Metabolic disorders Flashcards

Question 1

Q

Lysosomal storage disorders - overview

Answer

A

GM1 Ganliosidosis
Tay Sachs disease: Cherry red spot
Sandhoff disease: Cherry red spot
Landing disease: Cherry red spot
Gaucher disease
Niemann-Pick A/B: A with cherry red spot in some
Fabry disease: XLR*
Lipogranulomatosis/Farber’s disease
Metachromatic leukoydystrophy
Krabbe disease
Mucopolysaccharidosis - Type II Hunter: XLR
- Others: Hurler (I H), Scheie (1 S), Hurler-Scheie (1 H S), Sanfillipo (III), Morquio (IV), Maroteaux-Lamy (VI)
Oligosaccharidoses
- Sialidosis I: Cherry red spot
- Others: alpha-mannosidosis, mucolipidosis II, galactosidasosis
*Others are AR

Question 2

Q

Peroxisomal disorders

Answer

A

Peroxisomes are more numerous in cells that metabolize complex lipids
Characterized by dysmorphisms, neurologic abnromalities, hepato-intestinal dysfunction
Zellweger spectrum disorder
X-linked adrenoleukodystrophy: XLR
Classical refsum
*Others are AR

Question 3

Q

Disorders involving ER and Golgi body

Answer

A

Congenital disorder of glycosylation: AR

Question 4

Q

Aminoacidopathies

Answer

A

1/2 with neurological manifestations, usually psychomotor delay
PKU
Homocystinuria
Molybdenum cofactor deficiency/sulfite oxidase deficiency
Non-ketotic hyperglycemia
* All are AR

Question 5

Q

Organic acidemias/acidurias

Answer

A

Maple syrup urine disease
Isovaleric academia, propionic acidemia
Methylmalonic acidemia
Glutaric acidemia

Question 6

Q

Glycogen storage diseases

Answer

A

I Von Gierkes
II Pompe
V McArdles
VII Tarui

Question 7

Q

XLR

Answer

A

Fabry - lysosomal
Hunter - lysosomal
X-linked adrenoleukodystrophy - perixosomal
OTC deficiency type 2 - urea cycle
PDHC (pydruvate dehydrogenase complex) deficiency secondary to pyruvate dehydrogenase - congenital lactic academia, pyruvate carboxylase deficiency, disorder of energy metabolism
Menkes disease - NOS
Lesch-Nyhan - XL but NOS
Pelizaeus-Merzbacher disease - NOS

Question 8

Q

Urea cycle disorders

Answer

A

Carabmoyl phosphate synthetase deficiency (type 1)
Ornithine transcarbamylase deficiency (type 2): XLR
*Others are AR

Key is no metabolic acidosis, they are alkalotic

Typically associated with hyperammonemia, though some organic amino acidemias/urias can have elevated NH3

Question 9

Q

Mitochondrial disorders

Answer

A

Leigh syndrome
Kearns-Sayre: Mostly sporadic
CPEO
MERRF
MELAS
LHON
Alpers-Huttenlocher disease

Others are a mixture of AD, AR, and maternal

Question 10

Q

Congenital lactic acidemias

Answer

A

Pyruvate dehydrogenase complex deficiency: Pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, PEPCK deficiency

Question 11

Q

Fatty acid oxidation defects

Answer

A

Carnitine cycle defects: Carnitine transporter, CPT-1, Carnitine-Acylcarnitine translocase, CPT-2
Beta oxidation defects: MCAD deficiency, VLCAD, SCAD, Trifunctional protein deficiency
ALL ARE AR

Question 12

Q

Nieman Pick type A/B - gene/enzyme/accumulation

Answer

A

Lysosomal storage disease - sphingolipidoses
Genetics - AR, SMPD1
Deficiency - Sphingomyelinase
Accumulation - Sphingomyelin in CNS, liver, spleen

Question 13

Q

Niemann A/B clinical

Answer

A

Lysosomal storage disorders: sphingolipidoses

A: Clinical deterioration in the 1st YOL w/FTT, MASSIVE hepatosplenomegaly, hypotonia, head lag, inability to sit, decreased reflexes, most do not survive past 3 years old. Dx by measuring enzymes in leukocytes/fibroblasts. Tx with supportive care. BUZZ WORDS: Cherry red spot in 50%, F_oam cells (aka Niemann-Pick cells) in bone marrow - vacuolated histiocytes with lipid accumulation where sphingomyelin adopts the form of concentric lamellar bodies_

B: S(x)s start in late childhood adolescence, most have HS after infancy with hypercholesterolemia, pulmonary involvement is common (ILD), but rare neurological problems. Tx with BMT and replacement therapy tried but not for the A bc it does not improve neurological outcomes.

Question 14

Q

Niemann Pick C - G/E/A

Answer

A

*Not really a lysosomal storage disease, sphingolipidoses
AR, NPC1/NPC2 on 18q11
Leads to impaired cholesterol transport and metabolism that results in accumulation of sphingomyelin

[Normally, cholesterol is hydrolyzed in lysosomes and later transported to the plasma membrane; in Niemann-Pick type C, however, there is a problem in cholesterol transport and it, therefore, accumulates in perinuclear lysosomes.]

Question 15

Q

Niemann Pick C

Answer

A

*Not really a lysosomal storage disease, sphingolipidoses
Variable s(x)s that can present at any age: hepatosplenomegaly, cherry red spot, vertical supranuclear gaze palsy (high yield), developmental regression, ataxia, seizures, dystonia, cataplexy, pathology - visceral accumulation of lipids and foamy histiocytes with membrane-bound lamellar structures and lucent vacuoles. Neuronal ballooning → neuronal loss and cerebral and cerebellar atrophy
Dx: Filipin staining - Demonstrates impaired ability of cultured fibroblasts to esterify cholesterol. Unesterified cholesterol accumulates in perinuclear lysosomes, and this is detected by the fluorescent stain Filipin.
Tx: Miglustat - inhibits glycosphingolipid synthesis

Question 16

Q

Gaucher disease - G/A/E

Answer

A

Lysosomal storage disorders: Sphingolipidoses
AR, gene GBA
Deficiency of beta-glucocerebrosidase
Accumulation of glucocerebroside lipids

Question 17

Q

Gaucher disease - clinical

Answer

A

Lysosomal storage disorders: Sphingolipidoses
Most frequent LSD, most prevalent disease among Ashkenazi Jews
Type 1 - MC, typical adult onset, n_o neuro s(x)s, but with hepatosplenomegaly with anemia and thrombocytopenia, skeletal involvement, and pulmonary infiltrates._
Type 2 - infantile onset, severe progressive CNS disease, HS, death by 2 years old (also hydrops fetalis and cutaneous changes)
Type 3 - Intermediate between 2 and 3, onset age 2
Tx: Enzyme replacement for 1&3 (miglustat), Type 2 supportive

*Glucosylceramide forms fibrillary aggregates that accumulate in macrophages, leading to the cell cytoplasm presenting a characteristic ‘crumpled tissue paper’ appearance.

