Clinical Genetics: Single-gene, repeat-expansion and mitochondrial disorders

🧬 Single-gene, repeat-expansion and mitochondrial disorders - page 4 of the Clinical Genetics chapter. Individually rare, single-gene disorders together affect millions of people in the UK - and treatment is changing fast: CFTR modulators for cystic fibrosis, gene therapy for spinal muscular atrophy and haemophilia, and gene editing for sickle cell disease. This page covers the conditions that appear most in clinical practice and exams, with the clues that point to each.
Your four questions for every single-gene disorder: What is the gene and inheritance pattern? What are the cardinal features and complications? Is there a specific treatment (including new gene-based therapies)? Who in the family should be offered testing?

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Cystic Fibrosis

• Autosomal recessive - CFTR gene (chromosome 7) - a chloride channel; about 1 in 2,500 births in the UK; carrier frequency about 1 in 25 in white Northern Europeans.
• Commonest variant - F508del (present on at least one allele in about 90% of UK patients).
• Diagnosis - newborn blood spot screening (immunoreactive trypsinogen, then DNA testing) → sweat test (chloride 60 mmol/L or more is diagnostic); some present later (adults with bronchiectasis, male infertility, pancreatitis).
• Features:
  • Lungs - thick mucus, recurrent infection (Staphylococcus aureus, Haemophilus, Pseudomonas aeruginosa, Burkholderia cepacia complex, non-tuberculous mycobacteria), bronchiectasis, ABPA, haemoptysis, pneumothorax, respiratory failure.
  • GI - meconium ileus in newborns, pancreatic insufficiency (steatorrhoea, failure to thrive, fat-soluble vitamin deficiency), distal intestinal obstruction syndrome, CF-related liver disease, gallstones.
  • Endocrine - CF-related diabetes (annual screening from age 10), osteoporosis.
  • Fertility - congenital bilateral absence of the vas deferens (almost all men - infertile but sperm production normal - surgical sperm retrieval with ICSI); women reduced fertility.
  • Other - nasal polyps, sinusitis, finger clubbing, salt loss in heat.
• Treatment - specialist CF centres; airway clearance physiotherapy; nebulised dornase alfa and hypertonic saline; antibiotics (inhaled tobramycin or colistin for Pseudomonas); pancreatic enzyme replacement and high-calorie diet with vitamins A, D, E, K; CFTR modulators - elexacaftor/tezacaftor/ivacaftor (Kaftrio) for people with at least one F508del variant - large improvements in lung function and survival; lung transplant for end-stage disease.
• Infection control - people with CF should not meet each other (cross-infection risk).
• Median predicted survival now over 50 years and rising with modulators.

Sickle Cell Disease and Thalassaemia

• Autosomal recessive haemoglobinopathies - the commonest serious genetic disorders worldwide; more common in people of African, Caribbean, Mediterranean, Middle Eastern and South Asian ancestry.
• Sickle cell disease:
  • HBB missense variant (HbS - glutamic acid to valine at position 6); HbSS (sickle cell anaemia - most severe), HbSC, HbS/beta-thalassaemia.
  • Sickle cell trait (HbAS) - carriers, usually healthy (protects against malaria); rare complications - haematuria, renal medullary carcinoma, exertional rhabdomyolysis.
  • Features - vaso-occlusive pain crises, acute chest syndrome, stroke (transcranial Doppler screening in children), splenic sequestration and hyposplenism (pneumococcal infection - penicillin prophylaxis and vaccines), aplastic crisis (parvovirus B19), priapism, avascular necrosis of the hip, leg ulcers, retinopathy, nephropathy, pulmonary hypertension, gallstones.
  • Treatment - analgesia within 30 minutes for crises (NICE CG143), fluids, oxygen if hypoxic; hydroxycarbamide (raises HbF); transfusion and exchange transfusion; crizanlizumab (withdrawn in the UK); stem cell transplant; gene therapy - exagamglogene autotemcel (Casgevy - CRISPR gene editing) approved for selected patients.
• Beta-thalassaemia - reduced or absent beta-globin:
  • Trait (minor) - mild microcytic anaemia with raised HbA2; normal ferritin (don't mistake for iron deficiency).
  • Major - severe anaemia from 3–6 months, hepatosplenomegaly, bone expansion (frontal bossing) - lifelong transfusions and iron chelation (desferrioxamine, deferasirox, deferiprone); stem cell transplant; gene therapy (Casgevy also approved for transfusion-dependent thalassaemia).
• Alpha-thalassaemia - deletions of alpha-globin genes (4 genes): 1–2 deleted - trait; 3 - HbH disease; 4 - Hb Barts hydrops fetalis (fatal in utero without intrauterine transfusion).
• Screening - newborn blood spot (sickle cell) and the antenatal sickle cell and thalassaemia screening programme (see page 6).

