Inherited metabolic disorders

• Inherited metabolic disorders are individually rare but collectively account for a large share of acute illness, brain injury and death in full-term newborns, and they usually declare themselves only after a symptom-free first day or two.
• A sick newborn with non-specific features (poor feeding, vomiting, lethargy, seizures, coma, acidosis, hypoglycaemia, a raised ammonia) must trigger the same action every time: resuscitate, send basic first-line metabolic tests, and do not wait for a named diagnosis before starting treatment.
• Three patterns do most of the teaching: intoxication (MSUD, organic acidurias, urea cycle defects, galactosaemia), energy failure (glycogen storage disease, gluconeogenesis defects, mitochondrial and fatty acid oxidation disorders) and storage (lysosomal diseases, which are usually not acutely reversible).
• Newborn screening by dried blood spot, taken between day two and day four, catches many of these disorders before symptoms; panels and confirmatory pathways differ by country. ^[1]
• Management is shared: stop the substrate, provide glucose and calories, reverse catabolism, scavenge ammonia when it is raised, and transfer to a specialist centre. Diet then becomes a lifelong daily treatment.

By the end of this page you should be able to:

1. Recognise the clinical patterns that should raise suspicion of an inherited metabolic disorder in a neonate, and order the right first-line investigations.
2. Interpret basic metabolic results (ammonia, glucose, blood gas, anion gap, ketones, lactate) well enough to narrow the differential before confirmatory tests return.
3. Describe the defect, inheritance, clinical picture and treatment of PKU, galactosaemia and MSUD.
4. Outline urea cycle defects, including the emergency management of hyperammonaemia, and glycogen storage disease.
5. Compare the lysosomal storage diseases and use the homocystinuria and mitochondrial disease table to recall enzyme, inheritance, features and treatment.
6. Explain newborn screening and lifelong dietary management in these conditions.
7. Counsel a family in broad terms about inheritance, recurrence risk and the need for specialist follow-up.

Inherited metabolic disorders are grouped by mechanism rather than by single diseases. A useful bedside classification is the one used in the sick newborn: protein (amino acidopathies, organic acidurias, urea cycle defects), carbohydrate and energy (glycogen and gluconeogenesis defects, mitochondrial and fatty acid oxidation disorders), and macromolecule (lysosomal and peroxisomal storage diseases), with vitamin and cofactor disorders in a fifth group. ^[1]

Individually each disorder is rare, but collectively they are not. The incidence of inherited metabolic disorders as a group is estimated at roughly 1 in 500 to 1 in 1500 births, depending on the population and on how aggressively it is screened. ^[1] About half of all children with a urea cycle defect present with neonatal hyperammonaemia. ^[5] Urea cycle defects have an estimated incidence of 1 in 8000. ^[5] Hepatic glycogen storage diseases together have an incidence of about 1 in 20000 to 43000, and types I, III and IX account for about 80% of the hepatic forms. ^[9] Mitochondrial diseases are among the commonest inborn errors of metabolism overall, with a conservative estimated prevalence of about 1 in 5000. ^[7] Gaucher disease, the most common lysosomal storage disease, has a prevalence of roughly 1 in 40000. ^[8] Phenylketonuria occurs in about 1 in 100000 live births in Europe and about 1 in 4000 in Türkiye. ^[2]

Most inherited metabolic disorders are autosomal recessive, so consanguinity, an affected sibling, or an unexplained neonatal death in the family should always raise suspicion. ^[1] X-linked exceptions include ornithine transcarbamylase deficiency, Fabry disease, mucopolysaccharidosis II (Hunter) and the X-linked glycogen storage diseases; mitochondrial DNA disorders are passed on through the maternal line. ^[5][8][9] Maternal HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) in pregnancy can signal a fetal long-chain fatty acid oxidation defect, and an older sibling with developmental delay of unexplained cause is another pointer. ^[1] There is no known modifiable risk factor for sporadic disease. Populations with high rates of consanguinity, such as in parts of the Middle East and North Africa, have a higher birth incidence of several of these disorders, including homocystinuria, organic acidurias and MSUD. ^[1]

