Metabolic MedicinePart two

Hevi Pediatric Teaching Hospital

5-5-2013

• Disorders of Amino Acid Metabolism (tyrosinemia, homocystinuria, NKH, MSUD, and PKU)

• Urea Cycle Defects• Disorders of Organic Acid Metabolism ( propionic

acidemia, isovaleric acidemia, methylmalonic aciduria, and glutaric aciduria)

• Disorders of Fatty Acid Metabolism (MCAD)• Disorders of Carbohydrate Metabolism (hereditary

fructose intolerance, galactosemia, and GSDs)• PEROXISOMAL DISORDERS (Zellweger syndrome, X-

linked adrenoleukodystrophy)• MUCOPOLYSACCHARIDOSES (MPS) (Hurler syndrome)• SPHINGOLIPIDOSES (Gaucher disease, Niemann-Pick

disease)

Disorders of Amino Acid Metabolism

• Disorders of amino acid metabolism include

• tyrosinemia,

• homocystinuria,

• NKH,

• MSUD, and

• PKU.

Phenylketonuria• PKU is inherited in an autosomal recessive

• Classic PKU results from a deficiency of the PAH enzyme, which is responsible for converting phenylalanine into tyrosine.

• Other forms of PKU can be caused by deficiencies in the synthesis of biopterin, which is cofactor for the PAH enzyme.

• Clinical Manifestations of Untreated PKU

• Eczema.

• Hypopigmentation.

• Seizures.

• Limb spasticity.

• Mousy odor.

• Severe mental retardation.

• Women of childbearing age with PKU must maintain strict adherence to their diet because of the teratogenic effects of elevated phenylalanine.

• Infants born to mothers with uncontrolled PKU can have microcephaly, growthretardation, developmental delay, and congenital heart disease.

• Treatment

• Phenylalanine-restricted diet in infancy, ideally continued throughout lifetime.

• More recently, a synthetic form of biopterinhas become clinically available and allows further liberalization of diet in some patients.

Tyrosinemia

• There are five known inherited disorders of tyrosine metabolism.

• We will address tyrosinemia types I .

Tyrosinaemia (type 1)

• Tyrosinaemia type 1 results from a block in the catabolism of tyrosine, producing byproducts which damage the liver and kidney.

• Clinical features of tyrosinaemia• Early onset (severe) liver disease with

coagulopathy, proximal renal tubulopathy• Late onset: Faltering growth and rickets

(secondary to renal Fanconi)• Development of hepatocellular carcinoma in late

childhood/adolescence

• Diagnosis

• Tyrosine is raised in the plasma and the presence of succinylacetone in urine is pathognomonic.

• Confirm by liver enzymology(fumarylacetoacetase).

• Treatment

• Dietary restriction of tyrosine and phenylalanine with or without livertransplantation;

• however, the drug Nitisinone (NTBC)is now used in some patients to create a block upstream of the pathway of tyrosine metabolism, leading to accumulation of less toxic metabolites.

Maple Syrup Urine Disease (MSUD)

• MSUD results from deficient activity of the BCKD (branched-chain keto acid dehydrogenase )

• occurs in approximately 1 in 200,000 births.• It derives its name from the sweet smelling

urine of affected patients.• Deficiency of this enzyme leads to accumulation

of the BCAAs including leucine, isoleucine, and valine.

• Much of the toxicity is related to the elevated level of leucine, which is neurotoxic.

Clinical Manifestations(Vary According to Level of Functional Enzyme Present)

• Severe forms present in infancy with lethargy, vomiting, hypotonia, seizures, and/or death.

• Patients with intermediate levels of enzyme can present during childhood or adulthood with episodic neurologic decompensation, often during an intercurrent illness.

• Chronic progressive forms of MSUD exist and can present with gradual neurologic problems including seizures and developmental delay.

• Diagnosis:• Elevated branch-chain amino acids plus

alloisoleucine• Elevated branch-chain oxo-acids on urinary

organic acids• Enzymology on fibroblasts• Ammonia, lactate, and bicarbonate are often

normal.• Treatment• Restriction of intake of the BCAAs.• The enzyme cofactor thiamine is given in the

hope of improving residual enzyme activity.