Hereditary Haemochromatosis

• Autosomal recessive - HFE gene; C282Y homozygosity in about 1 in 150–200 people of Northern European (especially Celtic) descent; C282Y/H63D compound heterozygotes rarely develop significant iron overload.
• Reduced penetrance - many homozygotes never develop disease; men present earlier (women are protected by menstruation and pregnancy until menopause).
• Features - fatigue, arthropathy (especially second and third MCP joints - "iron fist"), erectile dysfunction, skin bronzing, abnormal LFTs, cirrhosis and hepatocellular carcinoma, diabetes ("bronze diabetes"), cardiomyopathy, hypogonadism.
• Tests - transferrin saturation (over 50% in men, over 45% in women - earliest marker) and ferritin (raised - but also raised in inflammation, alcohol, fatty liver, obesity); HFE genotyping; LFTs; liver MRI (iron quantification) or FibroScan; liver biopsy rarely.
• Treatment - venesection (about 450–500 mL weekly initially) until ferritin under 50 micrograms/L, then maintenance (ferritin 50–100); avoid iron and vitamin C supplements; moderate alcohol; HCC surveillance with ultrasound if cirrhosis.
• Prognosis - normal life expectancy if treated before cirrhosis or diabetes develops.
• Family - offer testing to first-degree relatives (siblings have a 1 in 4 risk of being homozygous).

Spinal Muscular Atrophy

• Autosomal recessive - homozygous deletion of SMN1 (chromosome 5); about 1 in 10,000 births; carrier frequency about 1 in 50.
• Degeneration of anterior horn cells - symmetrical proximal weakness, hypotonia, absent reflexes, tongue fasciculations; sensation and intellect normal.
• Severity depends on the number of copies of the backup gene SMN2 (more copies - milder):
  • Type 1 (Werdnig–Hoffmann) - onset under 6 months; never sits; "frog-leg" posture; respiratory failure - fatal by age 2 without treatment.
  • Type 2 - onset 6–18 months; sits but never walks.
  • Type 3 - walks, then loses ability; type 4 - adult onset, mild.
• Treatment - nusinersen (intrathecal antisense oligonucleotide), risdiplam (oral SMN2 splicing modifier), onasemnogene abeparvovec (Zolgensma - one-off IV gene therapy) - best results when given before symptoms.
• Newborn screening for SMA is being piloted and evaluated in the UK because early treatment changes outcome.
• Supportive - respiratory support, nutrition, scoliosis management.

Inborn Errors of Metabolism

• Mostly autosomal recessive enzyme defects; may present in newborns with poor feeding, vomiting, lethargy, seizures, hypoglycaemia, metabolic acidosis or hyperammonaemia after initially being well ("sepsis-like" presentation).
• Emergency tests in an unwell baby - glucose, blood gas, lactate, ammonia, ketones, plasma amino acids, acylcarnitines, urine organic acids - take samples during the acute illness.
• Key examples:
  • Phenylketonuria - phenylalanine hydroxylase deficiency - learning disability, seizures, fair skin, musty odour if untreated; newborn screening; low-phenylalanine diet for life; strict control before and during pregnancy (maternal PKU causes fetal damage).
  • MCADD (medium-chain acyl-CoA dehydrogenase deficiency) - hypoketotic hypoglycaemia with fasting or illness; sudden death; newborn screening; avoid fasting; emergency regimen (glucose drinks, IV 10% glucose).
  • Urea cycle disorders (e.g. ornithine transcarbamylase deficiency - X-linked) - hyperammonaemia, encephalopathy, respiratory alkalosis.
  • Galactosaemia - vomiting, jaundice, liver failure, E. coli sepsis and cataracts after milk feeds - lactose-free diet.
  • Lysosomal storage disorders - Gaucher (hepatosplenomegaly, bone pain, cytopenias), Fabry (X-linked - painful neuropathy, angiokeratomas, kidney and heart disease, stroke), Pompe, mucopolysaccharidoses (Hurler, Hunter) - enzyme replacement therapy for several.
  • Wilson's disease (ATP7B) - liver disease, neuropsychiatric features, Kayser–Fleischer rings, low caeruloplasmin - chelation (penicillamine, trientine) or zinc.
  • Homocystinuria - marfanoid build, downward lens dislocation, learning disability, thrombosis.

