Seizures & movement disorders workshop Case 1 Clinical features
Presented at 14 yrs • 3 months anorexia, dysarthria & dysphagia Examination • Parkinsonian gait • Reduced facial movement • Dysarthria, drooling • Tremor Which treatable metabolic disorder is most likely? Is there any specific examination feature to look for? Kayser-Fleischer ring What investigations would you do?
• MRI (T2) high signal in putamen & caudate nucleus bilaterally
• Copper 7 umol/l (normal 13-26) • Caeruloplasmin 20 mg/l (normal 200-350) • 24 hr urine copper high (basal & post-penicillamine)
• Homozygous p.H1069Q ATP7B mutation later identified (commonest European mutation, neurological presentations)
Diagnosis: Wilson disease How would you manage this patient? • D-Penicillamine 250 mg tds (20 mg/kg/d) Pyridoxine 25 mg od • Rash after 10 days, resolved with steroids – D-penicillamine restarted – 125 mg bd for 1 week, then 250 mg bd • Initial neurological deterioration – limb dystonia preventing walking – depression • Slow, limited progress over 2 years – oral & gastrostomy feeds – communicates with ‘organiser’ – wheelchair bound Case 2 History
• Male born at term by LSCS • Birth wt. 1.8 Kg • Seizures within 2 hours of birth Family history • 3rd degree consanguineous parents • 4 previous sibs expired with similar complaints. • One partially investigated & NKH suspected
7 Initial investigations • CBC / Platelets: Normal • ABG / Electrolytes: Normal • Urine Ketones: Negative • CRP: Normal • Ammonia: 33 umol/L (NR <150) • Lactate: 9.8 mmol/L (NR <2.1) • CSF Lactate: 0.5 mmol/L (NR <2.1) • Blood glucose: > 40 mg % (>2.2 mmol/L) • MRI: Not possible as patient on ventilator • EEG: Burst Suppression pattern
8 What further tests would you do?
• Blood TMS: Normal Carnitine / Acylcarnitines • Urine GC-MS: Normal • Plasma VLCFAs: Normal • Plasma Glycine: 541 umol/L (NR: 154 – 338) • CSF amino acids: Glycine: 13.6 umol/L (NR: 2–14) Pipecolic Acid: 5.2 umol/L (NR: 0–0.12) What diagnosis does this suggest? Result actually preceded by
9 Investigations & treatment
• Therapeutic trial: • immediate response to IV folinic acid • Now on oral pyridoxine & folinic acid
Subsequent ALDH7A1 (Antiquitin) sequencing • Homozygous premature termination mutation • Both parents are carriers
10 Some comments
• Therapeutical trial: normally with IV or enteral pyridoxine, if not successful, enteral pyridoxal-P • IV pyridoxine only available in India as part of multiple B vitamin preparation
• Best biochemical marker: alpha-aminoadipic semialdehyde (AASA) in urine, plasma or CSF
11 Case 3 History & examination
• 3yr old female • Non-consanguineous parents • Presented with developmental delay, hyperactivity & poor sleep • Episodes of vacancy & upward rolling of eyes first thing in morning • General medical examination normal • Mild hypotonia • Ataxic gait & oculomotor apraxia What investigations would you do? • CBC, routine biochemistry, thyroid function, microarray normal • Fasting blood glucose 90 mg/dL (5 mmol/L) • Blood acylcarnitines & amino acids (TMS) normal • Plasma homocysteine 8 mmoles/l (normal) • Urine organic acids (GCMS) normal • Brain MRI: normal • EEG: diffuse slowing, 2-3 HZ 100-300 mV activity Treatment • Multiple anticonvulsants: no significant improvement • Trials of biotin, pyridoxine & folinic acid: no response What investigations would you do now?
• CSF lactate 1.8 mmol/L (normal 0.8–2.2) • CSF glucose 26 mg/dl (1.4 mmol/l) normal >40 mg/dl • Blood glucose 96 mg/dL • CSF/blood glucose 0.27 • Sanger sequencing of SLC2A1, gene for GLUT1 transporter: Heterozygous nonsense variant How would you manage the patient?
• Ketogenic diet – Classic 4:1 ratio fat : protein + carbohydrate (3:1 in children <2 years) – or MCT based • If unable to manage, consider modified Atkins diet • If cannot manage this, consider shortening the overnight fast or uncooked cornstarch before bed Case 4 History
• Girl, born by LSCS at term, 3.3 kg • Presented on day 1 with seizures, resistant to AED, pyridoxine and pyridoxal-phosphate • No obvious dysmorphism Family history: non consanguineous parents • Brother died aged 9 months with seizures Initial tests: Blood glucose & ammonia: normal • Acylcarnitine profile: normal
18 Which are the main metabolic causes of seizures on day 1? • Hypoglycaemia • Hyperammonaemia • Pyridoxine dependency & PNPO deficiency • Serine deficiency disorders • Non-ketotic hyperglycinaemia • Molybdenum cofactor & sulphite oxidase deficiencies • Peroxisomal disorders • Mitochondrial disorders What investigations would you do? Biochemistry • Plasma amino acids: Normal except Sulfocysteine: 56 umol/L (NR <5.39), Cysteine undetectable • CSF amino acids: Normal • CSF lactate: 1.9 mmol/L
What else would you do?
