Inherited Metabolic Diseases Flashcards by Joshua Punsalan

Which is the most common pattern of inheritance among monogenic diseases?

a) Dominant
b) Recessive
c) Sex-linked

a) Dominant

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Usually cause manifest disease in heterozygotes

A) Autosomal Dominant
B) Autosomal Recessive
C) X-Linked

A) Autosomal Dominant

AD - heterozygotes
AR - homozygotes

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Variable degrees of penetrance and expressivity

A) Autosomal Dominant
B) Autosomal Recessive
C) X-Linked

A) Autosomal Dominant

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Onset soon after birth

A) Autosomal Dominant
B) Autosomal Recessive
C) X-Linked

B) Autosomal Recessive

AD - long after birth
AR - soon after birth

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“Female will suffer same fate as male if one X chromosome has been inactivated”

____ phenomenon

Lyon Phenomenon

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Enzyme abnormality

A) Autosomal Dominant
B) Autosomal Recessive
C) X-Linked

B) Autosomal Recessive

Enzyme abnormality - AR
Protein abnormality - X-linked

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Which of the following is TRUE of mitochondrial DNA inheritance?

a) Mitochondrial DNA can recombine, so that mutations through maternal lines are not accumulated
b) Replication and distribution of mDNA during cell division follows the nuclear mitotic cycle
c) Genetic error is often a single-point mutation -> alteration of a single amino acid
d) Uniform expression of mitochondrial mutations in different tissues and regions of the NS

TRUE: c) Genetic error is often a single-point mutation -> alteration of a single amino acid

Mitochondrial DNA canNOT recombine, so that mutations through maternal lines are actually accumulated
Replication and distribution of mDNA during cell division DOES NOT follow the nuclear mitotic cycle
VARIABLE expression of mitochondrial mutations in different tissues and regions of the NS

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Most mitochondrial genes code for proteins in the respiratory chain. Which part is the one most often disordered?

Complex IV: cytochrome-c oxidase

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What are the “two characteristics traceable to mitochondrial abnormalities?”

Ragged red fibers

2. Systemic lactic acidosis

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“First hint of trouble” in neonates w/ metabolic disease may be _____

feeding difficulties

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“First definite indication” of disordered NS function in neonates w/ metabolic disease

Seizures

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What are the 3 “most important/reliable indices of brain abnormality in neonates w/ metabolic disease”?

Hyperkinetic-hypertonic
Apathetic-hypotonic
Unilateral or hemisyndromic

If w/ 1 of the above, 2/3 chances that neuro sx appear by year 7

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What is the most common neonatal metabolic disease?

a) Biotinidase deficiency
b) Phenylketonuria
c) VLC acyl CoA dehydrogenase
d) Galactosemia
e) Cobalamin

b) Phenylketonuria

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What is the gene involved in pyridoxine-dependent seizures?

ALDH7A1 gene

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Treatment for biopterin deficiency

Tetrahydrobiopterin (BH4)

Low-phenylalanine diet

(BH4 is a cofactor of phenylalanine)

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Mutation in Biopterin deficiency?

Tetrahydrobiopterin (BH4)

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Galactosemia is caused by a a defect in?

galactose-1-phosphate uridyl transferase

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Nonketotic acidurias of infancy are known to have more devastating effects on the nervous system. They are a/w elevation of what component in the CSF?

Elevation of CSF glycine

Tx:
Na benzoate, dextrometorphan

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All inherited hyperammonemias are autosomal recessive EXCEPT?

N-acetyl glutamate synthetase
Carbamoyl phosphate synthetase (CPS)
Ornithine transcarbamylase (OTC)
Argininosuccinic acid synthetase (citrullinemia)
Argininosuccinase deficiency
Arginase deficiency

Ornithine transcarbamylase (X-linked)

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Appears during later childhood as progressive spastic paraplegia + MR

N-acetyl glutamate synthetase
Carbamoyl phosphate synthetase (CPS)
Ornithine transcarbamylase (OTC)
Argininosuccinic acid synthetase (citrullinemia)
Argininosuccinase deficiency
Arginase deficiency

Arginase deficiency

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Histologic finding in inherited hyperammonemia?

