Transcript GM1 Gangliosidosis

An Infant with Neuro-regression
Dr. KF Huen
TKOH
History
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F / 12 months
FT NSD at UCH with BW 2.655 kg
Uneventful perinatal course
No consanguinity
 Father - Chinese
 Mother - Chinese + Thai
 No family history of metabolic disease or
sudden/early infant death
History
 Presented with clinical sepsis in neonatal period
 No positive bacterial or viral culture
 Noted ↑ ALP up to 1350 U/L (< 281 U/L) with
bone isoenzyme predominant
 Calcium and phosphate normal
 Skeletal survey – no evidence of rickets or
previous fracture
 ALP gradually ↓ with serial monitoring,
normalized at 3m
History
 Noted hypotonia and developmental delay at 6
months of age
 Head lag, not able to roll over or sit, no reach out
 Plain CT brain – unremarkable
 Urine metabolic screen – negative
 Physiotherapy arranged for early training, slight
improvement in development
History
 At 9 months of age, better head control, able to sit with
curve back with support and able to reach out
 Noted neuro-regression at 11 months of age, head
control lost, not able to sit with support, not able to
reach out and no visual fixation and follow
 More easy choking on oral feeding
 Assessment in CAC at 12 months – significant global
delay (mental age = 1 month)
Examination
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HC 90-97 %
BW 50-75 %
BH 50-75%
Hypotonia with head lag
Paucity of anti-gravity movement
Coarse facial features – frontal bossing, flat nasal
bridge, hypertelorism, thick lips and gum
hypertrophy
Examination
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No cataract or corneal clouding
No fix and follow
Abdomen – hepatosplenomegaly
CVS – unremarkable
Chest – unremarkable
Hypotonia
Coarse Facial Features
Extensive Mongolian Spots
Investigations
 CBP – atypical lymphocytosis with a number of
lymphocytes with prominent cytoplasmic
vacuolation
 LFT – ALP 522 (< 281 U/L), ALT 39 (< 33
U/L)
 Skeletal survey – ovoid shaped vertebral bodies,
anterior beaking of T12 and especially L1 with
kyphosis, thickened skull vault, normal pituitary
fossa
Cytoplasmic Vacuolation
Vacuolated
lymphocytes
Lymphocytes with multiple medium-sized vacuoles (top left).
Some contained a large azurophilic granule (bottom left).
Majority of eosinophilic granulocytes were pale. Many contained large
granules unevenly distributed within the cytoplasm (right).
Although abnormally vacuolated lymphocytes may be observed in
infantile sialic acid storage disease, mannosidosis and GM1gangliosidosis,
the eosinophilic anomaly in addition is specific for GM1-gangliosidosis
type I (Giltzemann et al, 1985).
Two-dimensional glycosaminoglycan
electrophoresis of the patient’s urine
Presence of chondroitin
sulphate (CS), heparan
sulphate (HS) and
keratan sulphate (KS).
The presence of KS is
abnormal and is seen
in patients with
mucopolysaccharidosis
type IV (Morquio
syndrome) and GM1gangliosidosis.
