Metabolic disorders Flashcards

Question

Hexosaminidase A Deficiency

Answer 1

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

Answer 2

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

Answer 3

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

Answer 4

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

Answer 5

Lysosomal storage disorders: Sphingolipidoses _AR, deficiency of galactocerebroside B-galactosidase_ _Gene: GALC_

Answer 6

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

Answer 7

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

Answer 8

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

Answer 9

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

Answer 10

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_

Answer 11

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.

Answer 12

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

Answer 13

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

Answer 14

_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)_

Answer 15

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._

Answer 16

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_

Answer 17

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

Answer 18

Presents as a static encephalopathy

Answer 19

Amino acidopathies Organic acidemias Urea cycle defects Sugar intolerance

Answer 20

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._

Answer 21

_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

Answer 22

Aminoacidopathies Same phenotype from both enzyme dysfunction, cofactor deficiency

Answer 23

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_

Answer 24

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

Answer 25

Hemorrhagic component is important – can be confused for child abuse

Answer 26

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.

Answer 27

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

Answer 28

Disorder of metabolism Glycogen storage disorder type I Defect in _glucose-6-phosphate,_ AR _Affects liver/kidney_, resulting in hypoglycemic seizures

Answer 29

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

Answer 30

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

Answer 31

_Disorder of metabolism_ _Glycogen storage disorder type VII_ _Phosphofructokinase, AR_ _Also with cramps, exercise intolerance, increased CK_

Answer 32

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.

Answer 33

Disorder of energy metabolism Congenital lactic acidemias AR

Answer 34

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

Answer 35

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

Answer 36

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

Answer 37

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

Answer 38

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

Answer 39

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 40

AR Beta-oxidation is ![]() Schematic demonstrating [mitochondrial](https://en.wikipedia.org/wiki/Mitochondria) [fatty acid](https://en.wikipedia.org/wiki/Fatty_acid) [beta-oxidation](https://en.wikipedia.org/wiki/Beta-oxidation) and effects of [long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, LCHAD deficiency](https://en.wikipedia.org/wiki/Long-chain_3-hydroxyacyl-coenzyme_A_dehydrogenase_deficiency) In [biochemistry](https://en.wikipedia.org/wiki/Biochemistry) and [_metabolism_](https://en.wikipedia.org/wiki/Metabolism), **beta-oxidation** is the [catabolic process](https://en.wikipedia.org/wiki/Catabolism) by which [fatty acid](https://en.wikipedia.org/wiki/Fatty_acid)molecules are broken down[^[1]](https://en.wikipedia.org/wiki/Beta_oxidation#cite_note-1) in the [cytosol](https://en.wikipedia.org/wiki/Cytosol) in prokaryotes and in the [mitochondria](https://en.wikipedia.org/wiki/Mitochondria) in eukaryotes to generate [acetyl-CoA](https://en.wikipedia.org/wiki/Acetyl-CoA), which enters the [citric acid cycle](https://en.wikipedia.org/wiki/Citric_acid_cycle), and [NADH](https://en.wikipedia.org/wiki/NADH) and [FADH₂](https://en.wikipedia.org/wiki/FADH2), which are co-enzymes used in the [electron transport chain](https://en.wikipedia.org/wiki/Electron_transport_chain). It is named as such because the [beta carbon](https://en.wikipedia.org/wiki/Alpha_and_beta_carbon) of the fatty acid undergoes oxidation to a [carbonyl](https://en.wikipedia.org/wiki/Carbonyl) group. Beta-oxidation is primarily facilitated by the [mitochondrial trifunctional protein](https://en.wikipedia.org/wiki/Mitochondrial_trifunctional_protein), an enzyme complex associated with the [inner mitochondrial membrane](https://en.wikipedia.org/wiki/Inner_mitochondrial_membrane), although [very long chain fatty acids](https://en.wikipedia.org/wiki/Very_long_chain_fatty_acid) are oxidized in [peroxisomes](https://en.wikipedia.org/wiki/Peroxisome). 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 41

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

Answer 42

Cerebrotendinous xanthomatosis Galactosemia

Answer 43

Tay-Sachs Glutaric Aciduria Type 1 (Alexender's, Caravan)

Answer 44

Hunter's, also X-linked

Answer 45

Nuclear mutations affecting mitochondrial function MtDNA mutations and deletions

Answer 46

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 47

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 48

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 49

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 50

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 51

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 52

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 53

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 54

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 55

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 56

_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 57

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 58

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 59

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 60

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 61

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 62

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 63

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 64

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 65

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 66

_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 67

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 68

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 69

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 70

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 71

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 72

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 73

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

Answer 74

(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 75

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 76

(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 77

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 78

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.

Metabolic disorders Flashcards

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