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©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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©2013 Children's Mercy. All Rights Reserved. 09/13
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
©2013 Children's Mercy. All Rights Reserved. 09/13
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©2013 Children's Mercy. All Rights Reserved. 09/13
Past Medical History
� Born at term by C/S, meconium aspiration
� No surgeries
� Meds = ranitidine
� No allergies
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©2013 Children's Mercy. All Rights Reserved. 09/13
Family History
� Stroke
� Neurofibromatosis
� ADHD, behavioral disorders, learning disabilities
� No birth defects, epilepsy, developmental delay
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©2013 Children's Mercy. All Rights Reserved. 09/13
Social History
� Lives with mother and maternal
grandparents
� Exposed to smoke
� Eats 6-7 ounces of formula every 4 hours
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©2013 Children's Mercy. All Rights Reserved. 09/13
Review of Systems
� Constipation
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©2013 Children's Mercy. All Rights Reserved. 09/13
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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©2013 Children's Mercy. All Rights Reserved. 09/13
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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©2013 Children's Mercy. All Rights Reserved. 09/13
Where?
What?
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©2013 Children's Mercy. All Rights Reserved. 09/13
Differential Diagnosis
� Congenital myasthenia gravis
� Muscular dystrophy
� Inborn error of metabolism
� Mitochondrial disease
� Other genetic disorder
©2013 Children's Mercy. All Rights Reserved. 09/13
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©2013 Children's Mercy. All Rights Reserved. 09/13
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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©2013 Children's Mercy. All Rights Reserved. 09/13
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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©2013 Children's Mercy. All Rights Reserved. 09/13
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©2013 Children's Mercy. All Rights Reserved. 09/13
Hospital Course
� Cardiopulmonary arrest � transferred to
PICU
� Enrolled in STAT-Seq
� Mestinon trial = no response
� Discharged home on NJ feeds
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©2013 Children's Mercy. All Rights Reserved. 09/13
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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©2013 Children's Mercy. All Rights Reserved. 09/13
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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©2013 Children's Mercy. All Rights Reserved. 09/13
Laboratory Studies
� 2-OH-Glutaric (Ref Value <89): 145, 146
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©2013 Children's Mercy. All Rights Reserved. 09/13
Combined Glutaric Aciduria
� Severe neonatal epileptic encephalopathy
� Developmental delay
� Early death
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©2013 Children's Mercy. All Rights Reserved. 09/13
Combined Glutaric Aciduria
� Recessive mutation in SLC25A1 on
chromosome 22q11
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©2013 Children's Mercy. All Rights Reserved. 09/13
Nota et al 2013
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©2013 Children's Mercy. All Rights Reserved. 09/13
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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©2013 Children's Mercy. All Rights Reserved. 09/13
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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©2013 Children's Mercy. All Rights Reserved. 09/13
Treatment
� Citrate 1500 mg/kg/day
� Physical therapy
� Occupational therapy
� Speech therapy
� Vision therapy
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©2013 Children's Mercy. All Rights Reserved. 09/13
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.