Metabolic Flashcards
(330 cards)
1
Q
What are inborn errors of metabolism (IEM)?
A
Genetic conditions caused by enzyme defects that disrupt metabolic pathways, leading to toxic metabolite accumulation or energy deficiency.
2
Q
How are IEMs inherited?
A
Most are autosomal recessive; some are X-linked (e.g., OTC deficiency).
3
Q
What is the general pathophysiology of IEMs?
A
Enzyme deficiencies block metabolic pathways, causing buildup of substrates or lack of essential products.
4
Q
What are the major categories of metabolic disorders?
A
Amino acid disorders, organic acidemias, carbohydrate disorders, fatty acid oxidation defects, urea cycle defects, mitochondrial, lysosomal, and peroxisomal disorders.
5
Q
What is the typical presentation of IEM in neonates?
A
Lethargy, vomiting, poor feeding, seizures, hypotonia, unexplained acidosis or hypoglycemia, often after a symptom-free interval.
6
Q
What symptoms suggest a possible metabolic disorder in infancy?
A
Feeding intolerance, failure to thrive, hepatomegaly, unusual odor, neurologic symptoms, or lab abnormalities (e.g., hyperammonemia).
7
Q
What is a metabolic decompensation?
A
A life-threatening event triggered by metabolic stress, characterized by vomiting, coma, acidosis, hyperammonemia, or hypoglycemia.
8
Q
What triggers metabolic crises in IEM patients?
A
Infections, fasting, high protein intake, fever, physical stress (e.g., surgery).
9
Q
What laboratory findings raise suspicion for IEM?
A
Metabolic acidosis, increased anion gap, hyperammonemia, hypoglycemia, ketonuria, elevated lactate, abnormal liver enzymes.
10
Q
What are signs of hyperammonemia?
A
Irritability, vomiting, altered mental status, lethargy, seizures, cerebral edema, coma.
11
Q
What IEMs are associated with ketosis?
A
Organic acidemias, glycogen storage diseases, fatty acid oxidation disorders during fasting.
12
Q
What IEMs are associated with hypoketotic hypoglycemia?
A
Fatty acid oxidation defects (e.g., MCAD), some urea cycle disorders.
13
Q
What IEMs cause metabolic acidosis with increased anion gap?
A
Organic acidemias, lactic acidosis, some mitochondrial disorders.
14
Q
Which metabolic disorders present with hepatomegaly?
A
Glycogen storage diseases, galactosemia, hereditary tyrosinemia type I, Niemann-Pick.
15
Q
What metabolic causes can lead to developmental delay or regression?
A
Mucopolysaccharidoses, lysosomal storage disorders, mitochondrial disorders, phenylketonuria (PKU).
16
Q
What metabolic disorders present with seizures?
A
Nonketotic hyperglycinemia, pyridoxine-dependent epilepsy, some organic acidemias.
17
Q
What is the role of newborn screening in metabolic disorders?
A
Allows early detection of treatable IEMs before clinical symptoms develop.
18
Q
What is tandem mass spectrometry (MS/MS)?
A
A technique to identify amino acids, acylcarnitines, and other metabolites in dried blood spots.
19
Q
What samples are used for initial metabolic workup?
A
Blood, urine, and sometimes CSF; collected during acute illness is best.
20
Q
What are common diagnostic tools for metabolic disorders?
A
Plasma amino acids, urine organic acids, acylcarnitine profile, lactate, ammonia, glucose, ketones.
21
Q
What is the importance of urine organic acids in IEM workup?
A
Helps detect organic acidemias by identifying characteristic acid metabolites.
22
Q
What is plasma acylcarnitine profile used for?
A
Detects fatty acid oxidation disorders and some organic acidemias.
23
Q
Which disorders can be diagnosed via enzyme assays?
A
Lysosomal, peroxisomal, and some mitochondrial disorders.
24
Q
What role does molecular genetic testing play in IEM?
A
Used for confirming diagnosis, identifying carriers, and prenatal diagnosis.
25
What are the basic principles of management of IEMs?
Prevent catabolism, remove toxic metabolites, correct acidosis/electrolytes, and provide cofactors.
26
How are metabolic disorders classified by pathophysiology?
Toxic accumulation (e.g., PKU, MMA), energy deficiency (e.g., FAODs, mitochondrial), storage (e.g., Gaucher).
27
What are examples of disorders due to accumulation of toxic substances?
PKU, maple syrup urine disease, MMA, OTC deficiency.
28
What are examples of disorders due to energy production defects?
MCAD, VLCAD, pyruvate dehydrogenase complex deficiency, mitochondrial respiratory chain defects.
29
What are examples of disorders due to storage of complex molecules?
Gaucher, Niemann-Pick, MPS, Tay-Sachs.
30
What is the relevance of dietary therapy in IEMs?
Dietary restriction (e.g., low protein in PKU), supplementation (e.g., carnitine, thiamine), and emergency regimens are critical.
31
What are glycogen storage diseases (GSDs)?
Inherited disorders of glycogen metabolism due to enzyme deficiencies.
32
What is the general pathophysiology of GSDs?
Defective synthesis or breakdown of glycogen leads to its accumulation in tissues.
33
How are GSDs classified?
By enzyme defect and primary tissue involved (hepatic, myopathic, or mixed).
34
Which GSDs primarily affect the liver?