Astrocytic swelling

*2/2 accumulation of glutamate

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Deficiency in branched-chain aminoacidopathies?

a-keto acid dehydrogenase

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Branched chain aminoacidopathies have highest incidence in which populations?

Amish
Mennonite
Jewish

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Sugar levels in infants that cause seizures

a) Mature
b) Premature

Mature - < 30 mg/dL

Premature - < 20 mg/dL

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Hallmark of hereditary metabolic diseases of infancy

Failure to achieve psychosensorimotor milestones Regression of previously attained behaviors

What is the primary deficiency in GM1 gangliosidosis?

B-Galactosidase

What is the primary deficiency in GM2 gangliosidosis?

Tay Sachs - N-acetylhexosaminidase a subunit Sandhoff - N-acetylhexosaminidase B subunit

What is the primary deficiency in Metachromatic leukodystrophy?

Arysulfatase A

What is the primary deficiency in Krabbe disease?

Galactocerebrosidase

What is the primary deficiency in Fabry disease

a-Galactosidase A

What is the primary deficiency in Gaucher disease?

Glucocerebrosidase

What is the primary deficiency in Niemann-Pick disease? Types A & B Type C

Type A&B - Sphingomyelinase Type C - Cholesterol esterification

Diseases displaying a cherry-red macular spot

Go Get Some M F Cherries, Niemann ``` GM1 GM2 gangliosidosis Sialidosis Metachromatic leukodystrophy Farber Ceroid (Neuronal Ceroid Lipofuscinosis), late infantile Niemann Pick A-D ```

Which of the ff diseases in "Go Get Some M F Cherries, Niemann" does not actually have a true cherry-red spot?

Neuronal Ceroid Lipofuscinosis, late infantile form "Bull's-eye maculopathy"

Which of the following is NOT true of Tay-Sachs disease? a) Autosomal recessive b) Common in Ashkenazi Jews c) Deficiency of beta hexosaminidase A d) Accumulation of GM1 ganglioside e) (+) Cherry red spot w/ optic atrophy f) EEG is abnormal in early stages g) Brain doubles in weight

d) Accumulation of GM1 ganglioside Accumulation of GM2 ganglioside

Which of the following is TRUE regarding Tay Sachs and Sandhoff disease? a) Both affect patients of Jewish origin b) Tay-Sachs presents with visceral lipid storage c) Sandhoff Disease has a deficiency of hexosaminidase A and B d) None of the above

c) Sandhoff Disease has a deficiency of hexosaminidase A and B Sandhoff affects infants of NON-Jewish origins (unlike TS) Visceral lipid storage is found in Sandhoff Disease, not TS

Which type of Gaucher is non-neuronopathic?

Type I

Match: 1. Gaucher Disease 2. Niemann-Pick Disease a. Vertical gaze impariment b. Lateral gaze impairment

Gaucher - LATERAL gaze impairment (Gaulat) Niemann-Pick - VERTICAL gaze impairment

Which of the following is NOT true of Niemann-Pick Disease? a) Type A disease is the usual b) Foamy histiocytes c) Blindness and amaurotic nystagmus are symptoms, along w CRSpot d) Ashkenazi Jewish, AR e) None of the above

e) None of the above

Which of the following is NOT true of Generalized GM1 Gangliosidosis? a) Dysmorphic facial features (Pseudo-hurlers) b) Pseudocontractures c) GM 2 Ganglioside accumulation d) Hypoplasia and beaking of thoracolumbar vertebrae

c) GM 2 Ganglioside accumulation GM1!

Clinical symptoms of Krabbe Disease / Globoid Cell Leukodystrophy?

GOT B Generalized rigidity Opisthotonus (neck, trunk) Tendon reflexes depressed Blindness, Optic atrophy * deaf also

The biochemical pathology in Krabbe Disease involves which cells?

