Neurodegenerative disorders: an approach to investigation Robert Robinson Practical Paediatric Neurology Study Days April 2018
Aims An approach to investigating and diagnosing young children with progressive encephalopathies Targeted investigations according to Age of presentation Predominant neurological signs Presence of additional specific features Overlap with other talks
Overview Approach to diagnosis Neonatal encephalopathies Late infantile motor deficits Leukodystrophy
Progressive neurological (neurodegenerative) disorders Progressive (irreversible) deterioration >3 months with Loss of attained intellectual or developmental abilities and Cognitive Motor Development of abnormal neurological signs Spasticity, ataxia, dystonia, hypotonia, weakness Epilepsy Visual, hearing impairment
Causes of neurodegenerative disorders Epileptic encephalopathies Neuromuscular disorders Hydrocephalus Cerebrovascular disorders CNS tumours Chronic CNS inflammation and infection Progressive neurogenetic/neurometabolic encephalopathies
Prevalence rates Progressive encephalopathies 0.5/1000 Central motor deficit (= CP) 2/1000 Epilepsy 5/1000 Severe intellectual disability 5/1000 CNS tumours 0.05/1000 Duchenne muscular dystrophy 0.12/1000
Approach to diagnosis - 1 Age of presentation Neonatal & Early infantile (<1 year); Late infantile/early juvenile (1-5); (+ 5y ) Juvenile and adult Establish if static or progressive disorder
Developmental trajectories
Approach to diagnosis - 2 By predominant symptoms: Motor deficit: spastic, dystonic, ataxic, neuropathic, mixed, Dementia Epilepsy Defect of special senses Presence of specific features ( handles ) e.g.: Macro/microcephaly; Dysmorphic features; Cutaneous; Ocular; Coma; Dystonia
Always consider treatable causes of progressive neurological disease Epilepsy Autistic regression Infection Hydrocephalus Tumour Nutritional deficiencies eg B12 Abusive and factitious illness
Case example 1
Neonatal encephalopathy with seizures A 10 day old baby Hypotonic since birth Onset of seizures at 4 days No evidence of infection, normal glucose, calcium, biochemistry
Neonatal encephalopathy with seizures Differential Diagnosis Investigations
Neonatal encephalopathy with seizures Normal CSF (including glycine) Normal ammonia, lactate Normal amino acids Normal organic acids MRI
Neonatal encephalopathy with seizures
Neonatal encephalopathy with seizures - Laboratory investigations Elevated plasma very long chain fatty acids Elevated bile acid intermediates Mutation in PEX1 gene (7q21).
Peroxisomal disorders presenting in neonates Zellweger s disease Neonatal adrenoleucodystrophy Rhizomelic chondrodysplasia punctata
Neonatal metabolic encephalopathy: causes Amino acid disorders Organic acid disorders Mitochondrial disorders Peroxisomal disorders Lysosomal enzymes Purine and pyrimidine disorders Metal metabolism disorders Carbohydrate disorders Vitamin metabolism disorders Transport defects Leukodystrophies
Neonatal encephalopathy with seizures - clinical clues Deterioration after a normal interval Metabolic acidosis, ketosis, odd smell, hypoglycaemia Hyperammonaemia Low plasma urate Retinopathy Hair abnormality Dysmorphic features, skeletal abnormality EEG
Neonatal encephalopathy with seizures Basic investigations glucose; LFT s; blood gas Cranial ultrasound EEG MR / (CT) brain Microarray Ammonia, lactate, urate Biotinidase
Neonatal encephalopathy with seizures Extended investigations CSF glucose, lactate and amino acids CSF pyridoxal phosphate CSF MTHF Very long chain fatty acids Copper and caeruloplasmin Carnitine Urine and plasma creatine, GAMT Urine and plasma amino acids Urinary sulphite Urinary organic acids Urinary AASA Fibroblast culture; muscle biopsy;
Mitochondrial disorders diagnostic clues Metabolic acidosis Elevated plasma and CSF lactate Ophthalmoplegia and ptosis Cardiomyopathy
Molybdenum cofactor deficiency Clinical clues: Lens dislocation Urinary sulphite Plasma urate
Congenital disorders of glycosylation 18 disorders now recognised CDG1 caused by mutation in the gene encoding phosphomannomutase Neonatal presentation: Hypotonia Nystagmus Ophthalmoplegia Hepatic dysfunction Diagnosis by transferrin electrophoresis
Menke s disease X-linked disorder Abnormality of copper metabolism Encephalopathy with seizures and intracerebral haemorrhage Low plasma copper Vasculopathy Bony fragility
Leucodystrophy as a cause of neonatal encephalopathy Pelizaeus Merzbacher disease Classic (X-linked) onset weeks from birth Conatal/late onset forms (AR) Hypotonia Nystagmus Head-nodding, stridor Evolving spasticity Proteolipid (PLP) deletion
Genetic EIEE
Early infantile seizures and dementia - Causes Late / delayed presentation of neonatal onset disorders Plus: Tay Sachs Alpers disease Biotinidase deficiency Early infantile Batten s disease
Neuronal Ceroid lipofuscinoses (Batten Disease) Group of severe AR conditions Progressive blindness, seizures and neurodegeneration Originally classified as : Infantile (CLN1, PPT1) Late infantile (CLN2, TPP2) Juvenile (CLN3) Adult Now classified on basis of enzyme defect, genetics, pathological features, phenotype
Recombinant human tripeptidyl peptidase-1 (TPP1) 24 patients with CLN2 Significant attenuation in rate of decline in motor and language scores
Early infantile seizures and dementia - Investigations As for neonatal onset disorders Plus: VEP/ERG Lysosomal enzymes Electron microscopy skin, lymphocytes Mutation analysis CLN1, CLN2, CLN3, CTSD
Case example 2
Late infantile central motor deficit A girl presents at 1.5 year of age with normal development until 1 year Followed by slowing in motor development And now loss of independent walking
Late infantile central motor deficit OFC 75 th centile Gaze-evoked nystagmus in all directions Normal fundi Mild lower facial weakness Hypotonia in trunk and limbs Reflexes present in arms, absent in legs No visceromegaly
Late infantile central motor deficit
Late infantile central motor deficit Normal lysosomal enzymes Normal ammonia, lactate and amino acids Normal csf lactate, amino acids
Late infantile central motor deficit ENMG: Normal nerve conduction velocities Denervation on EMG Visual evoked potentials Abnormal, delayed responses Normal ERG
Late infantile central motor deficit Progressive deterioration continues Visual impairment Dysphagia Loss of social interaction What investigation needs to be done?