Homocystinuria

• Homocystinuria is an autosomal recessive condition.

• classically caused by cystathionine beta-synthase deficiency. This enzyme is responsible for metabolizing homocysteine to cystathionine.

• Pyridoxine is a cofactor for this enzyme.

• Clinical Manifestations• Mental retardation.• Eye lens dislocation(classically downward)• Marfanoid body habits(span greater than

height)high arched palate, arachnodactyly• Restricted joints movement.• Osteoporosis.• Acute vascular thrombosis.

• Treatment

• 50% of patients will respond to pyridoxinesupplementation.

• Folate should also be supplemented as depletion affects response.

• Other treatment modalities include methionine-restricted, cystine-supplemented diet.

• Betaine is effective at lowering homocysteine .

Nonketotic Hyperglycinemia

• NKH results from defects in the glycinecleavage system.

• Glycine is a neurotransmitter; excitatory centrally and inhibitory peripherally.

• Clinical features• Increased fetal movements (inutero seizures)• Hiccups and hypotonia. • Progressive apnea/encephalopathy.• Seizures.• Developmental delay.• EEG shows a burst suppression pattern;

• Diagnosis:

• elevated glycine on urinary or plasma amino acids.

• CSF glycine to plasma glycine ratio greater than 0.08 is diagnostic of NKH.

• Ketosis and acidosis are not seen.

• Enzymology ;is traditionally assessed in the liver, but a new assay using lymphocytes is now available.

• Treatment

• Sodium benzoate and dextromethorphan may help to reduce seizure activity and increase arousal in some patients.

• Sodium-Valproic Acid (Depakene) should be avoided since it can raise CSF glycine levels.

Urea Cycle Defects(Disorders of Protein/Nitrogen Metabolism)

• In normal individuals, excess nitrogen is converted into urea, which is excreted in the urine by a process known as the urea cycle.

• A defect in this cycle will lead to abnormal nitrogen metabolism, and an elevation in ammonia, which at high levels is neurotoxic.

• Excess nitrogen is also stored as glutamine and glycine, which are also elevated in these disorders.

• All disorders of the urea cycle are inherited in an autosomal recessive manner, except OTCdeficiency, which is inherited in an X-linked manner.

Clinical features of Urea cycle defects:

• Vomiting (may be a cause of cylical vomiting)• Encephalopathy. (intoxication following symptom

free period in neonate) .• Tachypnoea (ammonia stimulate respiratory

center)• Progressive spastic diplegia and developmental

delay (arginase deficiency)• Milder forms can present during childhood with

episodic encephalopathy triggered by intercurrent metabolic stress.

• Diagnosis

• The specific deficient enzyme in a patient with a suspected urea cycle defect can be identified by examining the patterns of urine organic acids and plasma amino acids.

• Final confirmation of the diagnosis requires enzymology.

Characteristics of urea cycle defects

• Treatment

• Acute treatment during crisis periods is centered around reducing the levels of ammonia by

• dialysis and IV medications designed to provide alternative mechanisms of nitrogen excretion, such as sodium benzoate and phenylbutyrate.

Disorders of Organic Acid Metabolism

• Defects in the catabolism of amino acids result in the accumulation of organic acids which are detected in urine.

• Disorders of organic acid metabolism include

• propionic acidemia, isovaleric acidemia, methylmalonic aciduria, and glutaric aciduria.

• Propionic acidaemia (PA) and methylmalonicaciduria (MMA) result from blocks in branched-chain amino acid degradation,

• isovaleric acidaemia (IVA) is the result of a block in leucine catabolism.

• glutaric aciduria type 1 (GA-1) results from a block in lysine and tryptophan metabolism.