GSD I, III, IV, VI, IX.
35
Which GSDs primarily affect muscle?
GSD II (Pompe), V (McArdle), VII.
36
What enzyme is deficient in GSD type I (Von Gierke disease)?
Glucose-6-phosphatase.
37
What are clinical features of GSD I?
Fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia, doll-like face.
38
What laboratory findings are seen in GSD I?
Hypoglycemia, hyperlipidemia, metabolic acidosis, high lactate, elevated uric acid.
39
What complications are associated with GSD I?
Short stature, delayed puberty, hepatic adenoma, renal disease.
40
What is the management of GSD I?
Frequent cornstarch feeds, avoid fasting, allopurinol for hyperuricemia, lipid control.
41
What enzyme is deficient in GSD type II (Pompe disease)?
Acid alpha-glucosidase (GAA).
42
What is the pathophysiology of Pompe disease?
Lysosomal glycogen accumulation due to GAA deficiency.
43
What are clinical features of infantile Pompe disease?
Cardiomegaly, hypotonia, macroglossia, respiratory distress, early death if untreated.
44
What are findings in late-onset Pompe disease?
Progressive muscle weakness, exercise intolerance, respiratory insufficiency.
45
What is the treatment for Pompe disease?
Enzyme replacement therapy (alglucosidase alfa).
46
What enzyme is deficient in GSD III (Cori disease)?
Debranching enzyme (amylo-1,6-glucosidase).
47
What are clinical features of GSD III?
Hepatomegaly, growth delay, fasting hypoglycemia, myopathy.
48
How is GSD III different from GSD I?
No lactic acidosis in GSD III; presence of muscle involvement differentiates it.
49
What enzyme is deficient in GSD IV (Andersen disease)?
Branching enzyme (glycogen branching enzyme).
50
What are clinical features of GSD IV?
Failure to thrive, hepatomegaly, hypotonia, progressive liver cirrhosis.
51
What is the prognosis of GSD IV?
Poor; often fatal in early childhood without liver transplant.
52
What enzyme is deficient in GSD V (McArdle disease)?
Muscle phosphorylase.
53
What are clinical features of GSD V?
Exercise intolerance, cramps, myoglobinuria after exercise.
54
What is the typical finding during exercise in GSD V?
Second wind phenomenon: improved exercise tolerance after rest.
55
What enzyme is deficient in GSD VI (Hers disease)?
Liver phosphorylase.
56
What are clinical features of GSD VI?
Mild hepatomegaly, ketosis, growth delay, improved with age.
57
How is GSD IX different from GSD VI?
GSD IX has phosphorylase kinase deficiency, can be X-linked and more variable.
58
What is the inheritance pattern of most GSDs?
Autosomal recessive.
59
Which GSDs are X-linked?
GSD IX (phosphorylase kinase deficiency).
60
What tests are used for diagnosis of GSDs?
Blood glucose, lactate, lipids, CK, liver enzymes, genetic testing, enzyme assay, biopsy.
61
What is classic galactosemia?
A life-threatening disorder caused by deficiency of GALT enzyme, leading to toxic galactose-1-phosphate accumulation.
62
What enzyme is deficient in classic galactosemia?
Galactose-1-phosphate uridyltransferase (GALT).
63
What is the inheritance pattern of galactosemia?
Autosomal recessive.
64
What are early clinical signs of classic galactosemia in neonates?
Jaundice, vomiting, hepatomegaly, failure to thrive, E. coli sepsis, cataracts.
65
What are long-term complications of untreated galactosemia?
Intellectual disability, speech delay, ovarian failure in females, poor growth.
66
What are common infections seen in galactosemia?
E. coli sepsis, especially in the neonatal period.
67
What lab findings support the diagnosis of galactosemia?
Elevated galactose and galactose-1-phosphate, positive reducing substances in urine.
68
What is the management of classic galactosemia?
Strict galactose-free diet (soy-based formula), monitor galactose-1-P levels.
69
What enzyme is deficient in galactokinase deficiency?
Galactokinase (GALK).
70
What is the clinical presentation of galactokinase deficiency?
Cataracts in infancy; no liver disease or neurodevelopmental issues.
71
How does galactokinase deficiency differ from classic galactosemia?
Galactokinase deficiency is milder, without systemic toxicity.
72
What enzyme is deficient in epimerase deficiency galactosemia?
UDP-galactose 4'-epimerase (GALE).
73
How is galactosemia diagnosed?
Newborn screening, GALT enzyme assay, genetic testing.
74
What are dietary sources of galactose?
Lactose-containing products: dairy, breast milk, some formulas.
75
What is hereditary fructose intolerance (HFI)?
A disorder of fructose metabolism causing toxicity after fructose intake.
76
What enzyme is deficient in HFI?
Aldolase B.
77
What are symptoms of HFI upon fructose ingestion?
Vomiting, lethargy, seizures, hepatomegaly, jaundice, hypoglycemia after fructose ingestion.
78
What foods trigger symptoms in HFI?
Fruits, table sugar (sucrose), honey, sweetened baby food.
79
What are long-term effects of untreated HFI?
Hepatomegaly, growth failure, renal tubular acidosis, hepatic failure.
80
What lab findings are suggestive of HFI?
Hypoglycemia, metabolic acidosis, elevated liver enzymes, reducing substances in urine.
