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Neuro Boards > Child Neurology and Metabolic Disorders > Flashcards

Child Neurology and Metabolic Disorders Flashcards

1
Q

spasmus nutans

A

Triad: head titubation, nystagmus, torticollis

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2
Q

Aicardi Syndrome

A

X-linked dominant (seen in girls).
Agensis of corpus callosum
Infantile spasms
Chorioretinal lacunae

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3
Q

Kearns-Sayre Syndrome

A

Mitochondrial disorder.
Progressive external ophthalmoplegia and pigmentary retinopathy.

Patients with Kearns-Sayre may also have: 
-cerebellar syndrome
-elevated CSF protein
-endocrine abnormalities
-heart block
mitochondrial myopathy
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4
Q

Walker-Warburg

A

muscular dystrophy, severe retinal and eye malformations (microphthalmia, cataracts, retinal dysplasia, optic atrophy. Cobblestone lissencephaly.

Muscle-Eye-Brain Dz muscular dystrophy with associated cerebral and eye findings of less severe phenotype than Walker-Warburg

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5
Q

Cockayne Syndrome

A

disorder of DNA repair
progeria, cataracts, photosensitive skin, short stature
lack adipose tissue
Neuro problems: ID, ataxia, basal ganglia calcification, patchy demyelination, peripheral neuropathy, pigmentary retinopathy, sensorineural hearing loss, contractures

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6
Q

Ataxia telangiectasia

A

defect in ATM gene on chromosome 11q
Truncal ataxia, eye telangiectasias, skin telangiectasia, recurrent sinopulmonary infections, reflexes decreased or absent and lose ability to walk by 12 years
High risk of cancer (lymphoma and leukemia)

Labs: AFP and CEA increased and IgA, IgG, IgE decreased
MRI: cerebellar atrophy

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7
Q

Incontinentia Pigmenti

A

X-linked dominant
Mutation at Xq in the NF-kappa-B essential modulator gene (NEMO)
Seizures, ID, spasticity

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8
Q

Klippel-Trenaunay-Weber Syndrome

A

Port-wine stain or hemangioma that may involve face, trunk or extremities + venous varicosities + unilateral limb hypertrophy due to bone and/or soft tissue enlargment
May have macrocephaly, intracranial angioma or spinal AV malformation

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9
Q

Linear sebaceous nevus syndrome

A

form of epidermal nevus syndrome characterized by a linear nevus usually on face or scalp.
Hemihypertrophy and/or hemimegalencephaly ipsilateral to the nevus can occur.
ID and seizures may be present

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10
Q

Osler-Weber-Rendu Syndrome (aka Hereditary Hemorrhagic Telangiectasia)

A

Genetics: AD
HHT1: muations in the endoglin gene at 9q
HHT2: muation in ACVRL1 at 12q

Skin angiomas and angiomas in the GI and GU tracts, nose, lung and CNS
Frequently present with recurrent epistaxis

Neuro complications: AVMs in lung lead to brain abscesses and embolic strokes; brain AVMs can cause intracranial hemorrhage and subarachnoid hemorrhage, paraparesis if spinal AVM bleeds

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11
Q

Genetics of TS

A

TS-1: Hamartin gene on 9q

TS-2: Tuberin gene on 16p

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12
Q

Neuro symptoms in Xeroderma Pigmentosa

A

Defective DNA repair–extreme photosensitivity

acquired microcephaly, dementia, sensorineural hearing loss, ataxia, and peripheral neuropathy

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13
Q

Cerebro-tendonous Xanthomatosis (aka Van Bogaert-Scherer-Epstein syndrome)

A

Excess cholestanol deposits in their brain and other tissues. LDL usually normal

“lipid nodules” especially collect in the cerebellum, Achilles’ tendons and eyes

Symptoms: tendineous or tuberous xanthomas, juvenile cataracts and progressive cerebellar ataxia (beginning after puberty)

