PBL 1: IEM by

PBL 1: IEM by https://padlet.com/manarmech/axgxlxickosooyae en-us 2022-04-04 19:35:33 UTC 2024-04-09 22:04:09 UTC hello@padlet.com Group 1: Intoxication type metabolic diseases manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2129976838 Amino acid disorders (= amino acidopathies)

AA needed for synthesis of compounds (proteins, peptide hormones, enzymes) needed for gluconeogenesis/ energy generation (20 total, 11 synthesized in vivo)
defect in metabolic pathways of AA
amino acidemias = abnormal accumulation of AA in urine
- symptoms result from accumulation of substance that cannot be metabolized.
- maple syrup disease/ phenylketonuria
presentation
- newborns: initially well to acutely symptomatic (metabolic decompensation with poor feeding and lethargy) after protein feeding
  - encephalopathy, coma or death if not treated
- older children: developmental delay/ regression
diagnosis
- newborn screening: tandem mass spectrometry
- biochem findings: metabolic acidosis, hyperammonemia, hypoglycemia (with increased ketosis), liver dysfunction, reduced substances in urine
- measure quantitative plasma AA
- qualitative urine organic acids
- enzyme analysis

Organic academias (= organic acidurias)

accumulation of abnormal/toxic organic acid metabolites + increased excretion of organic acids in urine
methylmalonic acidemia and propionic acidemia
presentation
- newborn period/early infancy: initially well to life-threatening epidote of metabolic decompensation with poor feeding, vomiting and lethargy
  - progression if not treated
- older children: developmental delay/ regression
diagnosis
- biochemical findings: metabolic acidosis with increased anion gap, mild/moderate hyperammonemia, sepsis like features secondary to bone marrow suppression, ketosis, hypoglycemia, liver dysfunction, secondary carnitine deficiency
- measure quantitative plasma AA
- qualitative urine organic acids
- enzyme analysis

Urea cycle disorders (UCDs)

urea cycle: transformation of nitrogen to urea for excretion from the body
deficiency of any enzymes in this pathway causes UCD
ornithine transcarbamylase deficiency and citrullinemia
presentation
- newborns: initially well to hyperammonemic after protein feeding
- patients with partial enzyme activity present later
diagnosis
- biochemical findings: hyperammonemia, respiratory alkalosis, ketosis, (liver dysfunction)

Metal metabolism disorders

hemochromatosis
- mutations in the HH gene (HFE), a disorder in which increased intestinal iron absorption can lead to total-body iron overload.
Wilson disease
- defect in hepatocellular copper transport, leading to the accumulation of copper in the liver and other tissues, including the brain.
Menkes disease and acrodermatitis enteropathica (zinc deficiency)

]]> 2022-04-05 04:38:37 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2129976838 Group 2: defects in the synthesis or breakdown of complex molecules manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2130458744 Peroxisomal disorders

Numerous catabolic (beta-oxidation of very long chain fatty acids (VLCFAs)) and anabolic (synthesis of bile acids and plasmalogen) functions in cellular metabolism occur in peroxisomes.
heterogeneous group of IEM that result in impairment of peroxisome function.
presentation
- microcephaly, dysmorphic facial features, hepatomegaly, hypotonia, and neurologic dysfunction to a varying extent.
- Zellweger syndrome and adrenoleukodystrophy
diagnosis
- increased plasma concentration of VLCFA and/or phytanic acid.

Lysosomal storage disorders (= storage diseases)

Lysosomes contain enzymes responsible for the degradation of a variety of compounds including mucopolysaccharides, sphingolipids, and glycoproteins.
- Deficient activity of enzymes leads to progressive accumulation of partially degraded material --> distention of the cell, disruption of cellular function, (failure of active transport of small molecules from lysosomes)
caused by defective lysosomal metabolism or export of naturally occurring compounds --> accumulation of various glycosaminoglycans, glycoproteins, or glycolipids in lysosome
classification: subdivided according to the involved compound or pathway
- Mucopolysaccharidoses (eg, Hurler syndrome).
- Sphingolipidoses
- Glycoproteinoses
- Disorders of lysosomal enzyme transport
- Lysosomal membrane transport disorders
- Other (eg, lysosomal acid lipase deficiency).
presentation: depending upon the location and extent of storage that occurs
- progressive hepatomegaly, splenomegaly, neurologic regression, short stature, coarsening of facial features, limitation/restriction of small and large joints, peripheral neuropathy, and/or ataxia
Diagnosis
- specific enzyme assay on samples of WBCs, serum, or skin fibroblast

