Clinical, laboratory presentation and outcome of classical galactosaemia in infants and children at Chris Hani Baragwanath Academic Hospital DR M MONARENG
Introduction • Classical galactosemia- autosomal recessive disorder of galactose metabolism • Deficiency of galactose-1-phosphate uridyltransferase (GALT) enzyme - chromosome 9p13, >100 mutations • GALT catalyses the conversion of galactose-1- phosphate and uridine diphosphate glucose to glucose 1-phosphate and uridine diphosphate galactose.
• Results in build up of toxic metabolites and in end products of the galactose pathway-cell recognition, immune system, neural development
Three phenotypes of GALT deficiency; Berry et al, 2017 • 1:Classic-genotype(Q188R) • 2:Clinical variant( S135L) • 3:Biochemical variant(Duarte variant) Division based on -GALT enzyme activity -Galactose metabolite levels -Genetic testing -Incidence of acute and chronic complications Postulate: Clinical variant associated with S135L genotype is found in African Americans and South Africans. African Americans with this genotype are thought to not develop long term complications
• World incidence 1/40 000 to 1/60 000 • Prevalence in SA: estimated 1/14 400 - 1/21 904 • Neonatal screening not routinely available • Studies are few and used small population samples • The most common mutation - Q188R in the Caucasian population - S135L in the non Caucasian population -SA negroid population S135L >91%
• In the neonatal period it can be a life threatening disease with multi organ involvement • In infancy and childhood it can present with cataracts and cirrhosis • In late childhood and adolescence can present with -verbal dyspraxia, -cognitive disability/learning disabilities -hypergonadotropic hypogonadism/POI Condition responds to galactose free diet and early diagnosis reduces morbidity and mortality especially in early infancy.
Study objectives Primary objectives • Determine number of cases with classical galactosemia seen at CHBAH Paediatric Gastroenterology Hepatology and Nutrition Unit(PGHNU) January 1994 - December 2013 • To document the - clinical, - laboratory characteristics and - outcome of these patients.
Secondary objective • To investigate the association of macrocytosis with classical galactosemia • To determine the frequency of association of metabolic acidosis with classical galactosemia
Methods Retrospective descriptive study Review of medical records Inclusion criteria • Patients with classical galactoseamia confirmed by GALT enzyme activity level • Presentation at CHBAH between January 1994 and December 2013 Exclusion criteria • Inherited types of galactoseamia other than classical • Suspected, not confirmed by GALT activity level • Secondary causes for hypergalactosaemia
Data collection and analysis • Data was collected from the CHBAH, PGHNU database and the National Health Laboratory Services(NHLS)records. • Demographic information ,anthropometry, history, clinical presentation and laboratory results were collected • Outcomes and long-term complications were documented where available • Ethics WITS Human Research Committee (Clearance number M140535).
Results-Demographics • 23 patients with classical galactosaemia were diagnosed during the study period • GALT activity: median 0.55 (0;1.7) • Urine reducing substances +ve on 21(91%), confirmed to be galactose • Mean age at diagnosis was 4.6 months (range 2 days to 24 months) vs 5.1mths CT, 72hrs Ireland • Female to male ratio was 1:0,64 • 22 (96%) patients were black and 1 (4%)white • Provinces: 19 from Gauteng 3 from North West and 1 from KZN
Results- Anthropometry WFA (23 pts) 70% were underweight • 12 (52%) were severely underweight, • 4 (17%) were underweight HFA (19 pts) 74% were stunted • 12 (63%) were severely stunted • 2 were stunted WFH (19 pts) 42% were wasted, • 4 moderately wasted • 4 severely wasted Head circumference ( 7 pts) 6 normal 1 macrocephalic due to hydrocephalus
GROWTH PARAMETERS :z scores Blue:> -2 , Red: -2 - -3, Green:< -3 14 12 10 NUMBER OF PATIENTS 8 6 4 2 0 WFA HFA WFH Z SCORES
Results-Clinical signs and symptoms The commonest presenting symptoms • yellow discoloration of the eyes(74%), • abdominal distention(65%)and • failure to gain weight(57%) Most frequent clinical features at diagnosis • hepatomegaly(100%), • pallor(78%), • jaundice(78%), • ascites(61%), • Splenomegaly(52%), • failure to thrive(52%) and • cataracts(55%)
Clinical symptoms and signs at presentation
Results-Laboratory findings • Metabolic acidosis (78%), • Coagulopathy (65%) • Liver derangements (61%) • Glucose (17 pts) : Hypoglycaemia 48% ;Hyperglycaemia 18%; N 34% • Anaemia 78% 61% macrocytic (>100fl) 39% normocytic • Infection 35%: urine, blood, CSF. Organisms E.coli, klebsiella, candida, staphylococcus.
Results-Histology • Liver biopsies not routinely performed as work up • Four patients underwent a closed biopsy; -3 for worsening liver function/suspected cirrhosis -1 diagnostic post mortem biopsy. • Two out of the 4 patients had the histological triad Pseudo acinar transformation Cholestasis Steatosis • 3/4 patients had some degree of fibrosis: bridging(3mth), incipient (2mth) and micronodular cirrhosis (8mth) • However triad not diagnostic • Histology scoring system not used
Results-Outcome Follow up of the 23 patients • 3 patients demised at presentation with susp sepsis (13%) • Other 20 pts - 1 lost to follow up a month post diagnosis. -16 followed up to the age of 1 year, -8 followed up to 5 years -2 up to adolescence • 6/ 20 still followed up by PGHNU (May 2017) • Long-term complications in those assessed included visual problems, developmental delay, and speech impairment.
Study limitation • Due to financial constraints and because it would not impact on management genetic testing was not routinely performed. • 1 mother tested positive and 2 children (separate families ) tested positive for S135L mutation • In view of limited genetic testing, study was unable to confirm previous South African data of the high prevalence (>90%) of the S135L genetic mutation in black patients with galactosaemia.
CONCLUSION • Classical galactosemia-suspect any sick infants as signs & symptoms non-specific on presentation. • Consider in any infant with cholestatic jaundice, hypoglycaemia and sepsis esp. in the neonatal period. Hyperglycaemia does not exclude GAL (18%) Absence of jaundice does not exclude GAL (20%) Infections other than E. coli should be considered – klebsiella,Enterobacter, staphylococcal and candida albicans as shown in our study
• Early diagnosis can reduce mortality and morbidity by preventing complications e.g. failure to thrive, cataracts, cirrhosis, sepsis and neurodevelopmental insults Death rate at presentation 13%. normal growth parameters after dietary intervention None of the children followed up progressed to portal hypertension or required liver transplant
However even with early intervention, some complications cannot be entirely prevented. Significant number of children had neurodevelop- mental delay, learning & speech difficulties Black children, who are suspected to have S135L, do develop long term complications
Recommendations • Documenting local experience, contributes to a heightened awareness of condition • Increases awareness of clinical presentation and encourages strategies aimed at early recognition such as neonatal screening • It emphasizes long term complications in black patients; encouraging a structured follow up programme to prevent, identify and manage complications.
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