Long Term Follow-Up Clinical Guidelines for X-linked Adrenoleukodystrophy

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1 Long Term Follow-Up Clinical Guidelines for X-linked Adrenoleukodystrophy Gerald Raymond, M.D. Department of Pediatrics and Neurology Penn State Medical Center Hershey, PA June 20, 2018

2 Disclosure Information Gerald Raymond, M.D. The speaker has the following financial relationships to disclose: Consultant for and recipient of research grants from Bluebird Bio (Cambridge, MA) which has an interest in gene therapy for ALD Consultant for Minoryx (Barcelona) Consultant for Vertex (Boston)

3 Outline Adrenoleukodystrophy overview Newborn Screening Clinical Follow up Rationale Consensus Controversies

Peroxisomal Disorders Assembly Disorders Zellweger Spectrum disorders Zellweger syndrome Neonatal Adrenoleukodystrophy Infantile Refsum Rhizomelic Chondrodysplasia Punctata Single Peroxisomal Protein

4 Peroxisomal Disorders Assembly Disorders Zellweger Spectrum disorders Zellweger syndrome Neonatal Adrenoleukodystrophy Infantile Refsum Rhizomelic Chondrodysplasia Punctata Single Peroxisomal Protein Disorders X-linked Adrenoleukodystrophy Acyl-CoA Oxidase Deficiency D-bifunctional Protein Deficiency (17β-hydroxysteroid dehydrogenase IV def; HSD17B4) DHAP Alkyltransferase Deficiency Alkyl DHAP Synthetase Deficiency Refsum Disease Hyperoxaluria type I

Defect in peroxisomal beta oxidation Accumulation of very long chain

5 Adrenoleukodystrophy (ALD) X-linked disorder - Xq28 Incidence 1:17,000, all races affected Peroxisomal ATPase Binding Cassette Protein (ABCD1) Defect in peroxisomal beta oxidation Accumulation of very long chain fatty acids (VLCFA) Affects myelin, adrenal cortex, Leydig cells of the testes

6 X-ALD (ABCD1) gene is approximately 20 kb long and consists of 10 exons All mutations Non-recurrent N % N % All ALD mutations in database 2475 N/A % missense mutations % % nonsense mutations % % frame shift mutations % % amino acid insertions/deletions 89 4 % 45 6 % splice site mutations 96 4 % 34 5 % one or more exons deleted 78 3 % 23 3 % benign variants 27 1 % 27 4 % Variants of unknown significance (VUS) 153 Synonymous variants Stephan Kemp, Ph.D.

7 ALD Phenotypes and their Relative Frequency Cerebral (35-40%) Diffuse inflammatory demyelination with rapid progression. Childhood form (onset 4-8 years) Adrenomyeloneuropathy (AMN) (40-45%) Distal axonopathy mainly in spinal cord. Paraparesis in young adults Progresses over decades Addison Disease only (20-30% at onset) Most develop AMN later Asymptomatic >50% of heterozygous women develop AMN in adult years

8 Childhood Cerebral ALD Initial normal development Onset between 4-10 years Earliest 2.75 years, Peak 7 years Initial presentation often subtle May resemble ADHD and respond to stimulants Progresses rapidly to vegetative state 1.9 years ± 2 years Adrenal insufficiency 85%

9 Adrenomyeloneuropathy Adult onset - mean age 25 years Gradual progression Spastic paraparesis Consistent with a normal life span, but cerebral disease occurs in ~20%.

10 Adrenal insufficiency (Addison disease) Primary adrenal cortical dysfunction A leading cause of adrenal insufficiency in males Majority will develop neurologic manifestations

Heterozygotes 20-50 % of women who are carriers will have symptoms Myelopathy and Peripheral Neuropathy Spastic

11 Heterozygotes % of women who are carriers will have symptoms Myelopathy and Peripheral Neuropathy Spastic paraparesis Dysesthesias Bladder and bowel symptoms May be a function of age Rare - cerebral or adrenal disease

12 Newborn Screening for ALD Developed methodology using DBS and tandem mass spect (2006) Studies to determine sensitivity and specificity Aidan s law in NY NBS screening started in NY on 12/30/2013 Added to the RUSP on 2/2016

13 But why screen? Adrenal insufficiency/crisis Childhood Cerebral disease Other family members New incidence New mutation Unaware of genetic condition

14 But why screen? Adrenal insufficiency/crisis Childhood Cerebral disease Other family members New incidence New mutation Unaware of genetic condition

