ESPEN Congress Madrid 2018

Inborn Errors Of Metabolism

Inborn errors of carbohydrate metabolismG. Pintos (ES)

INBORN ERRORS OF METABOLISM

INBORN ERRORS OF CARBOHYDRATE METABOLISMGuillem Pintos-Morell, MD, PhDCentre for Rare Diseases

University Hospital Vall d’Hebron, Barcelona

Universitat Autònoma de Barcelona

INBORN ERRORS OF METABOLISM

• CONFLICTS OF INTEREST➢ Speaker and travel grants

• Alexion, Amicus, BioMarin, Kyowa, Shire, Vitaflo

➢ Advisory boards• Lucane, Kyowa

• LEARNING OBJECTIVES➢ Basic metabolic pathways

➢ Common clinical presentations

➢ Laboratory diagnosis and biochemical markers

➢ Suggested management guidelines

➢ Frequent clinical complications

➢ Treatment recommendations

INBORN ERRORS OF CARBOHYDRATE METABOLISM

INBORN ERRORS OF CARBOHYDRATE METABOLISM

JM Saudubray. Orphan Academy, Paris 2010

CARBOHYDRATE METABOLIC PATHWAY

COMMON SIGNS & SYMPTOMS PRESENT IN IEM OF CARBOHYDRATES Fasting hypoglycaemia

Growth failure

Hepatomegaly

Increased AST & ALT

Hyperlipidaemia

Proximal renal tubular dysfunction

Hyperlactatemia

Increased uric acid

✓ GSD 0

✓ GSD I

✓ GSD III

✓ GSD IV

✓ GSD VI

✓ GSD IX

✓ GSD XI

➢ Gluconeogenesis disorders

• Fructose 1,6 bisphosphatase

• Hereditary Fructose Intolerance

GSD I metabolic profile

Metabolic profile in GSD I:

➢ Fasting hypoglycaemia, W/O ketoacidosis

➢ Hyperlactatemia (> 5 mmol/L)

➢ Hyperlipidaemia: Chol , TG

➢ Hyperuricemia

➢ CPK normal, no cardiac involvement

➢ Oral glucose challenge :

• glucose , lactate

➢ Response to glucagon:

• glucose -, lactate (fasting )

OVERVIEW OF HEPATIC GSDs

Differential diagnosis with other IEM of carbohydrate metabolism:

• Hypoglycaemia after more prolonged fasting or intercurrent illness

• Gastrointestinal symptoms, long-term liver and kidney damage

• Prolonged PT, hypoalbuminaemia, elevation of bilirubin, and proximal tubular dysfunction; hypoglycaemia provoked by fructose intake

• Improvement of symptoms with fructose restriction

Disorders of gluconeogenesis:

• Fructose 1,6 bisphosphatasedeficiency

• Hereditary fructose intolerance

Insuline Lactate Fatty acids β Hydroxibutyrate Alanine Cortisol, GH

Hyperinsulinism ↑↑ N N↓ N↓ N↓ ↑

β-oxidation defects ↓ N↑ ↑ N↓ ↑ ↑

Panhypopituitarism ↓ N ↑ ↑ N↓ ↓

Ketotic Hypoglycemia ↓ N ↑ ↑↑ ↓ ↑

Glycogenolysis GSD type I ↓ ↑↑ ↑ N↑ ↑ ↑

Glycogenolysis GSD III, VI, IX ↓ N ↑ ↑ ↑ ↑

Neoglucogenesis defects ↓ ↑ ↑ ↑↑ ↑ ↑

Hormonal profile and metabolic products in response to hypoglycemia in different

clinical situations

OVERVIEW OF HEPATIC GSDs GSD I (Van Gierke) Ia and Ib:

Ia: Glc-6-phosphatase a (G6PC)

Ib: Glc-6-phosphate transporter (G6PT, SLC37A4)

GSD Ia and Ib typical complications:

Liver adenomas – hepatocellular carcinoma

Chronic kidney disease with renal failure

Osteopenia–Osteoporosis

Nephrolithiasis

Gout

Anaemia, platelet dysfunction

GSD Ib:

Neutropenia, impaired neutrophil function

Inflammatory bowel disease

Differential diagnosis of GSD I:

• GSD 0: No hepatomegaly, fasting ketosis

• GSD III: Normal lactate and uric

• GSD IV: No hypoglycaemia until advanced liver dis. Prolonged PT

• GSD VI: only fasting hypoglycaemia and ketosis. Lactate is normal

• GSD IX: only fasting hypoglycaemia and ketosis. Lactate is normal

• GSD XI (Fanconi–Bickel synd due to GLUT 2 deficiency): GI symptoms, hypophosphataemic rickets

OVERVIEW OF HEPATIC GSDs

GSD IIIa/b (Cori, Forbes)

Debranching enzyme/AGL

GSD IIIa: Hepatic and myopathic

GSD IIIb: Hepatic

Associated features:

Liver fibrosis – Cirrhosis – Liver failure

Liver adenomas – Hepatocellular carcinoma

Progressive myopathy

Concentric hypertrophic cardiomyopathy

Cardiac dysfunction–Arrhythmias

Distinguishing features from GSD III:

• GSD 0: No hepatomegaly

• GSD I: Increased uric acid and lactate, lack of severe ketosis, nephromegaly, and lack of myopathy