AR with mutation in CYP27A1 on 2q

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14
Q

Pseudo-Xanthoma Elasticum (aka Gronblad-Strandberg Syndrome)

A

fragmentation and mineralization of elastic fibers in skin, eyes and blood vessels (premature atherosclerosis)
“Oblique mental creases” with diagonal grooves in chin
Orange Eyes
Red legs: intermittent claudication

Genetics: AR mutations in the ABCC6 gene on 16p

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15
Q

Wyburn-Mason Syndrome (aka Bonnet-Dechaumme-Blanc syndrome)

A

AVMs in the retina of one eye and in the CNS

May have other AVMs elsewhere in the body too

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16
Q

Fabry’s

A 
Alpha-galactosidase deficiency
X-linked recessive
Angiokeratomas
corneal deposits
autonomic dysfunction, small fiber neuropathy
arrhythmia
hypertrophic cardiomyopathy, heart failure
Hemorrhage or thrombosis
Renal failure
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17
Q

Farber’s

A

ceramidase deficiency, ceramide accumulates in tissues esp joints

presents in first few weeks to months of life
worsening hoarseness, subcutaneous nodules, macular cherry-red spots and progressive arthropathy
Neuro findings: hypotonia, weakness and developmental delay.

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18
Q

Gaucher’s

A

beta-glucosidase or glucocerebrosidase deficiency
Gaucher cells: histiocytes containing lipids–found in spleen, liver, lymph nodes, and bone marrow

Type 1: nonneuropathic (most common form)

Type 2: acute neuropathic form. Presents before 1 year of life with visceral organomegaly and developmental delay
Associated with trismus, strabismus, opisthotonus and spasticity.
Laryngeal stridor and aspiration pneumonia
Death by age 2 years.

Type 3: chronic neuropathic form. Presents in first decade and is characterized by cognitive deterioration, seizures, rigidity and ataxia. Horizontal supranuclear gaze palsy.
Hepatosplenomegaly, interstitial lung disease common

ERT for types 1 and 3.

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19
Q

Krabbe

A

galactosyl ceramide beta galactosidase

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20
Q

Metachromatic leukodystrophy

A

arylsulfatase A deficiency results in accumulation of galactosylceramide

Late-infantile is most common form:
1-2 yo with falling/gait problems, hypotonia at first
then mixed upper and lower motor neuron signs due to leukodystrophy + demyelinating peripheral neuropathy
Late in course, decerebrate posturing and blindness
Increase CSF protien, sulfatide in urine
MRI with symmetric demyelination with SPARING OF U-FIBERS
NCS with slowed motor and sensory NCS due to demyelination.

Can tx with BMT or HSCT

Juvenile form: 1st behavioral problems and difficulties in school

Adult: dementia or psych symptoms

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21
Q

Niemann-Pick Disease types A and B

A

sphingomyelinase deficiency

A: classic infantile neuronopathic form
-mutation in sphingomyelin phosphodiesterase-1 gene (SMPD1)
-persistent neonatal jaundice, FTT, hepatomegaly, DD, regression, may have seizures
-may have pulmonary infiltrates, lymphadenopathy, and significant abdominal distention
LIVER AND BONE MARROW SHOW FOAMY HISTIOCYTES (CONTAIN LIPID)
-death at 3-5 yo
-more common in Ashkenazi Jewish families

B: visceral form

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22
Q

Sandhoff

A

hexosaminidase A and B deficiency
GM2 gangliosidosis due to mutations of the beta subunit of hexosaminidase
AR, chromosome 5
Clinically and pathologically resembles Tay Sachs BUT Sandhoff has mild hepatosplenomegaly
Cherry red spot (like Tay Sachs)
death by age 3
Coarse granulations in histiocytes in the bone marrow

