Delay in diagnosis of rare

diseases
Professor Atul B Mehta
Royal Free Hospital,
UCL School of Medicine
RCP Advanced Medicine Course February 2017
 Overview
• Data to demonstrate that patients with rare
diseases often suffer a delay in diagnosis
• Focus on lysosomal storage disorders as an
example
• Consider the causes and the consequences of
the delay
• Consider strategies for reducing the delay
 MRCP Examination 1986
• A 24 year old male has a itchy rash over his
lower torso
• It bleeds when he scratches it
• He also has proteinuria
 Question
• What is the diagnosis ?
• How would you confirm it ?
• What 3 complications can occur ?
 Answer
• Fabry disease or Anderson Fabry disease

• Measure enzyme level – alpha galactosidase

A in plasma and/or leucocytes

• Hypertrophic cardiomyopathy
• Renal failure
• Cerebrovascular accident
 What is a rare disease ?
• Incidence of <1:2000 in the EU
• Orphan diseases; ultra-orphan - < 1: 50,000
• > 6,000 rare diseases are recognised
• 30 million sufferers in Europe
• Many (often inherited) diseases are
unrecognised; some may be common, eg DNA
repair defects underlying cancer
• Rarity is context
Varicose ulcers – very common and
easy to diagnose
LEG ULCER, a very common
finding in
SICKLE CELL DISEASE
 Possible reasons for delay
• Lack of awareness of a rare disease
• Overlooking mild early signs
• Lack of knowledge/failure of education or training
• Often not treatable – therefore perceived to have low
‘opportunity cost’
• Lack of an acknowledged pathway
• Cost of treatment
• Lack of a signature symptom or sign for the condition
• Unrecognised condition – a ‘new disease’
 Lysosomal storage disorders
• Individually rare to infrequent; but collectively account for ~1 in 5-7,000 newborns
Sandoff 2%
GM1 Gangliosidosis 2% Gaucher
14%
Mucolipidosis II/III 2%

Disease Incidence*
Niemann Pick A/B 3%
Hurler-Scheie
9%
Maroteaux-Lamy 3% • Gaucher 1 / 59,000

Niemann Pick C 4% • Fabry 1 / 117,000

Sanfilippo B 4%
• Hurler-Scheie 1 / 111,000
MLD
Tay-Sachs 4% 8%
• Pompe 1 / 201,000

Cystinosis 4% • Maroteaux-Lamy 1 / 235,000

Sanfilippo A
7%
Morquio
5%
*Meikle et al. JAMA 281(3):49-25, 1999
Pompe Fabry
5% Krabbe 7%
Hunter
5% 6%
 LYSOSOMAL STORAGE DISORDERS
• Inherited disorders – sex linked or autosomal
recessive; diverse mutations
• Lack of an enzyme leading to accumulation of a
substrate
• Multi-system disorders
• Milder, adult onset phenotypes increasingly
recognised
• Pathophysiology poorly understood – organ/tissue
damage not simply due to excessive substrate
• Variety of treatment approaches
Different disorders can be caused by defects in a
single metabolic pathway
LSD: pathophysiology

• Deficient enzyme activity

• Altered lysosomal Substrate
environment Accumulation:
• Defect in late stages of Age-related
endocytosis, impairment of
lysosomal biogenesis, and
autophagocytosis
Morphological Molecular,
changes: biochemical
Mutant, mis-folded protein
Disease-specific changes:
Cell-type restricted Cause, result, or
epiphenomenon of
the pathological
ER stress response
processes ?
LSD Unit established 1996. centrally funded. Largest of 6 in
UK. Over 500 patients with a range of LSDs, including Fabry
disease (350 patients) and Gaucher disease (140 patients)
 Gauchers Disease
Enlarged Liver
Skeletal Involvement
(lipid may account for 20% of
total organ mass) •osteoporosis

Excess Glycolipid •osteonecrosis

(glucocerebroside) •deformation
•bone pain

Bruising & Bleeding

Laboratory Findings
Enlarged Spleen
• anaemia
(may be 20 times
normal size) • thrombocytopaenia
• elevated chitotriosidase
• elevated ACE, AP, Ferritin
 How do we know Gaucher disease is
underdiagnosed?
• Mistry et al.
– Only 20% of 406 Haem/Onc physicians surveyed considered GD when
presented with its classic symptoms
• In 136 patients, mean time to diagnosis was 48 months
• Among 92 patients seen at our centre, diagnostic delay is
frequent
• 300,000 Ashkenazi community in UK - expect >300 Gaucher
pts in UK – but only 100 identified
• Among new patients seen at our centre, delayed diagnosis
continues to be an issue…

Mistry PK, et al. Am J Hematol 2007;82(8):697–701;

P.
 Diagnosing GD: findings from a single-centre survey

Primary presenting symptom Diagnosing speciality

Growth failure
Jaundice
Fatigue Orthopaedics Biochemistry General
Screening Haemophilia paediatrics
Pathological
fracture
Abdominal
symptoms Hepatology
Bone pain

Haematology
Obstetric
Bleeding
thrombocytopenia
/splenomegaly
Incidental
splenomegaly Incidental
abnormal FBC