Question 18

Q

Fabry Disease - G/A/E

Answer

A

Lysosomal storage disorders: Sphingolipidoses
XL deficiency of alpha-galactosidase A
Accumulation of ceramide trihexoside

Question 19

Q

Fabry disease - clinical

Answer

A

Lysosomal storage disorders: Sphingolipidoses
Female carriers have s(x)s
S(x)s result from storage of glycolipids in blood vessels, heart, peripheral nerves, kidney, cornea
Recurrent attacks of burning pain in distal extremities (acroparesthesias), cardiomyopathy (valvular disease, arrhythmias, ischemic heart disease), stroke (from endothelial and vascular smooth muscle involvement) , aneurysm, angiokeratomas over “bathing trunk” area, renal damage (secondary to endothelial and glomerular damage), corneal opacity
Dx: measure alpha-galactosidase in fibroblasts or leukocytes, genetic testing; see Maltese cross (birefringent lipid deposits) in urine (lysosomal storage of birefringent lipids, with membrane-bound lamellar deposits on electron microscopy)
Tx: enzyme replacement, phenytoin, carbamazepine, gabapentin - Na blockade

Question 20

Q

Farber’s disease - G/A/E

Answer

A

Lysosomal storage disorders: Sphingolipidoses
AR inheritance, deficiency in ceramidase, accumulation of ceramide

Question 21

Q

Farber’s disease - clinical

Answer

A

Lysosomal storage disorders: Sphingolipidoses
Infantile onset, swollen and painful deformed joints, progressive neuro s(x)s, subcutaneous nodules, dyspnea, death 2 y
Dx: Ceramidase activity in fibroblasts
Tx: Supportive, steroids for joint pain

Question 22

Q

GM1 Gangliosidosis - G/A/E

Answer

A

Lysosomal storage disorders: Sphingolipidoses
AR, deficiency of beta-galactosidase (as opposed to alpha-galactosidase A in Fabry disease), GLB1 gene
Accumulation in GM1 ganglioside, GM2 = Tay Sachs

Question 23

Q

GM1 Gangliosidosis - clinical

Answer

A

Lysosomal storage disorders: Sphingolipidoses
S(x)s:
Infantile - dysmorphic, hypotonia, rapid progression, hepatosplenomegaly, seizures, cherry red spot (50%), death by age 2
Juvenile - normal 1st year then lose skills, ataxia, seizures, spastic paresis, death by 10 y
Adult - dystonia or Parkinsonian features in childhood than severe dementia
Dx: B-galactosidase activity in leukocytes
Tx: Supportive care

Question 24

Q

GM2 Gangliosidoses - G/A/E

Answer

A

Lysosomal storage disorders: Sphingolipidoses
Hexosaminodase A deficiency - infantile version: Tay-Sachs
Sandhoff disease - combination of hexosaminidase A/B deficiency
Hexosamindase activator deficiency - rare
AR inheritance
Involved genes: HEXA/B, GM2A
Accumulation of GM2 ganglioside

Question 25

Q

Hexosaminidase A Deficiency

Answer

A

Lysosomal storage disorders: Sphingolipidoses
Infantile form Tay-Sachs, juvenile, adult
MC in Ashkenazi Jews
S(x)s: Infantile - developmental regression by 6 months, exaggerated startle, loss of visual attention, cherry red macula, hypotonia->spasticity, seizures, progressive macrocephaly, bright thalami on head CT, death 2-4 y. NO HS. Juvenile: Ataxia dementia 2nd year or later, cherry red macula rare. Adult: psychosis, dystonia, supranuclear opthalmoplegia, ataxia, anterior horn cell disease
Dx: enzyme activity in fibroblasts, leukocytes, plasma
Tx: supportive

Question 26

Q

Sandhoff disease - G/A/E + clinical

Answer

A

Lysosomal storage disorders: Sphingolipidoses
Hexosaminidase A/B deficiency
Accumulation of GM2 ganglioside
Same clinical features as Tay-Sachs EXCEPT can have HS
Dx: Enzyme activity in fibroblasts, leukocytes, plasma
Tx: Supportive

Question 27

Q

Metachromatic leukodystrophy - G/A/E

Answer

A

Lysosomal storage disorders: Sphingolipidoses
AR, 2/2 mutations in 1.) arylsulftase A gene resulting in arylsulfatase deficiency that leads to accumulation of sulfates or 2.) PSAP gene, leading to deficiency of a sphingolipid activator protein (SAP-B or saposin B) that normally stimulates the degradation of sulfatides by arylsulfatase A
Accumulates cerebroside sulfate

Question 28

Q

Metachromatic leukodystrophy - clinical

Answer

A

Lysosomal storage disorders: Sphingolipidoses
Central and peripheral demyelination
MRI with central demyelination sparing U-fibers (vs posterior demyelination in X-linked adrenoleukodystrophy)
Decreased velocity on NCS
Elevated CSF protein
Sxs: Infantile form - onset 1-2 years, absent DTRs, spastic quadriparxsis, dementia, optic atrophy, death; juvenile form - onset 3-16 years, initial decline in school performance, then ataxia, decreased DTRs, spastic quadraparesis, dementia. Can have seizures, bulbar symptoms, temor; adult form - more than 16, psychiatric symptoms, dementia, spastic paresis, optic atrophy, dystonia, may not have abnormal NCV
Dx: urine sulfatides elevated, enzyme activity may be decreased in leukocytes or fibroblasts but limitations
Tx: BMT, supportive

Question 29

Q

Krabbe disease (globoid cell leukodystrophy)

Answer

A

Lysosomal storage disorders: Sphingolipidoses
AR, deficiency of galactocerebroside B-galactosidase
Gene: GALC

Question 30

Q

Krabbe disease (globoid cell leukodystrophy - clinical)

Answer

A

Lysosomal storage disorders: Sphingolipidoses
Also see central and peripheral demyelination with MRI with central demyelination, sparing U-fibers (diffuse and not posteriorly predominant like X-linked adrenoleukodystrophy). Decreased velocity on nerve conduction studies. CSF with elevated protein.
S(x)s: Infantile form - begins 3-6 most with irritability = crabby baby, tonic spasms with stimulation, optic atrophy, blindness, deafness, unexplained fever, then opisthotonus, seizures, loss of bulbar function, death by 2 yo (also have demyelinating polyneuropathy with areflexa); late infantile form: begins 6 mos-3 years, irritability, failing vision, ataxia, motor deterioration, stiffness; adult form reported, can have normal NCS
Dx: Enzyme activity in fibroblasts or leukocytes. See multinuclear macrophages (globoid cell) in cerebral white mater.
Tx: supportive are for infantile (one small study showed benefit of unrelated umbilical cord blood stem cells when given to as(x) patients with infantile form), BMT for mild cases, later onset early in course of disease