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23
Q

Tay-Sachs

A

Hexosaminidase A
GM-2 gangliosidosis
mutations in alpha-subunit of the hexosaminidase A gene
AR, maps to chromosome 15
Increased frequency in Ashkenazi Jewish population
onset in first few months of life
irritability and sensitivity to noise with an increased startle
progressive weakness and hypotonic with hyperreflexia
seizures, blindness and megalencephaly
cherry-red spot
posturing at age 2, then become unresponsive
death by 5 years of life
CNS pathology: ballooned neurons with foamy cytoplasm

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24
Q

Pompe

A 
acid maltase (1,4 glucosidase)
aka Glycogen Storage Disease Type II

Infantile onset: neonatal hypotonia, macroglossia, cardiomegaly, hepatomegaly

Membrane-bound vacuoles, which are PAS + are found in muscle, liver, and Schwann cells.

Adult onset: usually present in 20s-30s; often with fatigue or leg and trunk weakness.
Increased CK and myotonia on EMG
Intracranial aneurysms due to glycogen deposition

Vacuolar myopathy on muscle biopsy

Enzyme replacement available

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25
Q

McArdle

A

muscle phosphorylase deficiency aka Glycogen Storage Disease type V
fatigue, muscle cramps and myoglobinuria (which may cause renal failure)
Associated with second wind phenomenon
Forearm ischemic lactate test abnormal–lack a risk in lactate with muscle use

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26
Q

Abetalipoproteinemia

A

AR, mutations in gene for microsomal triglyceride transfer protein (MTP) on chormosome 4–>near absence of apo-B containing lipoproteins in the plasma
ataxia, neuropathy, steatorrhea, retinitis pigmentosa and acanthocytosis

Loss of fat-soluble vitamins in stool–>Vit E deficiency (areflexia, sensory neuropathy and sensory ataxia)

Acanthocytosis on peripheral smear
Total cholesterol and triglyceride levels low

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27
Q

Acute Intermittent Porphyria

A

Deficient porphobilinogen deaminase
Results in increased porphobilinogen and delta-aminolevulinic acid

AD, gene on 11q
onset usually in adolescence or early adulthood
Attacks periodic and may be triggered by certain medications, fasting, infection or hormonal changes such as pregnancy

Symp: severe abdominal pain, fever, tachycardia and hypertension
Weakness due to a motor neuropathy. May progress to quadriparesis and respiratory failure resembling GBS.
Avoid barbiturates, carbamazepine, clonazepam, phenytoin, and valproate.
Treat attacks with IV dextrose and propranolol.

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28
Q

Aromatic L-Amino Acid Decarboxylase Deficiency (AADC deficiency)

A

AR inheritance
AADC an enzyme in synthesis of dopamine and serotonin
Presents in first few months of life with dystonia, athetosis, tongue thrusting, torticollis, oculogyric crisis, ptosis and autonomic dysfunction
Gross motor and speech delay. Ataxia later in life

Test: CSF neurotransmitters

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29
Q

Elevated very long chain fatty acids

A

Refsum disease, Rhizomelic chondroplasia punctata, adrenoleukodystrophy, zellweger syndrome

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30
Q

2 diseases with pathologic involvement of U-fibers

A

Alexander’s and Canavan’s

They also both have megalencephaly

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31
Q

Ataxia with Isolated Vitamin E Deficiency

A

aka Friedreich-like ataxia bc phenotype is similar
mutation in gene encoding alpha-tocopherol transfer protein (ATTP) on chromosome 8q

Symptoms begin in puberty. Have progressive ataxia, loss of proprioception, areflexia. Some patients have titubation, deafness, tendon xanthomas or retinitis pigmentosa

32
Q

Canavan disease

A

AR inheritance
Characterized by spongy degeneration of cerebral white matter.
Deficiency of aspartoacylase, which hydrolyzes N-acetyl-L-aspartic acid (NAA) to aspartic acid and acetic acid.