81
What is the treatment for HFI?
Strict avoidance of dietary fructose, sucrose, sorbitol.
82
What is essential fructosuria?
A benign disorder causing asymptomatic fructosuria.
83
How does essential fructosuria differ from HFI?
No symptoms; fructose detected in urine without toxicity.
84
What enzyme is deficient in essential fructosuria?
Fructokinase.
85
Is essential fructosuria harmful?
No, it is benign and does not require treatment.
86
How is HFI diagnosed?
Fructose tolerance test, genetic testing for ALDOB mutations.
87
What is the inheritance pattern of HFI and essential fructosuria?
Both are autosomal recessive.
88
What is the role of aldolase B in fructose metabolism?
The enzyme that cleaves fructose-1-phosphate into dihydroxyacetone phosphate (DHAP) and glyceraldehyde is Aldolase
89
Why does hypoglycemia occur in HFI?
Fructose-1-phosphate accumulation inhibits glycogenolysis and gluconeogenesis.
90
What is the clinical importance of distinguishing HFI from other hypoglycemic disorders?
To prevent inappropriate dietary or therapeutic exposure that worsens symptoms.
91
What are amino acid metabolism disorders?
Inborn errors of metabolism due to defective breakdown or synthesis of amino acids.
92
How are they typically inherited?
Most are autosomal recessive.
93
What is phenylketonuria (PKU)?
A disorder of phenylalanine metabolism leading to neurotoxicity if untreated.
94
What enzyme is deficient in PKU?
Phenylalanine hydroxylase (PAH).
95
What are clinical features of untreated PKU?
Intellectual disability, microcephaly, seizures, hypopigmentation, eczema, musty body odor.
96
What causes the musty odor in PKU?
Phenylacetic acid accumulation.
97
How is PKU diagnosed?
Newborn screening with elevated phenylalanine levels.
98
What is the treatment for PKU?
Low phenylalanine diet for life, sapropterin in responsive cases.
99
What is the role of tetrahydrobiopterin (BH4) in PKU?
BH4 is a cofactor for PAH; BH4-responsive PKU can be treated with sapropterin.
100
What are long-term complications if PKU is untreated?
Severe intellectual disability, behavioral issues, epilepsy, reduced brain growth.
101
What is maternal PKU syndrome?
Teratogenic effect of high maternal phenylalanine on fetus—causes microcephaly, CHD, ID.
102
What is maple syrup urine disease (MSUD)?
A branched-chain amino acid disorder causing neurotoxicity.
103
What causes MSUD?
Deficiency of branched-chain alpha-ketoacid dehydrogenase complex (BCKDC).
104
What are clinical features of MSUD?
Poor feeding, vomiting, lethargy, encephalopathy, seizures, coma in neonates.
105
What odor is characteristic of MSUD?
Maple syrup or burnt sugar odor in urine.
106
How is MSUD diagnosed?
Plasma amino acid profile showing elevated leucine, isoleucine, valine.
107
What is the treatment for MSUD?
Protein restriction, emergency formula, thiamine trial in some forms.
108
What is thiamine-responsive MSUD?
A milder form responsive to thiamine supplementation.
109
What are complications of MSUD during stress?
Acute metabolic crisis with lethargy, ketoacidosis, cerebral edema, coma.
110
What is homocystinuria?
A disorder of methionine metabolism resulting in high homocysteine.
111
What enzyme is deficient in classic homocystinuria?
Cystathionine beta-synthase (CBS).
112
What are clinical features of homocystinuria?
Marfanoid habitus, ectopia lentis (downward), thromboembolism, ID, osteoporosis.
113
How is homocystinuria differentiated from Marfan syndrome?
Lens dislocation is downward in homocystinuria; upward in Marfan syndrome; also ID in homocystinuria.
114
What is the treatment for homocystinuria?
Low methionine diet, betaine, pyridoxine, folate, B12.
115
What vitamin is used in some homocystinuria cases?
Vitamin B6 (pyridoxine).
116
What complications arise from elevated homocysteine?
Thrombosis, strokes, intellectual disability, lens dislocation.
117
What is tyrosinemia type I?
A disorder of tyrosine metabolism due to fumarylacetoacetate hydrolase deficiency.
118
What are signs of tyrosinemia type I?
Hepatomegaly, failure to thrive, bleeding, cabbage odor, liver failure.
119
What is the treatment for tyrosinemia type I?
NTBC (nitisinone), low tyrosine and phenylalanine diet.
120
What is alkaptonuria?
A disorder of homogentisic acid metabolism causing dark urine and ochronosis.
121
What are organic acidemias?
Inherited metabolic disorders due to enzyme deficiencies affecting amino acid catabolism, resulting in organic acid accumulation.
122
What is the general pathophysiology of organic acidemias?
Impaired metabolism leads to buildup of toxic organic acids, causing metabolic acidosis and multiorgan dysfunction.
123
How do organic acidemias typically present in neonates?
Poor feeding, vomiting, hypotonia, lethargy, encephalopathy, metabolic acidosis, hyperammonemia.
124
What triggers decompensation in organic acidemias?
Fasting, illness, high-protein intake, stress, vaccinations, infections.
125
What are the hallmark lab features of organic acidemias?
Metabolic acidosis with increased anion gap, hyperammonemia, ketosis, hypoglycemia, neutropenia.