Skeletal Survey – dysostosis multiplex
Thickened calvarium; enlarged sella
Flattening, beaking and kyphosis
Flaring of ilia of pelvis;
acetabular dysplasia
Coarse thickening of
phalanges and metacarpals;
Bullet-shaped appearance
Investigations
 Echo – no cardiomyopathy, normal LV function
 Ophthalmologic exam – bilateral cherry red spots
 ENT exam – both vocal cords smooth and
mobile, bilateral moderate-severe sensorineural
hearing deficit, bilateral flat tympanometry
 Speech therapist assessment – impaired
swallowing but normal vocal cord function
 MRI brain – gross delay in myelination process
MRI brain
Investigations
 Urine metabolic screen – negative for
mucopolysaccharide (by electrophoresis)
 Urine oligosaccharide pattern (TLC) compatible
with GM1 gangliosidosis
TLC - Heavily staining bands around zones of penta-saccharide,
octa-saccharide, and oligosaccharides with longer sugar chains
TTN
TTN
GM1
TTN
Investigations
 Leucocytes for enzyme assay –
 Hexosaminidase A & B activity normal (GM2
gangliosidosis – Tay-Sachs, Sandhoff)
 α-galactosidase activity normal (Fabry, Schindler)
 Deficient β-galactosidase activity 0.10 (1.0 – 6.0
nmol/min/mg protein)
Investigations
 β-galactosidase (GLB1) gene mutation analysis
 Index: compound heterozygous for
c.495-7delTCT and c.1734G>T
 Mother: heterozygous for c.1734G>T
 Father: mutation not detected
Diagnosis
GM1 gangliosidosis
Complications
 GERD and aspiration
 Developed repeated
episodes of cough,
noisy breathing and
vomiting
 Required continuous
naso-gastric tube
feeding
Complications
 Seizure
 Developed repeated episodes of apnoea &
desaturation and generalised tonic clonic
convulsion
 EEG – epileptic tendency
 Required phenobarbitone, phenytoin and
clobazam for seizure control
Complications
 Spasticity
 Spasticity over extremeties and tight Achilles
tendons
 Required physiotherapy and nocturnal anklefoot orthosis
Progress
 Parents preferred naso-gastric tube feeding than
gastrostomy feeding
 Experienced few episodes of gastro-esophageal
reflux and aspiration
 At 18 months of age, developed aspiration
pneumonia and hence respiratory failure, finally
succumbed
Review
GM1 gangliosidosis
Background
 Autosomal recessive lysosomal storage disorder
characterized by the generalized accumulation of
GM1 ganglioside, oligosaccharides, and the
mucopolysaccharide keratan sulfate and their
derivatives
 Deficiency of the lysosomal hydrolase, acid βgalactosidase (GLB1), causes GM1 gangliosidosis
and Morquio disease type B (ie.
mucopolysaccharidosis type IVB).
Background
Three clinical subtypes classified by age of onset:
 Infantile (type 1)
 Combines the features of a neurolipidosis (neurodegeneration,
macular cherry-red spots) with those of a mucopolysaccharidosis
(visceromegaly, dysostosis multiplex, coarse facial features)
 Most frequently presents in early infancy and may be evident at birth
 Juvenile (type 2)
 Slightly later age of onset and clinical variability in the classic physical
features
 Adult (type 3)
 Normal early neurologic development with no physical stigmata and
subsequent development of a slowly progressive dementia with
parkinsonian features, extrapyramidal disease and dystonia
Pathophysiology
 Acid β-galactosidase is a lysosomal hydrolase that catalyzes the removal
of the terminal β-linked galactose from glycoconjugates (eg. GM1
ganglioside), generating GM2 ganglioside
 Degrades other β-galactose-containing glycoconjugates, such as
keratan sulfate
 Deficiency of acid β-galactosidase results in the accumulation of
glycoconjugates in body tissues and their excretion in urine
 GM1 ganglioside and its derivative asialo-GM1 ganglioside (GA1),
glycoprotein-derived oligosaccharides, and keratan sulfate are found at
elevated intracellular concentrations
 Gangliosides are normal components of cell membranes, particularly
neurons, and GM1 is the major ganglioside in the vertebrate brain
 Accumulation of toxic asialo- and lyso-compound GM1 ganglioside
derivatives is believed to be neuropathic
Epidemiology
 Frequency
 Rare disorder, incidence not widely available
 High incidence of 1 per 3700 live births in Malta
 Race
 Found in all race, large number of Japanese patients
with adult form has been reported
 Sex
 Autosomal recessive traits, equal sex distributions
Clinical Course
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Infantile form (type 1)
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Juvenile form (type 2)
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Typically presents between birth and age 6 months with progressive organomegaly,
dysostosis multiplex, facial coarsening, and rapid neurologic deterioration within
the first year of life
Death usually occurs during the second year of life because of aspiration
pneumonia and cardiopulmonary failure
Typically presents at age 1-2 years with progressive psychomotor retardation
Little visceromegaly and milder skeletal disease
Death usually occurs before the second decade of life
Adult form (type 3)
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Typically presents during childhood or adolescence as a slowly progressive
dementia with prominent parkinsonian features and extrapyramidal disease,
particularly dystonia.
