Monitoring asymptomatic boys Dr James Davison Great Ormond Street Hospital London

Outline Adrenoleukodystrophy Assessments Outcomes Case report Routes to diagnosis Phenotypes Assessments Baseline Monitoring Outcomes Case report

Peroxisome and X-ALD VLCFA http://www.open.edu/openlearn/science-maths-technology/science/tour-the-cell/content-section-4.9

X-ALD – routes to diagnosis Phenotypes Route to Diagnosis Pre-symptomatic ABCD1 gene on X- chromosome Adrenal disease Antibody negative Adrenal insufficiency Childhood Cerebral ALD Adrenomyeloneuropathy Family cascade testing (Newborn screening) Adrenal presentation Hypoglycaemia Adrenal Crisis Abnormal neurology Behavioural, psychological, motor function, psychiatric

Baseline assessment VLCFA ABCD1 genetic testing Adrenal assessment Diagnosis Endocrine VLCFA ABCD1 genetic testing Adrenal assessment (Adrenal antibodies) Neurological Transplant baseline Functional history Neurological examination Psychological assessment MRI brain scan Tissue typing +/- donor search

Monitoring Annual assessment by endocrinologist Endocrine Neurological Annual assessment by endocrinologist Treatment as indicated by testing Adrenal replacement therapy Medical Alerts Clinical evaluation every 6 months Any new symptoms should prompt urgent re-evaluation Behavioural Cognitive Physical-neurological

Monitoring MRI every 6 months 3-12 years MRI annual after 12 years Neurological: imaging Baseline MRI MRI every 6 months 3-12 years MRI annual after 12 years *Earlier MRI if new symptoms. If minor abnormalities- repeat MRI 2-3 months (GAD) MRI: diffusion weighted imaging ± Gadolinium Normal Abnormal ±Early repeat MRI every 6months until 12 years (annual after 12 years)* Consider BMT

GOSH historic audit 31 males 9 advanced CCALD Baseline MRI 15 Abnormal 6 early CCALD 16 normal 10 BMT/ GT Surveillance monitoring 4 Abnormal 12 On-going surveillance

GOSH case report Recurrent episodes of low blood sugar when unwell 5 year old boy Recurrent episodes of low blood sugar when unwell Synacthen test Cortisol 0mins 178nmol/L 30mins 163nmol/L 60mins 157nmol/L ACTH 1106ng/L Started adrenal replacement therapy Adrenal antibodies negative VLCFA analysis ABCD1: c.1849C>T, p.(Arg617Cys) Parameter Test 1 Test 2 Reference C22 (umol/L) 43.3 47.6 ( 33.2 - 96.3 ) C24 (umol/L) 63.0 68.3 ( 25.2 - 71.4 ) C26 3.32 3.72 ( 0.23 - 1.79 ) C24/C22 ratio 1.45 1.43 ( 0 - 1.01 ) C26/C22 ratio 0.077 0.078 ( 0 - 0.026) Phytanate (umol/L) 2.89 6.11 ( 0 - 15.00) Pristanate (umol/L) 0.24 0.55 ( 0 - 2.00 )

GOSH case report Temper tantrums Normal neurological examination 5 year old boy Baseline MRI brain Temper tantrums Normal neurological examination Possible minor changes in corpus callosum

GOSH case report Bone marrow transplant 10/10 matched unrelated bone marrow transplantation with busulphan/ fludarabine/ campath conditioning Remains well several years post-transplant

Summary Professional awareness Newborn screening Early Diagnosis Monitoring Professional awareness Adrenal insufficiency  VLCFA Newborn screening Tissue typing early to avoid later delays Endocrine Neurological and MRI imaging Capture early CCALD to permit timely intervention

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