126
What is methylmalonic acidemia (MMA)?
A disorder of methylmalonic acid metabolism resulting in toxic metabolite accumulation.
127
What enzyme or cofactor defects cause MMA?
Methylmalonyl-CoA mutase deficiency or cobalamin (B12) metabolism defects.
128
What are clinical features of MMA?
Poor feeding, lethargy, vomiting, hypotonia, metabolic acidosis, hyperammonemia, developmental delay.
129
How is MMA diagnosed?
Elevated methylmalonic acid in urine/plasma, metabolic acidosis, ammonia, genetic testing.
130
What is the treatment for MMA?
Low-protein diet, carnitine, B12 (hydroxycobalamin in responsive forms), emergency care during crises.
131
What is propionic acidemia (PA)?
A disorder causing accumulation of propionic acid leading to metabolic crisis.
132
What enzyme is deficient in PA?
Propionyl-CoA carboxylase deficiency.
133
What are clinical features of PA?
Neonatal encephalopathy, vomiting, acidosis, hyperammonemia, neutropenia, thrombocytopenia.
134
How is PA differentiated from MMA?
MMA has elevated methylmalonic acid; PA does not. B12 response seen in some MMA types.
135
What is the treatment of PA?
Low-protein diet, carnitine, biotin trial, bicarbonate, antibiotics to reduce gut propionate production.
136
What are complications of MMA and PA?
Developmental delay, renal failure (MMA), cardiomyopathy, basal ganglia injury.
137
What is isovaleric acidemia?
A disorder of leucine metabolism resulting in isovaleric acid buildup.
138
What enzyme is deficient in isovaleric acidemia?
Isovaleryl-CoA dehydrogenase.
139
What are clinical features of isovaleric acidemia?
Vomiting, lethargy, metabolic acidosis, neutropenia, seizure risk.
140
What distinctive odor is associated with isovaleric acidemia?
Sweaty feet odor due to isovaleric acid accumulation.
141
How is isovaleric acidemia treated?
Protein restriction, carnitine, glycine supplementation, biotin trial.
142
What is multiple carboxylase deficiency?
A disorder of biotin metabolism causing multiple carboxylase enzyme deficiencies.
143
What enzymes are defective in multiple carboxylase deficiency?
Holocarboxylase synthetase (early) or biotinidase (late-onset).
144
What are features of multiple carboxylase deficiency?
Metabolic acidosis, alopecia, rash, neurologic symptoms, seizures.
145
What vitamin is used in treatment?
Biotin (lifelong high-dose therapy).
146
What is glutaric acidemia type I?
A lysine metabolism defect causing glutaric acid accumulation and striatal injury.
147
What are the clinical features of glutaric acidemia type I?
Macrocephaly, dystonia, spasticity, encephalopathy after illness or trauma.
148
What imaging findings are seen in glutaric acidemia I?
Frontotemporal atrophy, widened sylvian fissures ('bat-wing' appearance).
149
What is the acute management of organic acidemia crisis?
Stop protein intake, IV glucose, correct acidosis, carnitine, ammonia scavengers.
150
What is the long-term management strategy for organic acidemias?
Lifelong protein-restricted diet, emergency protocols, carnitine, metabolic team follow-up.
151
What are fatty acid oxidation disorders (FAODs)?
Inherited disorders of mitochondrial fatty acid oxidation enzymes.
152
What is the pathophysiology of FAODs?
Defective beta-oxidation leads to energy failure, hypoglycemia, and accumulation of toxic intermediates.
153
What are common clinical presentations of FAODs?
Hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, muscle weakness, sudden death.
154
What is MCAD deficiency?
Medium-chain acyl-CoA dehydrogenase deficiency; most common FAOD.
155
What are symptoms of MCAD deficiency?
Fasting intolerance, vomiting, hypoglycemia, seizures, coma, sudden death.
156
How is MCAD deficiency diagnosed?
Elevated medium-chain acylcarnitines (C6-C10) on newborn screening or plasma acylcarnitine profile.
157
What triggers metabolic crises in MCAD deficiency?
Fasting, infections, prolonged exercise, high-fat low-carbohydrate diet.
158
What is the treatment for MCAD deficiency?
Avoid fasting, frequent meals, emergency glucose administration, carnitine supplementation if deficient.
159
What is VLCAD deficiency?
Very long-chain acyl-CoA dehydrogenase deficiency affecting longer chain fatty acids.
160
What are clinical forms of VLCAD deficiency?
Severe neonatal form, infantile hepatomyopathic form, late-onset muscle form.
161
What symptoms are seen in severe VLCAD deficiency?
Cardiomyopathy, hypotonia, hepatomegaly, sudden death in infancy.
162
What is LCHAD deficiency?
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; affects long-chain fat oxidation.
163
What maternal complication is associated with fetal LCHAD deficiency?
Acute fatty liver of pregnancy (AFLP) and HELLP syndrome.
164
What are features of LCHAD deficiency in infants?
Hypoketotic hypoglycemia, cardiomyopathy, liver failure, peripheral neuropathy.
165
What is CPT-I deficiency?
Carnitine palmitoyltransferase I deficiency; impairs transport of fatty acids into mitochondria.
166
What are features of CPT-I deficiency?
Hypoketotic hypoglycemia, hepatomegaly, elevated free carnitine, low acylcarnitines.