Marked phenotypic variability
Age at death vary greatly
Clinical Features
 Neurologic findings
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Developmental delay, arrest, and regression
Generalized hypotonia initially, developing into spasticity
Exaggerated startle response
Hyperreflexia
Seizures
Extrapyramidal disease (adult subtype)
Dystonia (adult subtype)
Ataxia (adult subtype)
Dementia (adult subtype)
Clinical Features
 Dysmorphic features
 Frontal bossing
 Depressed nasal bridge
and broad nasal tip
 Large low-set ears
 Long philtrum
 Gingival hypertrophy and
macroglossia
 Coarse skin
 Hirsutism
 Ophthalmologic findings
 Macular cherry-red spots
 Optic atrophy
 Corneal clouding
Clinical Features
 Cardiovascular
 Dilated and/or hypertrophic
cardiomyopathy
 Abdomen
 Hepatosplenomegaly
 Inguinal hernia
 Skeletal abnormalities
 Lumbar gibbus deformity
and kyphoscoliosis
 Dysostosis multiplex
 Broad hands and feet
 Brachydactyly
 Joint contractures
 Hydrops fetalis
 Angiokeratoma corporis
diffusum
Genetics
 Gene located on chromosome band 3p21.33
 Cloning and sequencing of cDNA encoding human
GLB1 in 1988 by Oshima and others
 Various types of mutations identified in the acid βgalactosidase gene, including missense/nonsense,
duplication/insertion and splice site abnormalities
 Genotype and phenotype correlations provides a
molecular explanation for clinical variability
 Amount of residual enzyme activity determines disease
subtype and severity
Genetics
Exon
Amino Acid
DNA
2
Arg49→Cys
CGC→TGC
3
Gly123→Arg
GGG→AGG
3
Duplication-stop
condon
288-310
6
Arg208→Cys
CGC→TGC
9
Tyr316→Cys
TAT→TGT
11-12
Duplication
1103-1267
14
Arg457→Ter
CGA→TGA
15
Gly494→Cys
GGT→TGT
15
Lys577→Arg
AAG→AGG
Differential Diagnoses
 I-cell disease (mucolipidosis type II)
 Mucolipidosis type I (α-neuraminidase deficiencysialidosis)
 Mucopolysaccharidosis type IH
 Galactosialidosis (combined α-neuraminidase and
β-galactosidase deficiency)
 Oligosaccharidosis (eg. mannosidosis, fucosidosis,
sialidosis)
Investigations
 Acid β - galactosidase activity
 Diagnosis can be confirmed by measurement of acid β-galactosidase
activity in peripheral blood leukocytes
 Patients with the infantile form have almost no enzyme activity, while
patients with the adult form may have residual activity of 5-10% of
reference values
 Urine oligosaccharide / mucopolysaccharide pattern
 Galactose-containing oligosaccharides are excreted in the urine
 Complete blood picture
 Vacuolation of lymphocytes may be present in patients with GM1
gangliosidosis
Investigations
 Skeletal radiographs - changes characteristic of dysostosis multiplex
including thickened calvarium, J-shaped enlarged sella turcica, wide
spatula-shaped ribs, flared ilia, acetabular dysplasia and flat femoral
heads, wide wedge-shaped metacarpals, shortened long bones with
diaphyseal widening, and hypoplastic and anteriorly beaked
thoracolumbar vertebrae
 CT or MRI brain - diffuse atrophy and white matter demyelination
with or without basal ganglia changes
 Ultrasound of abdomen - organomegaly
 Echocardiography - signs of cardiomyopathy
 Electrocardiography - signs of cardiomyopathy
 Electroencephalography - generalized dysrhythmia and
epileptogenic foci
Treatment
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No effective medical treatment available for the underlying disorder
Symptomatic treatment for some neurologic sequelae but not alter the clinical
course significantly
Active research in the areas of enzyme replacement and gene therapy for GM1
gangliosidosis
Multidisciplinary approach
Clinical geneticist - for initial evaluation and diagnosis, to counsel families
regarding recurrence risk, and to help provide prenatal testing for future
