An Infant with Neuro-regression

1. An Infant with Neuro-regression Dr. KF Huen TKOH

2. History • 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

3. 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

4. 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

5. 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)

6. Examination • 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

7. Examination • No cataract or corneal clouding • No fix and follow • Abdomen – hepatosplenomegaly • CVS – unremarkable • Chest – unremarkable

8. Hypotonia

9. Coarse Facial Features

10. Extensive Mongolian Spots

11. 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

12. Cytoplasmic Vacuolation

13. Vacuolatedlymphocytes 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).

14. 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 GM1-gangliosidosis.

15. Skeletal Survey – dysostosis multiplex Thickened calvarium; enlarged sella Flattening, beaking and kyphosis

16. Flaring of ilia of pelvis; acetabular dysplasia Coarse thickening of phalanges and metacarpals; Bullet-shaped appearance

17. 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

18. MRI brain

19. Investigations • Urine metabolic screen – negative for mucopolysaccharide (by electrophoresis) • Urine oligosaccharide pattern (TLC) compatible with GM1 gangliosidosis

20. TLC - Heavily staining bands around zones of penta-saccharide, octa-saccharide, and oligosaccharides with longer sugar chains TTN TTN GM1 TTN

21. 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)

22. 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

23. Diagnosis GM1 gangliosidosis

24. Complications • GERD and aspiration • Developed repeated episodes of cough, noisy breathing and vomiting • Required continuous naso-gastric tube feeding

25. Complications • Seizure • Developed repeated episodes of apnoea & desaturation and generalised tonic clonic convulsion • EEG – epileptic tendency • Required phenobarbitone, phenytoin and clobazam for seizure control

26. Complications • Spasticity • Spasticity over extremeties and tight Achilles tendons • Required physiotherapy and nocturnal ankle-foot orthosis

27. 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

28. Review GM1 gangliosidosis

29. 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 β-galactosidase (GLB1), causes GM1 gangliosidosis and Morquio disease type B (ie. mucopolysaccharidosis type IVB).

30. 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

31. 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

32. 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

33. Clinical Course • Infantile form (type 1) • 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 • Juvenile form (type 2) • 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) • 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

34. Clinical Features • Neurologic findings • 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)

35. 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

36. 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 Clinical Features

37. 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 β-galactosidase 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

38. Genetics

39. Differential Diagnoses • I-cell disease (mucolipidosis type II) • Mucolipidosis type I (α-neuraminidase deficiency-sialidosis) • Mucopolysaccharidosis type IH • Galactosialidosis (combined α-neuraminidase and β-galactosidase deficiency) • Oligosaccharidosis (eg. mannosidosis, fucosidosis, sialidosis)

40. 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

41. 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

42. Treatment • 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

43. 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

44. Discussion

45. Clinical Features • Extensive Mongolian spots • 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.

46. Clinical Features • Hyperphosphatasemia • 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. • Hyperphosphatasemia in GM1 gangliosidosis.Denis R, Wayenberg JL, Vermeulen M, 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. • Hyperphosphatasemia in early diagnosed infantile GM1 gangliosidosis presenting as transient hydrops fetalis.Denis R, Wayenberg JL, Vermeulen M, Gorus F, Gerlo E, Lissens W, Liebaers I, Jauniaux E, Vamos E. Acta Clin Belg. 1996;51(5):320-7.

47. 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 GM1-gangliosidosis. Shield JPH, Stone J, Steward CG. J Inherit Metab Dis. 2005;28(5):797-8.

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