The basic problem is a deficiency of an enzyme or cofactor, which causes accumulation of a substrate that cannot be metabolised and deficiency of a product the cell needs. ^[1] Phenylalanine hydroxylase deficiency is a simple example: phenylalanine builds up and becomes toxic to the brain while tyrosine, needed for melanin and catecholamine synthesis, becomes deficient. ^[1] Three pathophysiological patterns cover most of what is seen clinically. ^[1]

1. Intoxication from accumulated toxic metabolites: galactose in galactosaemia, leucine in MSUD, ammonia in urea cycle defects and organic acidurias. These children are well for a short symptom-free period, then deteriorate as metabolites accumulate.
2. Energy failure: glycogen storage diseases, gluconeogenesis defects, mitochondrial disorders and fatty acid oxidation defects, in which the problem is lack of usable energy. Hypoglycaemia and lactic acidosis are the calling cards.
3. Storage: lysosomal and peroxisomal diseases, in which undegraded substrate accumulates inside the lysosome and damages organs slowly. These children are not usually acutely toxic but are progressive, and they often have dysmorphic features or skeletal changes.

The liver is usually the first organ damaged because most metabolic pathways run there, and hepatic failure can itself cause secondary hyperammonaemia by shutting down the urea cycle. ^[8]

Any sick neonate could, in principle, have an inherited metabolic disorder, and the commonest diagnostic mistake is to assume sepsis and stop looking. ^[1]

Salient points include consanguinity, a sibling with metabolic disease or unexplained developmental delay, unexplained neonatal deaths or sudden infant deaths in the family, a mother with HELLP syndrome, and a symptom-free interval after birth followed by rapid deterioration, which is characteristic of the intoxication group. ^[1] The initial symptoms are non-specific: poor feeding, vomiting and lethargy, often progressing to seizures and coma. ^[1] Symptoms may follow a feed or worsen during intercurrent illness, and progression after presentation gives useful clues. ^[1]

The baby looks encephalopathic: lethargy, hypotonia or hypertonia, seizures, coma. ^[1] Dysmorphic features point to a storage or peroxisomal disorder; most carbohydrate and protein defects are not dysmorphic in the newborn period. ^[1] Eye examination matters: a cataract in a neonate is highly suggestive of galactosaemia and may be present from birth. ^[1] Abnormal odours are surprisingly useful: MSUD smells of maple syrup, tyrosinaemia of boiled cabbage. ^[1] Tachypnoea with respiratory alkalosis is a classic pointer to hyperammonaemia and therefore to a urea cycle defect, because ammonia stimulates the respiratory centre. ^[1] Jaundice, bleeding and hepatomegaly suggest metabolic liver disease (galactosaemia, tyrosinaemia, mitochondrial disease), and cardiomegaly suggests a fatty acid oxidation defect, Pompe disease or glutaric aciduria type 2. ^[1]

The rational plan is three steps, and the first step is applied to every sick neonate. ^[1]

• First line: full blood count, liver and renal function, blood gas and anion gap, glucose, lactate, ammonia, urine ketones and reducing substances. ^[1]
• Second line: plasma amino acids, total and free carnitine, acylcarnitine profile, urine organic acids and, for suspected galactosaemia, the Beutler test (GALT enzyme activity). ^[1]
• Third line: enzyme assays, DNA studies, cerebrospinal fluid lactate and pyruvate, very-long-chain fatty acids, biopsy material. ^[1]

Ammonia handling matters: a free-flowing venous (or arterial) sample, not capillary, transported on ice and separated promptly gives a reliable result. ^[5] In hyperammonaemia, plasma ammonia and amino acids, urine organic acids and orotic acid should be requested together with the basic tests, without waiting for any result before starting treatment. ^[5]

A bedside differential pattern, adapted from the urea cycle guidelines, is helpful. ^[5]