pregnancies
Neurologist - for symptomatic therapy of multiple neurologic sequelae
Cardiologist - to evaluate for cardiomyopathy
Orthopaedic surgeon - to evaluate for dysostosis multiplex
Ophthalmologist - to evaluate for ocular stigmata
Otolaryngologist and audiologist - to assess for hearing loss
Treatment
 Diet
 No specific dietary modifications significantly alter the clinical
course
 May require tube feeding to provide adequate intake of energy;
however, not change the disease course
 some families may choose to forgo invasive alimentation
procedures
 Activity
 Neurologic and orthopaedic sequelae may preclude adequate
physical activity, benefit from physical and occupational therapy
Discussion
Clinical Features
 Extensive Mongolian spots
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This report describes three infants with generalized Mongolian spots, two
infants with GM1 gangliosidosis type 1, and one in association with Hurler
syndrome.
Mongolian spots result from entrapment of melanocytes in the dermis
because of arrested transdermal migration, which is regulated by tyrosine
kinase, from the neural crest into the epidermis.
Accumulated metabolites such as GM1 and heparan sulfate bind to tyrosine
kinase receptor which enhances nerve growth factor activity and leads to both
neurologic manifestations and aberrant neural crest migration.
Findings of generalized Mongolian spots in newborns may lead to an early
detection and early treatment before irreversible organ damage occurs.
Extensive Mongolian Spots: A Clinical Sign Merits Special Attention. Ashrafi MR,
Shabanian R, Mohammadi M, Kavusi S. Pediatr Neurol. 2006 Feb;34(2):143-145.
Clinical Features
 Hyperphosphatasemia
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Hyperphosphatasemia in infantile GM1 gangliosidosis: possible association with
microscopic bone marrow osteoblastosis.
Mogilner BM, Barak Y, Amitay M, Zlotogora J. J Pediatr. 1990 Nov;117(5):758-61.
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Hyperphosphatasemia in GM1 gangliosidosis. Denis R, Wayenberg JL, Vermeulen M,
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Hyperphosphatasemia in early diagnosed infantile GM1 gangliosidosis
presenting as transient hydrops fetalis. Denis R, Wayenberg JL, Vermeulen M, Gorus F,
Gorus F, Liebaers I, Vamos E. J Pediatr. 1992 Jan;120(1):164.
The authors report a case of unsuspected fetal storage disorder
initially diagnosed by placental examination performed because of a
transient ascites at 28 weeks of gestation. At birth mild dysmorphic
features and gradual neurological deterioration were observed. Highly
elevated alkaline phosphatase levels were repeatedly noticed.
Deficiency of beta-galactosidase was documented confirming GM1
gangliosidosis. Previous reports described the placental pathology
after positive prenatal diagnoses of lysosomal diseases. In the present
case, the postnatal diagnosis was made in view of the placental
pathologic findings. Our observation indicates the need for thorough
investigations in hydrops fetalis, in search for metabolic diseases.
Gerlo E, Lissens W, Liebaers I, Jauniaux E, Vamos E. Acta Clin Belg. 1996;51(5):320-7.
Treatment
 Bone marrow transplantation
 Donor bone marrow engraftment, which resulted in complete
normalization of white cell β-galactosidase levels in a patient
with presymptomatic juvenile onset GM1-gangliosidosis, did
not improve long-term clinical outcome.
 Bone marrow transplantation correcting β-galactosidase activity
does not influence neurological outcome in juvenile GM1gangliosidosis.
Shield JPH, Stone J, Steward CG. J Inherit Metab Dis.
2005;28(5):797-8.
Thank you
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