Congenital disorders of glycosylation (CDGs)

many enzymes, hormones, and other proteins require posttranslational glycosylation (with (oligosaccharides) to function normally.
caused by pathogenic variants in genes that encode the enzymes required for synthesis of these oligosaccharides
classification: based upon the defect in the pattern of glycosylation and the affected gene
- CDG Ia: most common type.
- CDG Ib: amenable to therapy with mannose
presentation
- wide range in age of onset ( mainly infancy)
- developmental delay, hypotonia, failure to thrive, hypoglycemia, and protein-losing enteropathy.

]]> 2022-04-05 11:22:41 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2130458744 Group 3: defects of energy metabolism manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2130459655 Carbohydrate disorders

disorders in cabohydrate metbolism can lead to hypoglycemia, liver dysfunction, myopathy and/or cardiomyopathy
deficiency of enzymes in pathways of glycogen metabolism
galactosemia, glycogen storage diseases
presentation
- children: lethargy, encelphalopathy, hypoglycemia in decreased carbohydrate intake/fasting, (hepatomegaly)
diagnosis
- biochemical findings: hypoglycemia and ketosis, metabolic acidosis, liver dysfunction, nonglucose-reducing substances in urine (carbohydrate intolerance (galactosemia/fructose intolerance)
- DNA analysis + enzyme activity in cultured skin fibroblasts, liver, WBC, RBC

Fatty acid oxidation disorders

mitochondrial fatty acid oxidation is important for energy production (during fasting)
medium-chain acyl-CoA dehydrogenase (MCAD) , fatty acids transportation defects, defects of beta-oxidation enzymes
presentation
- children: lethargy and encephalopathy during decreased carbohydrate intake or fasting, (hepatomegaly)
- biochemical findings: hypoglycemia NO ketosis, liver dysfunction, hyperammonemia and metabolic acidosis
- plasma acylcarnitine analysis
- enzyme activity in cultured skin fibroblasts
- DNA analysis

Mitochondrial disorders

Within the mitochondria, organic acids, fatty acids, and amino acids are metabolized to acetyl-CoA, which condenses with oxaloacetate to form citric acid, which is oxidized in the Krebs cycle
can affect muscle alone, muscle and brain, or multiple systems with variable involvement of the heart, kidney, liver, skeletal muscle, or brain
Cytochrome c oxidase deficiency , Kearns-Sayre syndrome
presentation
- Children: skeletal or visceral abnormalities, poor feeding, vomiting, cardiomyopathy, myopathy, liver failure, seizures, central nervous system abnormalities, developmental delay, retinopathy, blindness, deafness, focal neurologic findings , or renal abnormalities
diagnosis
- Biochemical features: metabolic acidosis, lactic acidosis, hypoglycemia with appropriate or increased ketosis, and liver dysfunction
- assay of enzyme activity in cultured skin fibroblasts, muscle, or liver or DNA testing.
- Muscle biopsy for routine histology and electron microscopy and magnetic resonance imaging (MRI) and/or spectroscopy of the brain may be helpful in diagnosis.

]]> 2022-04-05 11:23:42 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2130459655 manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2131426332 Purine and pyrimidine disorders

Purine and pyrimidine nucleotides are important constituents of RNA, DNA, nucleotide sugars and other high-energy compounds, and cofactors, such as adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD).
presentation
- varies widely, may include renal calculi, neurologic dysfunction, delayed physical and mental development, self-mutilation, hemolytic anemia, and immune deficiency.
- Lesch-Nyhan disease, gout, and adenosine deaminase deficiency.

Porphyrias

The porphyrias are genetic or acquired deficiencies in the activity of enzymes in the heme biosynthetic pathway.