PKU is caused by deficiency of phenylalanine hydroxylase (and, rarely, of its cofactor tetrahydrobiopterin), the enzyme that converts phenylalanine to tyrosine. ^[1] It is autosomal recessive. Without treatment, phenylalanine accumulates and is neurotoxic: intellectual disability, seizures, developmental delay, behavioural and psychiatric problems, a musty odour, hypopigmentation and skin disorders, microcephaly. ^[2] Infants are normal at birth; permanent cognitive impairment develops over the first months if the disorder is not treated. ^[2]

Most programmes detect PKU by newborn screening, where blood phenylalanine above 120 µmol/L with a phenylalanine-to-tyrosine ratio above 3 supports the diagnosis on tandem mass spectrometry. ^[2] Blood is taken on a dried blood spot between day two and day four. ^[1] Treatment should begin as soon as possible, preferably in the first week of life. ^[2] Most centres start a phenylalanine-restricted diet when blood phenylalanine is at or above 360 µmol/L, and aim to keep it in the 120 to 360 µmol/L range throughout life. ^[2] Breast milk is often used in combination with a phenylalanine-free formula, and individual tolerance is defined by gradual reintroduction of phenylalanine. ^[2] Some patients respond to sapropterin at a starting dose of 10 mg/kg/day; gene and enzyme replacement therapies remain experimental. ^[2] Aspartame-containing products should be avoided. ^[2] Maternal PKU syndrome is teratogenic, so women with PKU need strict metabolic control around pregnancy. ^[2]

Classic galactosaemia is deficiency of galactose-1-phosphate uridyltransferase (GALT), an autosomal recessive disorder. ^[3] Classic (severe) disease has GALT activity below 1%, a clinical variant has 1 to 15%, and a biochemical variant (Duarte) is usually asymptomatic. ^[3] It affects about 1 in 60000 live births generally, and about 1 in 47000 in Caucasian populations. ^[3] Galactose from lactose in milk accumulates, along with galactose-1-phosphate and galactitol, giving toxic metabolites.

Untreated infants become unwell after a few days of milk: poor feeding, vomiting, hypoglycaemia, hepatocellular damage, jaundice, bleeding disorder, failure to thrive, and E. coli sepsis. ^[3] A cataract can be present from birth. ^[1] Even with good early treatment, children with classic galactosaemia remain at risk for speech and motor problems and, in females, premature ovarian failure. ^[3]

Diagnosis is by a raised total galactose or reduced GALT activity on the newborn blood spot, taken within 72 hours of birth. ^[3] Treatment is a galactose- and lactose-free diet begun immediately when the disease is suspected, without waiting for confirmation: stop breast milk and standard formula and use soy or elemental (galactose-free) formula. ^[3] A more favourable outcome is seen when this begins in the first week of life. ^[3] In the longer term, animal milk and dairy products are restricted, while foods containing trace amounts of galactose (fruit, vegetables, legumes) are allowed; mature cheeses are allowed because of their low galactose content (under 25 mg per 100 g). ^[3] Calcium and vitamin D should be supplemented, because restriction risks deficiency. ^[3] Duarte galactosaemia is usually not treated. ^[3]

MSUD is deficiency of the branched-chain alpha-ketoacid dehydrogenase complex: leucine, isoleucine and valine, and their ketoacids, accumulate. ^[4] It is autosomal recessive. Classic disease is severe and presents in the newborn period; intermediate and intermittent forms exist and may become unwell only under catabolic stress. ^[4]

Classic neonates are initially well. Branched-chain amino acids and their metabolites rise and the characteristic maple-syrup odour appears in cerumen and then in urine; irritability, ketonuria, then encephalopathy with lethargy, apnoea, opisthotonus and fencing or bicycling movements follow, progressing to coma and respiratory failure if untreated. ^[1] Leucine is the neurotoxic metabolite and causes cerebral oedema.