Question 31

Q

Cerebrotendinous xanthomatosis - G/A/E and clinical

Answer

A

Lysosomal storage disorders: Sphingolipidoses
AR
CNS accumulation of cholestanol, cerebellar demyelination
Clinical - tendinous xanthomas, progressive ataxia, dementia, cataracts (HIGH YIELD)

Question 32

Q

Multiple sulfatase deficiency

Answer

A

Lysosomal storage disorders: Sphingolipidoses
AR, deficiency of arylsulfatases A, B, C, mucopolysaccharide sulfates, steroids sulfates, clinical picture between MLD and mucopolysaccharidoses

Question 33

Q

Mucopolysaccharidoses - general

Answer

A

Type of lysosomal storage disease
From deficiency of enzymes that degrade heparan sulfate - nervous tissue, dermatan sulfate - skin, lung, heart valves, and keratan sulfate - skeletal; these are all
Accumulation of mucopolysaccharides causes clinical features - coarse features, short stature, HS, bone and joint problems, reduced life span, corneal clouding and CNS s(x)s in some
Dx: measurement of glycosaminoglycans aka mucopolysaccharides in urine, measurement of enzyme activity in cultured fibroblasts or leukocytes
Tx: recombinant alpha-L-iduronidase for Hurler, H-S, moderate-severe S but only improves pulmonary f(x) and endurance, for hunter, enzyme replacement with idursulfase, limited success with umbilical cord blood, stem cell or bone marrow transplantation for some

Question 34

Q

MPS I

Answer

A

Lysosomal storage disorder: mucopolysaccharidoses
MPS I H/S/HS: accumulation of dermatan and heparan sulfate, S/HS also alpha-L-iduronidase implicated

The diagnosis of MPS type I is based on elevated urinary excretion of dermatan and heparan sulfate and confirmed with enzyme analysis in leukocytes and fibroblasts. Pathologically, there are cells with vacuolated appearance, expansion of perivascular spaces in the CNS, and neuronal lipidosis. Electron microscopy (not light microscopy) demonstrates reticulogranular material in epithelial and mesenchymal cells, and lamellar material in neurons, some of which adopt a layered appearance and are called zebra bodies. Enzyme replacement therapy can be used to treat non-CNS manifestations of the disease. Stem cell transplantation can be potentially helpful

Question 35

Q

MPS II/III

Answer

A

Lysosomal storage disorder: mucopolysaccharidoses
Hunter no corneal clouding bc “Hunters need to see” -> accumulation of dermatan and heparan sulfate (also Hunter XL because Hunters also hit the X)
MPS III: accumulation of heparan sulfate, main manifestation is ID

Hunter’s syndrome or MPS type II is caused by a defect in iduronate sulfatase, with accumulation of dermatan sulfate and heparan sulfate. These patients have the Hurler phenotype but lack the corneal clouding and have characteristic nodular ivory-colored lesions on the back, shoulders, and upper arms.

Question 36

Q

MPS IV/VI

Answer

A

MPS IV: N-acetylgalactosamine-6-sulfatase OR B-galactosidase deficiency resulting in accumulation of keratan sulfate
MPS VI: N-acetylgalactosamine-4-sulfatase

Question 37

Q

Peroxisomal disorders

Answer

A

Characterized by dysmorphisms, neurological abnormalities, hepato-intestinal dysfunction
Dx: begin with plasma very long chain fatty acids +/- phytanic acid

Question 38

Q

X-linked adrenoleukodystrophy - G/A/E/Imaging

Answer

A

Defect in ABCD1, peroxisomal membrane transport protein, causes impaired beta-oxidation of VLCFA

Posterior white matter changes sparing U-fibers, can have rim of contrast enhancement differentiating it from other white matter diseases (except Alexanders)

Question 39

Q

X-linked adrenoleukodystrophy - clinical

Answer

A

MC peroxisomal disorder
Childhood cerebral form (40%) - symptoms start at 4-8 years old, behavior problems in school, ADHD, seizures, regression of spatial orientation, auditory discrimination, speech, spastic paraparesis, visual loss, impaired swallow, death wi 2 years - by 10 years old, impaired cortical response in 85%
Adult cerebral form - dementia, seizures, psychiatric symptoms, spastic paraparesis after age 21, rapid progression
45% with adrenomyeloneuropathy (45%): slowly progressive spastic paraparesis, impaired vibratory sense in legs, bladder dysfunction, begins in 3rd decade, loss of myelinated axons in spinal cord and peripheral nerves, Addison’s disease in 67%, abnormal cerebral white matter in half, subtle cognitive deficits *Also some with pure adrenal form

Tx: Steroid replacement therapy, “Lorenzo’s oil” (4:1 glyceryl trioleate-glyceryl trierucate) to reduce levels of very long-chain fatty acids in plasma, may be beneficial in young asymptomatic patients but not in patients with neurologic deficits. Bone marrow transplantation may have a role in early stages of the disease.

Question 40

Q

Classic Refsum disease

Answer

A

Retinitis pigmentosa very unique feature here
Due to mutations in PHYH or PEX7 gene resulting in defects in alpha-oxidation leading to a build-up of phytanic acid

Question 41

Q

Classic Zellweger syndrome

Answer

A

Mutation in PEX gene ->accumulation of VLCFA, branched FA, AA, and toxic substrates

Question 42

Q

Smith Lemli Opitz

Answer

A

Presents as a static encephalopathy

Question 43

Q

Disorders causing intoxications

Answer

A

Amino acidopathies
Organic acidemias
Urea cycle defects
Sugar intolerance

Question 44

Q

PKU

Answer

A

Aminoacidopathies
Newborn screen
Lightly pigmented typically in board review questions

AR, disorder of phenylalanine metabolism 2/2 deficiency of p_henylalanine hydroxylase_ (converts phenylalanine to tyrosine) leads to accumulation of phenylalanine metabolized by phenylalanine transaminase→ phenylpyruvic acid→oxidized to phenylacetic acid: musty odor of the sweat and urine of these patients.

Also, Tetrahydrobiopterin is a cofactor for phenylalanine hydroxylase: its deficiency may produce hyperphenylalaninemia (and PKU). (Reduction of phenylalanine levels in blood and urine after trial of tetrahydrobiopterin makes this dx)

Newborn screening detects hyperphenylalaninemia, dx via elevation of phenylalanine levels in blood.

Tx: dietary restriction of phenylalanine, low-protein diet and phenylalanine-free feeding formula ASAP after birth, to prevent neurologic deterioration. Tetrahydrobiopterin is used as a tx adjunct in select patients.