167
What is CPT-II deficiency?
Carnitine palmitoyltransferase II deficiency; affects muscle fatty acid oxidation.
168
What symptoms are associated with CPT-II deficiency?
Muscle pain, rhabdomyolysis, myoglobinuria triggered by exercise, fasting, illness.
169
What is the typical lab finding during FAOD decompensation?
Hypoketotic hypoglycemia, elevated liver enzymes, low ketones, possible hyperammonemia.
170
What distinguishes hypoglycemia in FAODs from other causes?
Low ketone levels despite profound hypoglycemia.
171
What metabolic findings are absent in FAOD-related hypoglycemia?
Absent or minimal ketosis during hypoglycemia.
172
What is the role of plasma acylcarnitine profile in FAOD diagnosis?
Shows specific acylcarnitine accumulation patterns for different FAODs.
173
What is the typical acylcarnitine finding in MCAD deficiency?
Elevated C8, C6, C10:1 acylcarnitines.
174
What other diagnostic tests help in FAODs?
Urine organic acids, enzyme activity assays, genetic testing (ACADM gene for MCAD).
175
What is the role of carnitine in FAODs?
Carnitine binds and removes toxic fatty acyl groups; supplementation may be needed.
176
Why is fasting dangerous in FAODs?
Fasting depletes glycogen stores and forces reliance on impaired fatty acid oxidation.
177
What is the acute management of FAOD crises?
IV glucose, prevent catabolism, bicarbonate for acidosis, manage hyperammonemia if present.
178
How can FAODs be prevented?
Frequent feeding, avoid fasting, high-carbohydrate diet, emergency protocols during illness.
179
What are long-term complications of FAODs?
Developmental delay, cardiomyopathy, recurrent rhabdomyolysis.
180
What is newborn screening’s role in FAODs?
Early detection on newborn screening enables preventive care and improves outcomes.
181
What are urea cycle disorders (UCDs)?
Inherited disorders caused by enzyme deficiencies impairing ammonia detoxification into urea.
182
What is the main function of the urea cycle?
To remove excess nitrogen by converting ammonia into urea for excretion.
183
What is the pathophysiology of UCDs?
Blockage in the cycle leads to toxic ammonia accumulation.
184
What are common symptoms of UCDs?
Poor feeding, vomiting, lethargy, encephalopathy, coma, respiratory alkalosis.
185
What is hyperammonemia?
Elevated blood ammonia levels causing neurologic toxicity.
186
Why is hyperammonemia dangerous?
Ammonia crosses the blood-brain barrier, causing cerebral edema and encephalopathy.
187
What triggers a hyperammonemic crisis in UCDs?
High protein intake, fasting, infections, stress, postpartum period.
188
What lab findings are seen in UCDs?
Hyperammonemia, low BUN, respiratory alkalosis, elevated glutamine, low citrulline in some cases.
189
What is the typical acid-base status in UCDs?
Respiratory alkalosis early (contrast to metabolic acidosis in organic acidemias).
190
How is the diagnosis of UCDs made?
Ammonia levels >100–150 µmol/L in sick neonate, plasma amino acids, urine orotic acid, genetic testing.
191
What plasma amino acid finding suggests UCD?
Low citrulline (except elevated in ASS1 and ASL deficiencies).
192
What is the significance of elevated glutamine in UCDs?
Elevated glutamine reflects intracellular ammonia detoxification attempt.
193
Which UCD is X-linked?
Ornithine transcarbamylase (OTC) deficiency.
194
What enzyme is deficient in OTC deficiency?
Ornithine transcarbamylase (OTC).
195
What are the clinical features of OTC deficiency?
Severe neonatal hyperammonemia in males; milder in heterozygous females.
196
What distinguishes OTC deficiency from organic acidemias?
Respiratory alkalosis without severe acidosis; elevated urine orotic acid in OTC.
197
What is CPS1 deficiency?
Carbamoyl phosphate synthetase I deficiency.
198
What are features of CPS1 deficiency?
Severe hyperammonemia without orotic aciduria; presents neonatally.
199
What is ASS1 deficiency (citrullinemia type I)?
Deficiency of argininosuccinate synthetase (ASS1).
200
What are features of citrullinemia type I?
Hyperammonemia with elevated plasma citrulline.
201
What is ASL deficiency (argininosuccinic aciduria)?
Deficiency of argininosuccinate lyase (ASL).
202
What features are associated with ASL deficiency?
Hyperammonemia with elevated citrulline and argininosuccinic acid; hepatomegaly.
203
What is arginase deficiency?
Deficiency of arginase enzyme.
204
How does arginase deficiency differ from other UCDs?
Progressive spastic diplegia, milder hyperammonemia; presents later than other UCDs.
205
What are first-line treatments for hyperammonemia?
IV fluids, IV dextrose to suppress catabolism, ammonia scavengers.
206
What is the role of sodium benzoate and sodium phenylbutyrate?
Alternative pathways to remove nitrogen by conjugating it into excretable compounds.
207
What is the role of arginine supplementation in UCDs?
Provides essential urea cycle intermediates and improves ammonia detoxification.
208
When is dialysis indicated in UCDs?
Ammonia >200–300 µmol/L, severe encephalopathy, no response to medical therapy.
209
What is the dietary management of UCDs?