Management is lifelong dietary leucine restriction with branched-chain amino-acid-free medical foods, natural protein as a source of other amino acids, and daily supplementation of isoleucine and valine, titrated to laboratory monitoring. ^[4] Sick-day management at home is crucial and uses a leucine-free regimen high in calories (120 to 170 kcal/kg/day) with isoleucine and valine (15 to 30 mg/kg/day). ^[4] In acute decompensation, patients are treated with parenteral nutrition providing 150 to 200% of energy, 2.5 to 3 g/kg/day of branched-chain amino-acid-free amino acids, and an additional 20 to 120 mg/kg/day each of isoleucine and valine, with insulin 0.05 to 0.15 units/kg/hour. ^[4] Leucine is reintroduced once plasma leucine falls below 100 µmol/L. ^[4] Ondansetron 0.15 to 0.2 mg/kg supports control of vomiting. ^[4] Liver transplantation in specialist centres affords an unrestricted diet and protects against further crises. ^[4]

The urea cycle converts ammonia to urea in the liver. Defects in any of its enzymes (N-acetylglutamate synthase, carbamoylphosphate synthetase 1, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, arginase 1, plus the hyperornithinaemia-hyperammonaemia-homocitrullinuria transporter defect) cause hyperammonaemia. ^[5] Ornithine transcarbamylase deficiency is X-linked; the rest are autosomal recessive. ^[5] Incidence is about 1 in 8000. ^[5]

Complete deficiencies present in the first few days of life with hyperammonaemic coma, vomiting, tachypnoea with respiratory alkalosis, seizures, hepatic dysfunction and about 50% mortality; survivors have severe neurological disability and recurrent crises. ^[5] Partial (late-onset) deficiencies can present at any age, including adulthood, often triggered by infection, fasting, protein load, surgery, steroids or drugs such as valproate. ^[5] The brain is the target organ and outcome correlates with the duration of coma and peak ammonia. ^[5]

On standard testing, plasma citrulline is very low in ornithine transcarbamylase and carbamoylphosphate synthetase deficiency, high in argininosuccinate synthetase deficiency, and argininosuccinate is raised in argininosuccinate lyase deficiency. ^[5] Blood arginine is raised in arginase 1 deficiency and ornithine in HHH syndrome. ^[5] Newborn screening currently does not reliably detect ornithine transcarbamylase, carbamoylphosphate synthetase or N-acetylglutamate synthase deficiency, but may detect argininosuccinate synthetase, argininosuccinate lyase and arginase deficiency. ^[5]

Medical treatment in a crisis is described in the emergency section below. Long-term management is a low-protein diet keeping to safe protein intakes, enough energy to prevent catabolism, L-arginine or L-citrulline supplementation, and oral nitrogen scavengers. ^[5] Liver transplantation is curative for the enzyme defect (it allows normal diet and stops drug treatment) but does not reverse neurological damage, and is ideally performed between 3 and 12 months of age before irreversible damage. ^[5]

Glycogen storage diseases are autosomal recessive (with rare X-linked exceptions) defects of glycogen synthesis or breakdown. ^[9] Overall incidence is about 1 in 20000 to 43000, and about 80% of hepatic forms are types I, III and IX. ^[9]

• Type I (von Gierke): deficiency of glucose-6-phosphatase. Both glycogenolysis and gluconeogenesis fail, so fasting hypoglycaemia is severe, beginning often between 3 and 6 months. ^[9] Features: marked hepatomegaly, lactic acidosis, hypertriglyceridaemia and hyperuricaemia, bleeding tendency (platelet and von Willebrand abnormalities), doll-like facies. ^[9] Long-term: hepatic adenomas, renal disease, osteopenia, gout, anaemia, growth failure. ^[9]
• Type Ib: as type I plus neutropenia and inflammatory bowel disease. ^[9]
• Type III (Cori, Forbes): glycogen debrancher deficiency; hepatomegaly and ketotic hypoglycaemia that is milder than type I, with very high transaminases and myopathy. ^[9]
• Type IX: phosphorylase kinase deficiency; often mild and improving with age, but risk of liver fibrosis. ^[9]
• Type VI (Hers) and the muscle types (V, VII etc.): exercise intolerance, cramps, rhabdomyolysis.
• Type II (Pompe): lysosomal acid alpha-glucosidase deficiency (see below).
• Type 0: hepatic glycogen synthase deficiency; ketotic hypoglycaemia without hepatomegaly.