Oligodendrocytes

Pathologic findings in Krabbe Disease

White matter - marked reduction Myelin - degeneration Globoid cells (large histiocytes) Schwann cells - w/ tubular/crystalloid inclusions

What is the mutation in Farber Disease?

ASAH1 mutation

What are the symptoms of Farber disease?

Hoarse cry, respiratory distress Ankylosis Severe psychomotor delay Naglakad from far away.... pagod

Tigroid Pattern

Degenerated and intact myelin (cerebrum) Pelizaeus-Merzbacher Disease

Mutation in Canavan Disease

ASPA

AR, Aminoacylase II deficiency (NAA breakdown) Rapid regression of psychomotor function Macrocephaly, blindness, hearing loss Blonde hair, light complexion Increased urinary excretion of NAA WM attenuation, enlarged brain w/ normal ventricles Loss of purkinje cells, hyperplasia of Alzheimer II astrocytes

Canavan Disease

AD, GFAP mutation PM retardation Spasticity Seizures Macrocephaly Rosenthal fibers Destructive WM changes, particularly in frontal lobes

Alexander Disease

AR, PLOG mutation Loss of smile, disinterest Seizures, diffuse myoclonic jerks Microcephaly Blindness Trichorrhexis nodosa Walnut brain Spongiform vacuolization of GM

Alpers Disease

Peroxisomal disorder Mutation: PEX1 Dysmorphic features Multifocal seizures Cataracts, corneal clouding Stippled, irregular calcifications of patellae and greater trochanters Liver & renal dysfunction