Question 45

Q

Homocystinuria

Answer

A

Aminoacidopathies, 2/2 cystathionine-β-synthase deficiency (AR, gene: CBS at 21q22.3 that encodes the enzyme cystathionine-β-synthase), which catalyzes conversion of homocysteine+serine to cystathionine (that subsequently becomes cysteine and then cystine), with pyridoxine as cofactor (Homocysteine can also be methylated to methionine, a step that requires folate and vitamin B12)

Normal at birth, later with developmental delay and intellectual disability. Collagen metabolism affected from accumulation of homocysteine→, leading to involvement of other organs such as the eyes: ectopic lentis (down), bones: marfinoid habitus, and the vascular system: intimal thickening of the blood vessel walls and high incidence of thromboembolism, including strokes at early ages.

See elevation of blood and urine levels of homocystine, homocysteine, and methionine.

Two variants of this condition, one that is pyridoxine responsive and one not, suggesting some residual activity of the cystathionine-β-synthase in former .

Tx: Daily pyridoxine, maintained on a low-protein diet, specifically a diet low in methionine with cystine supplementation, and may be treated with betaine, a substance that lowers plasma homocysteine level by promoting its conversion to methionine. Folate and vitamin B12 also promote the conversion of homocysteine to methionine and decrease the levels of homocysteine.

*Extended newborn screen

**Marfan vs homocystinuria – in Marfan, the lens dislocation is up versus down

Question 46

Q

Molybdenum cofactor deficiency/sulfite oxidase deficiency

Answer

A

Aminoacidopathies
Same phenotype from both enzyme dysfunction, cofactor deficiency

Question 47

Q

Non-ketotic hyperglycinemia

Answer

A

Aminoacidopathies
Other diseases that cause elevated glycine in serum, but this is the only one that causes elevated glycine in CSF -> why dx focuses on glycine levels in CSF

Question 48

Q

Branched chain organic acidurias - general

Question 49

Q

Maple syrup urine disease

Answer

A

Disorder of intoxication

AR
No dehydration, no acidosis, normal NH3 is important

2/2 branched-chain α-ketoacid dehydrogenase complex deficiency → accumulation of branched amino acids (leucine, isoleucine, valine, essential AA) and ketoacids. Leucine, isoleucine, and valine norm transaminated to α-ketoacids then catabolized by oxidative decarboxylation by branched-chain α-ketoacid dehydrogenase complex.

3 main phenotypes - classic, intermittent, and intermediate form. 1.) Classic: most severe, presents in neonatal period w/ lethargy, poor feeding, and hypotonia ingestion proteins. At 2 to 3 DOLs, progressive encephalopathy develops w/ opisthotonus and abnormal movements. At ~ 1 wk, coma and respiratory failure, w/ subsequent cerebral edema and seizures, and death if untreated. 2.) Intermediate: presents in late infancy w/developmental delay, FTT, ataxia, and seizures. May have exacerbations with protein intake or infections. Some responsive to thiamine. 3.). Intermittent: normal in between episodes, and alteration of consciousness and ataxia occur w/illness or other stressors

Urine with a maple syrup odor: more prominent during exacerbations. Diagnose via elevated levels of branched-chain amino acids and ketoacids in blood and urine. Enzyme activity can be measured in fibroblasts and hepatocytes.

Tx w/low-protein diet, more specifically a branched- chain amino acid–restricted diet: start early in life (as soon as the diagnosis is suspected) to prevent cognitive decline. +Thiamine: some patients may be responsive to this vitamin. Orthotopic liver transplantation may be a therapy for these patients.

Extended newborn screening, thus allowing for pres(x) tx in pts w/classic form

Question 50

Q

Isovaleric, propionic, and methylmalonic aciduria

Question 51

Q

Glutaric aciduria type 1

Answer

A

Hemorrhagic component is important – can be confused for child abuse

Question 52

Q

Urea cycle defects

Answer

A

OTC is XL, others are AR

Clinical triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Ammonia induces glutamine accumulation, which leads to astrocyte swelling and brain edema.

Very high-serum concentration of ammonia, no evidence of organic acidemia (like with isovaeleric, propionic, and methylmalonic academia), normal anion gap, and normal serum glucose level.

Amino acid analyses help distinguish specific urea cycle disorders, and enzyme activity can be evaluated in liver biopsy specimens.

Treatment: Limitation of nitrogen intake in the diet and administration of essential amino acids (also arginine supplementation except in arginase deficiency). Calories can be supplied with carbohydrates and fat. During acute episodes, sodium benzoate (also used to treat nonketotic hyperglycemia) and sodium phenylacetic acid, sometimes dialysis may be required. Mannitol has been used for brain edema and increased intracranial pressure.

Question 53

Q

Disorders of metabolism - big picture

Answer

A

Include glycogen storage disease, congenital lactic acidemias - pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, PEPCK deficiency, fatty acid oxidation defects - carnitiine cycle defects, beta oxidation defects, Kreb’s cycle disorders are rare, mitochondrial respiratory chain disorders

For fatty/beta acid oxidation defects, can’t do ketogenic diet, so test for carnitines and acylcarnitines

PDHC deficiency for entry to TCA

Question 54

Q

Von Gierke

Answer

A

Disorder of metabolism
Glycogen storage disorder type I
Defect in glucose-6-phosphate, AR
Affects liver/kidney, resulting in hypoglycemic seizures

Question 55

Q

Pompe

Answer

A

Disorder of metabolism
Glycogen storage disorder type II
Defect in Acid Maltase, AR
Generalized involvement
Hypotonia - presents around 2 months, muscle and anterior horn cell disease, cardiomegaly, macroglossia, also juvenile and adult forms with milder presentations, treatment with enzyme replacement=myozyme=aglucosidase alpha

Question 56

Q

McArdles

Answer

A

Disorder of metabolism
Glycogen storage disorder type V
Defect in myophosphorylase, AR
Affects muscle
Symptomatically results in cramps, exercise intolerance, increased CK
No tx

Question 57

Q

Tarui

Answer

A

Disorder of metabolism
Glycogen storage disorder type VII
Phosphofructokinase, AR
Also with cramps, exercise intolerance, increased CK

Question 58

Q

Pyruvate dehydrogrenas complex deficiency

Answer

A

Disorder of energy metabolism
Congenital lactic acidemias
X-linked (AR)

PDH deficiency 2/2 defects in PDH complex: 3 main components (E1 with α and β subunits), E2 and E3), responsible 4 oxidative decarboxylation of pyruvate to carbon dioxide and acetyl coenzyme A. E1 deficiency MC, XLR inheritance, vs others: AR

See elevations of lactate and pyruvate, w/ low lactate:pyruvate ratio. Enzyme analysis in leukocytes, cultured fibroblasts, muscle, or liver biopsy specimens. May be cystic lesions in the white matter and basal ganglia, and certain cases of the neonatal form may have agenesis of the corpus callosum.