The treatment of hepatic types is to prevent hypoglycaemia: infants and children should be fed every 3 to 4 hours, with adolescents and adults not fasting more than 5 to 6 hours; uncooked cornstarch is given at 1 to 1.5 g/kg every 3 to 4 hours in young children and 1.5 to 2 g/kg every 4 to 5 hours in older children and adults; nocturnal tube feeding or an extended-release starch helps many through the night. ^[9] In type I, fructose, galactose and sucrose are restricted. ^[9] Neutropenic type Ib patients need granulocyte colony-stimulating factor. ^[9] Type I patients need urate-lowering and renal protection (angiotensin-converting enzyme inhibitors for microalbuminuria) and careful management of anaemia and hepatic adenomas. ^[9]

These are caused, for the most part, by enzyme deficiencies inside the lysosome, leading to accumulation of undegraded substrate and progressive multi-organ damage. ^[8] Most are autosomal recessive; Hunter (MPS II) and Fabry are X-linked. ^[8] Presentation is more insidious than the intoxication group: coarse facies, hepatosplenomegaly, skeletal dysplasia, developmental regression, cardiac valve disease and airway problems. ^[8] Many are now treatable, especially if diagnosis is early, with enzyme replacement therapy, substrate reduction or hematopoietic stem cell transplantation. ^[8] Tay-Sachs, Sandhoff, GM1 gangliosidosis, Krabbe and metachromatic leukodystrophy still have no disease-specific treatment and progress to premature death. ^[8] Niemann-Pick type A presents in the first months of life with a cherry-red spot and death by about 3 years. ^[8]

The clinical tempo separates them from the amino acid and organic acid disorders: storage diseases progress over months to years, and their somatic features (coarse facies, corneal clouding, claw hand, dwarfing, organomegaly) are often the only clues in early life. ^[8]

Homocystinuria due to cystathionine beta-synthase deficiency is an autosomal recessive sulphur amino acid disorder. ^[6] Four systems dominate: eye (ectopia lentis and severe myopia), skeleton (tall, long limbs, osteoporosis, scoliosis, arachnodactyly), central nervous system (developmental delay, intellectual disability, seizures, psychiatric problems) and vascular (thromboembolism, which is the major cause of early death and morbidity). ^[6] Untreated plasma total homocysteine is usually above 100 µmol/L (normal range about 10 to 15 µmol/L). ^[6] Without treatment, approaching 90% of pyridoxine-unresponsive patients have learning difficulties. ^[6] Responsiveness to pyridoxine (10 mg/kg/day up to 500 mg/day as a 6-week test) divides the disease into milder and more severe forms; non-responsive patients need a methionine-restricted diet with a methionine-free amino acid supplement, plus betaine as adjunct, folate and vitamin B12. ^[6] Treatment targets total homocysteine below 50 µmol/L in responsive patients and below 100 µmol/L in others. ^[6]

Mitochondrial diseases are common (prevalence about 1 in 5000) disorders of the respiratory chain from nuclear or mitochondrial DNA mutations. ^[7] Common features include ptosis, external ophthalmoplegia, proximal myopathy, exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy and diabetes mellitus. ^[7] Plasma lactate above 3 mmol/L, properly collected, suggests mitochondrial dysfunction. ^[7] Syndrome examples include Leigh (subacute neurodegeneration after an intercurrent illness, basal ganglia lesions), MELAS (stroke-like episodes, seizures, lactic acidosis), MERRF, Kearns-Sayre and Pearson (sideroblastic anaemia, pancytopenia, exocrine pancreatic failure). ^[7] There is no proven curative therapy. Management means preventing catabolism (avoid prolonged fasting, give dextrose-containing intravenous fluids before, during and after procedures), continuing outpatient therapies, investigating and treating acute illness aggressively, and giving intravenous arginine urgently for stroke-like episodes in MELAS after excluding other causes. ^[7] Patients should carry an emergency care plan and wear a Medic Alert bracelet. ^[7]