Duchenne and Becker Muscular Dystrophy

• X-linked recessive - dystrophin (DMD) gene at Xp21 - one of the largest human genes; about one third of cases are de novo.
• Duchenne muscular dystrophy - about 1 in 3,500–5,000 boys; frameshift variants (usually exon deletions) - absent dystrophin.
  • Presentation - delayed walking, frequent falls, difficulty climbing stairs and running (age 2–5), Gowers' sign (using hands to climb up legs to stand), calf pseudohypertrophy, waddling gait, toe walking; learning and behaviour difficulties in some.
  • Tests - very high CK (often 10–100 times normal) - a simple first test in any boy with delayed walking; then MLPA for exon deletions or duplications, then sequencing.
  • Course - loss of walking around age 10–12 (later with steroids); scoliosis; cardiomyopathy; respiratory failure; death typically in the 20s–30s (improving with ventilation and cardiac care).
  • Treatment - corticosteroids (prednisolone, deflazacort, vamorolone) prolong walking; ACE inhibitors and cardiac monitoring; non-invasive ventilation; spinal surgery; exon-skipping drugs and gene therapies (availability varies - specialist).
• Becker muscular dystrophy - in-frame variants - reduced or abnormal dystrophin - later onset (teens or adulthood), milder, walking into adulthood; cardiomyopathy may be severe.
• Female carriers - usually well; some develop weakness or dilated cardiomyopathy - offer cardiac surveillance.
• Anaesthesia - avoid suxamethonium and volatile agents (hyperkalaemia, rhabdomyolysis).

Haemophilia and Other X-linked Conditions

• Haemophilia A (factor VIII deficiency - F8; about 1 in 5,000 males) and haemophilia B (factor IX - F9; Christmas disease) - X-linked recessive; about one third de novo.
  • Features - haemarthrosis (knees, elbows, ankles - chronic arthropathy), muscle haematomas, bleeding after circumcision, dental extraction or surgery, intracranial haemorrhage.
  • Tests - prolonged APTT, normal PT and platelets; low factor VIII or IX; severity by factor level (severe under 1%).
  • Treatment - factor concentrates (prophylaxis), emicizumab (subcutaneous bispecific antibody - haemophilia A), gene therapy (approved for selected adults with haemophilia A and B); avoid IM injections and NSAIDs; inhibitor development is a key complication.
  • Carrier women may have low factor levels and bleed - check levels before surgery or delivery.
• G6PD deficiency - X-linked; common in African, Mediterranean, Middle Eastern and Asian ancestry - acute haemolysis with oxidant triggers - fava beans, infection, drugs (primaquine, dapsone, rasburicase, nitrofurantoin, sulfonamides, high-dose aspirin); bite cells and Heinz bodies; check G6PD before primaquine or rasburicase.
• Fabry disease - alpha-galactosidase A deficiency - neuropathic pain in hands and feet, angiokeratomas, hypohidrosis, proteinuria and CKD, LVH, stroke in young adults; females often affected; enzyme replacement or migalastat.
• Other X-linked - X-linked agammaglobulinaemia (Bruton's - recurrent bacterial infections after 6 months, absent B cells), Wiskott–Aldrich syndrome (eczema, thrombocytopenia with small platelets, infections), Lesch–Nyhan syndrome (HPRT - self-mutilation, gout), Kennedy disease, X-linked adrenoleukodystrophy (adrenal insufficiency and neurological decline in boys).

Huntington's Disease

• Autosomal dominant - CAG repeat expansion in HTT (huntingtin) on chromosome 4.
  • Under 27 - normal; 27–35 - intermediate (not affected, but may expand in children - especially through the father); 36–39 - reduced penetrance; 40 or more - full penetrance.
  • Anticipation - longer repeats cause earlier onset; large expansions mainly through the father (juvenile HD - onset under 20, rigidity, seizures).
• Onset usually age 30–50; progresses over 15–20 years.
• Features (triad):
  • Movement - chorea, impaired saccades, dysarthria, dysphagia, gait disturbance, later rigidity and dystonia.
  • Cognitive - executive dysfunction progressing to dementia.
  • Psychiatric - depression, irritability, apathy, obsessive-compulsive behaviour, psychosis; suicide risk is high (especially around diagnosis).
• Imaging - caudate atrophy on MRI.
• Treatment - no disease-modifying treatment yet (gene-lowering therapies are in trials); tetrabenazine or antipsychotics for chorea; SSRIs for depression; speech and language therapy (swallowing), dietetics (weight loss is common), physiotherapy; multidisciplinary specialist clinic; advance care planning while capacity remains.
• Predictive testing - structured counselling protocol (see page 2); driving (DVLA), insurance (see page 6), family planning (PGT-M, exclusion testing).