Tx: Ketogenic diet (high fat with low carbohydrates) and thiamine supplementation. Carnitine, coenzyme Q10, and biotin supplementation may be given (efficacy is not well established). Acetazolamide for episodes of ataxia.

Question 59

Q

Pyruvate carboxylase deficiency

Answer

A

Disorder of energy metabolism
Congenital lactic acidemias
AR

Question 60

Q

PEPCK deficiency

Answer

A

Disorder of energy metabolism
Congenital lactic acidemias
PEPCK converts OA to PEP, needed for gluconeogenesis
Cystolic form and mitochondrial form, AR

Question 61

Q

Fatty Acid Oxidation Defects - General

Answer

A

Disorder of energy metabolism
Test for carnitines and acylcarnitines before starting on ketogenic diet

Question 62

Q

Primary Carnitine Deficiency

Answer

A

Disorder of energy metabolism
Fatty Acid Oxidation Defects
SLC22A5, AR
Results in dilated cardiomyopathy, hypoketotic hypoglycemia, skeletal myopathy
Dx: Low levels of free carnitine and acylcarnitines in blood, increased carnitine in the urine, molecular testing or functional studies assessing the uptake of carnitine in cultured fibroblasts
Tx: High dose carnitine supplementation

Question 63

Q

CPT-1

Answer

A

Disorder of energy metabolism
Fatty Acid Oxidation Defects
CPT1A, AR
Results in hypoketotic hypoglycemia
Dx: Elevated carnitine in blood, molecular testing or functional studies assessing the uptake of carnitine in cultured fibroblasts
Tx: High dose carnitine supplementation

Question 64

Q

Carnitine/acylcarnitine translocase

Answer

A

Disorder of energy metabolism
Fatty Acid Oxidation Defects
SLC25A20, AR
Results in hypertrophic cardiomyopathy with hypoketotic hypoglycemia

Answer 63

A

Can present with neonatal cardiomyopathy with hypoketotic hypoglycemia and death in the first week, hypoketotic hypoglycemia during or after the first year, but MC is adult onset rhabdomyolysis

Answer 64

A

AR

Beta-oxidation is

Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, LCHAD deficiency

In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acidmolecules are broken down^[1] in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycle, and NADH and FADH₂, which are co-enzymes used in the electron transport chain. It is named as such because the beta carbon of the fatty acid undergoes oxidation to a carbonyl group. Beta-oxidation is primarily facilitated by the mitochondrial trifunctional protein, an enzyme complex associated with the inner mitochondrial membrane, although very long chain fatty acids are oxidized in peroxisomes.

The overall reaction for one cycle of beta oxidation is:

C_n-acyl-CoA + FAD + NAD⁺
+ H
₂O + CoA → C_n_-2-acyl-CoA + FADH
₂ + NADH + H⁺
+ acetyl-CoA

Answer 65

A

NP A/C, GM1 Ganglioside (infantile), Tay-Sachs, Sandhoff, Sialidosis, Galactosialidosis

Answer 66

A

Cerebrotendinous xanthomatosis

Galactosemia

Answer 67

A

Tay-Sachs
Glutaric Aciduria Type 1

(Alexender’s, Caravan)

Answer 68

A

Hunter’s, also X-linked

Answer 69

A

Tay-Sachs

Answer 70

A

Nuclear mutations affecting mitochondrial function

MtDNA mutations and deletions

Answer 71

A

Complex I

Answer 72

A

Sporadic or familial - only some cases wt/he typical maternal inheritance pattern, may result from mutations in mitochondrial or nuclear DNA encoding for different subunits of the respiratory chain

Lactate level is increased in blood and CSF. Lactate and pyruvate levels in blood are elevated during exacerbations.

Answer 73

A

Disorders causing intoxications; sugar intolerance

AR - 2/2 1.) galactose-1-phosphate uridyltransferase deficiency, 2.) galactokinase deficiency, and 3.) uridine diphosphate galactose 4′ epimerase deficiency (mutations in GALT, GALK, and GALE genes respectively). Galactose-1-phosphate uridyltransferase deficiency is MC→classic galactosemia, only type w/ intellectual impairment.

Answer 74

A

Disorders causing intoxications; sugar intolerance

Manifests 1st DOLs w/ feeding difficulties, vomiting, diarrhea, jaundice, hepatomegaly, FTT, lethargy, & hypotonia. Cataracts 2/2 accumulation of galactitol. Late neurologic sequelae: developmental delay, cog impairment, ataxia, & tremor, w/ MRI: white matter changes and cortical and cerebellar atrophy.

Presume dx in pt w/above s(x)s + reducing substances in urine, especially after feeding. Can test for enzymatic defect in plasma and/or erythrocytes.

Prenatal testing available

Answer 75

A

Disorders causing intoxications; sugar intolerance

Restrict lactose and galactose → may reverse cataracts and hepatomegaly and may prevent progression of neurologic disease (still may develop long-term neurologic sequelae, including learning disability, cognitive impairment, ataxia, and tremor)

Answer 76

A

SLC2A1, de novo vs AD in familial cases

Glucose: primary energy source for brain, w/fasting, glycogen → exhausted within minutes, ketones become alternative fuel (AA and fats can’t be used)

Glucose crosses blood–brain barrier via GLUT-1 (membrane- bound protein, SLC2A1 on chasm 1p34.2 → mutation: defect in glucose transport across BBB and brain cells → phenotypic heterogeneity w/some pts developed epileptic encephalopathy

CSF glucose low, normal serum glucose level, other CSF studies normal. EEG may show 2.5-4 Hz spike and waves, interictal EEG may improve w/glucose. Neuroimaging no specific abnormalities.

Tx: Ketogenic diet (improves seizure control and the abnormal movements, less effective for psychomotor impairment)

Answer 77

A

AR

2/2 deficiency of propionyl-CoA carboxylase: facilitates the carboxylation of propionyl-CoA to D- methylmalonyl-CoA, *requires coenzyme biotin

Normal at birth but s(x)s in early neonatal period, in infancy, or later in childhood - feeding difficulty, lethargy, hypotonia, dehydration, and attacks of metabolic acidosis with ketosis and hyperammonemia. May progress to have seizures and coma. Also, hepatomegaly, pancytopenia, and bleeding disorders including intracranial hemorrhage. Patients who survive have developmental delay and involuntary movements (resulting from basal ganglia involvement)

Answer 78

A

Suspected in newborn babies w/ketoacidosis, anion gap, and elevated propionic acid levels in the blood +/- urine (also elevations of glycine in plasma and urine, and methylcitrate and β-hydroxypropionate in urine); enzyme activity is reduced in leukocytes and fibroblasts

Tx: protein restriction, parenteral fluids for hydration, carnitine and biotin supplementation. Dialysis may be required in some patients. Antibiotics such as metronidazole may decrease the production of propionate by enteric bacteria.