Sepsis is the great mimic and often coexists; pursue both until one is proven. ^[1] Hypoxic-ischaemic encephalopathy, intracranial haemorrhage, drug withdrawal, severe liver disease and endocrinopathies can all present similarly. ^[1] The differential diagnosis of hyperammonaemia includes organic acidurias and fatty acid oxidation defects, and standard clinical and analytical criteria usually separate them. ^[5]

The single most important principle is speed. Prognosis in hyperammonaemia is driven by the duration of coma and the peak ammonia level; coma lasting over 3 days, or a peak over 1000 µmol/L, implies a very poor outlook. ^[5] Action steps, from the urea cycle guidelines: ^[5]

1. Stop protein intake.
2. Start intravenous 10% glucose (10 mg/kg/minute in a neonate, with or without insulin) to reverse catabolism. ^[5]
3. Send diagnostic samples in parallel.
4. Give drug treatment according to the ammonia level (below).
5. Transfer to a specialist centre; prepare dialysis if the ammonia is over 500 µmol/L or if there is no rapid fall within 3 to 6 hours. ^[5]

Drug thresholds and doses (consensus guideline): ^[5]

• Above the upper limit of normal: monitor ammonia every 3 hours.
• 100 to 250 µmol/L (150 to 250 in neonates): start IV L-arginine and nitrogen scavengers; in an undiagnosed patient, sodium benzoate 250 mg/kg as a bolus over 90 to 120 minutes then 250 to 500 mg/kg/day, sodium phenylbutyrate or phenylacetate on the same schedule, L-arginine hydrochloride 250 to 400 mg/kg bolus then 250 mg/kg/day, and N-carbamylglutamate 100 mg/kg by nasogastric tube then 25 to 62.5 mg/kg every 6 hours; in a known urea cycle defect, continue or add these according to the enzyme. ^[5]
• 250 to 500 µmol/L: as above, with all drugs intravenously, and hemo(dia)filtration prepared.
• 500 to 1000 µmol/L: hemo(dia)filtration immediately. ^[5]
• Over 1000 µmol/L: consider whether curative treatment or palliative care is appropriate.

In severe decompensation both scavengers are given in parallel as ultima ratio; maximal daily doses of sodium benzoate, sodium phenylbutyrate and L-arginine should not exceed 12 g each. ^[5] If haemodialysis or haemofiltration is started, scavenger doses are increased (350 mg/kg/day). Ondansetron 0.15 mg/kg may be given to prevent vomiting when boluses are used. Plasma ammonia results should be available within 30 minutes, and results are repeated every 3 hours until controlled. ^[5]

A baby born at known risk of a urea cycle disorder should be managed along published at-risk protocols: transfer to a neonatal unit, start 10% glucose at 4 mL/kg/hour within 30 minutes, monitor plasma ammonia at 6 hours, then sequentially at 6- or 12-hourly intervals while feeds are introduced. ^[5]

Beyond ammonia, other metabolic crises need their own protocols. MSUD management is described above. In glycogen storage disease, hypoglycaemia is treated with oral or intravenous glucose and the crisis prevented by prompt attention to feedings. ^[9] In mitochondrial disease, acute decompensation is managed with dextrose-containing intravenous fluids, stopping exposures to potentially toxic medications, and correcting metabolic derangements. ^[7] In homocystinuria, vascular events are managed with the standard vascular approach plus metabolic control. ^[6] Lipids may be used in mitochondrial patients when needed. ^[7]

Diet is the treatment for most of these disorders, and it is lifelong. ^[2][5]