Myotonic Dystrophy

• The commonest adult muscular dystrophy - autosomal dominant.
• Type 1 (DM1) - CTG repeat expansion in DMPK (chromosome 19); anticipation - large expansions through the mother cause congenital myotonic dystrophy (severe neonatal hypotonia, respiratory failure, feeding difficulties, talipes, learning disability).
• Type 2 (DM2) - CCTG repeat in CNBP - proximal weakness, milder, no congenital form.
• Features of DM1:
  • Myotonia - slow relaxation after grip ("can't let go" of a handshake), percussion myotonia of the thenar eminence.
  • Weakness and wasting - face (long thin "hatchet" face, ptosis), temporalis, sternocleidomastoids, distal limbs; frontal balding.
  • Eyes - early cataracts (often the first sign in mildly affected relatives - "Christmas tree" cataracts).
  • Heart - conduction defects and arrhythmias (heart block, AF, VT) - sudden death - annual ECG; pacemaker or ICD.
  • Endocrine - insulin resistance and diabetes, testicular atrophy, hypothyroidism.
  • Other - hypersomnolence, apathy, dysphagia, constipation, gallstones, respiratory weakness, anaesthetic risk (sensitivity to sedatives and opioids, respiratory failure).
• Diagnosis - repeat expansion testing; EMG ("dive bomber" myotonic discharges) if unclear.
• Management - annual ECG; cardiology; mexiletine for troublesome myotonia (cardiac review first); cataract surgery; glucose; sleep; alert card for anaesthesia.

⚠️ Safety Pearl: In myotonic dystrophy, the heart and the anaesthetic kill. Arrange an annual ECG and a low threshold for cardiology review, and warn anaesthetists - people with DM1 are very sensitive to sedatives, opioids and neuromuscular blockers.

Fragile X Syndrome and Premutation Disorders

• The commonest inherited cause of learning disability - CGG repeat expansion in FMR1 (Xq27.3); about 1 in 4,000 males and 1 in 8,000 females affected.
• Repeat sizes - normal under 45; intermediate 45–54; premutation 55–200; full mutation over 200 (gene silenced by methylation).
• Expansion from premutation to full mutation happens only through the mother.
• Fragile X syndrome (full mutation):
  • Males - moderate learning disability, autism features (gaze avoidance, hand-flapping), ADHD, anxiety; long face, large prominent ears, prominent jaw, macro-orchidism after puberty, joint hypermobility, mitral valve prolapse, seizures.
  • Females - milder and variable (X-inactivation) - learning difficulties, anxiety, shyness.
• Premutation carriers:
  • FXPOI (fragile X-associated primary ovarian insufficiency) - about 20% of female carriers - early menopause (under 40).
  • FXTAS (fragile X-associated tremor/ataxia syndrome) - mainly older male carriers (over 50) - intention tremor, cerebellar ataxia, parkinsonism, cognitive decline; MRI - middle cerebellar peduncle hyperintensity.
  • FXAND - anxiety and mood disorders.
• Testing - FMR1 repeat test (PCR and Southern blot); not detected by microarray or standard exome - request specifically in any child with unexplained learning disability or autism.
• Family - a single diagnosis can reveal premutation carriers across three generations - clinical genetics referral and cascade testing.

Friedreich's Ataxia and Other Repeat Disorders

• Friedreich's ataxia - the commonest inherited ataxia; autosomal recessive - GAA repeat expansion in FXN (frataxin).
  • Onset usually under 25 - progressive limb and gait ataxia, dysarthria, absent ankle and knee reflexes with extensor plantars, loss of joint position and vibration sense, pes cavus, scoliosis.
  • Hypertrophic cardiomyopathy (commonest cause of death), diabetes, optic atrophy, hearing loss.
  • Treatment - omaveloxolone (first approved disease-modifying drug - check UK availability), physiotherapy, cardiac and diabetes care.
• Spinocerebellar ataxias - autosomal dominant CAG repeats (SCA1, 2, 3, 6, 7) - adult-onset progressive ataxia with anticipation.
• C9orf72 - hexanucleotide (GGGGCC) repeat - the commonest genetic cause of motor neurone disease and frontotemporal dementia (often both in the same family) - autosomal dominant.
• Kennedy disease (spinobulbar muscular atrophy) - X-linked CAG repeat in the androgen receptor - bulbar and limb weakness, fasciculations, gynaecomastia, reduced fertility in men.
• CANVAS (RFC1 repeat - recessive) - cerebellar ataxia, neuropathy, vestibular areflexia, chronic cough.