Symptoms start at 2 months of age.
Hypotonia, regression, seizures, optic atrophy, macrocephaly. Tone gradually increases and later in the course, spasticity, opisthotonus and posturing can be seen

NAA increased in plasma and urine. MRS shows elevated NAA peak

33
Q

Carbohydrate-Deficient Glycoprotein Syndromes aka Congenital disorders of glycosylation

A

CDG-Ia is most common form–defect in gene PMM2, which encodes phosphomannomutase
May have pure neurologic or neurologic and systemic symptoms.
Neuro sympt: strabismus, dev delay, carebellar hypoplasia, seizures, stroke-like episodes, cerebellar ataxia
Characteristic features: inverted nipples, abnormal fat distribution
Dx: isoelectric focusing of serum transferrin isoforms

34
Q

Cerebrotendinous Xanthomatosis

A

AR disease of lipid metabolism
Mutation in sterol 27-hydroxylase gene on chromosome 2
Absence of bile acid chenodeoxycholic acid
Increased cholestanol in the plasma and tissues, including CNS–>cataracts, xanthomas, ataxia and dementia
Diffuse WM abnormalities, including the WM of the cerebellum. CT will show hyperdense nodules in the cerebellum

Tx: chenodeoxycholic acid.

35
Q

Diseases with cherry-red spot

A 
Farber's disease
Sialidosis
GM1-Gangliosidosis
Sandhoff's
Tay Sachs
Niemann-Pick Type A
36
Q

Galactosemia

A

Multiple enzyme deficiencies in galactose metabolism can cause galactosemia in newborns
AR mutations
Most severe: galactose-1-phosphate uridyltransferase=classic galactosemia

Symptoms present in newborns after feeding:
vomiting, diarrhea, jaundice and hepatomegaly
hypotonia, lethargy, may have cerebral edema

Cataracts by 1-2 month of age
E. coli sepsis common

37
Q

Glutaric acidemia type 1

A

AR organic acidemia due to deficiency of glutaryl coenzyme A dehydrogenase
Macrocephaly, dystonia, dyskinesias and developmental delay
MRI with frontotemporal atrophy with prominent Sylvian fissures that results in a “batwing” appearsance
can have retinal hemorrhages and subdural effusions that cause confusion with child abuse.

38
Q

Glutaric acidemia type 2

A

aka multiple acyl-CoA dehydrogenase deficiency
disorder of fatty acid oxidation due to deficiency of electron transport flavoprotein (ETF) or ETF -ubiquinone oxidoreductase

Two neonatal forms, one withy hypotonia and metabolic abnormalities. Hypoglycemia and metabolic acidosis. NO ketosis. Sweaty feet odor (similar to isovaleric acidemia)
Fatal in 1st month of life.

Ethylmalonic-adipicaciduria: presents later in life, similar to Reye syndrome. Intermittent encephalopathy, hepatomegaly, hypoglycemia, metabolic acidosis.
Responds to riboflavin

39
Q

GTP Cyclohydrolase Deficiency

A

most common cause of dopa-responsive dystonia
AD
gene on 14q

40
Q

Hartnup Disease

A

aminoaciduria due to a defect in transport of neutral amino acids in the kidney and small intestine

Intermittent ataxia, which may be associated with nystagmus, AMS, and patient may be hypotonia
photosensitive rash may resemble pellagra

Elevated levels of neutral amino acids are found in urine and stool

Tx: high-protein diet. Other tx include tryptophan or nicotinic acid

41
Q

Metabolic defects that can cause intermittent ataxia

A

MSUD, pyruvate dehydrogenase deficiency (Leigh syndrome), Hartnup disease, some urea cycle defects

42
Q

Homocystinuria

A 
can be cause by deficiency of: 
cystathionine beta-synthase (most common genetic form, due to defect in the gene CBS on 21q, which encodes cystathionine beta-synthase)--untreated characterized by Marfanoid features, ectopia lentis (lens downward deviation as opposed to Marfan syndrome when lens upward), ID, seizures, livedo reticularis, codfish vertebra, malar flush, and risk for thromboembolism
MTHFR
methionine synthase reductase
methionine synthase, aka MTR