Thomas AS, et al. Br J Haematol 2013;50:212–7 19

Time between onset of symptoms and
diagnosis (N=86)
30
Years, symptoms to diagnosis

20

10

Year of diagnosis
Thomas AS et al. Blood Cells Mol Dis 2013;50:212‒7
 Consequences of delay
• Onset of complications
• Failure to diagnose
• Inappropriate treatments
• Worsened prognosis
• Failure to diagnose other family members
• No consequences
• Psychological stress/anxiety
Advanced Gaucher disease

Personal presenter case

 Risk of developing avascular necrosis over time
100

80
AVN survival proportion

Timing of starting treatment after

diagnosis
60 <2 ≥2
Parameter
years years
40
AVN event 41 (4%) 172 (10%)
20

0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Years following initiation of therapy
Risk of AVN was reduced among patients who initiated treatment with ERT within
2 years of diagnosis vs initiating treatment ≥2 years after diagnosis
AVN, avascular necrosis; ERT, enzyme replacement therapy;
ICGG, International Collaborative Gaucher Group Mistry P et al. Br J Haematol 2009;147:561-70
 Fabry disease: >100 years from first patient
to first treatment

1989
α-Gal A gene
1898 mutations linked
First description to Fabry disease
of Fabry disease

1963 2001
Demonstration of Safety and efficacy of
Gb3 accumulation in recombinant α-Gal A
Fabry disease replacement therapy
demonstrated in
Johannes
Fabry disease patients
William
Fabry Anderson

α-Gal A, alpha-galactosidase A; ERT, enzyme replacement therapy; Gb3, globotriaosylceramide.

Mehta A et al. In: Mehta et al. (eds). Fabry disease: perspectives from five years of FOS, 2006; UK: Oxford PharmaGenesis; Germain DP. Orphanet J Rare 24
Dis 2010;5:30.
 Treating a Disease With Multiorgan Involvement Is
Challenging
Cardiac, Renal and Cerebrovascular events are common

Yousef Z et al. Eur Heart J. 2012

Date of Preparation: April 2015 - KWT/C-APROM/REP/15/0003

Fabry Disease: Disease Heterogeneity and
Diagnostic Delay

Between symptom onset

and diagnosis there is an
average delay of 8 to 14
years in males; and 16
to19 years in females

Thomas AS et al Expert Opin Med Diag 2013; 7:58

Many patients with Fabry disease
are initially misdiagnosed
 Over 25% of patients are misdiagnosed1
 In males, measurement of α-galactosidase A will
reveal low or no activity2,3
 Many females will have α-galactosidase A levels
within the normal range4
 DNA analysis will confirm diagnosis in both
genders2,3
 A pedigree analysis should be carried out, if
possible2,3

1. Mehta et al. Eur J Clin Invest 2004;34:236–42.

Fabry Disease May Be More Common Than We Think
• Reported incidences of Fabry disease in the general population:
1 in 476,000 to 1 in 117,0001
• Prevalence rates based on newborn screening initiatives:
1 in ~3,100 newborns in Italy1
1 in 1,500 newborn males in Taiwan1
Prevalence of Fabry Disease in Different Populations, 1999-20072
Method Incidence
4
Retrospective analysis of diagnosed cases vs numbers of birth 1 ꞉117,0004
Retrospective analysis of known cases of renal replacement therapy using dialysis ~1꞉16,0004
Secondary screening of patients having renal replacement therapy using dialysis 2꞉1,0005
Secondary screening of patients having renal replacement therapy using dialysis 1.6꞉1,0006
5꞉100 (men)
Secondary screening of patients with cryptogenic stroke
2,4꞉100 (women)7
Primary neonatal screening 1꞉3,100 (men)8
1.8꞉100 (men)9
Secondary screening of patients with hypertrophic cardiomyopathy
5꞉100 (women)

1. Germain DP. Orphanet J Rare Dis. 2010;5:30. 2. Hoffman B, Mayatepec E. Dtsch Arztebl Int. 2009;106:440-447.
3. Meikle PJ et al. JAMA. 1999; 281:249-254. 4. Thadhani R et al. Kidney Int .2002; 61:249–255. 5. Ichinose M et al. Clin Exp
Nephrol. 2005;9:228-232. 6. Kotanko P et al. J Am Soc Nephrol. 2004;15:1323-1329. 7. Rolfs A et al. Lancet. 2005;366:1794-1796.
8. Spada M et al. Am J Hum Genet. 2006;79:31-40. 9. Montserrat L et al. J Am Coll Cardiol. 2007; 50:2399-2403.
 A variant of unknown significance in the GLA gene causing
diagnostic uncertainty in a young female with isolated
hypertrophic cardiomyopathy

Proband and her mother: leukocyte enzyme activity in low normal

45.8 & 47.4 (nr: 47.2 – 154.7). No evidence of GB3 accumulation.

GLA, alpha galactosidase A; GB3, globotriaosylceramide.