20 What investigations would you do?
Biochemistry • Urine Sulfites: 40 mg/L ( NR <10) • Urine Uric Acid: 34 nmol/mmol creat ( NR 1800 ± 1150) • Urine Xanthine: 862 nmol/mmol creat ( NR 72 ± 69) • Urine Hypoxanthine: 376 nmol/mmol creat ( NR 70 ± 60) NGS • MOCS1 & GPHN normal • MOCS2 homozygous VUS
21 How would you treat this girl?
• Anticonvulsants • Physiotherapy • cPMP injections only relevant for MOCS1 defects • Milder cases might profit from a low sulphur diet i.e. Methionine/Cysteine Restriction
22 Case 5 History LSCS at term (gestational diabetes), birth weight 2.9 kg Moved from India to UK aged 2 months Abnormal movements reported by parents at 3 months Family history: Consanguineous parents
Investigations included plasma amino acids phenylalanine – 1330 umol/L (33-81)
How would you treat the patient? Low phenylalanine diet started with prompt fall in Phe What further tests would you do?
Blood spot Biopterin undetectable Total Neopterin 667 nmol/L (raised) DHPR activity 1.13 umol NADH/min/gHB (normal) CSF Biopterin 5.8 nmol/L (10-50) Total Neopterin 206 nmol/L (9-40) Neurotransmitter metabolites HVA 158 nmol/L (>295) 5-HIAA 21 nmol/L (>114) Tyrosine L-Dopa Dopamine HVA
Tryptophan 5-HTP Serotonin 5-HIAA
Phenylalanine Tyrosine
BH4 BH2 DHPR PTPS sequencing: 6-Pyruvoyltetrahydro-biopterin Homozygous previously PTPS unreported variant Both parents heterozygous Dihydro-neopterin GTP cyclohydrolase GTP How would you treat this patient?
• BH4 15 mg/day • Normal diet • 5-hydroxytryptophan slowly increased • L-Dopa with carbidopa } to 10 mg/kg/d Outcome • Phenylalanine normalised • Seizures stopped • Developmental progress but delayed Tyrosine L-Dopa Dopamine HVA
Tryptophan 5-HTP Serotonin 5-HIAA
Phenylalanine Tyrosine Repeat LP HVA 224 nmol/l (324-1098)
BH4 BH2 5HIAA 226 nmol/l (199-608) DHPR 5MTHF 65 nmol/l (72-305) 6-Pyruvoyltetrahydro-biopterin BH2 3.4 nmol/l (0.4-13.9) BH 13 nmol/l (27-105) PTPS 4 total neopterin 80 (7-65) Dihydro-neopterin How would you change treatment? GTP cyclohydrolase Why is BH still low? GTP 4 How would you change treatment?
• Increase L-Dopa dose & start calcium folinate – chronic treatment with L-Dopa can deplete 5MTHF
Why is BH4 still low? • BH4 does not cross BBB well, which is why L-Dopa & 5- Hydroxytryptophan treatment is needed Case 6 Clinical features
• Seizures since day 6 of life • No response to anticonvulsants, vitamin B6, folinic acid, biotin • Developmental delay noted at 4 months → specialist referral • Microcephaly, not otherwise dysmorphic • General medical examination normal • Head lag & truncal hypotonia, increased tone in limbs • Excessive startle & episodes of eyes rolling up • Fundi normal Investigations • Blood glucose/ABG/lactate – normal • Blood acylcarnitines by TMS – normal • Urine organic acids by GC-MS – vanillactic acid slightly increased • EEG – normal • BAER, VEP - normal • SSEP – Abnormal, absent cortical waves • CT Brain: prominent lat. ventricles & Sylvian fissure • MRI Brain: T2 hyperintensities in white matter • PLP1 sequencing normal • GM1, NCL1 & 2 enzyme assays – normal What further tests would you do? CSF neurotransmitters • Normal pterins • Abnormally low 5HIAA (102 nmol/l) & HVA (84 nmol/l) • Elevated L-Dopa (206 nmol/l), 3-OMD (1176 nmol/l) & 5-OHTrp (96 nmol/l) What diagnosis does this indicate? Vanillactate
3-O-Methyldopa
Tyrosine L-Dopa AADC Dopamine HVA BH4 Tryptophan 5-HTP PLP Serotonin 5-HIAA Molecular analysis
• DDC sequencing: homozygous known mutation • Confirms diagnosis of Aromatic L-amino acid decarboxylase deficiency What treatment would you try?