Congenital disorders of creatine metabolism

three identified congenital metabolic disorders that lead to creatine deficiency.
- autosomal-recessive --> affect the biosynthesis of creatine.
  - arginine/glycine amidinotransferase (AGAT) deficiency a
  - guanidinoacetate methyltransferase (GAMT) deficiency.
- defect in the transport of creatine into the brain and muscle
  - X-linked creatine transporter (CT) deficiency

]]> 2022-04-05 20:29:36 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2131426332 General manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2131433372

clinical manifestations of IEM may include findings in every system

Acute: episodic vomiting accompanied by dehydration or shock, lethargy and coma, rhabdomyolysis, and hypoglycemia associated with minor illnesses, stress, or a prolonged fast.

Chronic: growth delay/failure to thrive, hepatomegaly, cardiomyopathy, spastic diplegia, and developmental delay or regression.

]]> 2022-04-05 20:35:26 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2131433372 Neurological Manifestations manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2131477088 Lethargy and coma

amino acid disorders, organic acidemias, urea cycle disorders, fatty acid oxidation defects, mitochondrial disorders, and disorders of carbohydrate metabolism (usually in the context of acute or episodic decompensation as described above).
Depending upon the disorder, patients may be entirely neurologically normal prior to an acute metabolic decompensation or may have a longstanding history of developmental delay

Seizures

IEM are a rare cause of seizures in children, they can occur in all IEM

Developmental delay

IEM are cause in only 1 to 5 percent of cases of developmental delay
developmental delay and/or intellectual disability, particularly with progressive worsening, may occur in many IEM.
Disorders of urea cycle and amino acid metabolism, Organic acidemias, Disorders of creatine metabolism

Neuropathy

Peripheral neuropathy may be a feature of disorders of vitamin B12 (cobalamin) transport and processing, lysosomal disorders and certain mitochondrial disorders

Abnormal tone

Hypotonia may be a manifestation of fatty acid oxidation disorders, mitochondrial disorders, urea cycle defects, peroxisomal disorders, lysosomal acid maltase deficiency and cholesterol synthesis disorders

Myopathy

lysosomal and nonlysosomal glycogen storage diseases, disorders of fatty acid oxidation, and mitochondrial disorders. Patients may complain of exercise intolerance, muscle pain, and cramps rather than weakness

Ataxia (lack of voluntary coordination of muscle movements) and dystonia (muscles contract involuntarily)

ataxia: peroxisomal disorders, mitochondrial disorders, disorders of metal metabolism, and lysosomal storage disorders. a dysplastic cerebellum is seen in congenital disorders of glycosylation
Dystonia: may be a feature of mitochondrial disorders or organic acidurias after a metabolic crisis associated with damage to the basal ganglia

Neuropsychiatric

self-injurious behavior in Lesch-Nyhan syndrome
Increased activity and aggression in Sanfilippo syndrome and other mucopolysaccharidoses
Personality changes, deteriorating school performance, depression, paranoia, or catatonia in Wilson disease
Psychosis in some patients with adult Tay-Sachs disease, homocystinuria, the porphyrias, and purine disorders

]]> 2022-04-05 21:17:13 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2131477088 Gastrointestinal Manifestations manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2131513965 Vomiting and poor feeding

Recurrent vomiting, poor feeding, and associated dehydration are discussed in detail separately

Organomegaly

Hepatomegaly and/or splenomegaly can be seen in the following conditions:
- Glycogen storage diseases, Lysosomal storage diseases, galactosemia
- Hepatosplenomegaly and isolated splenomegaly occur primarily in lysosomal storage disorders,
- hepatomegaly is more typical of glycogen storage diseases and certain mitochondrial diseases. In addition, signs or symptoms that accompany hepatosplenomegaly may suggest a particular diagnosis:
  - - with hypoglycemia and poor growth is suggestive of glucose-6-phosphatase deficiency, glycogen debrancher deficiency, disorders of gluconeogenesis, or severe hyperinsulinism.
  - - with liver failure suggests hereditary fructose intolerance, galactosemia, tyrosinemia type 1, neonatal hemochromatosis, a mitochondrial disorder, or Wilson disease

Jaundice

galactosemia, citrin deficiency, alpha-1 antitrypsin deficiency, disorders of bile acid metabolism, transaldolase deficiency, peroxisomal disorders, neonatal hemochromatosis, and congenital disorders of glycosylation