Al-thilini K et al. Gene 2012;497:320–22.
Do treatments for LSDs work ?
 SRT for Gaucher : ENGAGE study primary analysis: mean absolute change
from baseline in spleen volume, hemoglobin level, liver volume, platelets
1
Spleen Volume +0.35 MN
1.5 Hemoglobin
0 (MN) (g/dL)
1
P<0.0001
-1
0.5 +0.73 g/dL
-2
0 P <0.0006
-3.72 MN
-3
-0.5
-4
-0.58 g/dL
-1
-5
0 3 6 9 -1.5
0.10 0 3 6 9 Months

0.05
Liver Volume (MN)
40
Platelet count (x
0.00 +0.3 MN 30 109/L)
-0.05 P<0.0072 +23.9 x 109/L
20

-0.10 -0.9 MN P <0.0001

10

-0.15
0

-0.20
-10
-6.98 x 109/L
0 3 6 9
Spleen Hemoglobin
-20
Liver volume Platelets Months
volume 0 3 6 9
Eliglusta 13.9 MN 12.1 g/dL 1.4 MN 75 x109/L
Baseline Values
t
Mistry PK et al. JAMA
Placebo 12.5 MN 12.8 g/dL 1.4 MN 79 x109/L 2015;313:695-706

MN: multiples of normal

 ERT for Gauchrer : 044 study long-term extension:
changes in organ volumes over time with
velaglucerase alfa

Normalized Spleen Volume Normalized Liver Volume

0 0
Mean change from Baseline in spleen volume

Mean change from Baseline in liver volume

–20

–20 –27.0%
–40
(%; 95% CI)

(%; 95% CI)

–64.5%
–60
–40

–80

–100 –60
Baseline* 12 24 39 51 63 Baseline* 12 24 39 51 63
n= 29 30 27 20 9 n= 36 39 36 28 9
Treatment duration (months) Treatment duration (months)

Hughes DA et al. Am J Hematol 2015;90:584-91 and online-only

supplementary material
Time to composite event : prompt versus
delayed initiation of ERT in Fabry disease

Prompt ERT
initiation was associated
with significant reduction
in risk for composite
events (HR, 0.836;
95% CI, 0.731–0.958)
when compared with
delayed initiation (even
when corrected for age
and sex)1
 FOS: Impact of Agalsidase Alfa ERT Over 10 Years on Left
Ventricular Massa

† P < .05 vs baseline among males.

‡ P < .05 vs baseline among females.
a Hospital-based retrospective chart
analysis of morphological and functional
cardiac changes after 10 years of ERT.
NYHA: New York Heart Association.
Kampmann C et al. SSIEM 2014. Poster P-451.
Date of Preparation:CApril
Kampmann et al. Eur- KWT/C-APROM/REP/15/0003
2015 Heart J. 2014; submitted.
 Role of chaperones – small molecules which
enhance activity of mutant enzymes
3´ Ribosome
5´ ER membrane
mRNA

Lumen Correct folding Protein Molecular chaperones

and assembly
Misfolding and
Wild-type
misassembly ASSC
protein

Mutant
protein

Golgi Golgi
Degradation Trends in Pharmacological Sciences.
Myeloma: barriers to diagnosis

Myeloma is uncommon;
and has no signature symptoms/signs.

Around 40% of myeloma patients experience a

significant delay in diagnosis and subsequently
poorer survival and quality of life outcomes.

Up to 20% of myeloma patients die within 60

days of being diagnosed, mainly due to a delay
in diagnosis.

Reference: Kariyawasan CC, Hughes DA, Jayatillake MM, Mehta AB.

(2007) QJM, 100:635-640.

www.myeloma.org.uk
 Experiences in primary care

One in five myeloma patients saw their GP five or more times before referral to
a specialist (National Cancer Patient Experience Survey 2014).

www.myeloma.org.uk
Routes to diagnosis

(NCIN Routes to Diagnosis 2006-2013).

www.myeloma.org.uk
 How can delay be reduced ?
• New tools
• Improve awareness
• Patient involvement and patient advocacy
• Media and television
• Screening – newborn or targeted populations
The patient journey
 The holistic approach to care
Suspicion of
rare disease Primary care

Referral centre

Family
pedigree The patient journey
Treatment

Specialist
centre

Home-based care
Heart: MRI T1 mapping
100,000 genomes project……
 Number of lysosomal storage disorder patients
500
450
400
350
Total LSD patients
300 Fabry
250 Gaucher

200 Pompe
MPS
150
Other
100
50
0
Apr-11 Apr-12 Apr-13 Apr-14 Apr-15 Apr-16

Patient numbers have grown by 87% since 2011 - an average yearly increase of 13.3%

Source: Service activity records 44

 Rio Ferdinand , Manchester United
~£30 million ($40 million) (2002) equals approx cost of
ERT for UK
 Gareth Bale
Real Madrid
~£85 million ($110 million) (2013)
2016 : Rising cost of ERT across a range of diseases –
outstrips inflation.
How much is Harry Kane worth ?
 Conclusions
• Sufferers of rare diseases often encounter a
delay in diagnosis
• This has physical, psychological and emotional
consequences for the patient and other family
members
• Concerted efforts and new tools are required
to reduce the delay