OR methylcobalamin synthesis defect

Also, Nitrous oxide toxicity (inhibits methylcobalamin synthase)
Also B12 deficiency (elevated homocysteine and methionine)

43
Q

Isovaleric acidemia

A 
AR organic acidemia due to deficiency of isovaleryl-CoA 
2 forms: 
Neonatal form: 
acidosis and coma in first week of life
Patient may have seizures
pancytopenia
URINE SMELLS LIKE SWEATY FEET

Chronic form:
recurrent vomiting, ketoacidosis, lethargy
MAY ALSO SMELL LIKE SWEATY FEET

44
Q

most common congenital cause of visual impairment

A

Leber Congenital Amaurosis

  • group of disorders of recessive retinal dystrophies
  • moderate to severe visual impairment at or near birth with nystagmus, midface hypoplasia, enophthalmos.
  • may also have ID
45
Q

deficiency of HGPRT (hypoxanthin guanine phosphoribosyl transferase)

A

Lesch-Nyhan Syndrome

46
Q

Lowe syndrome (Oculocerebrorenal syndrome)

A

X-linked recessive due to mutation in OCRL1 gene on Xq26.1

Eyes: bilateral congenital cataracts, glaucoma with or without buphthalmos, corneal cheloids, blindness
Neuro: neonatal hypotonia, delayed milestones, ID, seizures, peripheral europathy, decreased reflexes, obsessive-compulsive behaviors

Renal: proximal renal tubular acidosis, renal Fanconi syndrome

47
Q

MSUD

A

decreased branched chain keto-acid dehydrogenase, which metabolized the keto-acid forms of leucine, isoleucine, and valine
Newborn develops lethargy and difficulties with feeding, urine smells like maple syrup, progressive encephalopathy, episodes of apnea, opisthotonic posturing, bicycling or fencing movements, tone fluctuates between hypotonia and hypertonia

Patient becomes comatose. Seizures seen
CT/MRI: diffuse edema affecting white matter, including white matter of cerebellum
Labs: ketoacidosis, elevated plasma levels of branched chain amino acids and branched chain ketoacids
Elevated plasma L-alloisoleucine
Urine contains ketones and elevated levels of branched chain ketoacids.
Dinitrophenylhydrazine test is +
Tx: diet restricting isoleucine, leucine and valine

There is a form of MSUD that responds to thiamine

48
Q

Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD)

A

MOST COMMON DISORDER OF FATTY ACID OXIDATION

Presents in 1st year of life with episodes of lethargy and vomiting. Some patients have cardiopulmonary arrest.
Causes hypoketotic hypoglycemia that may be fatal.

Tx: carnitine and low fat diet

49
Q

Menkes Kinky Hair Disease

A

X-linked recessive disorder of copper transport
ATP7a mutations results in failure to absorb copper from gut
Presents at 2-3 months of age with hypotonia, seizures, regression and poor feeding. Stimulation-induced myoclonic jerks
Sparse “kinky” hair.
may have vasculopathy resulting in stroke or subdural hematomas
May have bone abnormalities such as rib fx and wormian bones giving appearance of child abuse.

50
Q

Methylmalonic Acidemia

A

Organic acidemia
Vitamin B12 deficiency or defects in methylmalonyl CoA mutase

Classic form of MMA: absence of methylmalonyl-CoA mutase. Neonate with vomiting, hypotonia, lethargy, metabolic acidosis, hyperammonemia and ketotic hyperglycinemia.