Neurofibromatosis and Tuberous Sclerosis

• Neurofibromatosis type 1 - autosomal dominant - NF1 (neurofibromin, chromosome 17) - about 1 in 2,500–3,000; half de novo; very variable expressivity.
  • Diagnostic features - 6 or more café-au-lait macules (over 5 mm before puberty, over 15 mm after), axillary or inguinal freckling, 2 or more neurofibromas or one plexiform neurofibroma, Lisch nodules (iris hamartomas), optic pathway glioma, bony lesions (sphenoid wing dysplasia, tibial bowing), a first-degree relative.
  • Complications - learning difficulties and ADHD, scoliosis, hypertension (renal artery stenosis, phaeochromocytoma), malignant peripheral nerve sheath tumour (painful, enlarging plexiform neurofibroma - urgent assessment), GIST, breast cancer (enhanced screening from 40), glioma.
  • Treatment - selumetinib (MEK inhibitor) for inoperable symptomatic plexiform neurofibromas in children; annual review with BP.
• NF2-related schwannomatosis (formerly neurofibromatosis type 2) - NF2 (merlin, chromosome 22) - bilateral vestibular schwannomas (hearing loss, tinnitus, imbalance), meningiomas, spinal ependymomas, juvenile cataracts; MRI surveillance; bevacizumab can shrink schwannomas.
• Tuberous sclerosis complex - autosomal dominant - TSC1 (hamartin) or TSC2 (tuberin) - mTOR overactivity.
  • Skin - ash leaf macules (hypomelanotic - Wood's lamp), facial angiofibromas (adenoma sebaceum), shagreen patch, ungual fibromas, forehead plaque.
  • Brain - cortical tubers, subependymal nodules, subependymal giant cell astrocytoma; infantile spasms (vigabatrin first line), epilepsy, learning disability, autism.
  • Other - cardiac rhabdomyomas (often found antenatally - regress), renal angiomyolipomas (bleeding risk), renal cysts, lymphangioleiomyomatosis (LAM - women), retinal hamartomas.
  • Treatment - mTOR inhibitors (everolimus, sirolimus) for SEGA, angiomyolipomas, LAM and refractory seizures; topical sirolimus for angiofibromas.

Marfan Syndrome and Inherited Connective Tissue Disorders

• Marfan syndrome - autosomal dominant - FBN1 (fibrillin-1, chromosome 15) - about 1 in 5,000; a quarter de novo.
  • Cardiovascular - aortic root dilatation and aortic dissection (the main cause of death), mitral valve prolapse.
  • Eye - ectopia lentis (lens dislocation - usually upwards), myopia, retinal detachment.
  • Skeletal - tall, arm span greater than height, arachnodactyly (wrist and thumb signs), pectus excavatum or carinatum, scoliosis, joint hypermobility, high-arched palate, flat feet.
  • Other - spontaneous pneumothorax, striae, dural ectasia.
  • Diagnosis - revised Ghent criteria (aortic root Z-score, ectopia lentis, FBN1 variant, systemic score, family history).
  • Management - regular echo or MRI of the aorta; beta-blockers or ARBs (losartan) to slow dilatation; prophylactic aortic root surgery (typically at 5.0 cm, earlier with risk factors or planning pregnancy); avoid contact sports and heavy isometric exercise; pregnancy is high-risk (dissection); avoid fluoroquinolones (aortic risk - MHRA).
• Loeys–Dietz syndrome (TGFBR1/2, SMAD3) - aggressive aortic and arterial aneurysms and tortuosity, bifid uvula, hypertelorism - earlier surgery.
• Ehlers–Danlos syndromes:
  • Hypermobile EDS - the commonest; clinical diagnosis (no gene identified) - joint hypermobility, pain, subluxations, fatigue.
  • Classical EDS (COL5A1/2) - very stretchy skin, atrophic "cigarette paper" scars, easy bruising.
  • Vascular EDS (COL3A1 - autosomal dominant) - thin translucent skin, easy bruising, characteristic face; arterial rupture, bowel perforation, uterine rupture in pregnancy - often presents with a catastrophic event in young adults; avoid invasive arterial procedures where possible; celiprolol.
• Osteogenesis imperfecta (usually COL1A1/2 - autosomal dominant) - fragile bones with recurrent fractures, blue sclerae, hearing loss, dentinogenesis imperfecta, short stature - IV bisphosphonates; distinguish from non-accidental injury.