Zellweger Disease | Cerebrohepatorenal Disease

``` Sex-linked recessive trait A/w premature birth Temperature instability Seizures Pili torti (hair breaks easily and twisted) Depigmented hair ``` Metaphysial spurring (mistaken for child abuse) Tortuosity and elongation of cerebral and systetmic arteries Mutation in ATP7A - failure of copper absorption Reduced Dopamine-b-hydroxylase (copper-dependent) INcreased dopamine (substrates) Reduced NE, DHPG (products)

Menkes Disease

List the inherited metabolic diseases of infancy that predominantly affect the GRAY MATTER

SLANT Gang, No Doubt ``` Sandhoff Leigh Alexander NCL Tay-Sachs ``` GM1 GANGliosidosis Neuroaxonal Dystrophy

List the inherited metabolic diseases of infancy that predominantly affect the WHITE MATTER

Krabbe SPAM Krabbe Spongy/Caravan Pelizaeus-Merzbacher Adrenoleukodystrophy Metachromatic leukodystrophy

List the inherited metabolic diseases of infancy that present with VISCEROMEGALY

Spin Farber, Later MP! Sandhoff Pompe Infantile Gaucher Niemann-Pick Farber Later: Mucolipidosis Polysaccharidoses

What is the triad for Gaucher?

OST-Gaucher Opisthotonos Strabismus Trismus

Presents with rapid pendular nystagmus (3)

Pendular nystagmus - wasak muscle ng mata - > taas CPK…….. Cockayne Pelizaeus Merzbacher Disease Krabbe

Macular Cherry-Red Spots

Ni Lick ng Tongue ang Cherry ni Macula…. Niemann-Pick Lipofuscinosis Tay-Sachs

Corneal Opacification (3)

Corneal opacification. Refer mo kay jay LIM Lowe Infantile GM1 G MPS

Cataracts

Zell Low, G Zellweger Lowe Galactosemia

Beaking of vertebral bodies is seen in

GM1 Gangliosidosis

Raucious dysphonia, multiple arthropathies

Farber

Storage granules, vacuolated lymphocytes

Niemann-Pick | GM1 G

Macrocephaly (3)

CAT w/ a big head…… idunno.. Can Alexander Tay Sachs? Canavan Alexander Tay-Sachs

Acousticomotor obligatory startle

Tay-Sachs

No tendon reflexes + (+) Babinski

MLK Metachromatic Leukodystrophy Krabbe Leigh

Intractable Seizures, Generalized/Multifocal Myoclonus, Plog Mutation, Walnut brain

Alpers

Normal NS at birth, impaired PM devt in latter 1st year IQ < 20 in 5-6 years Hyperactivity, self-injurious behavior Clumsy gait, fine tremor Rhythmia Blue-eyed, fair skin and hair color Skin rough and dry, musty body odor —- Diagnosis? Deficiency? Labs?

Dx: PKU Deficiency: Hepatic PA Hydroxylase Labs: High serum phenylalanine, elevated phenylpyruvic acid (blood, CSF, urine) Screening: Guthrie (ferric chloride test)

Guthrie (ferric chloride test): Emerald-green

PKU

Guthrie (ferric chloride test): Green-brown (permanent)

Histidinemia

Guthrie (ferric chloride test): Navy-blue

MSUD

Guthrie (ferric chloride test) Purple

Propionic Acid | Methylmalonic Acidemia

PKU variant: Dystonic extrapyramidal rigidity (Stiff-baby syndrome) is due to failure to synthesize ____

Tetrahydrobiopterin

Hereditary Tyrosinemia is a predominantly dermatologic aminoacidopathy that presents w/ DD, self-mutilation, ataxia, and language defects. Also w/ palmar and plantar keratosis, corneal erosions, corneal opacification. Which of the following is the most severe mutation? A) FAH B) TAT C) HPD

A) FAH (type 1)

Tyrosine Hydroxylase deficiency is sensitive to what treatment?

L-dopa

Transport error of natural AA across renal tubules leading to: - scaly rash, pellagrous skin changes - episodic personality disorder, cerebellar ataxia - triggered by sunlight, stress, sulfonamide drugs (SSS) Diagnosis? Treatment?

Hartnup Disease (SLC6A19 Mutation) Nicotinamide. Avoid triggers

Mutation in Metachromatic Leukodystrophy?

Arylsulfatase A (ARSA)

Which of the following is NOT true of Neuroaxonal Dystrophy? A) Progressive blindness, optic atrophy, normal retinae B) Course relentlessly progressive C) Eosinophilic spheroids of swollen axoplasm in posterior columns, clarke column, brainstem nuclei, and cortex D) EEG shows a characteristic high amplitude fast rhythms at birth E) Normal NCV despite EMG evidence of denervation

D) EEG shows a characteristic high amplitude fast rhythms at birth EEG DOES show characteristic high amplitude fast rhythms but this is seen after 2 years

What is the treatment of Infantile Opsoclonus-Myoclonus Syndrome? (Presents w/ myoclonus, dancing eyes)

Dexamethasone AEDs have no effect

Neuronal Ceroid Lupofuscinoses TPP1 mutation. Seizures and myoclonic jerks evoked by proprioceptive or other sensory stimuli Retinal degeneration Translucent vacuoles, azurophelic granules Tx: intraventricular cerolipinase alpha A) Infantile (Santavuori-Haltia) B) Infantile-Juvenile (Jansky-Bielschowsky) C) Juvenile D) Adult (Kuf)

B) Infantile-Juvenile (Jansky-Bielschowsky)

Neuronal Ceroid Lupofuscinoses CLN3 Mutation Visual loss, seizures, ataxia A) Infantile (Santavuori-Haltia) B) Infantile-Juvenile (Jansky-Bielschowsky) C) Juvenile D) Adult (Kuf)

C) Juvenile

Neuronal Ceroid Lupofuscinoses Widespread myoclonus EEG: spike-slow wave -> becomes isoelectric A) Infantile (Santavuori-Haltia) B) Infantile-Juvenile (Jansky-Bielschowsky) C) Juvenile D) Adult (Kuf)

A) Infantile (Santavuori-Haltia)

Neuronal Ceroid Lupofuscinoses CLN 6 mutation Dementia A) Infantile (Santavuori-Haltia) B) Infantile-Juvenile (Jansky-Bielschowsky) C) Juvenile D) Adult (Kuf)

D) Adult (Kuf)

MPS I

Hurler

MPS III

Sanfilippo

MPS II

Hunter

MPS IV

MOrquio

MPS VII

Sly

MPS VI

Maroteaux-Lamy

Enzyme deficiency and GAG in MPS I (Hurler)

A-L-Iduronidase (Dermatan & Heparan sulfate)

Enzyme deficiency and GAG in MPS II (Hunter)

Iduronate sulfatase (Dermatan and heparan sulfate)

Enzyme deficiency and GAG in MPS III (Sanfilippo)

Heparan N-sulfatase (Heparan sulfate)

Enzyme deficiency and GAG in MPS IV (Morquio)

Galactose 6-sulfatase (Keratan & chondroitin 6-sulfate)

Enzyme deficiency and GAG in MPS VI (Maroteaux-Lamy)

Arylsulfatase B (Dermatan sulfate)

Enzyme deficiency and GAG in MPS VII (Sly)

B-glucoronidase (dermatan, heparan, chondroitin 4 sulfate)

All of the MPS are AR except for 1. Which of the mucopolysaccharidoses is X-linked?

MPS II (Hunter) *Hunter X Hunter

Which of the MPS presents with normal intelligence?

MPS VI (Maroteaux-Lamy)

Which MPS has hypoplasia of the odontoid process, atlantoaxial dislocation, dural thickening around the cervical cord and inferior cerebellar surface?

MPS IV (Morquio)

Difference between MPS II (Hunter) and MPS I (Hurler)?

In MPS II, developmental delay and deafness are less common, also w no corneal clouding

Which Mucolipidoses (I-IV) presents with Gargoylism, cherry-red spots, and metachromatic changes in the sural nerve?

Mucolipidosis I

Which mucolipidosis is the most common?

Mucolipidosis II (I-cell disease)

Dysostosis multiplex is present in all of the following except: A) GM1 gangliosidosis B) Hurler Disease C) Mucolipidosis I D) Mucolipidosis II

C) Mucolipidosis I It is present in ML II, not I

Which mucolipidosis presents with gingival hyperplasia and tonic-clonic seizures in older patients?

Mucolipidosis II