Complications: spastic quadriparesis, ID, basal ganglia stroke, dystonia

MMA increased in plasma, urine and CSF. May have neutropenia and/or thrombocytopenia
Tx: low protein diet and carnitine, trial of B12

51
Q

Mitochondrial Encephalopathy, Lactic Acidosis and Stroke (MELAS)

A

presents in childhood with headaches, vomiting, GTCs, and stroke-like episodes (transient hemiparesis or blindness)

MRI: multiple infarctions that do not fit a vascular distribution, typically initially seen in occipital lobes

Labs: Elevated blood and CSF lactate
Muscle bx: ragged red fibers
Tx: carnitine and co-Q10

52
Q

mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

A

Diarrhea, episodes of pseudo-obstruction
Weakness, ptosis, progressive external ophtalmoplegia and sensorimotor polyneuropathy
MRI with leukoencephalopathy but no symptoms of CNS dysfunction

53
Q

alpha-L-iduronidase deficiency

A

Hurler (ID)
Hurler-Scheie (no ID)
Scheie (no ID)

MPS I
coarse facial features
dysostosis multiplex (characteristic skeletal findings)
AR
Accumulation of dermatan and heparan sulfate
Zebra bodies on electron microscopy

54
Q

Iduronate sulfatase defeciency

A

Hunter (ID)
MPS type II
X-linked, no corneal clouding (vs. common in the other MPS)
dysostosis multiplex (characteristic skeletal findings)
Accumulation of dermatan and heparan sulfate
Characteristic nodular ivory colored lesions on back, shoulders, and upper arms

55
Q

Multiple Carboxylase deficiencies:
Holocarboxylase Synthase Deficiency
Biotinidase Deficiency

A

HSD: early-onset
neonate with metabolic encephalopathy
alopecia, rash, ataxia, lactic acidosis, ketosis, hyperammonemia, thrombocytopenia

Biotinidase: late-onset
3 months of age with seizures and hypotonia
alopecia, rash, ataxia, respiratory disturbances, spastic paraparesis, hearing and vision loss

Tx both with biotin

56
Q

Multiple Sulfatase Deficiency

A

Lysosomal storage disorder due to mutations in sulfatase-modifying factor-1 gene (SUMF1)

Encodes an enzyme required for formation of the catalytic site of sulfatases

Neuro findings similar to metachromatic leukodystrophy due to deficiency of arylsulfatase A

Skeletal findings: similar to MPS patients due to iduronate deficiency

Ichthyosis due to steroid sulfatase deficiency

57
Q

Myoclonic Epilepsy and Ragged Red Fibers (MERRF)

A

mitochondrial disease, mutation in tRNA Lys gene typically responsible

lipomas, optic atrophy, deafness, short stature, myopathy, neuropathy
Myoclonic epilepsy

elevated lactate and pyruvate

58
Q

NARP (Neuropathy, ataxia, retinitis pigmentosa)

A
  • mitochondrial disease but NO ragged-red fibers and may not have lactic acidosis
  • point mutation in ATPase 6 gene
59
Q

Infantile NCL (CLN1)

A

defect in CLN1 gene at 1p, codes for palmitoyl protein thioesterase (PPT1)

  • Presents between 6 mo and 2 years
  • ataxia, myoclonic seizures, psychomotor regression, progressive vision loss, microcephaly
  • Electron microscopy shows granular osmiophilic deposits
60
Q

Niemann Pick Type C

A

mutation in NPC1 gene on 18q or NPC2 on 14q
ABNORMAL CHOLESTEROL TRANSPORT causes accumulation of sphingomyelin and cholesterol in lysosomes
-may present with neonates with jaundice and hepatomegaly OR infants with hypotonia and DD
BUT classic form is 3-8 yo with clumsiness progressing to ataxia, vertical supranuclear gaze palsy (problem with downgaze first), dysarthria, dementia, dysphagia, dystonia, gelastic cataplexy, choreoathetosis, and seizures