Answer 79

A

XLD

Deficiency of hypoxanthine guanine phosphoribosyltransferase: purine salvage pathway, encoded by HPRT1 gene on chromosome Xq26, deficiency of this enzyme leads to the accumulation of purines/uric acid.

Severe hypotonia → progressive limb and neck rigidity with dystonia, choreoathetotic movements, facial grimacing, seizures, spasticity, and intellectual impairment. severe hypotonia. Aggressive behavior, self- mutilation, and progressive dementia are hallmarks.

Others: hyperuricemia, gout, and nephrolithiasis.

Clinical dx: Child with neurologic manifestations, self- mutilation behavior, and hyperuricemia, suggests the diagnosis. Hypoxanthine guanine phosphoribosyltransferase activity can be assessed in fibroblasts, and genetic testing can also be used.

Tx: purine-restricted diet, hydration to prevent kidney stones, allopurinol to decrease the production of uric acid, and supportive care to prevent self-inflicted injuries and control of abnormal movements. Levodopa and tetrabenazine for neuropsychiatric manifestations.

Answer 80

A

AR

Lysosomal storage disorders

Accumulation of oligosaccharides, glycopeptides, and glycolipids->vacuolization of multiple cell types

General clinical features: coarse facial features, skeletal abnormalities, and psychomotor retardation

Include α-mannosidosis (α-mannosidase deficiency), β-mannosidosis (β-mannosidase deficiency), fucosidosis (α-fucosidase deficiency), aspartylglucosaminuria (aspartylglucosaminidase deficiency), and Schindler’s (α-N-acetylgalactosaminidase deficiency)

Abnormal urinary excretion of glycopeptides, as well as vacuolated lymphocytes with membrane- bound vacuoles, can be seen. Definitive diagnosis is made with analysis of enzyme activity

Answer 81

A

AR Glycoproteinoses, lysosomal storage disorder

Deficiency of lysosomal α-N-acetyl neuraminidase (sialidase) -> increased urinary excretion of sialic acid–containing oligosaccharides Type I sialidosis (cherry-red spot myoclonus syndrome): adult/adolescent onset w/ myoclonic epilepsy, visual deterioration, and cherry-red spots w0 dysmorphism. Type II: childhood form, myoclonic epilepsy and cherry-red spots in the retina but severe neurologic abnormalities, coarse facial features, severe dysostosis, and psychomotor retardation. The neonatal form is characterized by hydrops fetalis, nephrotic syndrome, and early death

Answer 82

A

AR, CLN1-CLN10, MC CLN1 and 2 for enzymes PTT1 and TPP1 respectively. CLN1 - infantile form, normal at birth w/s(x) onset 6 and 24 months: microcephaly, hypotonia, myoclonus, seizures, ataxia, progressive psychomotor retardation, and blindness. Neurons accumulate membrane-bound granular osmiophilic deposits (seen on electron microscopy) with subsequent neuronal loss with cortical atrophy. CLN2 - late infantile form, 2-4 years old, neurons accumulate curvilinear bodies, which are seen on electron microscopy. CLN3 - adolescent form, fingerprint bodies.

Adult form - 30 years old, dementia, psychiatric symptoms, ataxia with extrapyramidal s(x)s most prominently facial dyskinesias

Dx: clinical presentation w/electron microscopy of lymphocytes or cells from other tissues. Enzyme activity studies for PPT1 and TPP1 are also available, as is genetic testing for the CLN genes. The treatment is symptomatic.

Answer 83

A

Peroxisomal disorder, white matter abnormalities.

AR.

Called “cerebrohepatorenal syndrome” and is characterized by dysmorphic features, cataracts, sensorineural hearing loss, hypotonia, deformities in flexion of lower limbs with arthrogryposis, ID, seizures as well as liver dysfunction and cirrhosis and polycystic kidney disease

Diagnostic workup: increased plasma very long- chain fatty acids, decreased red blood cell plasmalogens, and decreased or absent hepatic peroxisomes. Enlarged brain w/ evidence of neuronal migration abnormalities such as pachygyria and/or polymicrogyria, white matter changes with lipid accumulation.

Tx: symptomatic. Most of these patients die early.

Answer 84

A

Infantile Refsum’s disease: psychomotor retardation, sensorineural hearing loss, retinal degeneration, anosmia, and mild dysmorphic features +/- y= be cirrhosis and adrenal atrophy.

Phytanic acid levels are elevated and peroxisomes are reduced or absent.

These patients may survive into adulthood.

Retinitis pigmentosa

Answer 85

A

Mitochondrial disorder, 2/2 single large-scale mitochondrial DNA deletion, less commonly a duplication - though most cases sporadic, affected women with large deletions ransmit the mutation in small % of cases

Triad of progressive external ophthalmoplegia, onset before 20 years, and >/= one of the following: short stature, pigmentary retinopathy, cerebellar ataxia, heart block, and i_ncreased CSF protein (>100 mg/dL)_ Most w. cognitive regression by third or fourth decade of life. Although the disorder is usually sporadic,

Answer 86

A

Type I issues with synthesis, with type 1a as most well described subtype: FTT, ID, cerebellar atrophy, polyneuropathy, hyptonia, weakness, involvement of liver, mult-organ involvement with lipodystrophy as below/Type 2 with abnormal processing and modification of glycans ->cognitive impairment with cerebellar ataxia or peripheral neuropathy

Key clinical feature: Lipodystrophy with prominent fat pads in the buttocks and suprapubic area, as well as inverted nipples

Labs: See carbohydrate-deficient transferrin in the serum and CSF, and these conditions are diagnosed on the basis of serum transferrin isoforms. Genetic confirmation some subtypes.

Treatment: Supportive.

Answer 87

A

AR, secondary to deficiency of methylmalonyl-CoA mutase (MUT, 6p12.3): catalyzes the isomerization of L-methylmalonyl-CoA to succinyl-CoA (required co-factor 5′-Deoxyadenosylcobalamin) for entry into the Kreb cycle - defects in this pathway result in ccumulation of propionyl-CoA, propionic acid, and methylmalonic acid, causing metabolic acidosis, hyperglycinemia, and hyperammonemia

S(x)s: normal at birth, s(x) wi the 1st WOL: lethargy, FTT, vomiting, dehydration, hypotonia, and respiratory distress. Hematologic abnormalities, including bleeding disorders →ICH. Survivors w/intellectual disability, developmental delay, and recurrent acidosis.

