Late onset Pompe Disease

(LOPD)

Nick Davies

Regional Neuromuscular Service

Queen Elizabeth Hospital

Birmingham

GLYCOGEN

GLUCOSE

PYRUVATE

LACTATE

TCA

cycle

NADH for electron transport chain

Phosphorylase kinase (VIII)

Debrancher (III)

Brancher (IV)

Myophosphorylase (V)

Acid maltase

(II)

Phosphofructokinase (VII)

Aldolase (XII)

Phosphoglycerate kinase (IX)

Phosphoglycerate mutase (X)

Lactate dehydrogenase (XI)

NADH

Pyruvate dehydrogenase

• limb girdle or myalgia/rhabdo

• elevated CK interictal or not

• neurophysiology - ?mixed

• other systems involved

• respiratory or not

Pompe disease is a rare AR lysosomal

storage disease (GSDII or acid maltase

disease)

Two groups

– Classic infantile phenotype

– Late onset (often) adult phenotype

(LOPD)

LOPD

– childhood, juvenile and adult onset

forms

– progressive deterioration of truncal,

proximal LLs and respiratory muscles

Case

61y male

Normal milestones

Odd gait since childhood

Worse in early 30s

In 50s developed slurring of speech

SOB on exertion

No myoglobinuria

Case

Examination

Cranials normal

NF 4+

Facial fasciculations

Some accessory muscle use

4+ proximal weakness

Trendelenburg gait

Areflexic

CK 694

EMG - myopathic

Case

pO2 11.2, pCO2 6.8 (2000)

FEV1 2.35, FVC 3.1 (standing)

FEV1 1.05, FVC 1.6 (supine)

NB gas transfer was low

2005 requiring NIPPV

Sister – since been diagnosed

LE H&E

LE H&E

LE PAS

CB H&E

CB H&E

CB Gomori

CB PAS

Muscle Biochemistry

Glycolysis Enzymes - normal

Glycogen 6.0 mg/g (0.5 - 10.5)

Acid Maltase (lysosomal) pH 4.0 1.7 nmol/g/min (7.0 -42)

Neutral Maltase (microsomal) pH 6.5 29.8 (3.0 - 26.0)

Lymphocyte Acid Alpha Glucosidase

<0.8mU/U hexosaminidase (3.7 -30.0)

Case

57y male

2/12 history of lethargy, poor mobility,

poor appetite, stomach cramps, weight loss

Developed confusional state

Admitted but respiratory arrest in ED

Type 2 respiratory failure, ITU, trache

Found to have basal pneumonia and PEs

Case

On recovery, gave history that 2.5 years

before, had moved to 3 storey house but had

to sleep on ground floor

If he lay flat, he would feel as if he was drowning

Morning headaches and daytime somnolence

Case

Examination

Cranials – normal

Arms – ShAb 4-/5

Legs – HF 2/5, DF 3/5

CK – normal

DBS positive

Compound het for 2 mutations in GAA

Chan J et al, Molecular Genetics and Metabolism, 2017

Diagnosis

CK may be normal to several 1000

EMG may show myotonic discharges

in addition to fibrillation etc

Muscle biopsy light microscopy can be normal

A combination of DBS, lymphocyte levels,

GAA gene analysis and possibly muscle biopsy

may be required to confirm the diagnosis

A longitudinal study of 16 untreated patients followed

for a mean of 16 years (range 4-29 years) observed

a mean rate of decline in respiratory function of 1.6%

per year and a gradual decline in proximal muscle

strength

• 8 patients (50%) became wheelchair-bound and

3 patients (19%) became ventilator-dependent

during the follow-up period

• 2/3 Pulmonary and muscle function decreased

together

• At an individual level, the rate and extent of

progression varied considerably among patients

van der Beek N et al. Neuromuscul Disord. 2009

Multicenter, multinational, prospective, observational study of 58 patients with late-onset Pompe disease All patients ambulatory and free of invasive ventilator support at enrollment Statistically significant declines were observed in the 12-month study period Evidence from LOPOS provides natural history data on patients with late-onset Pompe disease and helped to identify endpoints for LOTS

Wokke et al. Muscle Nerve. 2008

Study of safety and efficacy of alglucosidase alfa in

children and adults with Pompe disease

Randomized, double-blind, placebo-controlled

20 mg/kg alglucosidase alfa or placebo IV

administration biweekly

90 patients enrolled

Age 10-70

Trial period 18 months

Conclusions – in treated group, 6MWT increased by

25.1m, pulmonary function stabilized

Van der Ploeg AT et al NEJM 2010

Van der Ploeg AT et al NEJM 2010

Kuperus E et al., Neurology 2017

Prospective cohort study of 102 patients (aged 24-76) over 5 years

6MWT 376m to 416m, FVC increase by 7.3% (first 2-3 years of ERT)

Cost effectiveness study

Based on observational data of 283 patients

with LOPD begun in 2002

Cost per QALY 1.8 – 3.2 million Euros

Fabry cost per QALY 3.3 million Euros

Spinraza cost per QALY £400,000-600,000

Kanters T et al., Orphanet Journal of Rare Diseases 2017

Ebbink B et al. Developmental Medicine and Child Neurology, 2018

6y 9y 17y

6y 5y 13y

9y 9y 17y

5y 13y 13y

New treatments

Augmented ERT

- IGFII tagged-rhGAA (withdrawn)

- Chaperone + rhGAA

- Increase mannose-6-phosphate residues

Substrate reduction therapy (SRT)

Suppression of autophagy

Stimulation of lysosomal exocytosis

New treatments

Gene therapy

Animal models

AAV Intrathecal – KO mice

Cell lines

Antisense

Gene editing

Human trials

Diaphragm injections

Kohler L et al., Neurotherapeutics 2018

• 11 patients with adult onset AMD.

• Progressive pattern with adductor magnus, SM early on with later

changes to BFLH, ST and anterior thigh muscles.

• Muscle strength and MRI correlated.

Conclusions

Late onset Pompe disease should be

considered in anybody with respiratory

symptoms and muscle weakness

Scapular winging, rigid spine,

calf hypertrophy and tongue involvement

can occur or just hyperCKaemia

CK may however be normal

EMG may show myotonic discharges

in addition to fibrillation etc

Conclusions

Muscle biopsy light microscopy can be normal

A combination of DBS, lymphocyte levels,

GAA gene analysis (and possibly muscle biopsy)

may be required to confirm the diagnosis

ERT made a significant impact on survival in IOPD

but more effective treatment needs to be sought

for it and LOPD

qMRI should prove a useful tool in assessing

innovative therapies

Thanks to Professor Tracey Willis