Low-protein diet, frequent feeds, emergency sick-day plans.
210
What are long-term complications of UCDs?
Neurodevelopmental delay, cognitive impairment, recurrent crises.
211
What are lysosomal storage disorders (LSDs)?
Inherited metabolic diseases caused by deficiencies of lysosomal enzymes leading to accumulation of substrates.
212
What is the pathophysiology of LSDs?
Defective lysosomal degradation results in accumulation of undigested macromolecules inside cells.
213
What are the main clinical features of LSDs?
Organomegaly, coarse facies, skeletal abnormalities, neurologic deterioration, eye findings.
214
How are LSDs inherited?
Mostly autosomal recessive; Hunter syndrome is X-linked recessive.
215
What are sphingolipidoses?
LSDs affecting sphingolipid metabolism (e.g., Gaucher, Niemann-Pick, Tay-Sachs).
216
What are mucopolysaccharidoses (MPS)?
LSDs involving accumulation of glycosaminoglycans (e.g., Hurler, Hunter).
217
What is Gaucher disease?
Most common LSD; causes glucocerebroside accumulation.
218
What enzyme is deficient in Gaucher disease?
Beta-glucocerebrosidase deficiency.
219
What are clinical features of Gaucher disease type 1?
Hepatosplenomegaly, anemia, thrombocytopenia, bone pain, fractures; no CNS involvement.
220
What are features of Gaucher disease types 2 and 3?
Type 2: acute neuronopathic (infantile); Type 3: chronic neuronopathic form with slower CNS involvement.
221
What is the treatment for Gaucher disease?
Enzyme replacement therapy (ERT) with imiglucerase; substrate reduction therapy.
222
What is Niemann-Pick disease types A and B?
LSDs causing sphingomyelin accumulation in macrophages.
223
What enzyme is deficient in Niemann-Pick types A and B?
Acid sphingomyelinase deficiency.
224
What are features of Niemann-Pick disease type A?
Hepatosplenomegaly, failure to thrive, cherry-red spot, neurodegeneration; early death.
225
What is Tay-Sachs disease?
A GM2 gangliosidosis causing neurodegeneration.
226
What enzyme is deficient in Tay-Sachs disease?
Hexosaminidase A deficiency.
227
What are clinical features of Tay-Sachs disease?
Developmental regression, hypotonia, exaggerated startle, cherry-red spot on retina.
228
What is Sandhoff disease?
Similar to Tay-Sachs but involves both Hexosaminidase A and B deficiency.
229
What is Krabbe disease?
A leukodystrophy due to galactocerebrosidase deficiency.
230
What are features of Krabbe disease?
Irritability, hypertonia, psychomotor regression, optic atrophy, early death.
231
What is metachromatic leukodystrophy?
A demyelinating LSD caused by arylsulfatase A deficiency.
232
What enzyme is deficient in metachromatic leukodystrophy?
Arylsulfatase A deficiency.
233
What are mucopolysaccharidoses (MPS) characterized by?
Accumulation of glycosaminoglycans (GAGs) in various tissues.
234
What is Hurler syndrome (MPS I)?
MPS type I due to alpha-L-iduronidase deficiency.
235
What are clinical features of Hurler syndrome?
Coarse facial features, hepatosplenomegaly, developmental delay, corneal clouding, skeletal dysplasia.
236
What is Hunter syndrome (MPS II)?
MPS type II due to iduronate-2-sulfatase deficiency.
237
How is Hunter syndrome different from Hurler syndrome?
No corneal clouding; X-linked inheritance.
238
What is Sanfilippo syndrome (MPS III)?
MPS type III; primarily affects CNS causing severe neurodegeneration.
239
What is the diagnostic approach to LSDs?
Enzyme assays, urinary glycosaminoglycans, genetic testing, clinical features.
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What is the role of enzyme replacement therapy in LSDs?
Available for several LSDs (e.g., Gaucher, Fabry, Hurler) to slow disease progression.
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What are peroxisomal disorders?
Inherited metabolic conditions caused by defects in peroxisome formation or function.
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What is the function of peroxisomes in cells?
Breakdown of very long-chain fatty acids (VLCFAs), synthesis of plasmalogens, bile acid metabolism, detoxification.
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What is the pathophysiology of peroxisomal disorders?
Accumulation of VLCFAs, phytanic acid, bile acid intermediates, and impaired plasmalogen synthesis.
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What are general clinical features of peroxisomal disorders?
Neurologic impairment, dysmorphic features, liver dysfunction, vision and hearing loss, skeletal abnormalities.
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What are examples of peroxisomal biogenesis disorders (PBDs)?
Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), infantile Refsum disease.
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What are examples of single-enzyme peroxisomal disorders?
X-linked adrenoleukodystrophy (X-ALD), Refsum disease, acyl-CoA oxidase deficiency.
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What is Zellweger syndrome?
A severe peroxisomal biogenesis disorder presenting in the neonatal period.
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What are clinical features of Zellweger syndrome?
Hypotonia, seizures, craniofacial dysmorphism, hepatomegaly, failure to thrive, death in infancy.
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What are key laboratory findings in Zellweger syndrome?
Elevated VLCFAs, decreased plasmalogens, bile acid abnormalities.
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What is neonatal adrenoleukodystrophy (NALD)?
A milder form of Zellweger spectrum disorder with later onset and less severe features.