Clinical features of organic acidaemias

• Acute neonatal encephalopathy (intoxication), or chronic intermittent forms

• Dehydration ·• Marked acidosis (↑anion gap), ketosis .• Neutropenia +/- thrombocytopenia (acute marrow

suppression)• Progressive extra pyramidal syndrome (MMA, PA) basal

ganglia necrosis• Renal insufficiency (MMA) • Pancreatitis .• Cardiomyopathy (PA, MMA)• Patients with isovaleric acidemia are often described as

having a peculiar body odor (sweaty feet)

• Diagnosis

• Both the acylcarnitine profile and urine organic acid profile are essential in making a diagnosis.

• Treatment• Protein restriction.• Carnitine supplementation (provides alternate

methods of propionic acid and methylmalonicacid secretion).

• There are B12 responsive forms of methylmalonicaciduria.

• Propionate is partly produced by gut organisms, therefore decompensation in PA and MMA may be precipitated by constipation.

• Metronidazole is used in MMA and PA to alter the gut flora to reduce propionate production and help avoid constipation.

Glutaric Aciduria Type 1• Glutaric aciduria type 1 is due to a deficiency in glutaryl-

CoA .• Clinical Manifestations:• Macrocephaly• Normal development before catastrophic decompensation

(usually <1 year)• Choreoathetosis and dystonia (basal ganglia involvement)• Magnetic resonance imaging features: bifrontotemporal

atrophy, subdural haematomas, basal ganglia decreased signal

• Diagnosis

• Elevated levels of glutaric acid in the urine or CSF.

• Abnormal acylcarnitine profile.

• Patients do not generally have hypoglycemia, acidosis, or hyperammonemia.

• Treatment

• Lysine and tryptophan restricted diet.

• Carnitine supplementation.

• Support during intercurrent illnesses.

Disorders of Fatty Acid Metabolism

• The fat oxidation defects commonly present with hepatic, cardiac or muscle symptoms.

• Fatty acids are a major fuel source in the fasted state

• Fatty acids are oxidized by most tissues except the brain, which is reliant on hepatic fatty acid for ketone production.

• Fatty acids are the preferred substrate for cardiac muscle.

• during prolonged exercise they are a vital energy source for skeletal muscle.

• Long-chain free fatty acids are esterified in the cell cytosol and then enter the mitochondria as fatty acylcarnitines.

• Medium- and short-chain fatty acids are able to enter the mitochondria directly.

• They then undergo beta oxidation until they become acetyl-CoA, which is then used to make ketone bodies.

• These disorders are all inherited in an autosomal recessive manner.

Medium-chain acyl-CoA. dehydrogenase (MCAD) deficiency

• MCAD deficiency is the commonest fat oxidation disorder.

• Clinical features of MCAD deficiency• Hypoketotic hypoglycaemia(During prolonged fasting)• Encephalopathy• Reye-like syndrome: hepatomegaly, deranged liver

function• Mean age at presentation 15 months, commonest

precipitant is diarrhoea• Sudden infant death (consider in older infant> 6

months)

• Diagnosis

• Detection requires a strong clinical suspicion .

• The presence or absence of ketosis should be sought in all cases of hypoglycaemia.

• Plasma-free fatty acids are raised, while ketone formation is impaired.

• Urinary organic acids reveal a characteristic dicarboxylic aciduria in the acute state.

• Acylcarnitines are elevated .

• Management

• Prevention is better than cure.

• Once the diagnosis is known, further decompensations can be avoided by employing an emergency regimen of glucose polymer drinks during intercurrent illnesses or admission for a 10% dextrose infusion if the drinks are not tolerated.

Disorders of Carbohydrate Metabolism

• Disorders of carbohydrate metabolism include:

• hereditary fructose intolerance,

• galactosemia,

• and the GSDs (Glycogen storage disease)

Galactosemia• Galactosemia is a result of deficient (galactose-1-

phosphate uridyl transferase)

• Most patients present in the first or second week of life with hepatomegaly, jaundice, vomiting, hypoglycemia, hypotonia, and cataracts (oil droplet cataract)

• Neonates also present with Escherichia coli sepsis.

• Diagnosis

• Diagnosis is based on the clinical picture, the presence of reducing substances in the urine

• Enzymology : by measuring the level of galactose 1 phosphate uridyltransferase (Gal 1-Put) in red cells.