• Trial of pyridoxal phosphate – no effect 5-Hydroxytryptophan L-DOPA • MAO inhibitors AADC • Dopamine & serotonin agonists PLP Serotonin Dopamine • Anticholinergics Fluoxetine Pergolide • Truncal hypotonia & severe MAO developmental delay persisted 5-HIAA HVA • Periods lasting hours of oculogyric crises, limb stiffness, abnormal sucking, lip smacking, grimacing, vomiting, sweating Case 7 History
• Baby boy presented with seizures aged 3 months • Hypotonia, scanty blond hair, lax skin • Born at 36/40, weight 2.7 kg, hypothermia
• What tests would you do? What tests would you do?
• Glucose, electrolytes, calcium, magnesium, ammonia, amino acids, organic acids, biotinidase normal
• Cu 1.3 umol/L (12-25) • Caeruloplasmin 100 mg/L (200-450) • ATP7A Mutation identified later
• Uncle died of Menkes disease 15 years previously • Mutation analysis not possible at that time; mother ‘probably not carrier’ as fibroblast copper uptake normal How would you treat this boy?
• Copper-histidine injections ineffective after 1 month of age • Seizures controlled with phenobarbital • Subsequently changed to levetiracetam • Occasional myoclonic jerks • Poor feeding, chest infections & weight loss from 9 months • Improved with thickener in milk, tube fed from 14 months • At 1 yr, truncal hypotonia but increased tone in limbs Scanty, blond hair, frontal bossing • Died aged 16 months Case 8 History
• 34-35 weeks preterm • 3rd degree consanguineous parents • Emergency LSCS for pre-eclampsia and PROM • On day 3 developed lethargy, reduced consciousness, hypothermia, multiple generalised tonic-clonic seizures • Controlled with anticonvulsants by day 5 What investigations would you do? • Blood glucose, ammonia, lactate: Normal • Electrolytes, Calcium, Magnesium: Normal • CRP: Normal • ABG: Normal • Plasma Biotinidase: Normal • Red cell GALT: Normal • Blood carnitine & acylcarnitines: Normal • Urine OA by GC-MS: Normal • Plasma AA: ‘Normal’ but Serine 40 umol/l (normal 92-196) • Urine Purines & Pyrimidines by HPLC: Normal • CSF MTHF 76 nmol/L (NR >63) What would you do now? CSF – AA (µmol/L) SA Reference range 1 Aspartic Acid 4.6 6 – 18 2 Glutamic Acid 1.4 1 – 31 3 Asparagine 8.2 0 – 18 4 Serine 1.6 31-74 5 Glutamine 585 356 – 680 6 Histidine 5.4 11 – 25 7 Glycine 2.6 2 – 14 8 Threonine 1.5 22 – 53 9 Citrulline 3.3 1 – 5 10 Alanine 8.1 13 – 48 11 Arginine 15.3 13 – 35 12 Tyrosine 12.2 5 – 14 13 Cystine 0.4 - 14 Valine 0.5 10 – 38 15 Methionine 2.1 0 – 9 16 Tryptophan 3.8 17 Phenylalanine 4.2 6 – 19 18 Isoleucine 1.6 3 – 13 Molecular Studies
• Compound heterozygous mutations in PSPH How would you treat this baby?
• L-Serine 200-600 mg/kg/day in 5-6 divided doses • Glycine 200 mg/kg/day
Outcome • Thriving • Seizures controlled • Head growing but mild microcephaly persists • Developmental progress Case 9 Clinical features
• 2.5 Year-old male • Non consanguineous parents • Speech grossly delayed • Other milestones mildly delayed • No apparent seizures, ADHD or ASD • Normal examination, no dysmorphic features Investigations
• MRI: Prominent ventricles and mild sulcal prominence, hypomyelination of white matter • MRS: Very small creatine peak • On long Echo time spectra, the integral value of creatine was 0.28 and its peak amplitude was significantly reduced
What further tests would you do?
Compounds Results Reference Units Ranges Plasma GAA 1.80 1.1 – 4.1 μmol/L
Creatine 90.3 25.4 – 199.2 μmol/L
Creatinine 29.4 13.4 – 72.9 μmol/L
GAA / Creatine 0.0199 0.005 - 0.04
Urine GAA 4.3 2.2 – 14.5 μmol/kg/24Hr
Creatine 305.9 1.5 – 185 μmol/kg/24Hr
Creatinine 4.5
GAA / Creatine 0.014 0.012 – 9.66 Genetic studies (NGS Panel)
• SLC6A8 hemizygous VUS • variant is considered damaging by SIFT, PolyPhen and Mutation Taster • Diagnosis: Creatine Transporter Deficiency How would you treat this boy?
• No effective treatment currently available • Supplementation with creatine monohydrate, arginine & glycine sometimes tried