Polycystic Kidney Disease and Other Inherited Kidney Disease

• Autosomal dominant polycystic kidney disease (ADPKD) - the commonest inherited kidney disease (about 1 in 1,000) - PKD1 (chromosome 16 - more severe, ESRD around 55) or PKD2 (chromosome 4 - milder, ESRD around 75).
  • Features - bilateral enlarged cystic kidneys, hypertension (early), flank pain, haematuria, UTI and cyst infection, stones, progressive CKD.
  • Extrarenal - liver cysts (commonest), intracranial berry aneurysms (subarachnoid haemorrhage - screen with MR angiography if family history of aneurysm or SAH), mitral valve prolapse, diverticular disease, hernias.
  • Diagnosis - ultrasound (age-related cyst criteria - Ravine/Pei), genetic testing if uncertain or for living donor assessment.
  • Treatment - BP control (ACE inhibitor or ARB - target under 130/80 or tighter in young adults), high water intake, tolvaptan (vasopressin V2 antagonist - slows progression in rapidly progressive disease; LFT monitoring - NICE TA358), dialysis and transplantation.
• Autosomal recessive PKD - presents antenatally or in infancy - large echogenic kidneys, oligohydramnios, lung hypoplasia, congenital hepatic fibrosis.
• Alport syndrome - type IV collagen (mostly X-linked COL4A5) - haematuria, progressive CKD, sensorineural deafness, anterior lenticonus; carrier women may develop CKD; anti-GBM disease can occur after transplant.
• Others - von Hippel–Lindau (renal cysts and clear cell carcinoma - see page 5), tuberous sclerosis (angiomyolipomas), Fabry disease, cystinosis, HNF1B-related disease (renal cysts and diabetes), autosomal dominant tubulointerstitial kidney disease (UMOD - gout).

Hereditary Haemorrhagic Telangiectasia

• Autosomal dominant - ENG (HHT1) or ACVRL1 (HHT2), SMAD4 (HHT with juvenile polyposis); about 1 in 5,000.
• Curaçao criteria - recurrent spontaneous epistaxis, multiple telangiectasia (lips, tongue, fingers, nose), visceral AVMs (lung, liver, brain, GI), a first-degree relative - definite if 3 or more.
• Complications:
  • Pulmonary AVMs - right-to-left shunt - hypoxia, paradoxical embolism - stroke and brain abscess; screen with contrast echocardiography (bubble echo); embolisation; antibiotic prophylaxis for dental procedures.
  • GI bleeding and iron deficiency anaemia - iron, transfusion, tranexamic acid, bevacizumab.
  • Cerebral AVMs (haemorrhage), hepatic AVMs (high-output heart failure).
  • Pregnancy - higher risk (pulmonary AVM bleeding) - screen before or early in pregnancy.
• Epistaxis - humidification, topical treatments, laser, tranexamic acid, septodermoplasty.

Mitochondrial Disease in Practice

• Suspect mitochondrial disease with an unexplained combination of: ptosis and ophthalmoplegia, sensorineural deafness, diabetes, short stature, myopathy and exercise intolerance, cardiomyopathy or conduction block, stroke-like episodes not fitting vascular territories, seizures, ataxia, optic atrophy, raised lactate, maternal family history.
• Key syndromes:
  • MELAS (m.3243A>G) - stroke-like episodes (often occipital), seizures, migraine-like headaches, lactic acidosis; the same variant causes maternally inherited diabetes and deafness.
  • MERRF (m.8344A>G) - myoclonus, epilepsy, ataxia, myopathy with ragged red fibres, lipomas.
  • LHON - subacute painless sequential visual loss in young men (incomplete penetrance; smoking and alcohol increase risk); idebenone.
  • Chronic progressive external ophthalmoplegia and Kearns–Sayre (onset under 20, pigmentary retinopathy, heart block - pacemaker).
  • Leigh syndrome - infantile subacute necrotising encephalopathy.
  • POLG disease (nuclear, recessive) - epilepsy, liver failure - valproate is contraindicated (fatal liver failure).
• Tests - lactate, CK, ECG and echo, glucose, audiometry, MRI brain; genetic testing (blood, urine epithelial cells or muscle - heteroplasmy varies by tissue); muscle biopsy (ragged red fibres, COX-negative fibres) less often now.
• Management - specialist centre (NHS Highly Specialised Service - Newcastle, London, Oxford); treat complications (diabetes, cardiac, hearing aids, cochlear implants); avoid mitochondrial toxins where possible (valproate, aminoglycosides in m.1555A>G); exercise; reproductive options include mitochondrial donation and PGT.