• Galactosaemia should be considered in all cases of severe early-onset jaundice.

• Treatment includes a lactose-free diet throughout life.

• Long-term complications, in spite of good control, thought to be due to endogenous production of galactose from glucose.

• Includes: developmental delay, particularly involving speech, feeding problems and infertility in girls.

Hereditary Fructose Intolerance• It is result from a defect of fructose 1,6-bisphosphate

aldolase.

• When patients are exposed to fructose, they can have gastrointestinal symptoms with nausea and vomiting, seizures, and coma.

• Liver failure and proximal renal tubule defects can be seen.

• Exacerbations may occur following exposure to fructose contained in medicines

• A chronic form can also develop leading to growth failure and chronic renal and liver damage.

• Treatment :Lifelong avoidance of fructose.

Glycogen Storage Disorders

• Glucose is stored in the liver and muscles as glycogen.

• The glycogen storages disorders are a large class of disorders that cause defects in glycogen production or utilization.

• They primarily present with either muscle or liverabnormalities or both.

• Hepatic forms present with hepatomegaly and hypoglycaemia,

• the muscle forms present with weakness and fatigue.

GSD Ia (von Gierke disease)

• Enzyme :Glucose-6-phosphatase

• Major Organ Involvement: Liver, kidney

• Clinical Features :• Hypoglycemia ; Fasting tolerance is limited,

usually 1 -4 h. • Massive hepatomegaly in the absence of

splenomegaly is strongly suggestive of a hepatic GSD because glycogen is not stored in the spleen.

• Nephromegaly is common.• Abnormal fat distribution results in 'doll-like'

faces and thin limbs. • Long-term complications include renal

insufficiency, liver adenomas with potential for malignant change, gout, osteopenia and polycystic ovaries.

• Investigations: show raised plasma lactate levels, hyperuricaemia and hyperlipidaemia.

• Treatment consists of frequent feeds during the day with continuous feed overnight.

• From age 2, uncooked corn starch is introduced as a slow-release form of glucose, prolonging the gap between feeds.

• Allopurinol controls the uric acid level in the blood.

• Liver transplantation is reserved for patients with malignant change in an adenoma or failure to respond to dietary treatment.

GSD II (Pompe disease)• Enzyme :Lysosomal alpha-glucosidase , acid maltase deficiency• Major Organ Involvement: Muscle, • Clinical Features : generalized Myopathy, cardiomyopathy,

hypotonia, weakness, hyporeflexia and large tongue.• ECG reveals giant QRS complexes. • Vacuolated lymphocytes are seen on the blood film.• Confirmatory enzymology is performed on fibroblasts. • ERT (enzyme replacement therapy )recently available, which

extends life expectancy.

• GSD III Debrancher (Cori disease): affects liver and muscle.

• GSDIV Brancher (Andersen disease), GSD VI (Hers disease) and GSD IX: affects liver.

• GSD V (McArdle disease) and GSD VII(Taruidisease): affects Muscles.

PEROXISOMAL DISORDERS

• Peroxisomes harbour many vital cellular functions, including

• the synthesis of plasmalogens, (essential constituents of cell walls), cholesterol and bile acids, and

• the oxidation of very long- chain fatty acids and breakdown of phytanic acid (vitamin A) and glyoxylate.

• Disorders are biochemically characterized by the number of functions impaired.

• Multiple enzymes affected (peroxisomalbiogenesis defects) - Zellweger syndrome (ZS)

• Several enzymes involved- rhizomelicchondrodysplasia punctata (RCDP)

• Single enzyme block- X-linked adrenoleukodystrophy (XALD), Refsumdisease, hyperoxaluria

• Inheritance is autosomal recessive with the exception of the XALD.

• The first-line investigation is very-long-chain fatty acids which are elevated in ZS and XALD.

• Further investigation requires fibroblaststudies.

Zellweger syndrome

• ZS is the classic peroxisomal biogenesis disorder with distinctive dysmorphic features.

• prominent forehead, hypertelorism, large fontanelle.