Dx: Suspected in newborns w/ metabolic acidosis, ketosis, hyperglycinemia, and hyperammonemia. MMA is elevated in plasma and urine, enzyme activity can be analyzed in fibroblasts.

Tx: Protein restriction, and supplementation with intramuscular hydroxycobalamin and enteral carnitine, antibiotics to reduce the production of propionic acid by gut flora - in the acute setting, hydration and glucose administration w/discontinuation of protein intake.

B12- responsive forms of MMA: associated with mutations in genes affecting transport/synthesis of 5′- Deoxyadenosylcobalamin (cblA, cblB, or cblD variant 2 type), or deficiency of methylmalonyl-CoA epimerase. Patients with these forms may present later than patients with MUT mutations and may improve with specific forms of vitamin B12 supplementation.

Answer 88

A

AR, 2/2 mutations in biotinidase gene (BTD, 3p25.1).

Biotinidase normally cleaves biocytin (an amide formed from biotin and L- lysine), an intermediate in biotin metabolism, thereby recycling biotin; biotinidase also participates in processing of dietary protein- bound biotin, making it available to the free biotin pool.

Children with this enzymatic defect manifest with seizures, hypotonia, ataxia, developmental delay, hearing and vision loss, spastic paraparesis, and cutaneous abnormalities including alopecia.

Laboratory studies: ketoacidosis, hyperammonemia, and organic aciduria. Biotinidase enzyme activity can be analyzed in serum - profound biotinidase deficiency <10% of normal activity, and partial biotinidase deficiency between 10% and 30% of normal activity.

Treatment: oral free biotin supplementation, if begun early prevents intellectual disability and reverses most of the symptoms. However, once vision, hearing, and developmental/intellectual impairments occur, they are not reversible

Extended newborn screen

Answer 89

A

GM2 gangliosidosis is caused by deficiency of hexosaminidase A in Tay–Sachs disease or hexosaminidase A and B in Sandhoff’s disease. These isoenzymes are made of subunits, with hexosaminidase A containing alpha–beta, and hexosaminidase B containing beta–beta. Mutations in the HEXA gene disrupt alpha subunits only, giving rise to Tay–Sachs disease, whereas HEXBmutations disrupt the beta subunit, resulting in deficiency of both hexosaminidases A and B.

Answer 90

A

AR, lysosomal storage disorder

Onset is between 3 and 6 months of age: increased startle response and subsequent motor regression, spasticity, blindness with optic atrophy, and seizures. Delay in reaching developmental milestones, with subsequent developmental regression. A cherry- red spot in the macula is commonly seen, and these patients have macrocephaly. Progression to severe in ID occurs, and most children die by the age of 5 years.

The diagnosis is suspected in patients with psychomotor retardation and a cherry- red spot and is confirmed with the detection of hexosaminidase A deficiency with normal activity of hexosaminidase B. Targeted mutation analysis or gene sequencing of the HEXA gene to detect specific mutations may be helpful to identify asymptomatic carriers in the family and to differentiate between disease-causing mutations and so-called pseudodeficiency alleles that result in decreased hexosaminidase A activity in the laboratory but do not cause disease.

Treatment of Tay–Sachs disease is supportive.

Answer 91

A

AR disease, caused by defect in 1 of 3 proteins that make up the mitochondrial glycine cleavage system, resulting in a complete absence of function and accumulation of glycine in all body tissues. MC mutation in P protein (glycine decarboxylase gene) than 2nd most T protein (aminomethyltransferase) than <1% H protein (GCSH)

Onset in newborns, w/i hrs to day of birth, becomes irritable with poor feeding and hiccups→progressive encephalopathy with hypotonia, myoclonic seizures, and respiratory failure requiring mechanical ventilation; those who survive, will have profound ID, spasticity, and intractable epilepsy

Brain MRI w/hypoplastic or absent corpus callosum, gyral malformations, and cerebellar hypoplasia

EEG with burst suppression and hypsarrhythmia. Delta brushes not seen.

Elevation in serum and CSF glycine levels and ratio of CSF to plasma glycine concentration is >0.6 whereas normally it is <0.4

No real txs. Sodium benzoate to decrease plasma glycine but doesn’t effect CSF glycine, use dextromethorphan and ketamine to inhibit NMDA excitation by glycine.

Is this nonketotic hyperglycemic?

Answer 92

A

Porphyrias are a group of metabolic disorders caused by deficiency of a specific enzyme involved in the heme biosynthetic pathway. Most of the porphyrias are inherited in an autosomal dominant fashion, except 5-aminolevulinic acid dehydratase– deficient porphyria, which is autosomal recessive.

Acute intermittent porphyria: deficiency of porphobilinogen (PBG) deaminase, as primarily neurologic manifestations, HCP and VP have a combination of neurologic and cutaneous manifestations with photosensitivity, and porphyria cutanea tarda has cutaneous involvement with no neurologic manifestations. HCP and VP also with increased coproporphyrin III in the urine and stool

The acute porphyrias manifest with attacks of neurovisceral symptoms, with markedly elevated levels of plasma and urinary concentrations of the porphyrin precursors aminolevulinic acid (ALA) and porphobilinogen (PBG). Levels are usually elevated during attacks and may be normal in between. The attacks may be triggered by drugs such as antiepileptics (especially barbiturates), sulfonamides, and hormones among other medications. Attacks may also be triggered by a low-carbohydrate diet, infections, or other illnesses

Answer 93

A

AIP is the most common of the acute porphyrias with neurovisceral symptoms and is caused by deficiency of PBG deaminase (PBGD gene, 11q23). Onset occurs after puberty, with acute attacks of abdominal pain, sometimes associated with nausea, vomiting, diarrhea, fever, tachycardia, and leukocytosis. Commonly, these patients experience limb pain and muscle weakness resulting from a peripheral neuropathy that is predominantly motor and axonal, affecting more proximal than distal segments and more the upper than the lower extremities. Deep tendon reflexes are depressed. The radial nerve has been described as being classically involved, and in severe cases, there may be bulbar and respiratory involvement. Seizures can occur from neurologic involvement or may result from the hyponatremia that is seen in these patients. Neuropsychiatric symptoms such as anxiety, insomnia, depression, disorientation, hallucinations, and paranoia may occur.

The diagnosis is based on clinical suspicion and elevated urinary excretion of ALA and PBG during the attacks. Genetic testing and enzyme analysis are also helpful.

Management is focused on preventing attacks by avoiding precipitating factors. During attacks, these patients may need hospitalization for hydration and pain control. Carbohydrates decrease the synthesis of porphyrins and an infusion may be required. Hematin infusions may be helpful. For seizures, clonazepam and gabapentin may be helpful. Unfortunately, many AEDs precipitate attacks, especially barbiturates, which should be avoided.