Single-gene Disorders at a Glance

Condition	Gene / inheritance	Key features and treatment
Cystic fibrosis	CFTR - AR	Lung infection, pancreatic insufficiency, CBAVD; sweat test; Kaftrio
Sickle cell disease	HBB - AR	Crises, acute chest, hyposplenism; hydroxycarbamide; gene therapy
Haemochromatosis	HFE C282Y - AR	High transferrin saturation; arthropathy, cirrhosis, diabetes; venesection
SMA	SMN1 - AR	Floppy infant, absent reflexes, tongue fasciculation; nusinersen, risdiplam, Zolgensma
Duchenne	DMD - XLR	Gowers' sign, calf hypertrophy, very high CK; steroids; cardiomyopathy
Haemophilia A / B	F8 / F9 - XLR	Haemarthrosis, prolonged APTT; factor, emicizumab, gene therapy
Huntington's	HTT CAG - AD	Chorea, dementia, psychiatric; paternal anticipation
Myotonic dystrophy 1	DMPK CTG - AD	Myotonia, ptosis, cataracts, heart block; maternal anticipation
Fragile X	FMR1 CGG - X-linked	Learning disability, autism, large ears, macro-orchidism; premutation - FXPOI, FXTAS
Friedreich's ataxia	FXN GAA - AR	Ataxia, absent reflexes, extensor plantars, HCM, diabetes
NF1	NF1 - AD	Café-au-lait, freckling, neurofibromas, Lisch nodules, optic glioma
Tuberous sclerosis	TSC1/2 - AD	Ash leaf macules, angiofibromas, infantile spasms, angiomyolipomas; mTOR inhibitors
Marfan	FBN1 - AD	Aortic root dilatation, upward lens dislocation, tall; beta-blocker or ARB
ADPKD	PKD1/2 - AD	Cysts, hypertension, CKD, berry aneurysms; tolvaptan
HHT	ENG / ACVRL1 - AD	Epistaxis, telangiectasia, pulmonary AVMs (stroke, abscess)

Spot the Diagnosis

Clue	Diagnosis
Newborn with meconium ileus	Cystic fibrosis
Azoospermia with absent vas deferens in a man with sinusitis	Cystic fibrosis (CFTR variants)
Microcytic anaemia, normal ferritin, raised HbA2	Beta-thalassaemia trait
Bilateral MCP arthropathy, diabetes and raised transferrin saturation	Hereditary haemochromatosis
Floppy infant with tongue fasciculation and absent reflexes	Spinal muscular atrophy type 1
Boy of 4 who climbs up his legs to stand; CK 15,000	Duchenne muscular dystrophy
Recurrent knee haemarthrosis with prolonged APTT in a boy	Haemophilia
Haemolysis after primaquine	G6PD deficiency
Burning pain in the hands, angiokeratomas and proteinuria in a young man	Fabry disease
Chorea, depression and a father who died with dementia at 55	Huntington's disease
Can't release a handshake; ptosis, frontal balding and cataracts	Myotonic dystrophy type 1
Grandfather with tremor and ataxia, mother with menopause at 36, grandson with autism	Fragile X family
Teenager with ataxia, absent ankle jerks, extensor plantars and HCM	Friedreich's ataxia
MND and frontotemporal dementia in the same family	C9orf72 repeat expansion
Café-au-lait patches, axillary freckling and iris nodules	Neurofibromatosis type 1
Bilateral vestibular schwannomas at 25	NF2-related schwannomatosis
Infantile spasms and hypopigmented macules under Wood's lamp	Tuberous sclerosis complex
Tall man with an upward-dislocated lens and aortic root 4.8 cm	Marfan syndrome
Young woman with thin skin dies of spontaneous arterial rupture	Vascular Ehlers–Danlos syndrome
Recurrent fractures and blue sclerae in a child	Osteogenesis imperfecta
Hypertension, bilateral flank masses and a family history of SAH	ADPKD
Haematuria and deafness in a young man with CKD	Alport syndrome
Recurrent nosebleeds, lip telangiectasia and a brain abscess	HHT with pulmonary AVM
Diabetes and deafness passed down the maternal line, with stroke-like episodes	MELAS (m.3243A>G)
Liver failure after starting valproate in a child with epilepsy	POLG mitochondrial disease

Exam-style Scenarios

1. A 3-year-old boy is slow to walk, falls often and has big calves. He uses his hands to push up off his thighs when standing.
Answer: Duchenne muscular dystrophy until proven otherwise.