• Clinical features of Zelweger syndrome

• Dysmorphic faces;

• Severe neurological involvement including hypotonia, seizures and psychomotor retardation.

• Sensorineural deafness.

• Ocular abnormalities - retinopathy, cataracts

• Hepatomegaly and liver dysfunction

• Calcific stippling (especially knees and shoulders)

• Faltering growth.

• Diagnosis

• Loss of all peroxisomal functions - raised very-long-chain fatty acids, phytanate and bile acid intermediates and decreased plasmalogens.

• Confirmatory enzymology on fibroblasts.

• Treatment

• Management is supportive.

• Docosahexaenoic acid supplementation has been tried.

X-linked adrenoleukodystrophy(XALD)

• The paediatric cerebral form presents with severe neurological degeneration, usually between 5 and 10 years.

• Brothers in the same family may present at different ages.

• Clinical features of XAID• School failure, behaviour problems• Visual impairment• Quadreplegia• Seizures (late sign)• Adrenal insufficiency

• Adrenal involvement may precede or follow neurological symptoms by years.

• Some only develop neurological symptoms, and others just have adrenal insufficiency.

• All males developing adrenal failure should have very-long-chain fatty acid measurements taken to ensure that the diagnosis is not missed.

• Diagnosis

• Elevated very-long-chain fatty acids, blunted synacthen response or frank hypoglycaemia.

• Neuroimaging shows bilateral, predominantly posterior, white-matter invotvement.

• The differential diagnosis for neurodegenerationin the school-age child includes:

• Subacute sclerosing panencephalitis .

• Batten disease

• Wilson disease

• Niemann-Pick C disease.

• Management

• Lorenzo's oil (oleic and erucic acid) normalizes the very-long-chain fatty acids.

• Bone marrow transplantation is the mainstay of therapy in patients before neurodegeneration and those diagnosed after presentation with adrenal insufficiency.

• Adrenal function should be closely monitored, and steroid replacement therapy should be given once it is indicated.

MUCOPOLYSACCHARIDOSES (MPS)

• Mucopolysaccharides (glycosaminoglycans) are structural molecules integral to connective tissues such as cartilage.

• Degradation occurs within lysosomes, requiring specific enzymes.

• Patients with MPS appear normal at birth and usually present with developmental delay in the first year.

• The features of storage become more obvious with time.

ClassificationType Disorder Inheritanc

e

Corneal

clouding

Skeleton Hepato-

Splenomegaly

MR

I Hurler AR + +++ +++ +++

II Hunter XL - +++ +++ +++

III Sanfillipo AR + + + +++

IV Morquio AR + +++ + -

VI Maroteaux

-LamyAR + +++ +++ -

VII Sly AR + +++ +++ +++

• Hurler syndrome is the classical MPS with storage affecting the body and CNS.

• Sanfillipo syndrome predominantly affects the CNS.

• Morquio and Maroteaux-Lamy syndromes affect the body with Atlantoaxial instability often necessitating prophylactic cervical spinal fusion in the first 2-3 years.

• Hunter syndrome is phenotypically similar to Hurler syndrome, however there is no corneal clouding and scapular nodules are seen.

Hurler syndrome

• Hurler syndrome typifies the MPS group and their associated clinical problems.

• The enzyme deficiency is a-iduronidase, a deficiency .

• Clinical features of Hurler syndrome• Coarse faces, macroglossia, hirsutism, corneal

clouding• Airway/ear, nose, throat problems,secretory otitis

media.• Dysostosis multiplex• Cardiomyopathy, valvular disease• Hepatosplenomegaly• Hernias- umbilical, inguinal, femoral• Stiff joints ·• Developmental delay and retardation

• Radiographs show a characteristic skeletal dysplasia known as dysostosis multiplex

• The earliest radiographic signs are thick ribs and ovoid vertebral bodies.

• The lower ribs are broad and spatulate .

• The skull is large, the orbits shallow and the sella turcica shoe shaped or J-shaped .

• The bones of the upper extremities become short and taper toward the ends, often with enlargement of the mid-portions.

• The ends of the radius and ulna angulate toward each other.