Answer 94

A

HCP is caused by coproporphyrinogen oxidase deficiency, and VP is caused by protoporphyrinogen oxidase deficiency. In both, the neurovisceral manifestations are similar to AIP, but in HCP and VP, there are cutaneous manifestations with photosensitivity, abnormal skin fragility, and bullous skin lesions on sun-exposed areas. HCP and VP cause increased urinary and fecal levels of coproporphyrin III.

Answer 95

A

An autosomal recessive familial neuropathy, caused by mutations affecting the adenosine triphosphate cassette transporter protein (ABCA1 gene, 9q31), resulting in a deficiency of high-density lipoprotein (HDL), with very low serum cholesterol and high triglyceride concentrations. Given the severely reduced HDL level, cholesteryl esters accumulate in various tissues, including tonsils, peripheral nerves, cornea, bone marrow, and other organs of the reticuloendothelial system. A typical clinical finding is the enlarged orange tonsils.

The diagnosis is suspected on the basis of clinical features and a lipid profile showing HDL deficiency, with low total cholesterol and high triglyceride levels. Foamy macrophages 9like Niemann-Pick diseases) are present in the bone marrow and other tissues. There is no specific treatment.

Answer 96

A

Menkes disease is an X-linked recessive disorder resulting from a mutation in ATP7A (Xq21.1), a copper transporter, resulting in defective copper transport across the intestines and across the blood–brain barrier, with low levels of copper in the plasma, liver, and brain. Various enzymes require copper as a cofactor, including cytochrome c oxidase, dopamine β-hydroxylase, and lysyl oxidase among others.

Histopathologically, the cortex, thalamus, and subcortical nuclei demonstrate loss of neurons and gliosis. The cerebellum shows loss of granular neurons and Purkinje cells. Laboratory studies demonstrate low serum levels of ceruloplasmin and copper.

Also known as kinky hair syndrome, is a disorder of intracellular copper transport characterized by the presence of brittle coarse and lightly pigmented hair (pili torti), hyperelastic include seizures, severe developmental delay, cerebral vasculopathy with tortuous and kinked intra and extracranial vessels, progressive cerebral atrophy, and subdural hematomas and/or hygromas. Other organ systems are involved, including the skeletal, gastrointestinal, and genitourinary tract. Abnormal fullness of the cheeks, osteoporosis, and metaphyseal dysplasia are often seen. Cephalohematomas and spontaneous bone fractures are seen in newborns, which may raise the suspicion for nonaccidental trauma.

Answer 97

A

There is no specific treatment. These patients may have some benefit from coenzyme Q10 and L-carnitine. Acute L-arginine intravenous infusion and daily supplementation may attenuate the severity of strokes and reduce the frequency of these events, respectively.

Answer 98

A

Autosomal recessive disorder caused by a molecular defect in the gene for the microsomal triglyceride transfer protein (MTTP gene), which is localized in chromosome 4q23. his protein normally catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid from phospholipid surfaces. The defect of this protein results in fat malabsorption and lipid-soluble vitamin deficiencies, especially of vitamin E, which causes most of the clinical manifestations.

manifests from birth with failure to thrive, vomiting, and loose stools. During infancy, there is progressive psychomotor retardation with cerebellar ataxia and gait disturbance. Proprioceptive sensation is lost in the hands and feet, with less compromise of pinprick and temperature sensation. Deep tendon reflexes are depressed. This is likely from demyelination of posterior columns and peripheral nerves. Visual disturbance is the result of retinitis pigmentosa, and nystagmus is common.

Laboratory studies demonstrate acanthocytosis, absence of very low-density lipoproteins, absence of apolipoprotein B, low levels of vitamin E, and severe anemia.

Treatment involves the restriction of triglycerides in the diet, and large doses of vitamin E with supplementation of vitamins A, D, and K.

Answer 99

A

Chronic/hereditary demyelinating
AR, peroxisomal disorder with elevated serum phytanic acid, retinitis pigmentosa, cardiac failure
– Treat with low phytanic acid diet

Answer 100

A

(Glycogenosis type V)

Autosomal recessive disorder caused by myophosphorylase deficiency. Myophosphorylase facilitates conversion of glycogen into glucose-6-phosphate; its deficiency will lead to glycogen accumulation/lack of glucose release from glycogen. The typical presentation is exercise- induced weakness and muscle cramps (physiologic contractures: electrically silent when an EMG needle is inserted into the contractured muscles). Unlike normal muscles, when the muscle is exercised there is no production of lactic acid.

On exertion, a sensation of fatigue may ensue; however, if the patient slows down or rests briefly, this sensation may disappear and the patient may be able to continue with the exercise. This is called a “second-wind phenomenon,” which is typically seen in McArdle’s disease, and results from mobilization and use of blood glucose.

Answer 101

A

Tarui disease (glycogenosis type VII) is caused by phosphofructokinase (PFK) deficiency in muscle and erythrocytes. This enzyme participates in the conversion o_f glucose-6-phosphate into glucose-1-phosphate_, and therefore, it is similar to McArdle’s disease from the muscular standpoint. In addition, some patients may develop jaundice (due to hemolysis) and gouty arthritis due to PFK deficiency in erythrocytes. Immunohistochemical analysis distinguishes these two disorders.

Answer 102

A

(Glycogenosis type III) is caused by a deficiency in the debranching enzyme, leading to glycogen accumulation. These patients can present with a childhood form with liver disease and weakness or with an adult form characterized by myopathic weakness.

Answer 103

A

Andersen’s disease (glycogenosis type IV) is caused by a deficiency in the glycogen branching enzyme, and is characterized by hepatomegaly from polysaccharide accumulation, cirrhosis, and liver failure.

Answer 104

A

AR, deficiency of the lysosomal enzyme acid maltase (also known as α-1,4-glucosidase). This enzyme participates in the breakdown of glycogen to glucose; its deficiency leads to glycogen accumulation, causing the typical histopathologic findings on muscle biopsy: vacuolated sarcoplasm with glycogen accumulation that stains strongly with acid phosphatase.

There are three forms of acid maltase deficiency: 1.) P_ompeii’s disease: infantile form presenting in first few months of life with difficulty feeding, cyanosis, dyspnea, macroglossia, hepatomegaly, cardiomegaly, and hypotonic weakness. This form progresses rapidly and patients die in the first few months_. 2.) Childhood form, which has an onset in the second year of life, manifests with proximal weakness, motor developmental delay, hypotonia, enlarged calves, and rarely with cardiomegaly, hepatomegaly, and mental retardation. These patients may die of pulmonary infections and respiratory failure. Adult form, which presents in the second to fourth decades of life, manifests with slowly progressive proximal weakness and typically weakness of the diaphragm, leading to neuromuscular respiratory problems. These patients do not typically have cardiomegaly, hepatomegaly, or mental retardation.

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Metabolic disorders Flashcards

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