• PKU: low-phenylalanine diet with phenylalanine-free medical foods; monitor blood phenylalanine regularly; reintroduce phenylalanine gradually to define individual tolerance; avoid aspartame. Target 120 to 360 µmol/L. ^[2]
• Galactosaemia: galactose-free (lactose-free) diet; remove breast milk and standard formula and use soy or elemental formula in infancy; lifelong dairy restriction, mature cheeses low in galactose allowed; supplement calcium and vitamin D. ^[3]
• MSUD: leucine restriction with BCAA-free medical foods, gradual reintroduction of natural protein to tolerance, and daily isoleucine and valine supplementation; frequent home monitoring of amino acids; sick-day protocol for intercurrent illness. ^[4]
• Urea cycle defects: individualised low-protein diet keeping to safe protein intakes, enough energy to prevent catabolism, essential amino acid supplementation, oral nitrogen scavengers, arginine or citrulline, with sodium benzoate rescue regimens at home if intercurrent illness begins. ^[5]
• Glycogen storage disease: frequent feeds, avoidance of fasting, uncooked cornstarch and nocturnal feeding; high protein in ketotic types. ^[9]
• Homocystinuria: pyridoxine if responsive; otherwise a methionine-restricted diet with a methionine-free amino acid supplement, betaine as adjunct, plus folate and vitamin B12. ^[6]
• Mitochondrial disease: avoid prolonged fasting; give dextrose-containing intravenous fluids before, during and after procedures; manage acute illness aggressively. ^[7]

Nutrition is complex and should be overseen by a specialist metabolic dietitian. ^[2][5][6]

Untreated or late-treated disease leaves permanent damage: intellectual disability, seizures, spasticity, movement disorders, microcephaly, vision and hearing loss. ^[1][2][4] In MSUD, acute crises cause cerebral oedema and, rarely, brain herniation. ^[4] In urea cycle defects, hyperammonaemia itself is the neurotoxin, and severe liver disease adds portal hypertension, cirrhosis and, in argininosuccinate lyase deficiency, hepatocellular carcinoma risk. ^[5] Galactosaemia, even with good diet, carries long-term risk of ovarian failure, speech disorder and motor problems. ^[3] Homocystinuria's major threat is thromboembolism, which is the principal cause of early death and morbidity, alongside lens dislocation and skeletal deformity. ^[6] Glycogen storage disease type I can lead to hepatic adenomas, renal disease, osteopenia, gout, anaemia and growth failure. ^[9] Lysosomal diseases are progressive, with organomegaly, coarse facies, cardiac valve disease, airway and skeletal problems; Hurler and Hunter patients without effective early treatment have a life expectancy in the second or third decade. ^[8] Mitochondrial disease can decompensate with any intercurrent illness. ^[7]

Prognosis has improved enormously with newborn screening and early treatment, but it depends heavily on the severity of the defect and on how long diagnosis takes. ^[1] In PKU, children who begin treatment in the first weeks of life and maintain phenylalanine in range have normal general cognitive ability, although executive function, attention and fine motor skills may be subtly affected. ^[2] In galactosaemia, diet reverses the neonatal illness but not the long-term neurological and gonadal complications. ^[3] In MSUD, careful long-term control reduces crises and hospitalisation. ^[4] In urea cycle defects, outcomes correlate with the duration and peak level of hyperammonaemia, and transplantation can normalise biochemistry and diet but cannot undo brain injury already done. ^[5] In mitochondrial disease there is no curative therapy; supportive and emergency management aim to prevent decompensation. ^[7]

Newborn screening is the cornerstone, performed on dried blood spots taken between day two and day four, with special protocols for low-birth-weight infants, transfusion and parenteral nutrition. ^[1][3] Prenatal diagnosis is possible in many families once the causative variants are known, by chorionic villus sampling or amniocentesis, with genetic testing as the preferred method. ^[5] For autosomal recessive disease, each sibling's risk and carrier status should be discussed; carrier testing of relatives is offered. ^[5][6] Family screening for homocystinuria using plasma total homocysteine is recommended when an index case is found. ^[6] Counselling should include the natural history of mild or late-onset forms, which can be very different from the classical picture. ^[6]