• CK first (massively raised), then MLPA of the DMD gene, then sequencing if negative.
• Refer to a neuromuscular centre - steroids, cardiac and respiratory monitoring, physiotherapy.
• Offer carrier testing to the mother and female relatives; carriers need cardiac assessment.

2. A 45-year-old man has fatigue, joint pain in his hands and erectile dysfunction. ALT 82, ferritin 1,450 micrograms/L, transferrin saturation 78%.
Answer: Hereditary haemochromatosis.

• HFE genotyping (C282Y homozygote expected); assess for liver fibrosis (FibroScan or MRI; biopsy rarely) - ferritin over 1,000 raises cirrhosis risk; glucose, testosterone.
• Weekly venesection until ferritin under 50, then maintenance; HCC surveillance if cirrhosis.
• Offer testing to siblings (1 in 4 risk of homozygosity) and children.

3. A 38-year-old woman has bilateral cataracts and difficulty letting go of objects. Her 2-week-old baby is on the neonatal unit with severe hypotonia and feeding difficulties.
Answer: Myotonic dystrophy type 1 in the mother; congenital myotonic dystrophy in the baby (maternal anticipation).

• DMPK CTG repeat testing.
• Mother - annual ECG and cardiology (conduction disease), glucose, anaesthetic alert.
• Clinical genetics - other relatives at risk; reproductive options.

4. A 22-year-old man has a spontaneous pneumothorax. He is tall with long fingers, pectus excavatum and myopia. His father died suddenly at 40.
Answer: Marfan syndrome.

• Echocardiogram (aortic root), slit-lamp exam (ectopia lentis), FBN1 testing; apply Ghent criteria.
• Beta-blocker or ARB; regular aortic imaging; prophylactic root surgery when indicated; avoid contact sports and fluoroquinolones.
• Cascade testing for siblings and children.

5. A 30-year-old woman has recurrent nosebleeds and telangiectasia on her lips. Her mother had a stroke at 45. She plans a pregnancy.
Answer: Hereditary haemorrhagic telangiectasia.

• Screen for pulmonary AVMs (contrast echo, then CT) before pregnancy - embolise if present (risk of stroke, brain abscess and haemorrhage in pregnancy).
• Check FBC and iron; manage epistaxis; consider brain MRI.
• Genetic testing (ENG, ACVRL1); screen relatives.

Key Points

• CF - CFTR (F508del); sweat test; Kaftrio transforms outcomes; CBAVD in men.
• Sickle cell and thalassaemia - AR haemoglobinopathies; gene editing therapy now available for some.
• Haemochromatosis - HFE C282Y; transferrin saturation first; venesection to ferritin under 50.
• SMA - SMN1 deletion; treat early with nusinersen, risdiplam or gene therapy.
• Duchenne - very high CK; MLPA; steroids; carrier women need cardiac checks.
• Huntington's - CAG 40+; paternal anticipation; high suicide risk; predictive testing protocol.
• Myotonic dystrophy - CTG; maternal anticipation; annual ECG; anaesthetic risk.
• Fragile X - test specifically (not seen on microarray); premutation causes FXPOI and FXTAS.
• NF1, tuberous sclerosis, Marfan, ADPKD and HHT are autosomal dominant with variable expressivity.
• Marfan - aortic root surveillance and surgery; upward lens dislocation (homocystinuria - downward).
• Mitochondrial disease - deafness, diabetes, ptosis, stroke-like episodes; avoid valproate in POLG.

Guidelines and Further Reading

• NICE NG78: Cystic fibrosis - diagnosis and management; Cystic Fibrosis Trust standards of care
• NICE CG143: Sickle cell disease - managing acute painful episodes in hospital
• British Society for Haematology: Guidelines on haemochromatosis, sickle cell disease and thalassaemia
• TREAT-NMD / international standards of care for Duchenne muscular dystrophy and SMA
• UK Haemophilia Centre Doctors' Organisation (UKHCDO) guidelines
• Revised Ghent nosology for Marfan syndrome; Curaçao criteria for HHT
• NICE TA358: Tolvaptan for treating ADPKD
• Highly Specialised Service for Rare Mitochondrial Disorders (NHS England)
• BNF - for current doses