``` AR Hepatosplenomegaly, enlarged salivary glands Excessive sweating Gargoyle facies Beaking Angiokeratoma corporis diffusum ```

Fucosidosis (FUCA1 mutation)

What is the mutation in Cockayne Syndrome?

ERCC

Pendular nystagmus Stunting of growth Amyotrophy w/ reduced NCV Photosensitivity Small brain, leukodystrophy Severe cerebellar cortical atrophy Primary segmental demyelination

Cockayne Syndrome

Which Mucolipidosis has normal urinary sialic acid excretion?

Mucolipidosis IV

Which diseases present with Ocular apraxia?

Ataxia-telangiectasia | Niemann-Pick disease

Which of the following is NOT true of Bassen-Kornzweig Acanthocystosis? A) Presents with ataxia, sensory neuropathy B) Common in ages 6-12 years C) Vitamin E deficiency may be a pathogenic actor D) MTTP mutation E) None of the above

E) None of the above

Which of the following is NOT true of Familial Hypobetalipoproteinemia? A) Presents with the HARP syndrome B) Autosomal recessive C) Mutations in gene encoding b-lipoprotein B D) Tx: dietary fat restriction, vit. E supplementation E) None of the above

B) Autosomal recessive Familial Hypobetalipoproteinemia is Autosomal Dominant

What are the 2 mutations in Lafora-Body Polymyoclonus w/ Epilepsy?

EPM2A (laforin) NHLRC1 (Malin)

Usual location of seizures in Lafora-Body Polymyoclonus with epilepsy? A) Frontal B) Temporal C) Parietal D) Occipital

D) Occipital

What is the mutation in Wilson Disease?