]]> 2022-04-05 21:55:39 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2131513965 Other Manifestations manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2131559007 Cardiomyopathy

Hypertrophic or dilated, related to impaired energy metabolism or storage material.
- Hypertrophic --> lysosomal acid maltase deficiency (glycogen storage disease type II, Pompe disease) and in the mucopolysaccharidoses.
- Dilated --> fatty acid oxidation disorders, organic acidemias, and mitochondrial disorders

Dysmorphic features (at birth or may develop with age ]

Peroxisomal disorders (eg, high forehead, large anterior fontanelle, hypoplastic supraorbital ridges, epicanthal folds, low and broad nasal bridge, high-arched palate, and deformed ear lobes in Zellweger syndrome)
Lysosomal storage diseases (eg, coarse facial features may be present at birth in mucolipidosis II and (GM1)-gangliosidosis; in other mucopolysaccharidoses, coarsening of the facial features develops with age
Homocystinuria due to cystathionine-beta-synthetase deficiency (long face and lanky body habitus
Smith-Lemli-Opitz syndrome (cleft palate, congenital heart disease, hypospadias, polydactyly, and syndactyly)
Congenital disorders of protein glycosylation

Ophthalmologic

Ophthalmologic presentations of IEM include cataracts, corneal opacities or clouding, cherry-red spots, retinitis pigmentosa, and dislocated lense

Dermatologic

Rashes: biotinidase deficiency, methylmalonic acidemia, propionic acidemia
Photosensitivity
Hyperkeratosis and ichthyosis
Skin ulceration: Prolidase deficiency
Skin nodules: Farber disease, congenital disorders of protein glycosylation
Angiokeratoma: Fabry disease and other lysosomal storage diseases
Pearly papules: MPS I H
Hypopigmentation: Untreated phenylketonuria
Melanocytic nevi: Lysosomal storage diseases such as Hurler syndrome, MPS I H] and GM1 gangliosidosis type

Hydrops fetalis (= Nonimmune hydrops fetalis (abnormal fetal fluid collections)

Lysosomal storage diseases
Neonatal hemochromatosis
Mitochondrial respiratory chain disorders
Congenital disorders of glycosylation
Glycogen branching enzyme deficiency (glycogen storage disease IV, Andersen disease)
RBC enzyme abnormalities

Abnormal odors

Abnormal odor of the patient's breath, urine, perspiration, saliva, or cerumen should prompt consideration of organic acidemias, amino acid disorders, urea cycle defects, and fatty acid oxidation disorders
- Burnt sugar, curry, or maple syrup – Maple syrup urine disease
- Sweaty socks or cheese-like – Isovaleric acidemia
- Fruity, ammoniacal – Methylmalonic acidemia or propionic acidemia
- Mouse urine, musty – Phenylketonuria
- Cabbage-like, rotten eggs – Tyrosinemia
- Malt or hops – Methionine malabsorption
- Cat urine - 3-methylcrotonic acidemia, 3-hydroxy-3-methylglutaric aciduria
- Fish-like – Trimethylaminuria and carnitine excess

Urine changes

Abnormal urine color or odor
Color changes may only be apparent after the urine stands for some time (permitting oxidation). --> alkaptonuria

]]> 2022-04-05 22:49:18 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2131559007 manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2131561482 2022-04-05 22:52:08 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2131561482 manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2131565081 Presentation

many classic presentations of IEM occur in infancy, almost all metabolic disorders can have later onset presentations including late adulthood

clinical evaluation

focus: The history should focus on previous episodes of metabolic decompensation, identification of potential triggering events, and family history of metabolic disease or members with similar presentations

physical examination

signs& symptoms of metabolic disease
- lethargy, poor thriving, poor feeding
- watch out can be normal at first and develop later on

