britton zuccarelli md child neurology resident … case conference 4-4-2014.pdfbritton zuccarelli md...

©2013 Children's Mercy. All Rights Reserved. 09/13©2013 Children's Mercy. All Rights Reserved. 09/13

Britton Zuccarelli MD

Child Neurology Resident PGY3

April 4 2014

Case Presentation

©2013 Children's Mercy. All Rights Reserved. 09/13

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History of Present Illness 6 month old ““““floppy”””” baby with ““““droopy

eyelids””””

� Normal development until 2 months

� Bilateral ptosis, no pattern or fatigability

� Coughing/gagging with feeds

� Frequent ED visits for respiratory issues


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Past Medical History

� Born at term by C/S, meconium aspiration

� No surgeries

� Meds = ranitidine

� No allergies


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Family History

� Stroke

� Neurofibromatosis

� ADHD, behavioral disorders, learning disabilities

� No birth defects, epilepsy, developmental delay


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Social History

� Lives with mother and maternal

grandparents

� Exposed to smoke

� Eats 6-7 ounces of formula every 4 hours


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Review of Systems

� Constipation


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Physical Examination

� Vitals: WNL, Wt 25th% Length 25th%HC

10th%

� Bilateral ptosis � Somewhat down-turned mouth� Comfortable tachypnea� No neurocutaneous markers


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Neurological Examination

� Mental status: no babbling� CN: does not fix or track� Motor: significant hypotonia, no spasticity� Reflexes: normal� Sensation: grossly intact � Coordination: does not reach for toy� Gait: developmentally inappropriate to

assess


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Where?

What?


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Differential Diagnosis

� Congenital myasthenia gravis

� Muscular dystrophy

� Inborn error of metabolism

� Mitochondrial disease

� Other genetic disorder


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Laboratory Studies

� Chromosomes: NORMAL female karyotype

� Microarray: No DNA copy number variants (CNVs) of known

clinical significance

� Serum acylcarnitine profile: NORMAL

� Urine organic acids profile: essentially NORMAL

� ACh-Receptor binding antibody: NEGATIVE

� Serum mUSK antibody: NEGATIVE

� ACh-Receptor modulating antibody: NEGATIVE

� Serum carbohydrate transferrin profile: NORMAL

� FISH for 22q11.2 deletion: NEGATIVE

� Methylation and copy number analysis of 15q11.2 for Prader-

Willi (PWS): NEGATIVE


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Diagnostic Tests

� EMG: Limited nerve conduction and repetitive nerve

stimulation study shows normal responses. Study

aborted due to mild respiratory distress secondary to

upper airway congestion.

� Echocardiogram 12/18/13: normal echocardiogram for

age.

� EEG: This is a mildly abnormal EEG secondary to the

presence of generalized slowing. There were no clear

focal slowing and no epileptiform discharges noted.

There were no seizures noted.


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Hospital Course

� Cardiopulmonary arrest � transferred to

PICU

� Enrolled in STAT-Seq

� Mestinon trial = no response

� Discharged home on NJ feeds


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STAT-Seq

� Whole genome sequencing

� ~7500 genetic diseases caused by SNPs

– 3500 are known, 500 have treatments

� 4 million SNPs � ~3000 SNPs

� Turn around time = 50 hours


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STAT-Seq Results

� Compound heterozygous mutation in the

SLC25A1 gene

– pSer193Trp- category 1

– pAla28Thr- category 2

� Combined D-2- and L-2-OH glutaric

aciduria


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Laboratory Studies

� 2-OH-Glutaric (Ref Value <89): 145, 146


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Combined Glutaric Aciduria

� Severe neonatal epileptic encephalopathy

� Developmental delay

� Early death


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Combined Glutaric Aciduria

� Recessive mutation in SLC25A1 on

chromosome 22q11


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Nota et al 2013


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Further Testing

� Enantiomer testing

Controls

� D-2-HGA 81.4 2.8 - 17

� L-2-HGA 26.7 1.3 - 18.9


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Further Testing

� Repeat urine organic acids

Date 2-OH-Glutaric (Ref Value <89)

Admission 145

+ 9 days 146

+ 6 weeks 401

+ 8 weeks 419

+12 weeks 519


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Treatment

� Citrate 1500 mg/kg/day

� Physical therapy

� Occupational therapy

� Speech therapy

� Vision therapy


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References

� Genetics Home Reference. 2-hydroxyglutaric aciduria. March 2014.

� Kranendijk et al. Progress in understanding 2-hydroxyglutaric

acidurias. Journal of Inherited Metabolic Diseases 35:571-587,

2012.

� Muntau et al. Combined D-2- and L-2-Hydroxyglutaric Aciduria with

Neonatal Onset Encephalopathy: A Third Biochemical Variant of 2-

Hydroxyglutaric Aciduria? Neuropediatrics 31: 137-140, 2000.

� Nota et al. Deficiency in SLC25A1, Encoding the Mitochondrial

Citrate Carrier, Causes D-2- and L-2-Hydroxyglutaric Aciduria. The

American Journal of Human Genetics, 92:627-631, April 2013.


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Questions?

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