Clinical, laboratory presentation and outcome of classical - - PowerPoint PPT Presentation

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
• f 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

2 4 6 8 10 12 14 WFA HFA WFH

NUMBER OF PATIENTS 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.