-FOAMY CELLS IN BONE MARROW, LIVER, SPLEEN AND SEA-BLUE HISTIOCYTES IN BONE MARROW

61
Q

Nonketotic hyperglycinemia

A

AR due to defect in glycine cleavage
aka glycine encephalopathy
neonates lethargic, hypotonic with hiccups, apnea, multifocal myoclonus, seizures with EEG showing burst suppression
Elevated CSF glycine and elevated CSF:plasma glycine ratio

62
Q

Pelizaeus-Merzbacher

A

Classic: X-linked recessive due to mutation in PLP1 gene encoding proteolipid protein (PLP)
infant with pendular nystagmoids (roving eye mvmts), head tremor/nodding, later spasticity, ataxia and optic atrophy
MRI with symmetric dysmyelination. Tigroid appearance due to small regions of normal neurons and myelin in midst of abnormal WM.
Death in adolescence or early adulthood

Connatal form: AR or X-linked. Presents earlier and progresses faster. Less myelin

63
Q

Phenylketonuria (PKU)

A

AR due to deficiency of phenylalanine hydroxylase, which converts phenylalanine to tyrosine
Defects in tetrahydrobiopterin synthesis and regeneration also cause hyperphenylalaninemia

-DD, light pigmentation (blond hair/blue eyes, pale skin), eczema, mousy/musty odor
Untreated–>microcephaly, spasticity, seizure, ID
MRI: increased signal in periventricular regions on T2 due to dysmyelination

64
Q

Phosphofructokinase Deficiency/Tarui’s Disease/Glycogen Storage Disease Type VII

A

AR metabolic myopathy
presents in childhood
exercise intolerance–>cramps, fatigue, myoglobinuria
abnormal forearm ischemic lactate test (like McArdle)
NO second wind phenomenon (unlike McArdle)

65
Q

Proprionic Acidemia

A

defect in proprionyl-CoA carboxylase

  • enzyme requires biotin
  • important in metabolism of valine, isoleucine, methionine, threonine, cholesterol, and odd-chain fatty acids
  • presents in first 3 months of life with metabolic decompensation: vomiting, dehydration, lethargy, acidosis
  • seizures may occur
  • ketotic hyperglycinemia and hyperammonemia
  • neutropenia and thrombocytopenia
  • PROPRIONIC ACID ELEVATED IN THE URINE

Tx: protein restricted diet and carnitine

66
Q

Pyridoxine Dependency

A

Presents in neonatal period with refractory seizures
Mutations in ALDH7A1 gene on 5q, which encodes antiquitin

Elevated pipecolic acid and alpha-aminoadipic semialdehyde (AASA)

67
Q

Refsum Disease

A

Classic form: Childhood onset

  • defect in gene encoding phytanoyl-CoA hydroxylase, required for oxidation of phytanic acid–>phytanic acid accumulates
  • night blindness in 1st-2nd decade of life
  • retinitis pigmentosa, ataxia, anosmia, deafness, chronic hypertrophic demyelinating sensorimotor neuropathy with onion bulbs, ichthyosis and diabetes
  • skeletal defects (ex: epiphyseal dysplasia)
  • cardiac failure
  • CSF protein v. high
  • Tx: diet low in phytanic acid

Infantile:
-disorder of peroxisomal assembly
steattorrhea, retinitis pigmentosa, DD, peripheral neuropathy, deafness
-phytanic acid and VLCFA accuulate

68
Q

Sialidosis

A 
alpha neuraminidase (sialidase) deficiency
elevated sialyloligosaccharides in urine

Type I
Progressive myoclonic epilepsy
cherry red spot

Type II--resembles Hurler syndrome
dysmorphic features and skeletal abnormalities
cherry red spot
hepatosplenomegaly
DD
69
Q

Sjogren-Larsson Syndrome

A

leukoencephalopathy due to decreased activity of fatty aldehyde dehydrogenase

Triad of:
ichthyosis
ID
spastic diplegia or quadriplegia

70
Q

Succinic semialdehyde dehydrogenase (SSADH) Deficiency

A

DD, childhood-onset hypotonia, ataxia, seizures, and behavior disturbances
MRI: abnormalities in the globus pallidus on T2 weighted images
Urine organic acids: presence of 4-hydroxybutyric aciduria/gamma-hydroxybutyric aciduria