Pregnancy in a woman with PKU demands tight biochemical control before conception and throughout pregnancy, because high maternal phenylalanine is teratogenic (maternal PKU syndrome). ^[2] Women with galactosaemia should be advised about ovarian failure risk. ^[3] OTC-deficient women may first present after delivery. ^[5] Homocystinuria management in pregnancy includes prophylaxis against thrombosis. ^[6] In a patient with PKU or MSUD, transitions from infant formula to solid food and through adolescence are managed jointly with a metabolic dietitian. ^[2][4]

Much of the world's burden of these disorders sits where neonatal screening and specialist metabolic units are unavailable. ^[1] The same clinical recognition rules still apply: poor feeding, vomiting, lethargy, jaundice or hepatomegaly, an odd odour, a cataract. ^[1] A wide arterial or venous ammonia can be run even in many small laboratories; the preanalytical handling (free-flowing sample, on ice, separated promptly) matters more than the technology. ^[5] A "metabolic screen" request is meaningless; tests should be directed by the clinical pattern, using the three-step approach of basic tests first, then amino acid, acylcarnitine and organic acid profiles, then confirmatory assays. ^[1] Samples can be stored (dried blood spots, frozen plasma and urine) for later specialist interpretation if transport is delayed. ^[1] Management then depends on what is available: stop protein, provide glucose, keep the baby hydrated, transfer when possible, and send histology for any resected tissue.

• Inherited metabolic disorders are individually rare but collectively common, and they present non-specifically early in life.
• The "intoxication" group presents after a symptom-free interval with vomiting, lethargy and encephalopathy; the "energy failure" group presents with hypoglycaemia and lactic acidosis; storage disorders progress more slowly and often have dysmorphism.
• Always consider sepsis and metabolic disease together. Both can worsen the other.
• First-line tests on every sick neonate: full blood count, glucose, blood gas and anion gap, lactate, ammonia, liver and renal function, urine ketones and reducing substances.
• Hyperammonaemia is an emergency. Stop feeds, start IV 10% glucose, and when ammonia is above 100 µmol/L begin scavenger therapy within 30 minutes; prepare or start dialysis over 500 µmol/L. ^[5]
• PKU needs a lifelong low-phenylalanine diet, started early, with blood phenylalanine kept in the 120 to 360 µmol/L range; some patients respond to sapropterin.
• Galactosaemia is treated by immediate galactose- and lactose-free feeding; the die is largely cast in the first week of life.
• MSUD needs leucine restriction with BCAA-free medical foods and isoleucine and valine supplementation; intercurrent illness needs a sick-day protocol or, if severe, parenteral therapy.
• Urea cycle defects are the non-ketotic hyperammonaemia emergencies; about half present neonatally with high mortality, and transplantation is the only cure for the severe neonatal form.
• Glycogen storage disease type I is the classic hypoglycaemic newborn with hepatomegaly and lactic acidosis; feeding every few hours with uncooked cornstarch is the backbone of treatment.
• Lysosomal diseases are progressive and many are now treatable with enzyme replacement or transplantation if started early; Tay-Sachs and Niemann-Pick type A currently have no disease-specific therapy.
• Classical homocystinuria threatens the eye, skeleton, brain and vessels; pyridoxine response determines the clinical spectrum and the diet.
• Mitochondrial disease is a clinical chameleon; the practical rules are to prevent catabolism, to give glucose in illness and to recognise MELAS as a neurological emergency treatable with arginine.
• Newborn screening and early specialist, multidisciplinary, lifelong care are what convert these diagnoses from tragedies into manageable conditions.

Inborn errors are best read alongside neonatal sepsis, congenital hypothyroidism, neonatal hypoglycaemia, acid-base disorders and childhood failure to thrive. Region-specific newborn screening panels and dietary formularies should be checked against local guidance.