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How does NALD differ from Zellweger syndrome?
NALD has less severe hypotonia and longer survival than Zellweger syndrome.
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What is infantile Refsum disease?
A mild Zellweger spectrum disorder with sensory neuropathy and retinitis pigmentosa.
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What is X-linked adrenoleukodystrophy (X-ALD)?
An X-linked disorder of VLCFA metabolism leading to demyelination and adrenal insufficiency.
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What gene is mutated in X-ALD?
ABCD1 gene mutation on X chromosome.
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What tissues are primarily affected in X-ALD?
Brain white matter, adrenal cortex, testes.
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What are clinical features of childhood cerebral X-ALD?
Behavioral changes, cognitive decline, adrenal insufficiency, vision loss, rapid neurologic deterioration.
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What lab test screens for X-ALD?
Plasma VLCFA levels (especially elevated C26:0).
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What are MRI findings in X-ALD?
Symmetrical white matter changes, especially parieto-occipital regions.
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What is the treatment for X-ALD?
Early HSCT (hematopoietic stem cell transplant) in cerebral disease; adrenal hormone replacement.
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What is Lorenzo’s oil?
A mixture of oleic and erucic acids aimed to normalize VLCFA levels; limited proven benefit.
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What is adult-onset adrenomyeloneuropathy (AMN)?
Adult X-ALD variant causing slowly progressive spastic paraparesis and bladder dysfunction.
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What are clinical features of AMN?
Progressive leg weakness, ataxia, adrenal insufficiency later in life.
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What is peroxisomal D-bifunctional protein deficiency?
A severe disorder of peroxisomal beta-oxidation enzymes.
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What are features of D-bifunctional protein deficiency?
Neonatal hypotonia, seizures, severe growth retardation, liver dysfunction, early death.
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What is rhizomelic chondrodysplasia punctata (RCDP)?
A skeletal dysplasia due to defective plasmalogen synthesis.
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What are features of RCDP?
Short proximal limbs, cataracts, facial dysmorphism, severe growth retardation.
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What biochemical abnormalities are seen in peroxisomal disorders?
Elevated VLCFAs, phytanic acid, pristanic acid, abnormal bile acids, low plasmalogens.
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What is the role of very long-chain fatty acids (VLCFA) in diagnosis?
Elevated plasma C26:0 and abnormal C24:0/C22:0 and C26:0/C22:0 ratios.
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How is diagnosis of peroxisomal disorders confirmed?
Biochemical testing, enzyme assays, molecular genetic analysis.
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What is the general prognosis of peroxisomal biogenesis disorders?
Poor; Zellweger syndrome often fatal within first year; milder forms vary in severity.
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What are mitochondrial disorders?
Inherited or sporadic disorders caused by defects in oxidative phosphorylation (OXPHOS) machinery.
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What is the primary function of mitochondria?
Energy production via oxidative phosphorylation (ATP synthesis).
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What is the pathophysiology of mitochondrial disorders?
Impaired oxidative phosphorylation leads to energy failure and lactic acidosis.
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What are general clinical features of mitochondrial diseases?
Multisystem involvement including CNS, muscle, cardiac, GI, endocrine dysfunction.
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What tissues are most affected by mitochondrial dysfunction?
Brain, muscle, heart, liver, kidney—high-energy requiring tissues.
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What is maternal inheritance?
Mitochondrial DNA (mtDNA) is inherited solely from the mother.
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What is heteroplasmy?
Presence of a mix of normal and mutant mitochondria within a cell.
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What is threshold effect in mitochondrial diseases?
A certain proportion of mutant mitochondria must be exceeded before dysfunction appears.
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What is MELAS syndrome?
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes.
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What are clinical features of MELAS?
Stroke-like episodes, seizures, short stature, hearing loss, diabetes, lactic acidosis.
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What is MERRF syndrome?
Myoclonic Epilepsy with Ragged-Red Fibers.
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What are clinical features of MERRF?
Myoclonus, epilepsy, ataxia, muscle weakness, hearing loss.
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What is Leigh syndrome?
A subacute necrotizing encephalopathy of infancy or early childhood.
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What are features of Leigh syndrome?
Psychomotor regression, hypotonia, brainstem signs, basal ganglia lesions on MRI.
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What is Kearns-Sayre syndrome (KSS)?
A mitochondrial disease affecting eye muscles, heart, and retina.
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What are features of KSS?
Progressive external ophthalmoplegia, ptosis, pigmentary retinopathy, heart block.
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What is Pearson syndrome?
A fatal disorder presenting with sideroblastic anemia and exocrine pancreatic dysfunction.
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What is the inheritance pattern of most mitochondrial DNA mutations?
Maternal inheritance pattern; both sons and daughters affected.
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How are nuclear DNA mutations involved in mitochondrial diseases?
Mutations in nuclear genes encoding mitochondrial proteins can cause autosomal recessive/dominant disorders.
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What lab findings suggest mitochondrial disease?
Elevated lactate and pyruvate, elevated CSF lactate, low plasma alanine.
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What is lactic acidosis in mitochondrial disorders?
Chronic lactic acidosis is a hallmark of mitochondrial dysfunction.
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What is the role of MRI in mitochondrial disease?
May show bilateral symmetric basal ganglia or brainstem lesions.
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What is ragged-red fiber?