Late infantile central motor deficit Skin biopsy: Mutation in PLA2G6 gene Diagnosis: Infantile neuroaxonal dystrophy
Late infantile central motor deficit - Causes Ataxia telangiectasia ( others Leucodystrophies (metachromatic + Infantile neuroaxonal dystrophy Arginase deficiency Late variant gangliosidoses
Late infantile central motor deficit - Causes PDH deficiency (x-linked) Mitochondrial cytopathies Rett syndrome CDG CNS tumours Hydrocephalus
Late infantile central motor deficit - Clinical clues Recurrent infection Visual impairment Neuropathy Lactic acidosis Disorders of eye movement Stroke-like episodes
Leukodystrophies Genetically determined progressive neurological disorders Abnormalities of structure and development of myelin Recognised by their clinical, imaging and pathology characteristic
Hereditary white matter disorders Lysosomal disorders Peroxisomal disorders Mitochondrial disorders DNA repair disorders Defects in myelin proteins Amino acidopathies and organic acidopathies Many others, including congenital muscular dystrophy
Leukodystrophies in childhood May 1997-November 2014 n=349, 18 diagnoses Developmental Medicine & Child Neurology 11 FEB 2016 DOI: 10.1111/dmcn.13027 http://onlinelibrary.wiley.com/doi/10.1111/dmcn.13027/full#dmcn13027-fig-0001
Metachromatic leukodystrophy Arylsulfatase A deficiency Late infantile, juvenile and later variants Late infantile Progressive spasticity and ataxia Absent reflexes and optic atrophy Most die before 8 Juvenile Present at 6-10 years Behavioural disorder, dementia, extrapyramidal movements
Krabbe s leucodystrophy Early infantile and later presenting variants Galactocerebrosidase deficiency Early infantile Onset in first 6 months progressive spasticity, optic atrophy and peripheral neuropathy Death often by 2.5 years May be misdiagnosed as cerebral palsy
X-linked adrenoleukodystrophy
Alexander s leukodystrophy Onset from early infancy to later childhood Progressive spasticity, macrocephaly, dementia Characteristic MR scans frontal predominance No known biochemical disorder Some may be familial GFAP gene deletion in 90%
Canavan s disease Onset before 1 year Spasticity, macrocephaly, optic atrophy Death in mid to late childhood Urinary excretion of N- acetyl aspartate Spongiform appearance of white matter ASPA mutations (aspartoacylase)
Megalencephalic leukoencephalopathy with subcortical cysts Infantile onset macrocephaly Delayed onset motor deterioration with spasticity and ataxia Preserved cognition Late onset epilepsy Subcortical cysts in anterior and temporal areas + diffuse white matter abnormality MLC1/HEPACAM mutations Improving phenotype (heterozygous)
Vanishing white matter disease Childhood ataxia with central nervous system hypomyelination Progressive spastic and ataxic disorder Episodes of sudden deterioration may follow minor head injury Relative preservation of cognition Optic atrophy and blindness Diffuse white matter abnormality, progressing to CSF signal Mutations in 5 genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5) account for 90%
Investigations for leukodystrophy MR brain scan and MRS ENMG Lysosomal enzymes Early morning fresh urine for metachromatic material Very long chain fatty acids N-acetyl aspartate Plasma and CSF lactate DNA for Mitochondrial, PLP, GFAP
PIND study May 1997-Nov 2014 3758 children meeting the criteria for PIND. Diagnosis established in 1580 (42%) 193 distinct disorders. 803/1580 (51%) had leukodystrophy or genetic leukoencephalopathy 349 children leukodystrophies 18 diagnoses 454 children with genetic leukoencephalopathies 38 diagnoses Mucopolysaccharidoses (n=100) GM1 and GM2 gangliosidoses (n=91) Mitochondrial disorders (n=50).
Progressive intellectual and neurological deterioration cases with definite diagnoses: the six most commonly reported disease groups. Verity C et al. Arch Dis Child 2010;95:361-364 Copyright BMJ Publishing Group Ltd & Royal College of Paediatrics and Child Health. All rights reserved.
What about next generation sequencing? Gene panels Whole exome sequencing Whole genome sequencing Phenotyping resources: OMIM Genereviews Phenotips Treatable ID
Summary Investigate first for commoner, treatable and reversible disorders (infection, epilepsy etc) Establish whether static or progressive Categorise according to age and predominant area of regression Look for diagnostic clues Target investigations