• claw hand of the patient with Hurler syndrome is pathognomonic of dysostosis multiplex.

• The metacarpals are broad at their distal ends and taper at their proximal ends.

• The phalanges are thickened and bullet-shaped.

• The clavicle is absolutely characteristic, while the lateral portion may be hypoplastic or even absent.

• The vertebrae are hypoplastic, scalloped posteriorly and beaked anteriorly, especially at the thoracolumbar junction .

• There is anterior vertebral wedging, with typically a hooked-shaped vertebre.

• Diagnosis

• Urinary screen for glycosaminoglycans (raised dermatan and heparan sulphate).

• Enzymology confirmed on white cells.

• Management

• Treatment depends on early recognition to allow early bone marrow transplantation, which significantly modifies the phenotype.

• Enzyme replacement clinical trials are currently underway.

• Supportive care is the mainstay of untransplanted patients, with particular regard to the chest and airway requiring 3-monthly sleep studies.

SPHINGOLIPIDOSES

• Sphingolipids are complex membrane lipids.

• They are all derived from ceramide and can be divided into three groups:

• cerebrosides, sphingomyelins and gangliosides.

• Lysosomal hydrolases break these molecules down;

• deficiencies result in progressive storage and disease.

• Typical features include psychomotor retardation, neurological degeneration including epilepsy, ataxia and spasticity, with or without hepatosplenomegaly.

Tay-Sachs disease

• Clinical features:• Developmentar regression within first year.• Macrocephcdy• Hyperacusis• Cherry-red spot.• Spastic quadriplegia

• Diagnosis

• The presence of vacuolated lymphocytes on the blood film is a further clue.

• Hexosaminidase A deficiency is confirmed on white cell enzymology.

• Management

• Currently, management is supportive. However, research into substrate-deprivation therapy, thereby avoiding accumulation in the first place, is under investigation.

Gaucher disease

• Glucocerebrosidase deficiency results in the accumulation of cerebroside in the visceral organs +/- the brain depending on the type.

• Clinical features of Gaucher disease• Type 1• Non-neuronopathic (commonest)• Splenomegaly > hepatomegaly• Anaemia, bleeding tendency• Skeletal pain, deformities, osteopenia• Abdominal pain (splenic infarcts)

• Type 2• Acute neuronopathic• Severe CNS involvement (especially bulbar),

rapidly progressive• Convergent squinting and horizontal gaze palsy• Hepatosplenomegaly• Type 3• Sub-acute neuronopathic• Convergent squint and horizontal gaze palsy

(early sign)• Splenomegaly > hepatomegaly• Slow neurological deterioration

• Diagnosis

• Elevated angiotensin-converting enzyme (ACE) and acid phosphatase are markers for the disease.

• Bone marrow aspiration may reveal Gaucher cells

• White cell enzymes for glucocerebrosidase give the definitive diagnosis.

• The enzyme chitotriosidase is markedly elevated and may be used to follow disease activity.

• Management

• Enzyme replacement therapy is effective in visceral disease in types 1 and 3.

• Bone marrow transplant has been used in the past, and may have benefit for cerebral involvement in type 3.

• Splenectomy has been used to correct thrombocytopenia and anaemia and relieve mechanical problems but may accelerate disease elsewhere.

• There is no effective treatment for type 2.

Niemann-Pick disease

• Niemann-Pick (sphingomyelinoses)

• Types A and B are biochemically and genetically distinct from C and D.

Type 1 (sphingomyelinase deficiency)

• Clinical features of type 1

• Type A (infantile)

• Feeding difficulties

• Hepatomegaly > splenomegaly

• Cherry-red spot ·

• lung infiltrates

• Neurological decline, deaf, blind, spasticity

• Type B (visceral involvement)

• Milder course, no neurological involvement

• Hepatosplenomegaly

• Pulmonary infiltrates .

• Ataxia

• Hypercholesterolaemia

• Diagnosis

• Bone marrow aspirate for Niemann-Pick cells.

• White cell enzymes.

• Genotyping may help distinguish between the two types before the onset of neurological signs.

• Management

• Supportive.

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