]]> 2022-04-05 22:56:33 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2131565081 Laboratory Evaluation manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2131572958 performed tests evaluation of IEM

initial basic tests
Specialised tests (samples obtained at time of acute presentation )
- Plasma amino acids
  - AA in plasma/serum to confirm diagnosis of urea cycle disorders and other AA metabolism disorders
  - high pressure liquid chromatography HPLC or masss spectroscopy MS/MS
  - acedemias vs acedurias
- Urine organic acids
  - quantitative by gas chromatography GC/MS
  - qualitative assay of compounds
- Lactate and pyruvate
  - in arterial blood, present when abnormal ocidative metabolism in often mitochondrial disorders, GSDs etc.
- Acylcarnitine profile
  - Analysis of acylcarnitine conjugates is performed by MS/MS and can be measured in a plasma sample or a filter-paper bloodspot.
  - for diagnosis of fatty acid oxidation disorders. It also may detect organic acidemias in which the acylcarnitine profile is abnormal
Molecular genetic testing
- next-generation sequencing (NGS) methods, including whole-exome sequencing (WES)
- gene therapy (in vivo/ ex vivo)
- AON's (RNA therapy)
- personalized genomic medicine
Other

]]> 2022-04-05 23:05:48 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2131572958 Newborn Screening manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2131579288 goal of newborn screening

confirmation of IEM before manifestations

criteria of screening

check image

What are risks of screening

false-positives and false-negatives (screening too early)
test resets not available in first days of life when some IEM may be present
no screening for all IEM

in USA 4mil screened (12500 diagnoses)
--> proven to decrease morbidity and mortality

]]> 2022-04-05 23:13:09 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2131579288 manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2131579988 2022-04-05 23:13:59 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2131579988 manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2131580515 2022-04-05 23:14:35 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2131580515 Inborn Errors of Metabolism/ Congenital Metabolic Disorders manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2132199170

result from absence/abnormality in enzymes/cofactors

accumulation or deficiency of metabolites

Early recognition is crucial, as it defines the outcome following referral to specialists for appropriate management.

Diagnostic delay may result in acute metabolic decompensations, progressive neurological injury or death.

autosomal - recessive most common

incidence: 1/100 000 (individuallly), 1/800-2500 (collectively)

]]> 2022-04-06 08:05:53 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2132199170 manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2132213835 2022-04-06 08:17:47 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2132213835 manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2132337049 2022-04-06 09:57:57 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2132337049 pathogenesis manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2132338277

In less frequent cases, alterations that result in abnormalities of more than one enzyme can affect several metabolic steps.

i.e. multiple sulfatase deficiency → lysosomal storage disorder caused by impaired posttranslational modification of sulfatases.

Disorders of cofactors can also affect multiple enzymes

B12 transport and synthesis defects may lead to accumulation of both methylmalonic acid and homocysteine.

How are gene mutations related to IEMs?

defect in one specific gene.
multiple subunits encoded by different genes and catalyse more than one metabolic reaction.

]]> 2022-04-06 09:59:04 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2132338277 heel prick & tandem mass spectrometry manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2132372204 Normal nursery (heel prick)

blood spot of healthy newborns to analysis (should be performed within week, but after 3 days bc otherwise mother can compensate)

TMS: detect molecules by measuring their weight and is a series of two mass spectrometers sampling/ indentifying/weighing molecules

]]> 2022-04-06 10:30:08 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2132372204 effects on other organs manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2132376949 haematological abnormalities
- anaemia, thrombocytopenia, pancytoopenia
liver abnormalities
- hyperammonemia and jaundice
kidney abnormalities
- renal fanconi syndrome, tubular acidosis, renal cysts]]> 2022-04-06 10:34:10 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2132376949 prognosis manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2132381944

generally most are (partially) treatable --> meds(injections)/ dietary changes

focus on early detection

if clinical manifestations are missed detrimental effects (including death) may follow

emphasis on educating patient (eg dietary calculations)

highly dependent on

which type of metabolic disorder
- eg mitochondrial metabolic diseases affect many organs and thus has a worse prognosis
amount of genes affected

]]> 2022-04-06 10:39:05 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2132381944 manarmech https://padlet.com/manarmech/axgxlxickosooyae/wish/2132383582 Lecture
1) intoxication type
2) defects synthesis/breakdown complex molecules
3) defects energy metabolism ]]> 2022-04-06 10:40:38 UTC https://padlet.com/manarmech/axgxlxickosooyae/wish/2132383582