ATP7B

What intervention halts progression of Wilson Disease?

Liver transplantation

When is the usual onset of neurologic symptoms in Wilson Disease?

2nd decade

What are the usual first neurologic symptoms in Wilson Disease?

Extrapyramidal, oropharyngeal muscles involved

True or false: In Wilson Disease, an abnormality in behavior precedes other neurologic signs by a year or more

True

What kind of tremor is seen in Wilson Disease?

Wing-beating tremor

True or false: Parkinsonian features in Wilson Disease respond to L-dopa

False

Which of the following is true regarding the histopathologic findings in Wilson Disease A) Frank cavitation in the lenticular nuclei is seen in the chronic form B) Shrinkage and light-brown discoloration of the lenticular nuclei can be seen in the rapidly advancing and fatal form C) There is marked hyperplasia of Alzheimer type II cells in the cortex, BG, brainstem, and cerebellum D) None of the above

C) There is marked hyperplasia of Alzheimer type II cells in the cortex, BG, brainstem, and cerebellum ** Frank cavitation in the lenticular nuclei is seen in the RAPIDLY ADVANCING and FATAL form ** Shrinkage and light-brown discoloration of the lenticular nuclei can be seen in the MORE CHRONIC form

2 particular side effects of D-penicillamine in the treatment of Wilson Disease

Rash Abrupt worsening of neurologic signs

The “Eye of the Tiger” sign on MRI can be seen in which condition?

``` Hallervorden-Spatz disease Panthotenate kinase (PANK)-associated neurodegeneration ```

What is the mutation in Lesch-Nyhan Syndrome?

HPRT1 mutation

X-linked hereditary choreoathetosis with self-mutilation (esp of the lips) and hyperuricemia

Lesch-Nyhan Syndrome

Treatment for self-mutilation in Lesch-Nyhan syndrome

Fluphenazine (Prolixin)

True or false: Serum Ca levels are markedly elevated in Fahrs disease

False. Serum Ca normal

How does X-linked adrenoleukodystrophy present in heterozygous female carriers?

Chronic, mild, nonprogressive spastic paraparesis

What is a specific laboratory marker for X-linked adrenoleukodystrophy?

Excess of VLCFAs

Only known treatment in X-linked ADL?

Bone marrow transplantation

In Cerebrotendinous Xanthomatosis, patients present with cataracts and xanthomas of tendons and lungs at chilhood, then with cognitive, cerebellar, and neuropathic sx later on. What is the mutation and basic defect?

CYP27A mutation Defect in synthesis of primary bile acids -> inc hepatic production of cholesterol and cholestanol

What disease simulates Marfan syndrome (tall habitus, skeletal features, hair, ectopia lentis but downward) and has mental retardation, CV lesions, dementia, epilepsy, and polyneuropathy? What’s the mutation? What is the treatment?

Homocystinuria CBS (cystathionine beta synthase) mutation Tx: Pyridoxine, folate, cobalamin

What is the inheritance pattern for Fabry Disease?

X-linked

AKA angiokeratoma corporis diffusum Deficit: enzyme alpha-galactosidase A Intermittent lancinating pains and dysesthesias of the extremities Evocation by fever, hot weather, and vigorous exercise Thrombotic cerebral infarctions Periumbilical angiokeratomas

Fabry Disease

The following inherited metabolic diseases are associated with stroke EXCEPT: A) Homocystinuria B) Fabry Disease C) Sulfite Oxidase Deficiency D) Hallervorden-Spatz Disease

D) Hallervorden-Spatz Disease | - pigmentary degeneration of the globus pallidus

Subacute Necrotizing Encephalomyelopathy Abrupt appearance of neurologic symptoms Similar lesions to Wernicke Disease but spares mamillary bodies Lactic acidosis

Leigh Disease

Neuropathy, Ataxia, Retinitis Pigmentosa Syndrome has a defective ATPase-6 of complex ___ of the mitochondrial respiratory chain.

Complex V