• GSD IV hepatic: No hypoglycaemia until advanced liver disease

• GSD IV neuromuscular: Hypotonia, amylopectin-like inclusions, muscle atrophy

• GSD VI: no muscle involvement

• GSD IX: X-linked form typically less severe clinically

• GSD XI (Fanconi–Bickel synd due to Glut-2 deficiency): GI symptoms, hypophosphataemic rickets, RTA

• The glycogenosis presenting more frequently with hypoglycaemia is GSD type I (1:100.000-1:300.000 RN)

• Clinical presentation: severe hypoglycaemia with normo-ketosis, hepatomegaly and growth failure

• Hyperlactataemia and metabolic acidosis

• GSD type III (deficit of debranching enzyme), type VI (hepatic phosphorylase deficiency) and GSD 0/XII (glycogen synthase deficiency), may present also hypoglycaemia, but less frequently

Good metabolic control:

• Glucose > 72 mg/dL

• TG < 531 mg/dL

• Uric acid < 6 mg/dL

• Lactate < 22 mg/dL

GSDs and hypoglycaemia

G6P metabolic pathways

The primary anabolic and catabolic pathways of G6P in the gluconeogenic organs, liver, kidney and intestine.

• Production of intracellular glucose by the hydrolysis of G6P

• Produced in the terminal step of gluconeogenesis and glycogenolysis by G6Pase-⍺

• Control of interprandial blood glucose homeostasis

GSD-Ia, Ib, and Irs manifest distinct and overlapping phenotypes

GSD I: LONG TERM COMPLICATIONS

Short stature

Liver adenomas

Hepatocellular carcinoma

Bleeding diathesis due to impaired platelet function

Anaemia

Decreased bone mass. Increased risk for osteoporosis and fractures

Proximal renal tubular dysfunction. Glomerular impairment that may progress to ESRF (FSGS)

Polycystic ovaries

Increased risk for IBD, hypothyroidism

Early atherosclerosis, acute pancreatitis, xanthomata

Doll-like facesGrowth delayShort statureDistended abdomen: hepatomegaly, nephromegalyHypoglycaemia, seizuresRecurrent bacterial infectionsOral and/or intestinal mucosa ulcerations

GSD TYPE I: CLINICAL CHARACTERISTICS

GSD I: LONG TERM COMPLICATIONS

Wang DQ etal. J Pediatr 2011; 159:442-446

NUTRITION MANAGEMENT OF GSDs

Infantile period:

Feeds every 3-4 hours

Soy milk

Alternative: continuous feeds through NG tub or gastrostomy @ 8-10 to 4-8 mg/kg/min, depending on the age

As children grow: uncooked corn starch (1-2.5 g/kg/dose)

Low fat content

MCT, EFA (essential fatty acids)

High protein

65% of total energy intake from CH

✓ Education to caregivers and patients

✓ Glucose monitoring

✓ Risks:

• Obesity

• Insulin resistance

• Micronutrient deficiency

DIFERENT APPROACHES TO NUTRITION MANAGEMENT IN GSDs

➢ To maintain similar energy intake that general or peer population and incorporate dietary starch within the 65% target, thereby limiting fat or protein intake

➢ To take a similar diet to peers but with treatment starch as extra leading to a greater energy intake and risk of obesity

➢ To take less energy than is required with a particular risk of micronutrient deficiencies

✓ Risks:• Obesity

• Insulin resistance

• Micronutrient deficiency

• Patients benefit from the extended release cornstarch by avoiding the overnight dose while maintaining metabolic control

• There is no difference between missed doses of traditional therapy and the extended release therapy, but the longer duration between doses increases the risk

• The extended release formulation is about 15 times more expensive than regular cornstarch

• However, an emergency department visit due to a missed overnight cornstarch dose would be more expensive than several years of the extended release formulation

Hypoglycemia and metabolic control with extended release cornstarch

Ross KM at al. JIMD Reports. DOI 10.1007/8904_2015_488

GSD TYPE I: CLINICAL CHARACTERISTICS

Doll-like faces

Growth delay

Short stature

Distended abdomen: hepatomegaly, nephromegaly

Hypoglycaemia, seizures

Recurrent bacterial infections

Oral and/or intestinal mucosa ulcerations

Case report (Moest W et al. Hepatology 2018; 68 (2): 780-2):• 25 year-old women at ED for acute abdominal pain in right upper quadrant and fever• Laboratory tests:

• hypoglycemia (2.5 mmol/L)• hyperlactatemia (9.1 mmol/L)• hyperlipidemia (triglycerides 10.6 mmol/L, total cholesterol (6.1 mmol/L)• No urinary ketones

• Working diagnosis: sepsis with abdominal focus• Treatment: symptoms recover quickly with a bolus of 10% glucose and 5% maintenance but blood glucose levels persist relatively low• Medical history: 4 months before was referred because fatigue, weight loss, nocturnal sweating, hypermenorrhea, and nose bleeding associated with microcytic anemia• Abdominal imaging: hepatomegaly with multiple hepatocellular adenomas• Referred to centre of expertise with the working diagnosis of GSD• Genetic analysis: homozygous mutation in G6PC gene• Further medical history:

• Child of a first-degree cousins. Since 7-8 years of age she was evaluated because tiredness, failure to thrive (-2.5 SD, delayed bone age), hepatomegaly, increased erythrocyte sedimentation rate, and hyperuricemia. Signs of fasting intolerance during the day and night (hungry, sweating, and had to woke 1-2 times to eat and drink carbohydrate containing substances).

• Evolution: good response to uncooked cornstarch (40 g/4 h, day and night, initially). After 5 weeks, nocturnal 120 g of extended-release cornstarch for the 8 h of sleep