Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
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
• 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
Sanfilippo B 4%
• Hurler-Scheie 1 / 111,000
MLD
Tay-Sachs 4% 8%
• Pompe 1 / 201,000
Haematology
Obstetric
Bleeding
thrombocytopenia
/splenomegaly
Incidental
splenomegaly Incidental
abnormal FBC
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
80
AVN survival proportion
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
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
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
-0.15
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
–20 –27.0%
–40
(%; 95% CI)
–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)
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
Mutant
protein
Golgi Golgi
Degradation Trends in Pharmacological Sciences.
Myeloma: barriers to diagnosis
Myeloma is uncommon;
and has no signature symptoms/signs.
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
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%