG on X-chromosome

• 6-55 : normal
• 55-230 : premutation carrier
• 230->1000 : disease state / full mutation

- features: elongated face, prognathism, macroorchidism, large low set floppy ear, short stature, hyperflexible joints, high arched palate, ADHD, autism