Aggregates of abnormal mitochondria seen on Gomori trichrome staining of muscle.
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What tissues are used for muscle biopsy in mitochondrial disease diagnosis?
Skeletal muscle biopsy (e.g., vastus lateralis).
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What is the role of genetic testing in mitochondrial disorders?
Confirms specific mtDNA or nuclear gene mutations causing mitochondrial disease.
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What is the treatment approach for mitochondrial diseases?
Supportive and symptomatic; no cure; focus on energy conservation and preventing crises.
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What are common supportive therapies in mitochondrial disease?
Physical therapy, nutritional support, seizure control, cardiac monitoring.
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What is a mitochondrial cocktail?
Coenzyme Q10, L-carnitine, thiamine, riboflavin, arginine, antioxidants.
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What are examples of mitochondrial toxins to avoid?
Valproate, aminoglycosides, chloramphenicol (mitochondrial toxic drugs).
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What is the prognosis in mitochondrial disorders?
Variable depending on mutation; MELAS and Leigh have poorer outcomes, KSS survival into adulthood.
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What defines hypoglycemia in neonates and children?
Plasma glucose <40 mg/dL in neonates; <50–60 mg/dL in older infants and children.
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What are common metabolic causes of hypoglycemia?
Fatty acid oxidation defects (FAODs), glycogen storage diseases, hyperinsulinism, hormonal deficiencies, organic acidemias.
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What is the pathophysiology of hypoglycemia in FAODs?
Failure of ketogenesis and gluconeogenesis during fasting leads to energy depletion.
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What is ketotic hypoglycemia?
A benign condition causing hypoglycemia with ketosis in toddlers after fasting or illness.
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What are features of ketotic hypoglycemia?
Occurs in healthy children after overnight fasts; resolves with glucose intake; no hepatomegaly.
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What is hypoketotic hypoglycemia?
Low blood glucose without appropriate rise in ketones; suggests FAOD or hyperinsulinism.
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Which disorders cause hypoketotic hypoglycemia?
MCAD deficiency, VLCAD deficiency, congenital hyperinsulinism.
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What is hyperinsulinism?
Excessive insulin secretion despite hypoglycemia.
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How does congenital hyperinsulinism present?
Seizures, irritability, poor feeding, macrosomia at birth, hypoglycemia unresponsive to fasting.
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What lab findings suggest hyperinsulinism?
High insulin, low ketones, low free fatty acids, inappropriate suppression of ketogenesis.
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What is the treatment for congenital hyperinsulinism?
Diazoxide, octreotide, surgery for focal lesions (e.g., partial pancreatectomy).
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What is the significance of critical samples during hypoglycemia?
Helps distinguish between different causes of hypoglycemia.
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What should be collected during a hypoglycemic episode?
Glucose, insulin, cortisol, GH, free fatty acids, ketones, lactate, ammonia, acylcarnitines, urine organic acids.
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What is the role of plasma ketones in evaluating hypoglycemia?
Low/absent ketones suggest hyperinsulinism or FAOD; high ketones suggest GSD or ketotic hypoglycemia.
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How does cortisol deficiency cause hypoglycemia?
Cortisol deficiency impairs gluconeogenesis and glycogenolysis.
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What is the role of growth hormone in glucose metabolism?
Growth hormone promotes lipolysis and gluconeogenesis; deficiency leads to hypoglycemia.
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What endocrine causes should be excluded in persistent hypoglycemia?
Adrenal insufficiency, growth hormone deficiency, hypothyroidism.
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What is the Whipple triad?
Symptoms of hypoglycemia + low plasma glucose + resolution of symptoms with glucose administration.
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What is the approach to hypoglycemia evaluation?
Analyze critical labs, screen for metabolic/endocrine causes, imaging as indicated.
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What are clues suggesting an inborn error of metabolism in hypoglycemia?
Recurrent, fasting-induced hypoglycemia, hepatomegaly, metabolic acidosis, unusual odors.
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What is newborn metabolic screening?
Population-based test detecting specific inborn errors early to allow prompt treatment.
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What is tandem mass spectrometry (MS/MS) used for in newborn screening?
Detects amino acid disorders, organic acidemias, FAODs, and others using dried blood spots.
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What disorders are detected by newborn screening using MS/MS?
PKU, MSUD, MCAD deficiency, MMA, citrullinemia, etc.
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What is the importance of early diagnosis of metabolic hypoglycemia?
Prevents neurodevelopmental damage, coma, death.
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What is the emergency management of hypoglycemia?
IV dextrose bolus (2 mL/kg D10W) and infusion (4–6 mg/kg/min); monitor glucose levels.
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When is glucagon administration appropriate?
For hypoglycemia caused by hyperinsulinism or GSD if IV access delayed.
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What is the long-term management of metabolic hypoglycemia?
Frequent high-carbohydrate meals, emergency glucose supply, uncooked cornstarch (in GSD).
328
What is the role of frequent feeding in metabolic disorders?
Prevents catabolic states that can precipitate hypoglycemia.
329
What diagnostic tests follow abnormal newborn screening?
Repeat specific biochemical, enzymatic, and molecular tests to confirm diagnosis.
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What is the prognosis of metabolic hypoglycemia with early treatment?
Good if hypoglycemia is rapidly recognized and treated; cognitive outcomes depend on timing.