(elevation in ACTH) Rarely low Na, high K Often not considered in an individual in shock

15 Primary Adrenal Insufficiency 90% of at risk males will develop May present acutely or chronically Hypoglycemia Difficulty fighting infections Dehydration Hyperpigmentation (elevation in ACTH) Rarely low Na, high K Often not considered in an individual in shock Earliest documented crisis 22 months resulted in death Therapy is oral replacement Hydrocortisone Fludricortisone

16 Childhood cerebral adrenoleukodystophy ~35 % of at risk males Peak age 7 years Range years Initial symptoms attention, learning, behavioral Progresses rapidly MRI precedes disease

17 Treatment of CCALD Hematopoietic stem cell transplant (HSCT) Early cerebral disease Allogeneic Donor siblings, matched-unrelated donors, umbilical cord blood Gene therapy Lentivirus vector Transfect hematopoietic stem cells In affect, individual serves as their own donor Treatment with less disease improves survival and functional outcome

18 Recommendations for follow-up Confirmation Biochemical and gene testing ABCD1 Genetic Counseling Identification and recommendation for screening atrisk males Vogel et al Mol. Genet. Metab (4) Adrenal function monitoring Referral to Pediatric Endocrinology Surveillance for cerebral ALD

19 Can you predict who is at risk?

20 Can you predict who is at risk? Family history

21 Can you predict who is at risk? Family history

22 Can you predict who is at risk? Family history Variant in ABCD1

23 Can you predict who is at risk? Family history Variant Many Mutations Non-recurrent

24 Can you predict who is at risk? Family history Mutation Many Mutations Non-recurrent Elevation of VLCFA defines disorder Where is VLCFA threshold? Immune or oxidative stress modifiers?

25 Adrenal function monitoring Referral to Pediatric Endocrinology Pediatric Endocrinology Society Task force is preparing recommendation Starting at 3 months of age, begin screening by cortisol and ACTH Continue to monitor by blood levels every 3-6 months Individualized Role of ACTH stimulation test Stress dosing for illness and procedures Does MRI sedation warrant stress dosing?

26 Surveillance for childhood cerebral ALD MRI precedes disease by months if not years Earliest CCALD 2.75 years; unknown when MRI became abnormal Neurologic findings are late manifestations Inattention and school issues are multifactorial and cannot be relied on Best outcomes of current therapies are with boys with early MRI disease, but asymptomatic on neuropsychologic testing

27 MRI surveillance Start at 12 months Yearly till 3 years Every 6 months till age 13 years Not as helpful DTI,DWI, MRS

28 Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy. Loes, D; Fatemi, A; Melhem, E; Gupte, N; Bezman, L; MD, MPH; Moser, H; Raymond, G Neurology. 61(3): , August 12, DOI: /01.WNL MRI Severity ScaleThis MRI Severity Scale has been designed specifically for X-linked adrenoleukodystrophy and has been shown to correlate with severity of neurologic deficits and to be predictive of disease progression. Different brain regions are considered in the MRI severity score. Each area is scored as 0 if normal, 0.5 if unilateral involvement, and 1 if the lesion or atrophy is bilateral. The maximum severity score is 34; a score of >=1 is considered abnormal.wm = white matter American Academy of Neurology. Published by American Academy of Neurology. 2

29 Development of Myelin Normal Terminal myelination Early cerebral disease

30 What about contrast? Present in active, inflammatory disease Not clear when it develops, but thought to follow T2-weighted image Concerns about safety Only use when there is a concern for lesion? Ideal if there was real time review

31 Common questions Who should order the MRI? Pediatrician, Geneticist, Endocrinologist, Neurologist Doesn t matter as long as someone looks at the report and gives feedback to family What to do after 13 years of age Continue MRI yearly and endocrine care Is neuropsychological testing recommended? Not routinely If there is a questionable spot on the MRI Outside review and rescan in three months What to do if there is an MRI lesion Refer to BMT center

32 Acknowledgements Patients and their families Funding provided by NIH, GCRC, Brian s Hope, Myelin Project, ELA, ULF, and Aidan Seeger Foundation

X-ALD Newborn Screening and Follow-up testing in USA

X-ALD Newborn Screening and Follow-up testing in USA Ann B Moser, the Hugo W. Moser Research Institute, Kennedy Krieger Institute and Johns Hopkins Univ. ALD Life Meeting, London, May 5, 2018 14:00 Dr