71
Q

sulfite oxidase deficiency

A

isolated defect or seen in molybdenum cofactor deficiency

results in abnormal metabolism of sulfated amino acids
sulfite oxidase deficiency causes severe neonatal seizures, developmental delay and hypotonia
lack of sulfite oxidase leads to abnormal production of s-sulfocysteine, which leads to ocular lens dislocation

72
Q

Tangier Disease

A

deficiency of alpha-lipoprotein
associated with mutation in the ATP-binding cassette-1 gene on 9q
Large orange tonsils, lymphadenopathy, and splenomegaly
sensory neuropathy affecting distal upper extremities and atrophy of the intrinsic muscles of the hand
Labs: decreased cholesterol and LDL, very low HDL, high triglycerides

73
Q

Tyrosine Hydroxylase Deficiency

A

One cause of Dopa-responsive dystonia due to mutation in tyrosine hydroxylase gene on 11p and is AR
catalyzes rate-limiting step of dopamine synthesis, conversion of tyrosine to levodopa
Requires tetrahydrobiopterin as a cofactor

74
Q

Wilson’s Disease

A

AR
mutations in ATP7b on chromosome 13q, gene encodes copper transporting adenosine triphosphatase, which transports copper from hepatocyte into bile

Patients <10 yo: liver failure
Patients >10 yo: neuro or psych symptoms (wing-beating tremor, Kayser-Fleischer rings, sunflower cataracts, risus sardonicus

Labs: decreased serum copper, decreased serum ceruloplasmin, increased 24 hour copper excretion
MRI: face of giant panda on T2 due to decreased signal in superior colliculi and increased signal in medial substantia nigra and tegmentum
Path Alzheimer type I and type II astrocytes

Tx: chelation, D-penicillamine, ammonium tetrathiomolybdate, zinc, or triethylene tetramine dihydrochloride

75
Q

Wolman Disease

A

Acid lipase deficiency
Neuro symp: hypotonia and developmental delay beginning in infancy
Other: jaundice, vomiting, diarrhea, malabsorption, poor weight gain, adrenal insufficiency (calcified adrenals), hepatosplenomegaly.

76
Q

Zellweger syndrome (Cerebro-Hepato-Renal Syndrome)

A

AR disorder of peroxisome biogenesis
Similar to neonatal adrenoleukodystrophy, which is also a disorder of peroxisomal assembly associated with deficiency of multiple peroxisomal enzymes

Characteristic appearance: prominent forehead, epicanthal folds, large fontanelle, cataracts or Brushfield spots (typically associated with Down syndrome)
renal cysts, hepatomegaly
-calcific stippling of patellae and hips on xray
-weakness and hypotonia
-DD, impaired vision and hearing
-seizures
-migration defects: polymicrogyria, heterotopia, pachygyria
-deficiency of myelin but less severe than in adrenoleukodystrophy
-labs increased bilirubin, iron, CSF protein, VLCFA

77
Q

Pyruvate Dehydrogenase Deficiency

A

Caused by defects of the PDH complex, which is responsible for the oxidative decarboxylation of pyruvate to carbon dioxide and acetyl CoA.

3 main components:
E1 def=x-linked
E2,E3=AR
Clinical presentation variable: severe neonatal lactic acidosis with death in neonatal period to less severe forms manifested in infancy, in which patients have lactic and pyruvic acidosis and episodic or progressive ataxia, nystagmus, dysarthria, lethargy, weakness with areflexia, hypotonia, and psychomotor retardation which can be profound. Episodic exacerbations which can be spontaneous or triggered by infections, stress, or high carb meals.
Tx: ketogenic diet and thiamine supplementation

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